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  • CLASSES

    GLP-1 Receptor Agonists
    GLP-1 Receptor Agonists for Obesity

    BOXED WARNING

    Medullary thyroid carcinoma (MTC), multiple endocrine neoplasia syndrome type 2 (MEN 2), thyroid cancer, thyroid C-cell tumors

    Liraglutide is contraindicated in patients with a personal or family history of certain types of thyroid cancer, specifically thyroid C-cell tumors such as medullary thyroid carcinoma (MTC), or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). Liraglutide has been shown to cause dose-dependent and treatment duration-dependent malignant thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. A statistically significant increase in cancer was observed in rats receiving liraglutide at 8-times clinical exposure compared to controls. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. Cases of MTC in patients treated with liraglutide for diabetes have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans. In clinical trials, there were 7 reported cases of papillary thyroid carcinoma in patients treated with liraglutide and 1 case in a comparator-treated patient (1.5 vs. 0.5 cases per 1,000 patient-years). Most of these papillary thyroid carcinomas were less than 1 cm in greatest diameter and were diagnosed after thyroidectomy, which was prompted by finding on protocol-specified screening with serum calcitonin or thyroid ultrasound. Patients should be counseled on the potential risk and symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). Although routine monitoring of serum calcitonin is of uncertain value in patients treated with liraglutide, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation.

    DEA CLASS

    Rx

    DESCRIPTION

    Subcutaneous incretin mimetic (GLP-1 receptor agonist); used once daily; not a first-line therapy due to the boxed warning regarding rodent C-cell tumors and the uncertain risk to humans
    Victoza product is used in adult and pediatric patients 10 years and older with type 2 diabetes mellitus (DM) and to reduce the risk of non-fatal and fatal cardiovascular events (e.g., myocardial infarction or stroke) in adults, if these patients also have cardiovascular disease
    Separate product (Saxenda) used for weight reduction and maintenance in obese pediatric patients 12 years and older and obese adults or overweight adults with at least 1 weight-related comorbidity

    COMMON BRAND NAMES

    Saxenda, Victoza

    HOW SUPPLIED

    Saxenda/Victoza Subcutaneous Inj Sol: 1mL, 6mg

    DOSAGE & INDICATIONS

    For the treatment of type 2 diabetes mellitus as an adjunct to diet and exercise.
    Subcutaneous dosage (Victoza)
    Adults

    0.6 mg subcutaneously once daily for 1 week, then 1.2 mg subcutaneously once daily, initially. May increase dose after at least 1 week to 1.8 mg subcutaneously once daily if additional glycemic control is needed. The 0.6 mg dose is a starting dose intended to reduce gastrointestinal symptoms during initial titration and is not effective for glycemic control.[38653]

    Children and Adolescents 10 to 17 years

    0.6 mg subcutaneously once daily, initially. May increase dose after at least 1 week to 1.2 mg subcutaneously once daily and then after at least 1 week to 1.8 mg subcutaneously if additional glycemic control is needed.[38653]

    For the reduction of cardiovascular mortality and CV events (e.g., non-fatal myocardial infarction or non-fatal stroke) in type 2 diabetes mellitus patients who also have established CV disease.
    Subcutaneous dosage (Victoza)
    Adults

    Initially, 0.6 mg subcutaneously once daily for 1 week. The 0.6 mg dose is a starting dose intended to reduce gastrointestinal (GI) symptoms during initial titration and is not effective for glycemic control. After 1 week, increase the dose to 1.2 mg subcutaneously once daily. If acceptable glycemic control not achieved, the dose can be increased to 1.8 mg subcutaneously once daily. If a dose is missed, resume the once daily regimen as prescribed with the next scheduled dose. If more than 3 days have elapsed since the last dose, reinitiate at 0.6 mg in order to alleviate any GI symptoms associated with reinitiation of treatment. The dose should then be retitrated appropriately. The concurrent use of liraglutide and prandial insulin has not been studied.[38653] When liraglutide is added to insulin detemir, a reduction in the dose of insulin detemir may be needed to reduce the risk of hypoglycemia. The manufacturer of insulin detemir recommends initiating therapy with insulin detemir at 10 units subcutaneously once daily when combining with a GLP-1 receptor agonist.[22300] When initiating liraglutide, consider reducing the dose of concomitantly administered insulin secretagogues (e.g., sulfonylureas) to reduce the risk of hypoglycemia.[38653] In addition to improving glycemic control a long-term, multicenter, randomized, double-blind, placebo-controlled trial (LEADER) of 9,340 patients with inadequately controlled type 2 DM and established, stable atherosclerotic cardiovascular disease reported that the risk of major adverse CV events (MACE: cardiovascular death, first occurrence of non-fatal myocardial infarction, or non-fatal stroke) was significantly reduced in the liraglutide group (13%) compared to the placebo group (14.9%) (HR 0.87; 95% CI 0.78 to 0.97; p less than 0.001 for noninferiority; p = 0.01 for superiority).

    For the treatment of obesity and for chronic weight management as an adjunct to a reduced-calorie diet and increased physical activity.
    NOTE: Liraglutide is indicated in adults with an initial body mass index (BMI) of 30 kg/m2 or more or 27 kg/m2 or more in the presence of other risk factors (e.g., hypertension, type 2 diabetes, or dyslipidemia) and pediatric patients with a body weight more than 60 kg and an initial BMI corresponding to 30 kg/m2 for adults by international cut-offs.
    Subcutaneous dosage (Saxenda)
    Adults

    0.6 mg subcutaneously once daily for 1 week, then increase dose by 0.6 mg/week to 3 mg subcutaneously once daily. Consider delaying dose escalation for 1 additional week if patients do not tolerate a dose increase. Discontinue use if patient cannot tolerate 3 mg/dose; efficacy has not been established at lower doses. Discontinue use if the patient has not had a reduction in body weight of at least 4% from baseline at 16 weeks after starting therapy. Pharmacotherapy should be offered as chronic treatment along with lifestyle modifications to patients with obesity when the potential benefits outweigh the risks. Short-term pharmacotherapy has not been shown to produce longer-term health benefits and is not generally recommended. A generalized hierarchy for medication preferences that would be applicable to all patients cannot currently be scientifically justified. Individualized weight loss pharmacotherapy is recommended, based upon factors such as the specific characteristics of each weight loss medication, the presence of weight-related complications, and the medical history of the patient. Combination therapy should only occur when such therapy is approved by the governing agency or when sufficient safety and efficacy data assure a favorable benefit-to-risk ratio.

    Children and Adolescents 12 to 17 years

    0.6 mg subcutaneously once daily for 1 week, then increase dose by 0.6 mg/week to 3 mg subcutaneously once daily. May lower dose to previous level if patient does not tolerate a dose increase during dose escalation; dose escalation may take up to 8 weeks. May reduce target dose to 2.4 mg/dose if 3 mg/dose is not tolerated. Discontinue use if patient cannot tolerate 2.4 mg/dose; efficacy has not been established at lower doses. Discontinue use if the patient has not had a reduction in BMI of at least 1% from baseline after 12 weeks on maintenance dose.

    Children 7 to 11 years†

    0.3 mg subcutaneously once daily for 1 week, then increase the dose by 0.3 mg/week to 1.2 mg/dose, then increase dose by 0.6 mg/week to 3 mg subcutaneously once daily. In a small trial, pediatric patients (age 7 to 11 years) at Tanner stage 1 with obesity were randomized (2:1) to receive 7 to 13 weeks of treatment with liraglutide (n = 16) or placebo (n = 8). A significant decrease in BMI Z score from baseline to end of treatment (estimated treatment difference: -0.28; p = 0.0062) was reported. Body weight was not significantly decreased and may be due to the short duration of treatment.[64813]

    MAXIMUM DOSAGE

    Adults

    1.8 mg/day subcutaneously for the treatment of type 2 diabetes mellitus; 3 mg/day subcutaneously for the treatment of obesity.

    Geriatric

    1.8 mg/day subcutaneously for the treatment of type 2 diabetes mellitus; 3 mg/day subcutaneously for the treatment of obesity.

    Adolescents

    1.8 mg/day subcutaneously for the treatment of type 2 diabetes mellitus; 3 mg/day subcutaneously for the treatment of obesity.

    Children

    12 years: 1.8 mg/day subcutaneously for the treatment of type 2 diabetes mellitus; 3 mg/day subcutaneously for the treatment of obesity.
    10 to 11 years: 1.8 mg/day for the treatment of type 2 diabetes mellitus; safety and efficacy for the treatment of obesity have not been established; however, doses up to 3 mg/day have been used off-label.
    7 to 9 years: Safety and efficacy have not been established; however, doses up to 3 mg/day have been used off-label for the treatment of obesity.
    1 to 6 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment is required.  

    Renal Impairment

    No dosage adjustment is required.

    ADMINISTRATION

    Hazardous Drugs Classification
    NIOSH 2016 List: Group 2
    NIOSH (Draft) 2020 List: Table 2
    Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.

    Injectable Administration

    Visually inspect for particulate matter and discoloration prior to administration whenever solution and container permit. The solution is clear, colorless, and contains no particles. Do not use injections which are unusually viscous, cloudy, discolored, or if particles are present.
    Do NOT mix liraglutide with insulin. When using liraglutide (Victoza) concomitantly with insulin, administer as separate injections. The 2 injections may be injected in the same body region, but the injections should not be adjacent to each other.
    Liraglutide (Saxenda) for the treatment of obesity is not recommended in combination with insulin.
    Diabetic medication or other medication pens should never be shared among patients. Even if the disposable needle is changed, sharing may result in transmission of hepatitis viruses, HIV, or other blood-borne pathogens. Do not share pens among multiple patients in an inpatient setting; use multidose vials, if available, or reserve the use of any pen to 1 patient only.

    Subcutaneous Administration

    Administer once daily at any time of day, independently of meals.
    Liraglutide is available as a pre-filled pen.
    Pen needles are not included and must be purchased separately.
    Use liraglutide pen with Novo Nordisk disposable needles.
    The liraglutide pen must be primed prior to the first use. See the pen user manual for directions.
    Inject subcutaneously into the thigh, abdomen, or upper arm.
    Double-check dosage prior to administration.
    Press down on the center of the dose button to inject until 0 mg lines up with the pointer. Inject over 6 seconds to ensure the full dose is injected. Keep thumb on the injection button until the needle is removed from the skin.
    Rotate administration sites with each injection to prevent lipodystrophy.
    For patients who are self-administering liraglutide, adequate oral as well as written instructions on the use of the injector pen should be supplied before they self-administer a dose.
    Missed dose: If a dose is missed, resume the once-daily regimen as prescribed with the next scheduled dose. Do not administer an extra dose or increase the dose to make up for the missed dose. If more than 3 days have elapsed since the last dose, reinitiate therapy at 0.6 mg once daily and retitrate the dose, to reduce the occurrence of gastrointestinal adverse reactions associated with reinitiation of treatment.
    Storage: After initial use, the pen can be stored for 30 days at controlled room temperature (59 to 86 degrees F; 15 to 30 degrees C) or in a refrigerator (36 to 46 degrees F; 2 to 8 degrees C). Keep the pen cap on when not in use. Protect the pen from excessive heat and sunlight. Always remove and safely discard the needle after each injection and store the pen without an injection needle attached. This will reduce the potential for contamination, infection, and leakage while also ensuring dosing accuracy.

    STORAGE

    Saxenda:
    - After initial use, may be stored for 30 days at controlled room temperature (59 to 86 degrees F) or in refrigerator (36 to 46 degrees F)
    - Avoid direct heat and sunlight
    - Avoid excessive heat (above 104 degrees F)
    - Discard 30 days after first use
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Do not use if product has been frozen
    - Refrigerate (between 36 and 46 degrees F)
    Victoza:
    - After initial use, may be stored for 30 days at controlled room temperature (59 to 86 degrees F) or in refrigerator (36 to 46 degrees F)
    - Avoid direct heat and sunlight
    - Avoid excessive heat (above 104 degrees F)
    - Discard 30 days after first use
    - Do not freeze
    - Do not use if product has been frozen
    - Store unopened containers in refrigerator (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    History of angioedema

    Liraglutide is contraindicated in patients with a history of a serious hypersensitivity reaction, such as a history of angioedema or anaphylaxis to liraglutide. There is a risk of serious hypersensitivity reactions with liraglutide use. Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported during postmarketing use with liraglutide. Use caution in patients with a history of anaphylaxis or angioedema to other GLP-1 receptor agonists because it is unknown whether such patients will be predisposed to serious reactions with liraglutide. If a serious hypersensitivity reaction is suspected, discontinue liraglutide and consider other potential causes for the event, then initiate alternative therapy.

    Medullary thyroid carcinoma (MTC), multiple endocrine neoplasia syndrome type 2 (MEN 2), thyroid cancer, thyroid C-cell tumors

    Liraglutide is contraindicated in patients with a personal or family history of certain types of thyroid cancer, specifically thyroid C-cell tumors such as medullary thyroid carcinoma (MTC), or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). Liraglutide has been shown to cause dose-dependent and treatment duration-dependent malignant thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. A statistically significant increase in cancer was observed in rats receiving liraglutide at 8-times clinical exposure compared to controls. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. Cases of MTC in patients treated with liraglutide for diabetes have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans. In clinical trials, there were 7 reported cases of papillary thyroid carcinoma in patients treated with liraglutide and 1 case in a comparator-treated patient (1.5 vs. 0.5 cases per 1,000 patient-years). Most of these papillary thyroid carcinomas were less than 1 cm in greatest diameter and were diagnosed after thyroidectomy, which was prompted by finding on protocol-specified screening with serum calcitonin or thyroid ultrasound. Patients should be counseled on the potential risk and symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). Although routine monitoring of serum calcitonin is of uncertain value in patients treated with liraglutide, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation.

    Type 1 diabetes mellitus

    Liraglutide should not be used for the treatment of type 1 diabetes mellitus. Liraglutide has not been evaluated for use in combination with prandial insulin.

    Hypoglycemia

    Hypoglycemia should be monitored for by the patient and clinician when liraglutide treatment is initiated and continued for type 2 diabetes mellitus (T2DM) and for weight reduction and maintenance. In clinical trials, hypoglycemia was increased when liraglutide was used in combination with a sulfonylurea for T2DM. Although specific dose recommendations are not available, the clinician should consider a dose reduction of the sulfonylurea when used in combination with liraglutide.[38653] In addition, when liraglutide is used in combination with insulin detemir, the dose of insulin should be evaluated; in patients at increased risk of hypoglycemia consider reducing the dose of insulin at initiation of liraglutide, followed by careful titration.[22300] In pediatric patients 10 years of age and older, the risk of hypoglycemia is higher with liraglutide treatment regardless of concomitant antidiabetic therapies.[38653] In a pediatric clinical trial for weight reduction, clinically significant hypoglycemia, defined as a blood glucose less than 54 mg/dL, occurred in 1.6% of the liraglutide-treated patients compared to 0.8% of placebo-treated patients. Adequate blood glucose monitoring should be continued and followed. Patient and family education regarding hypoglycemia management is crucial; the patient and patient's family should be instructed on how to recognize and manage the symptoms of hypoglycemia. Early warning signs of hypoglycemia may be less obvious in patients with hypoglycemia unawareness which can be due to a long history of diabetes mellitus (where deficiencies in the release or response to counter regulatory hormones exist), with autonomic neuropathy, intensified diabetes control, or taking beta-blockers, guanethidine, or reserpine. Patients should be aware of the need to have a readily available source of glucose (dextrose, d-glucose) or other carbohydrate to treat hypoglycemic episodes. In severe hypoglycemia, intravenous dextrose or glucagon injections may be needed. Because hypoglycemic events may be difficult to recognize in some elderly patients, antidiabetic agent regimens should be carefully managed to obviate an increased risk of severe hypoglycemia. Severe or frequent hypoglycemia in a patient is an indication for the modification of treatment regimens, including setting higher glycemic goals.[61491] Liraglutide may have particular benefits when used in patients with T2DM who are overweight. According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, weight loss medications should be considered as an adjunct to lifestyle therapy in all patients with T2DM as needed for weight loss sufficient to improve glycemic control, lipids, and blood pressure. During controlled trial evaluation of liraglutide 3 mg as an adjunct to lifestyle therapy versus lifestyle therapy alone for diabetes prevention, a greater weight loss and more profound reductions in incident diabetes occurred with liraglutide plus lifestyle therapy than lifestyle therapy alone.[62881]

    Pancreatitis

    Use liraglutide with caution in patients with risk factors for pancreatitis. After initiation and dose increases, patients should be closely observed for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue liraglutide; if pancreatitis is confirmed do not resume liraglutide. Liraglutide has been studied in a limited number of patients with a history of pancreatitis; it is unknown if these patients are at increased risk for the development of pancreatitis while using liraglutide. There have been reports of acute and chronic pancreatitis in patients taking liraglutide during premarketing clinical trials. In some of these patients, other risk factors for pancreatitis were present, such as gallstones or alcoholism. Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has also been reported postmarketing in patients treated with liraglutide. In a pediatric clinical trial, pancreatitis was reported in 1 (0.8%) of the 125 pediatric patients receiving liraglutide; treatment was discontinued in the patient.[38653] [58673] The FDA and the EMA have stated that after review of published and unpublished reports, the current data do not support an increased risk of pancreatitis and pancreatic cancer in patients receiving incretin mimetics. The agencies have not reached any new conclusions about safety risks of the incretin mimetics, although they have expressed that the totality of the data that have been reviewed provides reassurance. Continue to consider precautions related to pancreatic risk until more data are available.[53573] [56778] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, patients receiving liraglutide for weight loss should be monitored for the development of pancreatitis. Liraglutide should be avoided in patients with prior or current pancreatitis; otherwise, there are insufficient data to recommend withholding liraglutide for weight loss due to concerns of pancreatitis. According to the AACE/ACE Obesity Guidelines, either liraglutide or orlistat may be considered in patients with a substance abuse disorder (including alcoholism) who require treatment with a weight loss medication; many other agents have abuse potential.[62881]

    Renal failure, renal impairment

    Use caution when initiating or increasing doses of liraglutide for type 2 diabetes mellitus (T2DM) or weight loss in patients with renal impairment. There are limited data available regarding the use of liraglutide in patients with end-stage renal disease (renal failure). There have been postmarketing reports of acute kidney injury, renal failure, and worsening of chronic renal failure, which sometimes has required hemodialysis in patients treated with liraglutide or other GLP-1 receptor agonists; in many of these cases, altered renal function has been reversed with supportive treatment and discontinuation of potentially causative agents.[38653] [58673] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, liraglutide for weight loss can be used in patients with mild to moderate renal impairment (i.e., CrCl 30 to 79 mL/minute). Liraglutide can be considered in selected patients with end-stage renal disease with a high level of caution. The AACE/ACE Obesity Guidelines recommend discontinuation of liraglutide in patients with severe renal impairment (CrCl less than 30 mL/minute) who develop volume depletion, such as may occur from nausea, vomiting, or diarrhea. Liraglutide is considered a preferred weight loss medication in patients with a history of or at risk for nephrolithiasis.[62881]

    Cholelithiasis, gallbladder disease

    Use liraglutide with caution in patients with known gallbladder disease or a history of cholelithiasis. In patients for whom acute gallbladder events are suspected, gallbladder studies are indicated.[38653] In the LEADER trial, 3.1% of liraglutide-treated patients versus 1.9% of placebo-treated patients reported an acute event of gallbladder disease. In liraglutide clinical trials for weight loss in adults, 2.2% of liraglutide-treated patients reported adverse events of cholelithiasis versus 0.8% of placebo-treated patients. The incidence of cholecystitis was 0.8% in liraglutide-treated patients versus 0.4% in placebo-treated patients. The majority of liraglutide-treated patients with adverse gallbladder events required cholecystectomy. Substantial or rapid weight loss can increase the risk of cholelithiasis; however, the incidence of acute gallbladder disease was greater in liraglutide-treated patients than in placebo-treated patients even after accounting for the degree of weight loss.[38653] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, close monitoring for cholelithiasis is recommended in patients undergoing weight loss therapy, regardless of modality. In high-risk patients, liraglutide should be used with caution. Effective preventative measures for patients at risk for cholelithiasis include a slower rate of weight loss, increasing/including some dietary fat in the diet (assuming the patient has been on a very low-calorie diet containing little or no fat), or administration of ursodeoxycholic acid.

    Hepatic disease

    Use liraglutide with caution in patients with hepatic disease. There is limited experience in patients with mild, moderate, or severe hepatic impairment. According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, all weight loss medications, including liraglutide, should be used cautiously in patients with hepatic impairment and should be avoided in patients with severe hepatic impairment (i.e., Child-Pugh score greater than 9).

    Tachycardia

    No particular cautions are recommended by the manufacturer when using liraglutide for the treatment of type 2 diabetes mellitus (T2DM) in patients with heart disease; liraglutide is indicated to reduce the risk of major adverse cardiovascular events (MACE), such as reduced risk for cardiovascular mortality, non-fatal myocardial infarction, or non-fatal stroke in adults with T2DM and established cardiovascular disease. In a clinical trial evaluating cardiovascular outcomes with liraglutide in patients with type 2 DM, the primary endpoint of MI, stroke, or cardiovascular death was significantly reduced in the liraglutide group (13%) compared to the placebo group (14.9%) (HR 0.87; 95% CI 0.78 to 0.97; p less than 0.001 for noninferiority; p = 0.01 for superiority).[38653] Similar data regarding MACE for obese patients with cardiac disease using liraglutide for weight loss are not available. Sinus tachycardia was observed during various clinical studies. Mean increases in resting heart rate of 2 to 3 beats per minute (bpm) were observed with routine clinical monitoring in liraglutide-treated adult patients compared to placebo in clinical trials. More patients treated with liraglutide, compared with placebo, had changes from baseline at two consecutive visits of more than 10 bpm (34% versus 19%, respectively) and 20 bpm (5% versus 2%, respectively). At least one resting heart rate exceeding 100 bpm was recorded for 6% of liraglutide-treated patients compared with 4% of placebo-treated patients, with this occurring at two consecutive study visits for 0.9% and 0.3%, respectively. Tachycardia was reported as an adverse reaction in 0.6% of liraglutide-treated patients and in 0.1% of placebo-treated patients. In a clinical pharmacology trial that monitored heart rate continuously for 24 hours, liraglutide was associated with a heart rate that was 4 to 9 bpm higher than that observed with placebo. In a pediatric clinical trial, mean increases from baseline in resting heart rate of 3 to 7 bpm were observed with liraglutide treatment. Heart rate should be monitored at regular intervals consistent with usual clinical practice. Patients should inform health care providers of palpitations or feelings of a racing heartbeat while at rest during liraglutide treatment. For patients who experience a sustained increase in resting heart rate while taking liraglutide, discontinue liraglutide. According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, liraglutide is a preferred weight loss medication in patients with existing hypertension and may be considered as an alternative agent in patients with established coronary artery disease (CAD) with appropriate monitoring of heart rate. Liraglutide is not a preferred weight loss medication in patients with a history or risk of cardiac arrhythmias but is reasonable to use with caution if weight loss goals are met, with careful monitoring of heart rate and rhythm. Data are insufficient regarding the benefits of the use of liraglutide in patients with heart failure; the AACE/ACE Obesity Guidelines recommend caution.[62881]

    Depression, schizophrenia, suicidal ideation

    When liraglutide is used for weight management, administer with caution in patients with depression and avoid use in patients with a history of suicide attempts or active suicidal ideation; monitor patients receiving liraglutide for the emergence or worsening of depression, suicidal thoughts or behavior, and any unusual changes in mood or behavior. Discontinue liraglutide in patients who develop suicidal thoughts or behaviors. In adult clinical trials of liraglutide for weight loss, 0.3% of patients receiving liraglutide reported suicidal ideation vs. 0.1% of the patients receiving placebo; one of these liraglutide-treated patients attempted suicide. In pediatric clinical trials of liraglutide for weight loss, one (0.8%) of the 125 patients receiving liraglutide died by suicide.[58673] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, liraglutide may be considered for weight management in patients with depression; however, monitor all patients undergoing weight loss therapy for mood disorders, depression, and suicidal ideation. Evidence assessing safety and efficacy of weight loss medications in patients with a psychotic disorder (e.g., schizophrenia) is insufficient, and the AACE/ACE Obesity Guidelines recommend caution. Patients receiving an antipsychotic should be treated with structured lifestyle modifications to promote weight loss and weight gain prevention; guidelines suggest that metformin may be beneficial for modest weight loss and metabolic improvements in patients receiving an antipsychotic.[62881]

    Gastroparesis

    Liraglutide may slow gastric emptying. Liraglutide has not been studied in patients with pre-existing gastroparesis.

    Geriatric

    Liraglutide has been studied in adults 65 years of age or older during clinical trials; safety and efficacy were not different in geriatric adults versus younger adults when the drug is used for type 2 diabetes mellitus (T2DM) or weight reduction.[38653] [58673] In general, however, geriatric adults with diabetes mellitus are especially at risk for hypoglycemic episodes. The specific reasons identified include intensive insulin therapy, decreased renal function, severe liver disease, alcohol ingestion, defective counter regulatory hormone release, missing meals/fasting, and gastroparesis. Because hypoglycemic events may be difficult to recognize in some elderly patients, antidiabetic agent regimens should be carefully managed to obviate an increased risk of severe hypoglycemia. Severe or frequent hypoglycemia is an indication for the modification of treatment regimens, including setting higher glycemic goals. 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.[60742] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, there are limited data on the use of liraglutide for weight reduction in older adults and extra caution is advisable in this population. Geriatric patients selected for weight loss therapy should have structured lifestyle interventions including reduced calorie meal plans and exercise, clear health-related goals including blood pressure reduction, diabetes prevention in high-risk patients with pre-diabetes, and improvements in osteoarthritis, mobility, and physical functioning. Overweight geriatric patients being considered for a weight loss medication should be evaluated for osteopenia and sarcopenia.[62881]

    Contraception requirements, pregnancy

    Liraglutide (Saxenda) for the treatment of obesity or weight management is contraindicated during pregnancy because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm due to the potential hazard of maternal weight loss to the fetus.[58673] According to the American Association of Clinical Endocrinologists the and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, weight loss medications must not be used during pregnancy. The AACE/ACE ObesityGuidelines recommend contraception requirements for women of childbearing potential; those receiving liraglutide for weight reduction should use adequate contraception and discontinue liraglutide if pregnancy occurs.[62881] There are no adequate data or clinical studies of liraglutide (Victoza) use for the treatment of type 2 diabetes mellitus in pregnant women; use in pregnancy only if the potential benefit justifies the potential risk to the fetus. Because of the toxicities found in animal studies, it may be prudent to avoid liraglutide until data in human pregnancy are available.[38653] Rat studies have noted abnormalities and variations in the kidneys, and irregular skeletal ossification effects when liraglutide was given at or above 0.8 times the human systemic exposures, based on the maximum recommended human dose (MRHD) of 1.8 mg/day (determined from AUC). Reduced growth and increased total major abnormalities occurred in rabbits at systemic exposures below human exposure at the MRHD (determined from AUC).[38653] 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 women with diabetes mellitus or gestational diabetes mellitus (GDM) requiring medical therapy; insulin does not cross the placenta.[64926] [62358]

    Breast-feeding

    Liraglutide excretion into human milk is unknown. Consider the benefits of breast-feeding, the risk of potential infant drug exposure to liraglutide, and the risk of an untreated or inadequately treated condition.[38653] [58673] In lactating rats, liraglutide was excreted unchanged in milk at concentrations approximately 50% of maternal plasma concentrations; the human relevance of thyroid C-cell tumors observed in mice and rats is unknown.[38653] [58673] If liraglutide is discontinued in a lactating woman with type 2 diabetes mellitus (T2DM) and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Other oral hypoglycemics may be considered as possible alternatives during breast-feeding. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected.[46303] Also, while the manufacturers of metformin recommend against breast-feeding while taking the drug, 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.[31407] [31408] [31409] Tolbutamide is regarded as usually compatible with breast-feeding.[27500] 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.[31568] 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.[46104] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, the use of liraglutide for weight reduction is not recommended in breast-feeding women.[62881]

    ADVERSE REACTIONS

    Severe

    cholecystitis / Delayed / 0.2-3.1
    pancreatitis / Delayed / 0.3-0.8
    suicidal ideation / Delayed / 0.3-0.8
    AV block / Early / 0.3-0.3
    new primary malignancy / Delayed / 0.2-0.2
    anaphylactoid reactions / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known

    Moderate

    palpitations / Early / 0-34.0
    hypoglycemia / Early / 1.6-24.2
    constipation / Delayed / 4.8-19.4
    antibody formation / Delayed / 8.6-8.6
    depression / Delayed / 4.0-4.0
    cholelithiasis / Delayed / 0.3-3.1
    hypertension / Early / 3.0-3.0
    erythema / Early / 0-2.0
    orthostatic hypotension / Delayed / 1.1-1.1
    hypotension / Rapid / 1.1-1.1
    sinus tachycardia / Rapid / 0.6-0.6
    bundle-branch block / Early / 0.3-0.3
    elevated hepatic enzymes / Delayed / 0.2-0.2
    hyperamylasemia / Delayed / 0.1-0.1
    gastritis / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    edema / Delayed / Incidence not known

    Mild

    nausea / Early / 23.9-42.4
    vomiting / Early / 8.7-34.4
    diarrhea / Early / 9.3-22.4
    headache / Early / 9.1-21.2
    injection site reaction / Rapid / 2.0-13.9
    dizziness / Early / 5.8-12.1
    anorexia / Delayed / 10.0-10.0
    dyspepsia / Early / 4.0-9.6
    fever / Early / 8.0-8.0
    fatigue / Early / 4.8-7.5
    influenza / Delayed / 7.4-7.4
    infection / Delayed / 4.3-6.0
    sinusitis / Delayed / 5.6-5.6
    abdominal pain / Early / 5.4-5.4
    back pain / Delayed / 5.0-5.0
    gastroesophageal reflux / Delayed / 4.7-4.7
    eructation / Early / 4.5-4.5
    flatulence / Early / 3.2-4.0
    cough / Delayed / 4.0-4.0
    rash / Early / 3.2-3.2
    insomnia / Early / 2.4-2.4
    xerostomia / Early / 2.3-2.3
    asthenia / Delayed / 2.1-2.1
    anxiety / Delayed / 2.0-2.0
    dysgeusia / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    malaise / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Acetaminophen; Aspirin: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    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.
    Acetohexamide: (Moderate) Consider reducing the sulfonylurea dose when initiating liraglutide to reduce the risk for hypoglycemia. Patients receiving liraglutide in combination with a sulfonylurea may have an increased risk of hypoglycemia, including severe hypoglycemia.
    Aliskiren; Valsartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Amlodipine; Benazepril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Amlodipine; Olmesartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Amlodipine; Valsartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    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. Monitor blood glucose and HbA1C when these drugs are used together.
    Angiotensin II receptor antagonists: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Angiotensin-converting enzyme inhibitors: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Caffeine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Carisoprodol: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Dipyridamole: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Omeprazole: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Pravastatin: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Atazanavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents 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 protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    atypical antipsychotic: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Azilsartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Azilsartan; Chlorthalidone: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Benazepril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    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.
    Bismuth Subsalicylate: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    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.
    Candesartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Captopril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    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.
    Chloroquine: (Major) Careful monitoring of blood glucose is recommended when chloroquine and antidiabetic agents, including the incretin mimetics, 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.
    Chlorpromazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Chlorpropamide: (Moderate) Consider reducing the sulfonylurea dose when initiating liraglutide to reduce the risk for hypoglycemia. Patients receiving liraglutide in combination with a sulfonylurea may have an increased risk of hypoglycemia, including severe hypoglycemia.
    Chlorthalidone; 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.
    Choline Salicylate; Magnesium Salicylate: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    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.
    Clarithromycin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    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.
    Codeine; Phenylephrine; Promethazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Codeine; Promethazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Corticosteroids: (Moderate) Monitor blood glucose during concomitant corticosteroid and incretin mimetic use; an incretin mimetic dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose 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.
    Cyclosporine: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including liraglutide. Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related.
    Daclatasvir: (Moderate) Closely monitor blood glucose levels if daclatasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as daclatasvir.
    Danazol: (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. Monitor blood glucose and HbA1C when these drugs are used together.
    Darunavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents 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 protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir : (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
    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 protease inhibitors. Patients taking antidiabetic agents 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.
    Disopyramide: (Moderate) Disopyramide may enhance the hypoglycemic effects of antidiabetic agents. Patients receiving this combination should be monitored for changes in glycemic control.
    Elbasvir; Grazoprevir: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
    Enalapril, Enalaprilat: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Enalapril; Felodipine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Eprosartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Esterified Estrogens; Methyltestosterone: (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. Monitor blood glucose and HbA1C when these drugs are used together.
    Ethotoin: (Minor) Ethotoin can decrease the hypoglycemic effects of incretin mimetics by producing an increase in blood glucose levels. Patients receiving incretin mimetics should be closely monitored for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
    Fibric acid derivatives: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Fluoxetine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fluoxetine use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Fluoxymesterone: (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. Monitor blood glucose and HbA1C when these drugs are used together.
    Fluphenazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Fosamprenavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Fosinopril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Fosphenytoin: (Minor) Fosphenytoin can decrease the hypoglycemic effects of incretin mimetics by producing an increase in blood glucose levels. Patients receiving incretin mimetics should be closely monitored for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
    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.
    Glecaprevir; Pibrentasvir: (Moderate) Closely monitor blood glucose levels if glecaprevir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as glecaprevir. (Moderate) Closely monitor blood glucose levels if pibrentasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as pibrentasvir.
    Glimepiride: (Moderate) Consider reducing the sulfonylurea dose when initiating liraglutide to reduce the risk for hypoglycemia. Patients receiving liraglutide in combination with a sulfonylurea may have an increased risk of hypoglycemia, including severe hypoglycemia.
    Glimepiride; Rosiglitazone: (Moderate) Consider reducing the sulfonylurea dose when initiating liraglutide to reduce the risk for hypoglycemia. Patients receiving liraglutide in combination with a sulfonylurea may have an increased risk of hypoglycemia, including severe hypoglycemia.
    Glipizide: (Moderate) Consider reducing the sulfonylurea dose when initiating liraglutide to reduce the risk for hypoglycemia. Patients receiving liraglutide in combination with a sulfonylurea may have an increased risk of hypoglycemia, including severe hypoglycemia.
    Glipizide; Metformin: (Moderate) Consider reducing the sulfonylurea dose when initiating liraglutide to reduce the risk for hypoglycemia. Patients receiving liraglutide in combination with a sulfonylurea may have an increased risk of hypoglycemia, including severe hypoglycemia.
    Glyburide: (Moderate) Consider reducing the sulfonylurea dose when initiating liraglutide to reduce the risk for hypoglycemia. Patients receiving liraglutide in combination with a sulfonylurea may have an increased risk of hypoglycemia, including severe hypoglycemia.
    Glyburide; Metformin: (Moderate) Consider reducing the sulfonylurea dose when initiating liraglutide to reduce the risk for hypoglycemia. Patients receiving liraglutide in combination with a sulfonylurea may have an increased risk of hypoglycemia, including severe hypoglycemia.
    Green Tea: (Moderate) Green tea catechins have been shown to decrease serum glucose concentrations in vitro. Patients with diabetes mellitus taking incretin mimetics should be monitored closely for hypoglycemia if consuming green tea.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Hydroxychloroquine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and hydroxychloroquine use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Hydroxyprogesterone: (Minor) Progestins, like hydroxyprogesterone, can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Indapamide: (Moderate) A potential pharmacodynamic interaction exists between indapamide and antidiabetic agents, like incretin mimetics. Indapamide can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia.
    Indinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Insulin Aspart: (Moderate) Monitor blood glucose during concomitant insulin aspart and liraglutide use; consider decreasing the insulin aspart dose when starting liraglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Degludec: (Moderate) Monitor blood glucose during concomitant insulin degludec and liraglutide use; consider decreasing the insulin degludec dose when starting liraglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Degludec; Liraglutide: (Moderate) Monitor blood glucose during concomitant insulin degludec and liraglutide use; consider decreasing the insulin degludec dose when starting liraglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Detemir: (Moderate) Monitor blood glucose during concomitant insulin detemir and liraglutide use; consider decreasing the insulin detemir dose when starting liraglutide. The recommended starting dose of insulin detemir is 10 units/day in persons with type 2 diabetes mellitus inadequately controlled with a glucagon-like peptide-1 (GLP-1) receptor agonist. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Glargine: (Moderate) Monitor blood glucose during concomitant insulin glargine and liraglutide use; consider decreasing the insulin glargine dose when starting liraglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Glargine; Lixisenatide: (Moderate) Monitor blood glucose during concomitant insulin glargine and liraglutide use; consider decreasing the insulin glargine dose when starting liraglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Glulisine: (Moderate) Monitor blood glucose during concomitant insulin glulisine and liraglutide use; consider decreasing the insulin glulisine dose when starting liraglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Lispro: (Moderate) Monitor blood glucose during concomitant insulin lispro and liraglutide use; consider decreasing the insulin lispro dose when starting liraglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Lispro: (Moderate) Monitor blood glucose during concomitant insulin lispro and liraglutide use; consider decreasing the insulin lispro dose when starting liraglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Lispro; Insulin Lispro Protamine: (Moderate) Monitor blood glucose during concomitant insulin lispro and liraglutide use; consider decreasing the insulin lispro dose when starting liraglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Regular: (Moderate) Monitor blood glucose during concomitant regular insulin and liraglutide use; consider decreasing the regular insulin dose when starting liraglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin, Inhaled: (Moderate) Monitor blood glucose during concomitant insulin and liraglutide use; consider decreasing the insulin dose when starting liraglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Irbesartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Isocarboxazid: (Moderate) Monitor blood glucose during concomitant incretin mimetic and monoamine oxidase inhibitor (MAOI) use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    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.
    Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    Ledipasvir; Sofosbuvir: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Levothyroxine: (Minor) 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 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. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis.
    Levothyroxine; Liothyronine (Porcine): (Minor) 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 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. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis.
    Levothyroxine; Liothyronine (Synthetic): (Minor) 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 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. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis.
    Linezolid: (Moderate) Hypoglycemia, including symptomatic episodes, has been noted in post-marketing reports with linezolid in patients with diabetes mellitus receiving therapy with antidiabetic agents, such as insulin and oral hypoglycemic agents. Diabetic patients should be monitored for potential hypoglycemic reactions while on linezolid. If hypoglycemia occurs, discontinue or decrease the dose of the antidiabetic agent or discontinue the linezolid therapy. Linezolid is a reversible, nonselective MAO inhibitor and other MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or oral hypoglycemic agents.
    Liothyronine: (Minor) 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 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. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis.
    Lisinopril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Lonapegsomatropin: (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.
    Loop diuretics: (Minor) Loop diuretics, such as bumetanide, furosemide, and torsemide, may cause hyperglycemia and glycosuria in patients with diabetes mellitus, probably due to diuretic-induced hypokalemia. Because of this, a potential pharmacodynamic interaction exists between these drugs and all antidiabetic agents, including incretin mimetics. This interference can lead to a loss of diabetic control, so diabetic patients should be monitored closely if these drugs are initiated.
    Lopinavir; Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Lorcaserin: (Moderate) In general, weight reduction may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with antidiabetic agents, such as insulin and/or insulin secretagogues (e.g., sulfonylureas). In clinical trials, lorcaserin use was associated with reports of hypoglycemia. Blood glucose monitoring is warranted in patients with type 2 diabetes prior to starting and during lorcaserin treatment. Dosage adjustments of anti-diabetic medications should be considered. If a patient develops hypoglycemia during treatment, adjust anti-diabetic drug regimen accordingly. Of note, lorcaserin has not been studied in combination with insulin.
    Losartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    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.
    Magnesium Salicylate: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    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.
    Meperidine; Promethazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    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.
    Methenamine; Sodium Salicylate: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Methyltestosterone: (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. Monitor blood glucose and HbA1C when these drugs are used together.
    Metyrapone: (Moderate) In patients taking insulin or other antidiabetic agents, the signs and symptoms of acute metyrapone toxicity (e.g., symptoms of acute adrenal insufficiency) may be aggravated or modified.
    Moexipril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Monoamine oxidase inhibitors: (Moderate) Monitor blood glucose during concomitant incretin mimetic and monoamine oxidase inhibitor (MAOI) use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Nandrolone Decanoate: (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. Monitor blood glucose and HbA1C when these drugs are used together.
    Nebivolol; Valsartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Nelfinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents 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.
    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 levels) and may increase plasma glucose. Tobacco smoking is known to aggravate insulin resistance. Cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Nirmatrelvir; Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    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.
    Olanzapine; Fluoxetine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fluoxetine use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Olmesartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents 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.
    Oxandrolone: (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. Monitor blood glucose and HbA1C when these drugs are used together.
    Oxymetholone: (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. Monitor blood glucose and HbA1C when these drugs are used together.
    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.
    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.
    Pentoxifylline: (Moderate) Pentoxiphylline has been used concurrently with antidiabetic agents without observed problems, but it may enhance the hypoglycemic action of antidiabetic agents. Patients should be monitored for changes in glycemic control while receiving pentoxifylline in combination with antidiabetic agents.
    Perindopril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Perindopril; Amlodipine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Perphenazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Perphenazine; Amitriptyline: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Phenelzine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and monoamine oxidase inhibitor (MAOI) use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Phenothiazines: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Phenytoin: (Minor) Phenytoin can decrease the hypoglycemic effects of liraglutide by producing an increase in blood glucose levels. Monitor for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
    Pioglitazone; Glimepiride: (Moderate) Consider reducing the sulfonylurea dose when initiating liraglutide to reduce the risk for hypoglycemia. Patients receiving liraglutide in combination with a sulfonylurea may have an increased risk of hypoglycemia, including severe hypoglycemia.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (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. Monitor blood glucose and HbA1C when these drugs are used together.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (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. Monitor blood glucose and HbA1C when these drugs are used together.
    Prochlorperazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Promethazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Promethazine; Dextromethorphan: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Promethazine; Phenylephrine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Protease inhibitors: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Quinapril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Quinolones: (Moderate) Monitor blood glucose during concomitant incretin mimetic and quinolone use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Ramipril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Regular Insulin: (Moderate) Monitor blood glucose during concomitant regular insulin and liraglutide use; consider decreasing the regular insulin dose when starting liraglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Regular Insulin; Isophane Insulin (NPH): (Moderate) Monitor blood glucose during concomitant insulin NPH and liraglutide use; consider decreasing the insulin NPH dose when starting liraglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant regular insulin and liraglutide use; consider decreasing the regular insulin dose when starting liraglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Reserpine: (Moderate) Reserpine may mask the signs and symptoms of hypoglycemia. Patients receiving reserpine concomitantly with antidiabetic agents, such as incretin mimetics, 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 protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Sacubitril; Valsartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Salicylates: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Salsalate: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Saquinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Sofosbuvir: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Sofosbuvir; Velpatasvir: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir. (Moderate) Closely monitor blood glucose levels if velpatasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as velpatasvir.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir. (Moderate) Closely monitor blood glucose levels if velpatasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as velpatasvir. (Moderate) Closely monitor blood glucose levels if voxilaprevir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as voxilaprevir.
    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.
    Sulfonamides: (Moderate) Monitor blood glucose during concomitant incretin mimetic and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Sulfonylureas: (Moderate) Consider reducing the sulfonylurea dose when initiating liraglutide to reduce the risk for hypoglycemia. Patients receiving liraglutide in combination with a sulfonylurea may have an increased risk of hypoglycemia, including severe hypoglycemia.
    Sympathomimetics: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking incretin mimetics. 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) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents, including liraglutide. 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.
    Tegaserod: (Moderate) Tegaserod can enhance gastric emptying in patients with diabetes. Typically, blood glucose could be affected, which, in turn, may affect the clinical response to antidiabetic agents. However, incretin mimetics have been shown to slow gastric emptying. The clinical effects of these competing mechanisms is not known. The dosing of antidiabetic agents may require adjustment and blood glucose should be closely monitored when coadministered with tegaserod.
    Telmisartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Telmisartan; Amlodipine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Testosterone: (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. Monitor blood glucose and HbA1C when these drugs are used together.
    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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Thiethylperazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Thioridazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Thyroid hormones: (Minor) 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 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. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis.
    Tipranavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Tolazamide: (Moderate) Consider reducing the sulfonylurea dose when initiating liraglutide to reduce the risk for hypoglycemia. Patients receiving liraglutide in combination with a sulfonylurea may have an increased risk of hypoglycemia, including severe hypoglycemia.
    Tolbutamide: (Moderate) Consider reducing the sulfonylurea dose when initiating liraglutide to reduce the risk for hypoglycemia. Patients receiving liraglutide in combination with a sulfonylurea may have an increased risk of hypoglycemia, including severe hypoglycemia.
    Trandolapril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Trandolapril; Verapamil: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Tranylcypromine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and monoamine oxidase inhibitor (MAOI) use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Triamterene: (Minor) Triamterene can decrease the hypoglycemic effects of antidiabetic agents, such as incretin mimetics, by producing an increase in blood glucose levels. Patients on antidiabetics should be monitored for changes in blood glucose control if triamterene is added or deleted. Dosage adjustments may be necessary.
    Triamterene; Hydrochlorothiazide, HCTZ: (Minor) Triamterene can decrease the hypoglycemic effects of antidiabetic agents, such as incretin mimetics, by producing an increase in blood glucose levels. Patients on antidiabetics should be monitored for changes in blood glucose control if triamterene is added or deleted. Dosage adjustments may be necessary.
    Trifluoperazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Valsartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.

    PREGNANCY AND LACTATION

    Pregnancy

    Liraglutide excretion into human milk is unknown. Consider the benefits of breast-feeding, the risk of potential infant drug exposure to liraglutide, and the risk of an untreated or inadequately treated condition.[38653] [58673] In lactating rats, liraglutide was excreted unchanged in milk at concentrations approximately 50% of maternal plasma concentrations; the human relevance of thyroid C-cell tumors observed in mice and rats is unknown.[38653] [58673] If liraglutide is discontinued in a lactating woman with type 2 diabetes mellitus (T2DM) and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Other oral hypoglycemics may be considered as possible alternatives during breast-feeding. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected.[46303] Also, while the manufacturers of metformin recommend against breast-feeding while taking the drug, 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.[31407] [31408] [31409] Tolbutamide is regarded as usually compatible with breast-feeding.[27500] 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.[31568] 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.[46104] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, the use of liraglutide for weight reduction is not recommended in breast-feeding women.[62881]

    MECHANISM OF ACTION

    Liraglutide is an incretin mimetic; specifically, liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist with 97% amino acid sequence homology to endogenous GLP-1 (7—37). GLP-1 (7—37) represents < 20% of total circulating endogenous GLP-1. Liraglutide binds and activates the GLP-1 receptor. GLP-1 is an important, gut-derived, glucose homeostasis regulator that is released after the oral ingestion of carbohydrates or fats. In patients with type 2 diabetes, GLP-1 concentrations are decreased in response to an oral glucose load. GLP-1 enhances insulin secretion; it increases glucose-dependent insulin synthesis and in vivo secretion of insulin from pancreatic beta cells in the presence of elevated glucose. In addition to increases in insulin secretion and synthesis, GLP-1 suppresses glucagon secretion, slows gastric emptying, reduces food intake, and promotes beta-cell proliferation. Liraglutide does not increase insulin secretion or suppress glucagon secretion at normal or low glucose concentrations.
     
    GLP-1 is also a physiological regulator of appetite and caloric intake and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation. Liraglutide acts to reduce body weight through decreased caloric intake; it does not increase 24-hour energy expenditure.

    PHARMACOKINETICS

    Liraglutide is given via subcutaneous administration. Liraglutide is more than 98% bound to plasma protein. After a single radioactive liraglutide dose was administered to healthy subjects, the major component in plasma was intact liraglutide for the initial 24 hours. The mean apparent volume of distribution after subcutaneous administration of a 0.6 mg and 3 mg dose of liraglutide is approximately 13 L and 20 to 25 L, respectively. The metabolism of liraglutide mirrors that of large proteins without a specific organ as a major route of elimination. After a radioactive liraglutide dose, intact liraglutide was not detected in urine or feces; only a minor part of the administered dose was excreted as metabolites in the urine (6%) or feces (5%). The mean apparent clearance after subcutaneous injection of a single dose of liraglutide is approximately 0.9 to 1.4 L/hour. Liraglutide is resistant to dipeptidyl peptidase-4 (DDP-4), the endogenous enzyme responsible for the degradation of GLP-1; this allows for a long half-life (13 hours) and once daily dosing.
     
    Affected cytochrome P450 (CYP450) enzymes and drug transporters: None

    Intravenous Route

    The mean volume of distribution after IV administration is 0.07 L/kg.

    Subcutaneous Route

    After subcutaneous injection, liraglutide binds to albumin at the injection site, and after that is released slowly into circulation. Peak plasma concentrations are achieved in roughly 8 to 12 hours; after a 0.6 mg subcutaneous dose, mean peak concentration was 35 ng/mL and total area under the curve (AUC) was 960 ng x hour/mL. Liraglutide Cmax and AUC increased proportionally over the therapeutic dose range of 0.6 to 1.8 mg. At a dose of 1.8 mg, the average steady-state concentration over 24 hours was approximately 128 ng/mL. In obese patients (BMI 30 to 40 kg/m2), the average steady-state concentration over 24 hours was approximately 116 ng/mL. Similar absorption is achieved with subcutaneous administration of liraglutide in the abdomen, thigh, or arm. The absolute bioavailability of liraglutide after subcutaneous injection is approximately 55%.[38653] [58673]