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    Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral sodium-glucose co-transporter 2 (SGLT2) inhibitor
    Used to improve glycemic control in adults with type 2 diabetes mellitus and to reduce the risk of cardiovascular death if these patients also have cardiovascular disease
    Blocks reabsorption of glucose by kidneys, increasing glucose excretion; not effective in patients with severe renal impairment

    COMMON BRAND NAMES

    JARDIANCE

    HOW SUPPLIED

    JARDIANCE Oral Tab: 10mg, 25mg

    DOSAGE & INDICATIONS

    For the treatment type 2 diabetes mellitus in combination with diet and exercise, and for the reduction of cardiovascular mortality in these patients who also have established cardiovascular disease.
    Oral dosage
    Adults

    10 mg PO once daily, taken in the morning, with or without food. The dose can be increased to 25 mg PO once daily in those who require additional glycemic control. In addition to improving glycemic control, a multicenter, multi-national, randomized, double-blind parallel group trial (EMPA-REG OUTCOME study) of 7,020 patients with inadequately controlled type 2 DM and established, stable, atherosclerotic cardiovascular disease reported that empagliflozin treatment reduced the risk of major adverse CV events (MACE: cardiovascular death, first occurrence of non-fatal myocardial infarction, or non-fatal stroke) by 14% relative to placebo (HR 0.86, 95% CI 0.74 to 0.99).

    MAXIMUM DOSAGE

    Adults

    25 mg/day PO.

    Geriatric

    25 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Not indicated.

    Neonates

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustments are needed.

    Renal Impairment

    eGFR >= 45 mL/min/1.73 m2: No dosage adjustment needed.
    eGFR < 45 mL/min/1.73 m2: Do not initiate empagliflozin in these patients. In patients currently taking the drug, empagliflozin should be discontinued when eGFR is persistently < 45 mL/min/1.73 m2.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Administer tablets once daily in the morning, with or without food.

    STORAGE

    JARDIANCE:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Angioedema

    Empagliflozin is contraindicated in patients who have demonstrated a hypersensitivity to empagliflozin or its ingredients. Serious hypersensitivity reactions or anaphylaxis, including angioedema, have been reported in patients receiving empagliflozin. Instruct patients to immediately stop empagliflozin and seek medical attention if they experience symptoms suggestive of a hypersensitivity reaction.

    Diabetic ketoacidosis, type 1 diabetes mellitus

    Empagliflozin should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis (DKA). Fatal cases of ketoacidosis have been reported in patients receiving empagliflozin. In addition, the FDA has identified 73 cases of ketoacidosis in patients with type 1 or type 2 diabetes treated with SGLT2 inhibitors. All patients required emergency room visits or hospitalization to treat the ketoacidosis. Signs and symptoms at presentation were consistent with severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. However, the presence of ketoacidosis was not immediately recognized, and treatment was delayed because the presenting blood glucose levels were below those typically expected for DKA (often less than 250 mg/dL). Factors identified in some reports as having potentially triggered the ketoacidosis included infection, low carbohydrate diet or an overall reduction of caloric intake, reduction in dose of exogenous insulin or discontinuation of exogenous insulin, discontinuation of an oral insulin secretagogue, and alcohol use. The FDA is continuing to investigate this issue and is requiring manufacturers of SGLT2 inhibitors to conduct a required postmarketing study, including specialized follow-up to collect additional information for a period of 5 years. Before initiating an SGLT2 inhibitor, consider factors in the patients’ histories that may predispose them to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. In patients treated with an SGLT2 inhibitor, consider monitoring for ketoacidosis and temporarily discontinuing the drug in clinical situations known to predispose to ketoacidosis, such as prolonged fasting due to acute illness or surgery. Patients should report any signs of ketoacidosis and immediately seek medical attention if they experience symptoms such as difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue or sleepiness. Health care professionals should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing these signs or symptoms. If ketoacidosis is suspected, discontinue empagliflozin and institute treatment, which may include insulin, fluids, and carbohydrate replacement.

    Dialysis, hypovolemia, renal failure, renal impairment

    Empagliflozin is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end stage renal failure or in patients on dialysis. Empagliflozin is not expected to be effective in these patients.  Empagliflozin should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2. Discontinue empagliflozin in patients developing an eGFR that is persistently less than 45 mL/min/1.73 m2 while on treatment. Empagliflozin causes intravascular volume contraction and can cause renal impairment. Empagliflozin increases serum creatinine and decreases eGFR; patients with hypovolemia or the elderly may be more susceptible to these changes. The glucose lowering benefit of empagliflozin decreases in patients with worsening renal function. The efficacy and safety of empagliflozin were evaluated in a study that included patients with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2) and moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2). The risks of renal impairment, volume depletion adverse reactions, and urinary tract infection-related adverse reactions increased with worsening renal function. Before initiation of treatment and at least annually thereafter, obtain an estimated glomerular filtration rate (eGFR) to assess renal function. More frequent monitoring is recommended in patients with moderate renal impairment (eGFR less than 59 mL/min/1.73 m2) and the elderly at treatment initiation. Renal impairment may occur as a result of certain medical conditions such as cardiovascular collapse, acute heart attack, and septicemia. Acute kidney injury, some requiring hospitalization and dialysis, has been reported during the postmarketing period with empagliflozin and other SGLT2 inhibitors; some reports involved patients younger than 65 years of age. The FDA identified 101 confirmable cases of acute kidney injury, some requiring hospitalization and dialysis, with canagliflozin (73 patients) or dapagliflozin (28 patients) use during the time period from March 2013 to October 2015. There are likely additional cases. In approximately half of the cases, acute kidney injury occurred within 1 month of starting the drug, and most patients improved after discontinuation. Hospitalization for evaluation and management of acute kidney injury was necessary in 96 of the 101 cases, and 22 cases involved admission to an intensive care unit. Four deaths occurred during hospitalization, 2 of which were cardiac-related. Fifteen patients received dialysis. Of the 101 cases, 51 reported concomitant angiotensin converting enzyme (ACE) inhibitor use, 26 reported concomitant diuretic use, and 6 reported concomitant nonsteroidal anti-inflammatory drug (NSAID) use. A prior history of chronic renal disease was reported in 10 of the 101 cases. Forty-five of the 101 cases reported a change in serum creatinine or eGFR at the time of diagnosis. Eleven patients did not recover, which included the 4 deaths noted previously. Three patients recovered with sequelae upon discontinuation. If acute kidney injury occurs, promptly discontinue the drug and treat the renal impairment. Consider factors that may predispose patients to acute kidney injury prior to starting them on empagliflozin, including hypovolemia; chronic renal insufficiency; congestive heart failure; and concomitant medications such as diuretics, ACE inhibitors, angiotensin II receptor blockers (ARBs), and NSAIDs. Consider temporarily discontinuing empagliflozin in any setting of reduced oral intake such as acute illness or fasting, or with fluid losses such as gastrointestinal illness or excessive heat exposure.

    Dehydration, hypotension

    Empagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating empagliflozin. Patients at risk include those with dehydration or hypovolemia, particularly in patients with impaired renal function (i.e., eGFR less than 60 mL/min/1.73 m2), the elderly, patients receiving diuretics, or patients with low systolic blood pressure. Volume status should be assessed and corrected before initiating empagliflozin in patients with one or more of these characteristics. Monitor for signs and symptoms after initiating therapy.

    Balanitis, pyelonephritis, vaginitis

    There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including empagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Patients should be told to report any signs of urinary tract infection and seek medical attention if they experience symptoms such as a feeling of burning when urinating or the need to urinate often or right away, pain in the lower part of the stomach area or pelvis, increased temperature, or blood in the urine. If urinary tract infection is suspected, evaluate and treat promptly if indicated. Use empagliflozin cautiously in patients with a history of genital fungal infection, including vaginitis or balanitis, and in uncircumcised males since these patients may be more likely to develop genital mycotic infections during treatment with empagliflozin. Monitor and treat appropriately.

    Adrenal insufficiency, hypoglycemia, hypothyroidism, malnutrition, pituitary insufficiency

    Conditions that predispose patients to developing hypoglycemia may alter antidiabetic agent needs, and may require close monitoring during the use of empagliflozin. Conditions associated with hypoglycemia include debilitated physical condition, drug interactions, malnutrition, uncontrolled adrenal insufficiency, pituitary insufficiency or hypothyroidism. More frequent blood glucose monitoring may be necessary in patients with these conditions. Empagliflozin may also increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with empagliflozin.

    Burns, fever, hypercortisolism, hyperglycemia, hyperthyroidism, infection, surgery, trauma

    Conditions that predispose patients to developing hyperglycemia may alter empagliflozin efficacy. Hyperglycemia related conditions include drug interactions, female hormonal changes, high fever, severe psychological stress, and uncontrolled hypercortisolism or hyperthyroidism. More frequent blood glucose monitoring may be necessary in patients with these conditions. Temporary use of insulin in place of oral antidiabetic agents (such as empagliflozin) may be necessary during periods of physiologic stress (e.g., burns, systemic infection, trauma, surgery, or fever).

    Hypercholesterolemia

    Dose-related increases in LDL cholesterol (LDL-C) occur with empagliflozin, and these changes may require treatment or adjustment of previous therapy in patients with pre-existing hypercholesterolemia. Monitor LDL-C and treat as per standard of care after initiating empagliflozin therapy.

    Geriatric

    In clinical trials with empagliflozin, 32% of patients were 65 years and older and 6% were 75 years and older. No dosage adjustment is recommended based on age alone; however, monitor closely for adverse effects. Geriatric patients 75 years and older who received empagliflozin experienced a higher incidence of adverse reactions related to reduced intravascular volume and urinary tract infection compared to patients treated with placebo. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, the use of antidiabetic medications should include monitoring (e.g., periodic blood glucose) for effectiveness based on desired goals for that individual and to identify complications of treatment such as hypoglycemia or impaired renal function.

    Pregnancy

    There are no adequate and well-controlled studies of empagliflozin in pregnant women, and use is not recommended during the second and third trimesters of human pregnancy. Based on results from animal studies, empagliflozin may affect renal development and maturation. Rat studies demonstrate that empagliflozin crosses the placenta and reaches fetal tissues. In rat and rabbit studies, empagliflozin was not teratogenic at 48-times and 128-times, respectively, the maximum clinical human dose of 25 mg. However, at higher doses (139 to 154 times the 25 mg maximum human clinical dose), maternal and fetal toxicity, including malformations of limb bones, were evident. Maternal toxicity did not occur in pre- and postnatal development studies, starting at gestation day 6 through to lactation day 20 (weaning) at approximately 16 times the 25 mg maximum clinical dose in pregnant rats; reduced body weight was observed in the offspring. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. The potential risks to human kidney development are of concern. Empagliflozin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Poorly controlled diabetes during pregnancy also increases fetal risk. The American College of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA) continue to recommend human insulin as the standard of care in pregnant women with diabetes mellitus and gestational diabetes mellitus (GDM) requiring medical therapy; insulin does not cross the placenta.

    Breast-feeding

    It is not known if empagliflozin is excreted in human milk; however, due to a potential for serious adverse reactions in the nursing infant, it is recommended to avoid breast-feeding during its use, or to discontinue the drug, taking into account the importance of the therapy to the mother. Empagliflozin is secreted in the milk of lactating rats reaching levels 5 times higher than that in maternal plasma. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. If empagliflozin is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Other oral hypoglycemics may also be considered as possible alternatives in some patients. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected. Also, while the manufacturers of metformin recommend against breast-feeding while taking the drug, metformin may be a possible alternative for some patients. Data have shown that metformin is excreted into breast milk in small amounts and adverse effects on infant plasma glucose have not been reported in human studies. Tolbutamide is usually considered compatible with breast-feeding. Glyburide may be a suitable alternative since it was not detected in the breast milk of lactating women who received single and multiple doses of glyburide. If any oral hypoglycemics are used during breast feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants

    The safety and effectiveness of empagliflozin have not been established in adolescents and children under the age of 18 years; there is no role of empagliflozin in the treatment of infants.

    ADVERSE REACTIONS

    Severe

    phimosis / Delayed / 0-1.0
    diabetic ketoacidosis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    hypoglycemia / Early / 0.4-28.4
    cystitis / Delayed / 7.6-9.3
    hypercholesterolemia / Delayed / 4.6-6.5
    candidiasis / Delayed / 1.6-6.4
    vaginitis / Delayed / 5.4-6.4
    hyperlipidemia / Delayed / 2.9-3.9
    balanitis / Delayed / 1.6-3.1
    hypovolemia / Early / 0-1.0
    hypotension / Rapid / 0-1.0
    dehydration / Delayed / 0-1.0

    Mild

    infection / Delayed / 0-4.0
    polyuria / Early / 3.2-3.4
    increased urinary frequency / Early / 3.2-3.4
    arthralgia / Delayed / 2.3-2.4
    nausea / Early / 1.1-2.3
    polydipsia / Early / 1.5-1.7
    diuresis / Early / 0-1.0
    syncope / Early / 0-1.0
    orthostatic hypotension / Delayed / 0-1.0
    nocturia / Early / 0-1.0
    rash / Early / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acebutolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Acetazolamide: (Minor) Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus who are receiving antidiabetic agents. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Aliskiren; Amlodipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Aliskiren; Valsartan: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Amiloride: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Amlodipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Amlodipine; Atorvastatin: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Amlodipine; Benazepril: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Amlodipine; Olmesartan: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Amlodipine; Telmisartan: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Amlodipine; Valsartan: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    Amprenavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Androgens: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Angiotensin II receptor antagonists: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Angiotensin-converting enzyme inhibitors: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Atazanavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Atazanavir; Cobicistat: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Atenolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Atenolol; Chlorthalidone: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    atypical antipsychotic: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
    Azilsartan: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Azilsartan; Chlorthalidone: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Benazepril: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Bendroflumethiazide; Nadolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Beta-blockers: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Betaxolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Bisoprolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Bortezomib: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
    Brimonidine; Timolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Bumetanide: (Moderate) When empagliflozin is initiated in patients already receiving loop diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Loop diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. Patients receiving empagliflozin should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Calcium-channel blockers: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Candesartan: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Captopril: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Carbonic anhydrase inhibitors: (Minor) Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus who are receiving antidiabetic agents. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Carteolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Carvedilol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Chloroquine: (Major) Careful monitoring of blood glucose is recommended when chloroquine and antidiabetic agents, including the SGLT2 inhibitors, are coadministered. A decreased dose of the antidiabetic agent may be necessary as severe hypoglycemia has been reported in patients treated concomitantly with chloroquine and an antidiabetic agent.
    Chlorothiazide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Chlorthalidone: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Chlorthalidone; Clonidine: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. (Minor) Increased frequency of blood glucose monitoring may be required when clonidine is given with antidiabetic agents. Since clonidine inhibits the release of catecholamines, clonidine may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Clonidine does not appear to impair recovery from hypoglycemia, and has not been found to impair glucose tolerance in diabetic patients.
    Chromium: (Moderate) Chromium dietary supplements may lower blood glucose. As part of the glucose tolerance factor molecule, chromium appears to facilitate the binding of insulin to insulin receptors in tissues and to aid in glucose metabolism. Because blood glucose may be lowered by the use of chromium, patients who are on antidiabetic agents may need dose adjustments. Close monitoring of blood glucose is recommended.
    Ciprofloxacin: (Moderate) Careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents, including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Clarithromycin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    Clevidipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Clonidine: (Minor) Increased frequency of blood glucose monitoring may be required when clonidine is given with antidiabetic agents. Since clonidine inhibits the release of catecholamines, clonidine may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Clonidine does not appear to impair recovery from hypoglycemia, and has not been found to impair glucose tolerance in diabetic patients.
    Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Corticosteroids: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
    Darunavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Darunavir; Cobicistat: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Diazoxide: (Minor) Diazoxide, when administered intravenously or orally, produces a prompt dose-related increase in blood glucose level, due primarily to an inhibition of insulin release from the pancreas, and also to an extrapancreatic effect. The hyperglycemic effect begins within an hour and generally lasts no more than 8 hours in the presence of normal renal function. The hyperglycemic effect of diazoxide is expected to be antagonized by certain antidiabetic agents (e.g., insulin or a sulfonylurea). Blood glucose should be closely monitored.
    Dienogest; Estradiol valerate: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Diltiazem: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Dorzolamide; Timolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Drospirenone; Estradiol: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Drospirenone; Ethinyl Estradiol: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Enalapril, Enalaprilat: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Enalapril; Felodipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Eprosartan: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Esmolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Estradiol; Levonorgestrel: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Estradiol; Norethindrone: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Estradiol; Norgestimate: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Estrogens: (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis.
    Ethacrynic Acid: (Moderate) When empagliflozin is initiated in patients already receiving loop diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Loop diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. Patients receiving empagliflozin should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Ethanol: (Moderate) Patients should be advised to limit alcohol (ethanol) ingestion when treated with an antidiabetic agent. Ethanol inhibits gluconeogenesis, which can contribute to or increase the risk for hypoglycemia. In some patients, hypoglycemia can be prolonged. If a patient with diabetes ingests alcohol, they should be counselled to to avoid ingestion of alcohol on an empty stomach, which increases risk for low blood sugar. Patients should also be aware of the carbohydrate intake provided by certain types of alcohol in the diet, which can contribute to poor glycemic control. If a patient chooses to ingest alcohol, they should monitor their blood glucose frequently. Many non-prescription drug products may be formulated with alcohol; instruct patients to scrutinize product labels prior to consumption.
    Ethinyl Estradiol; Desogestrel: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Etonogestrel: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Levonorgestrel: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norelgestromin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norethindrone: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norgestimate: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norgestrel: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethotoin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
    Etonogestrel: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Felodipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Fibric acid derivatives: (Moderate) Dose reductions and increased frequency of glucose monitoring may be required when antidiabetic agents are administered with fibric acid derivatives (e.g., clofibrate, fenofibric acid, fenofibrate, gemfibrozil). Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Fluoxetine: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Fluoxetine; Olanzapine: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Fosamprenavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Fosinopril: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Fosphenytoin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
    Furosemide: (Moderate) When empagliflozin is initiated in patients already receiving loop diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Loop diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. Patients receiving empagliflozin should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Garlic, Allium sativum: (Moderate) Patients receiving antidiabetic agents should use dietary supplements of Garlic, Allium sativum with caution. Constituents in garlic might have some antidiabetic activity, and may increase serum insulin levels and increase glycogen storage in the liver. Monitor blood glucose and glycemic control. Patients with diabetes should inform their health care professionals of their intent to ingest garlic dietary supplements. Some patients may require adjustment to their hypoglycemic medications over time. One study stated that additional garlic supplementation (0.05 to 1.5 grams PO per day) contributed to improved blood glucose control in patients with type 2 diabetes mellitus within 1 to 2 weeks, and had positive effects on total cholesterol and high/low density lipoprotein regulation over time. It is unclear if hemoglobin A1C is improved or if improvements are sustained with continued treatment beyond 24 weeks. Other reviews suggest that garlic may provide modest improvements in blood lipids, but few studies demonstrate decreases in blood glucose in diabetic and non-diabetic patients. More controlled trials are needed to discern if garlic has an effect on blood glucose in patients with diabetes. When garlic is used in foods or as a seasoning, or at doses of 50 mg/day or less, it is unlikely that blood glucose levels are affected to any clinically significant degree.
    Gemifloxacin: (Moderate) Careful monitoring of blood glucose is recommended when other quinolones andantidiabetic agents, including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Green Tea: (Moderate) Green tea catechins have been shown to decrease serum glucose concentrations in vitro. Patients with diabetes mellitus taking antidiabetic agents should be monitored closely for hypoglycemia if consuming green tea products.
    Hydantoins: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydroxychloroquine: (Major) Careful monitoring of blood glucose is recommended when hydroxychloroquine and antidiabetic agents, including the SGLT2 inhibitors, are coadministered. A decreased dose of the antidiabetic agent may be necessary as severe hypoglycemia has been reported in patients treated concomitantly with hydroxychloroquine and an antidiabetic agent.
    Hydroxyprogesterone: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Indapamide: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy.
    Indinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Irbesartan: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Isocarboxazid: (Moderate) Selected monoamine oxidase inhibitors (MAOIs) have potentiated hypoglycemia in animal models; there are conflicting data regarding hypoglycemic reactions in humans. These effects do not appear to be due to MAO activity, but rather, a change in gluconeogenesis or insulin sensitivity related to a hydrazine chemical structure. It is not clear if all MAOIs affect blood glucose control or potentiate antidiabetic medications. When initiating MAOIs in a patient receiving antidiabetic agents, the patient should monitor their blood glucose and report any changes in blood sugar control.
    Isoniazid, INH: (Minor) Although rare, isoniazid, INH may increase blood glucose concentrations. Patients should be closely monitored for changes in glycemic control if isoniazid therapy is initiated or discontinued.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Minor) Although rare, isoniazid, INH may increase blood glucose concentrations. Patients should be closely monitored for changes in glycemic control if isoniazid therapy is initiated or discontinued.
    Isoniazid, INH; Rifampin: (Minor) Although rare, isoniazid, INH may increase blood glucose concentrations. Patients should be closely monitored for changes in glycemic control if isoniazid therapy is initiated or discontinued.
    Isradipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Labetalol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Lanreotide: (Moderate) Monitor blood glucose levels regularly in patients with diabetes, especially when lanreotide treatment is initiated or when the dose is altered. Adjust treatment with antidiabetic agents as clinically indicated. Lanreotide inhibits the secretion of insulin and glucagon. Patients treated with lanreotide may experience either hypoglycemia or hyperglycemia.
    Leuprolide; Norethindrone: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Levobetaxolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Levobunolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Levocarnitine: (Moderate) Chromium dietary supplements may lower blood glucose. As part of the glucose tolerance factor molecule, chromium appears to facilitate the binding of insulin to insulin receptors in tissues and to aid in glucose metabolism. Because blood glucose may be lowered by the use of chromium, patients who are on antidiabetic agents may need dose adjustments. Close monitoring of blood glucose is recommended.
    Levofloxacin: (Moderate) Careful monitoring of blood glucose is recommended when levofloxacin and antidiabetic agents, including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Levonorgestrel: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Levothyroxine: (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Levothyroxine; Liothyronine (Porcine): (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Levothyroxine; Liothyronine (Synthetic): (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Liothyronine: (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Lisinopril: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Lithium: (Moderate) Lithium may cause variable effects on glycemic control when used in patients receiving antidiabetic agents. While early reports of hyperglycemia in patients treated with lithium have not been confirmed by more recent studies, it may be prudent to monitor blood glucose concentrations closely if lithium is coadministered with antidiabetic agents. Dosage adjustments of antidiabetic agents may be necessary.
    Lomefloxacin: (Moderate) Careful monitoring of blood glucose is recommended when other quinolones andantidiabetic agents, including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Loop diuretics: (Moderate) When empagliflozin is initiated in patients already receiving loop diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Loop diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. Patients receiving empagliflozin should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Lopinavir; Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Losartan: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Lovastatin; Niacin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
    Mecasermin rinfabate: (Moderate) Use caution in combining mecasermin, recombinant, rh-IGF-1 or mecasermin rinfabate (rh-IGF-1/rh-IGFBP-3) with antidiabetic agents. Patients should be advised to eat within 20 minutes of mecasermin administration. Glucose monitoring is important when initializing or adjusting mecasermin therapies, when adjusting concomitant antidiabetic therapy, and in the event of hypoglycemic symptoms. An increased risk for hypoglycemia is possible. The hypoglycemic effect induced by IGF-1 activity may be exacerbated. The amino acid sequence of mecasermin (rh-IGF-1) is approximately 50 percent homologous to insulin and cross binding with either receptor is possible. Treatment with mecasermin has been shown to improve insulin sensitivity and to improve glycemic control in patients with either Type 1 or Type 2 diabetes mellitus when used alone or in conjunction with insulins.
    Mecasermin, Recombinant, rh-IGF-1: (Moderate) Use caution in combining mecasermin, recombinant, rh-IGF-1 or mecasermin rinfabate (rh-IGF-1/rh-IGFBP-3) with antidiabetic agents. Patients should be advised to eat within 20 minutes of mecasermin administration. Glucose monitoring is important when initializing or adjusting mecasermin therapies, when adjusting concomitant antidiabetic therapy, and in the event of hypoglycemic symptoms. An increased risk for hypoglycemia is possible. The hypoglycemic effect induced by IGF-1 activity may be exacerbated. The amino acid sequence of mecasermin (rh-IGF-1) is approximately 50 percent homologous to insulin and cross binding with either receptor is possible. Treatment with mecasermin has been shown to improve insulin sensitivity and to improve glycemic control in patients with either Type 1 or Type 2 diabetes mellitus when used alone or in conjunction with insulins.
    Medroxyprogesterone: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Megestrol: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Mestranol; Norethindrone: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Methazolamide: (Minor) Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus who are receiving antidiabetic agents. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Methyclothiazide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Metoclopramide: (Moderate) Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including empagliflozin. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Metolazone: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Metoprolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Moexipril: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Monoamine oxidase inhibitors: (Moderate) Selected monoamine oxidase inhibitors (MAOIs) have potentiated hypoglycemia in animal models; there are conflicting data regarding hypoglycemic reactions in humans. These effects do not appear to be due to MAO activity, but rather, a change in gluconeogenesis or insulin sensitivity related to a hydrazine chemical structure. It is not clear if all MAOIs affect blood glucose control or potentiate antidiabetic medications. When initiating MAOIs in a patient receiving antidiabetic agents, the patient should monitor their blood glucose and report any changes in blood sugar control.
    Moxifloxacin: (Moderate) Careful monitoring of blood glucose is recommended when other quinolones andantidiabetic agents, including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Nadolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Nebivolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Nebivolol; Valsartan: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present. (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Nelfinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Niacin, Niacinamide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
    Niacin; Simvastatin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
    Nicardipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Nicotine: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine concentrations) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Nifedipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Nimodipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Nisoldipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Norethindrone: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Norfloxacin: (Moderate) Careful monitoring of blood glucose is recommended when other quinolones andantidiabetic agents, including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Norgestrel: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Octreotide: (Moderate) Monitor patients receiving octreotide concomitantly with insulin or other antidiabetic agents for changes in glycemic control and adjust doses of these medications accordingly. Octreotide alters the balance between the counter-regulatory hormones of insulin, glucagon, and growth hormone, which may result in hypoglycemia or hyperglycemia. The hypoglycemia or hyperglycemia which occurs during octreotide acetate therapy is usually mild, but may result in overt diabetes mellitus or necessitate dose changes in insulin or other hypoglycemic agents. In patients with concomitant type1 diabetes mellitus, octreotide is likely to affect glucose regulation, and insulin requirements may be reduced. Symptomatic hypoglycemia, which may be severe, has been reported in type 1 diabetic patients. In Type 2 diabetes patients with partially intact insulin reserves, octreotide administration may result in decreases in plasma insulin levels and hyperglycemia.
    Ofloxacin: (Moderate) Careful monitoring of blood glucose is recommended when other quinolones andantidiabetic agents, including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Olmesartan: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Orlistat: (Minor) Weight-loss may affect glycemic control in patients with diabetes mellitus. In many patients, glycemic control may improve. A reduction in dose of oral hypoglycemic medications may be required in some patients taking orlistat. Monitor blood glucose and glycemic control and adjust therapy as clinically indicated.
    Pasireotide: (Moderate) Monitor blood glucose levels regularly in patients with diabetes, especially when pasireotide treatment is initiated or when the dose is altered. Adjust treatment with antidiabetic agents as clinically indicated. Pasireotide inhibits the secretion of insulin and glucagon. Patients treated with pasireotide may experience either hypoglycemia or hyperglycemia.
    Pegvisomant: (Moderate) Monitor blood glucose levels regularly in patients with diabetes, especially when pegvisomant treatment is initiated or when the dose is altered. Adjust treatment with antidiabetic agents as clinically indicated. Pegvisomant increases sensitivity to insulin by lowering the activity of growth hormone, and in some patients glucose tolerance improves with treatment. Patients with diabetes treated with pegvisomant and antidiabetic agents may be more likely to experience hypoglycemia.
    Penbutolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Pentamidine: (Moderate) Pentamidine can be harmful to pancreatic cells. This effect may lead to hypoglycemia acutely, followed by hyperglycemia with prolonged pentamidine therapy. Patients on antidiabetic agents should be monitored for the need for dosage adjustments during the use of pentamidine.
    Perindopril: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Perindopril; Amlodipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Phenelzine: (Moderate) Selected monoamine oxidase inhibitors (MAOIs) have potentiated hypoglycemia in animal models; there are conflicting data regarding hypoglycemic reactions in humans. These effects do not appear to be due to MAO activity, but rather, a change in gluconeogenesis or insulin sensitivity related to a hydrazine chemical structure. It is not clear if all MAOIs affect blood glucose control or potentiate antidiabetic medications. When initiating MAOIs in a patient receiving antidiabetic agents, the patient should monitor their blood glucose and report any changes in blood sugar control.
    Phenothiazines: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
    Phenytoin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
    Pindolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Potassium-sparing diuretics: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy.
    Progesterone: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Progestins: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Propranolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Protease inhibitors: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Quinapril: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Ramipril: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Reserpine: (Moderate) Reserpine may mask the signs and symptoms of hypoglycemia. Patients receiving reserpine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Sacubitril; Valsartan: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Salicylates: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents.
    Saquinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Selegiline: (Moderate) Selected monoamine oxidase inhibitors (MAOIs) have potentiated hypoglycemia in animal models; there are conflicting data regarding hypoglycemic reactions in humans. These effects do not appear to be due to MAO activity, but rather, a change in gluconeogenesis or insulin sensitivity related to a hydrazine chemical structure. It is not clear if all MAOIs affect blood glucose control or potentiate antidiabetic medications. When initiating MAOIs in a patient receiving antidiabetic agents, the patient should monitor their blood glucose and report any changes in blood sugar control.
    Somatropin, rh-GH: (Moderate) Patients with diabetes mellitus should be monitored closely during somatropin (recombinant rhGH) therapy. Antidiabetic drugs (e.g., insulin or oral agents) may require adjustment when somatropin therapy is instituted in these patients. Growth hormones, such as somatropin, may decrease insulin sensitivity, leading to glucose intolerance and loss of blood glucose control. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors for diabetes mellitus.
    Sotalol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Sparfloxacin: (Moderate) Careful monitoring of blood glucose is recommended when other quinolones andantidiabetic agents, including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Spironolactone: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy.
    Sulfonamides: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Sympathomimetics: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Tacrolimus: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Tegaserod: (Moderate) Because tegaserod can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of antidiabetic agents may require adjustment in patients who receive tegaserod concomitantly.
    Telmisartan: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Thiazide diuretics: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Thyroid hormones: (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Timolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Tipranavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Tobacco: (Minor) Tobacco smoking is known to aggravate insulin resistance. The cessation of tobacco smoking may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in either smoking status occurs; dosage adjustments in antidiabetic agents may be needed.
    Torsemide: (Moderate) When empagliflozin is initiated in patients already receiving loop diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Loop diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. Patients receiving empagliflozin should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Trandolapril: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Trandolapril; Verapamil: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium, and glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ACE inhibitors may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Tranylcypromine: (Moderate) Selected monoamine oxidase inhibitors (MAOIs) have potentiated hypoglycemia in animal models; there are conflicting data regarding hypoglycemic reactions in humans. These effects do not appear to be due to MAO activity, but rather, a change in gluconeogenesis or insulin sensitivity related to a hydrazine chemical structure. It is not clear if all MAOIs affect blood glucose control or potentiate antidiabetic medications. When initiating MAOIs in a patient receiving antidiabetic agents, the patient should monitor their blood glucose and report any changes in blood sugar control.
    Triamterene: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy.
    Trovafloxacin, Alatrofloxacin: (Moderate) Careful monitoring of blood glucose is recommended when other quinolones andantidiabetic agents, including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Valsartan: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.
    Verapamil: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies of empagliflozin in pregnant women, and use is not recommended during the second and third trimesters of human pregnancy. Based on results from animal studies, empagliflozin may affect renal development and maturation. Rat studies demonstrate that empagliflozin crosses the placenta and reaches fetal tissues. In rat and rabbit studies, empagliflozin was not teratogenic at 48-times and 128-times, respectively, the maximum clinical human dose of 25 mg. However, at higher doses (139 to 154 times the 25 mg maximum human clinical dose), maternal and fetal toxicity, including malformations of limb bones, were evident. Maternal toxicity did not occur in pre- and postnatal development studies, starting at gestation day 6 through to lactation day 20 (weaning) at approximately 16 times the 25 mg maximum clinical dose in pregnant rats; reduced body weight was observed in the offspring. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. The potential risks to human kidney development are of concern. Empagliflozin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Poorly controlled diabetes during pregnancy also increases fetal risk. The American College of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA) continue to recommend human insulin as the standard of care in pregnant women with diabetes mellitus and gestational diabetes mellitus (GDM) requiring medical therapy; insulin does not cross the placenta.

    It is not known if empagliflozin is excreted in human milk; however, due to a potential for serious adverse reactions in the nursing infant, it is recommended to avoid breast-feeding during its use, or to discontinue the drug, taking into account the importance of the therapy to the mother. Empagliflozin is secreted in the milk of lactating rats reaching levels 5 times higher than that in maternal plasma. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. If empagliflozin is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Other oral hypoglycemics may also be considered as possible alternatives in some patients. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected. Also, while the manufacturers of metformin recommend against breast-feeding while taking the drug, metformin may be a possible alternative for some patients. Data have shown that metformin is excreted into breast milk in small amounts and adverse effects on infant plasma glucose have not been reported in human studies. Tolbutamide is usually considered compatible with breast-feeding. Glyburide may be a suitable alternative since it was not detected in the breast milk of lactating women who received single and multiple doses of glyburide. If any oral hypoglycemics are used during breast feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Empagliflozin is an inhibitor of sodium-glucose co-transporter 2 (SGLT2), the transporter responsible for reabsorbing the majority of glucose filtered by the tubular lumen in the kidney. SGLT2 is expressed in the proximal renal tubules. By inhibiting SGLT2, empagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion, improving blood glucose control. This urinary glucose excretion with empagliflozin also results in increased urinary volume. Following the administration of empagliflozin 10 mg and 25 mg orally once daily, increases in the amount of glucose excreted in the urine were observed immediately in adult patients with type 2 diabetes mellitus and were maintained at the end of a 4-week treatment period averaging at approximately 64 grams/day and 78 grams/day, respectively.

    PHARMACOKINETICS

    Empagliflozin is administered orally. The apparent steady-state volume of distribution was estimated to be 73.8 L based on a population pharmacokinetic analysis. Empagliflozin is approximately 86.2% protein bound. No major metabolites of empagliflozin were detected in human plasma. In vitro studies suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9. The apparent terminal elimination half-life was estimated to be 12.4 hours and apparent oral clearance was 10.6 L/hour based on population pharmacokinetic analysis. Following once-daily dosing, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state, which was consistent with empagliflozin half-life. Following a dose of empagliflozin, 54.4% and 41.2% total radioactivity is excreted in urine and feces, respectively. The majority of drug-related radioactivity recovered in feces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug.
     
    Affected Cytochrome P450 (CYP450) enzymes and drug transporters: None
    Based on in vitro data, empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. Empagliflozin also does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. No effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of the major CYP450 isoforms or UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. The effect of UGT induction on empagliflozin exposure has not been evaluated. Empagliflozin is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but it does not inhibit these efflux transporters at therapeutic doses. Empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates. Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Empagliflozin does not inhibit any of these human uptake transporters at clinically relevant plasma concentrations and, therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of these uptake transporters.

    Oral Route

    Following oral administration, peak plasma concentrations (Cmax) of empagliflozin occurred at 1.5 hours post-dose. Thereafter, plasma concentrations declined in a biphasic manner with a rapid distribution phase and a relatively slow terminal phase. The steady state mean plasma AUC and Cmax were 1870 nmol/hour/L and 259 nmol/L, respectively, with empagliflozin 10 mg/day. The steady state mean plasma AUC and Cmax were 4740 nmol/hour/L and 687 nmol/L, respectively, with 25 mg/day empagliflozin. Systemic exposure of empagliflozin increased in a dose proportional manner within the therapeutic dose range. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar, suggesting linear pharmacokinetics with respect to time. Administration of a high-fat and high-calorie meal prior to empagliflozin administration resulted in slightly lower exposure; AUC decreased by approximately 16% and Cmax decreased by approximately 37%, compared to fasted conditions; however, the observed effect of food on empagliflozin was not considered clinically relevant. Empagliflozin may be administered with or without food.