Hypoglycemia in adult patients that were able to self-treat for type 2 diabetes occurred in 9.7% of patients taking liraglutide monotherapy, in 7.5% of patients taking liraglutide plus glimepiride, and in 27.4% of patients taking liraglutide in combination with glimepiride and metformin. Hypoglycemia requiring the assistance of another person for treatment occurred in 11 patients treated with liraglutide and in 2 comparator-treated patients. Of these 11 patients treated with liraglutide, 6 patients were concomitantly using metformin and a sulfonylurea, 1 was concomitantly using a sulfonylurea, 2 were concomitantly using metformin (blood glucose values were 65 and 94 mg/dL), and 2 were using liraglutide as monotherapy (1 of these patients was undergoing an intravenous glucose tolerance test, and the other was receiving insulin as treatment during a hospital stay). For these 2 patients on liraglutide monotherapy, the insulin treatment was the likely explanation for the hypoglycemia. In the 26-week open-label trial comparing liraglutide to sitagliptin, the incidence of hypoglycemic events defined as symptoms accompanied by a fingerstick glucose less than 56 mg/dL was comparable among the treatment groups (approximately 5%).[38653] Hypoglycemia (blood glucose less than 54 mg/dL) was reported in 24.2% of pediatric patients with type 2 diabetes receiving liraglutide vs. 10.3% of patients receiving placebo during a 52 week trial period. There was 1 severe episode in the placebo group in an insulin-treated patient. During a clinical trial for weight management in pediatric patients, 15.2% of 125 liraglutide-treated patients had hypoglycemia with a blood glucose less than 70 mg/dL and symptoms compared to 4% of 126 placebo-treated patients. Clinically significant hypoglycemia (blood glucose less than 54 mg/dL) occurred in 1.6% of 125 liraglutide-treated patients and in 0.8% of 126 placebo-treated patients. There were no severe hypoglycemic episodes (an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions) with liraglutide.[38653] [58673] [64323] Hypoglycemia was reported in 23% of adult patients with type 2 diabetes receiving liraglutide for weight management (Saxenda). In a clinical trial involving adult patients with type 2 diabetes mellitus and overweight or obesity, severe hypoglycemia (defined as requiring the assistance of another person) occurred in 3 (0.7%) of 422 liraglutide-treated patients and in none of the 212 placebo-treated patients. Each of these 3 liraglutide-treated patients was also taking a sulfonylurea. In the same trial, among patients taking a sulfonylurea, documented symptomatic hypoglycemia (defined as documented symptoms of hypoglycemia in combination with a plasma glucose 70 mg/dL or less) occurred in 48 (43.6%) of 110 liraglutide-treated patients and 15 (27.3%) of 55 placebo-treated patients. The doses of sulfonylureas were reduced by 50% at the beginning of the trial per protocol. Among patients not taking a sulfonylurea, documented symptomatic hypoglycemia occurred in 49 (15.7%) of 312 liraglutide-treated patients and 12 (7.6%) of 157 placebo-treated patients. In clinical trials involving patients without type 2 diabetes receiving liraglutide for weight management (Saxenda), there was no systematic capturing or reporting of hypoglycemia, as patients were not provided with blood glucose meters or hypoglycemia diaries. Spontaneously reported symptomatic episodes of unconfirmed hypoglycemia were reported by 46 (1.6%) of 2,962 liraglutide-treated patients and 19 (1.1%) of 1,729 placebo-treated patients. Fasting plasma glucose values obtained at routine clinic visits of 70 mg/dL or less, irrespective of hypoglycemic symptoms, were reported as hypoglycemia in 92 (3.1%) liraglutide-treated patients and 13 (0.8%) placebo-treated patients. The presence of anti-liraglutide antibodies may be associated with a higher incidence of hypoglycemia. In clinical trials, these events were usually classified as mild and resolved while patients continued on treatment. When initiating liraglutide in patients taking insulin secretagogues (such as sulfonylureas), consider reducing the dose of the insulin secretagogue to reduce the risk for hypoglycemia, and monitor blood glucose. In order to decrease the risk of hypoglycemia, the manufacturer of Saxenda (liraglutide for weight management) also recommends reducing the dose of the insulin secretagogue (for example, by one-half) to reduce the risk for hypoglycemia. Conversely, if discontinuing liraglutide in patients with type 2 diabetes, monitor for an increase in blood glucose.[58673]

In the controlled clinical trials of at least 26 weeks duration in patients with diabetes, gastrointestinal events were the most common category of adverse events among liraglutide-treated antibody-negative patients (43%, 18%, and 19% of antibody-negative liraglutide-treated, placebo-treated, and active-control-treated patients, respectively). The most common reasons for withdrawal in the patients treated with liraglutide for diabetes were nausea (2.8%) and vomiting (1.5%); the comparator group had no patients withdraw due to nausea and 0.1% due to vomiting. Withdrawal due to gastrointestinal adverse events mostly occurred during the first 2 to 3 months of treatment for diabetes; the percentage of patients who reported nausea declined over time. In the 52-week monotherapy trial for diabetes, nausea and vomiting occurred at a high rate overall in the liraglutide treated adult patients (28.4% and 10.9%, respectively) compared to glimepiride-treated patients (8.5% and 3.6%, respectively); nausea and vomiting were among the most common adverse events associated with liraglutide.[38656] In a 52-week trial for diabetes, nausea (28.8% vs. 13.2% placebo), vomiting (25.8% vs. 8.8% placebo), and diarrhea (22.7% vs. 16.2% placebo) were the most commonly reported adverse events in pediatric patients ages 10 to 17 treated with liraglutide.[64323] Gastrointestinal events from liraglutide in patients with diabetes were dose-dependent and also included diarrhea (17.1% vs. 8.9% glimepiride) and constipation (9.9% vs. 4.8% glimepiride).[38656] In 26-week combination therapy trials (i.e., liraglutide used with metformin, glimepiride, metformin plus rosiglitazone, and metformin plus glimepiride) in patients with diabetes, nausea occurred in 7.5% to 34.6% of patients and vomiting occurred in 6.6% to 12.4% of patients. Other gastrointestinal adverse events that were seen during the 26-week combination therapy trials in patients with diabetes were dyspepsia, anorexia, and decreased appetite.[38655] [38657] [38658] [38654] In a 26-week trial comparing liraglutide and sitagliptin in patients with diabetes, both in combination with metformin, the following gastrointestinal events were reported at a higher incidence with liraglutide compared to sitagliptin: nausea (23.9% vs. 4.6%), diarrhea (9.3% vs. 4.6%), and vomiting (8.7% vs. 4.1%). Ileus was reported during post-marketing experience.[38653] In the clinical trials of liraglutide for weight management, approximately 68% of adult patients receiving liraglutide and 39% of patients receiving placebo reported gastrointestinal disorders; the most frequently reported was nausea (39% vs. 14% placebo). Other common adverse reactions that occurred at a higher incidence among adult patients receiving liraglutide for weight management included diarrhea (20.9%), constipation (19.4%), vomiting (15.7%), dyspepsia (9.6%), xerostomia (2.3%), gastritis, gastroesophageal reflux disease (4.7%), flatulence (4%), eructation (4.5%), abdominal pain (5.4%), upper abdominal pain (5.1%), abdominal distension (4.5%), and anorexia (10%). In adult patients receiving liraglutide for weight management, most gastrointestinal events were mild or moderate and did not lead to discontinuation of therapy; 6.2% of patients receiving liraglutide discontinued treatment as a result of gastrointestinal adverse reactions compared to 0.8% of patients receiving placebo. The most common adverse reactions leading to discontinuation were nausea (2.9%), vomiting (1.7%), and diarrhea (1.4%). The percentage of adult patients reporting nausea declined as treatment continued. In a pediatric clinical trial for weight management, nausea (42.4%), vomiting (34.3%), diarrhea (22.4%), gastroenteritis (12.8%), abdominal discomfort (4.8%), constipation (4.8%), dyspepsia (4%), and flatulence (3.2%) were reported in liraglutide-treated patients. Of the pediatric patients receiving liraglutide for weight management, 8% discontinued treatment as a result of gastrointestinal adverse reactions compared to 0% of patients receiving placebo. The most common adverse reactions leading to discontinuation were vomiting (4.8%) and nausea (3.2%). There have been reports of gastrointestinal adverse reactions, such as nausea, vomiting, and diarrhea, associated with dehydration, volume depletion, and renal impairment in adult patients receiving liraglutide for weight management. Dysgeusia was mainly reported within the first 12 weeks of treatment with liraglutide for weight management and was often co-reported with gastrointestinal events such as nausea, vomiting, and diarrhea.[58673]

Hepatic adverse reactions and adverse reactions of the gallbladder have been reported with liraglutide. Elevated hepatic enzymes were reported in patients treated with liraglutide for weight management. Increases in alanine aminotransferase (ALT) 10 times or more the upper limit of normal (ULN) were observed in 5 (0.15%) liraglutide-treated patients (two of whom had ALT more than 20- and 40-times the ULN) compared with 1 (0.05%) placebo-treated patient during the liraglutide clinical trials. Clinical evaluation to exclude alternative causes of ALT and aspartate aminotransferase (AST) increases was not done in most cases; therefore, the relationship to liraglutide is uncertain. Some increases in ALT and AST were associated with other confounding factors (such as gallstones). In 5 clinical trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (defined as elevations to no more than twice the upper limit of the reference range) occurred in 4% of liraglutide-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients; other hepatic function tests were not found to be abnormal. During postmarketing experience with liraglutide elevated hepatic enzymes, hyperbilirubinemia, cholestasis, and hepatitis have been reported. In clinical trials of patients receiving liraglutide for weight management (doses up to 3 mg), 2.2% of patients receiving liraglutide reported adverse events of cholelithiasis versus 0.8% of patients receiving placebo. 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 events of cholelithiasis and cholecystitis 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. In clinical trials of liraglutide for diabetes management, the incidence of cholelithiasis (0.3%) and cholecystitis (0.2%) was the same in both liraglutide-treated and placebo-treated patients. In the LEADER trial, 3.1% of liraglutide-treated patients versus 1.9% of placebo-treated patients reported an acute gallbladder disease event, such as cholelithiasis or cholecystitis. The majority of events required hospitalization or cholecystectomy.[38653] [61921] Patients should be informed that substantial or rapid weight loss can increase the risk of cholelithiasis. Cholelithiasis may also occur in the absence of substantial or rapid weight loss. Patients should be instructed to contact their physician if cholelithiasis is suspected for appropriate clinical follow-up. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.[38653] [58673]

In clinical trials in patients receiving liraglutide for diabetes, there were 13 cases (9 acute and 4 chronic) of pancreatitis in patients treated with liraglutide and 1 case among comparator-treated patients (2.7 vs. 0.5 cases per 1,000 patient-years). In 1 case of a patient treated with liraglutide for diabetes, the patient experienced pancreatitis with necrosis and eventually died; clinical causality could not be established. In some of these patients other risk factors for pancreatitis were present, such as cholelithiasis or alcoholism. Conclusive data to establish a risk of pancreatitis with liraglutide is lacking. Postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis has been observed in patients treated with liraglutide for diabetes.[38653] In clinical trials of adult patients receiving liraglutide for weight management, acute pancreatitis was confirmed by adjudication in 9 (0.3%) of 3,291 patients compared to 2 (0.1%) of 1,843 patients receiving placebo. In addition, there were 2 cases of acute pancreatitis in patients receiving liraglutide who prematurely withdrew from these trials, occurring 74 and 124 days after the last dose, 1 case in a liraglutide-treated patient during an off-treatment follow-up period within 2 weeks of discontinuing liraglutide, and 1 case that occurred in a patient who completed treatment and was off-treatment for 106 days. In a pediatric clinical trial for weight management, pancreatitis was reported in 1 (0.8%) of the 125 patients receiving liraglutide; treatment was discontinued in this patient. Additionally, increased lipase was reported in 3.2% of patients. In adult patients receiving liraglutide for weight management, 2.1% had a lipase value at anytime during treatment of 3 times or more the upper limit of normal (ULN) compared with 1% of placebo-treated patients. Hyperamylasemia (defined as an amylase value at anytime in the trial of 3 times or more the ULN) was reported in 0.1% of patients receiving liraglutide versus 0.1% of patients receiving placebo. In a placebo-controlled trial in renal impairment patients receiving liraglutide for diabetes management, a mean increase of 33% for lipase and 15% for amylase from baseline was observed for liraglutide-treated patients while placebo-treated patients had a mean decrease in lipase of 3% and a mean increase in amylase of 1%. In the LEADER trial, serum lipase and amylase were routinely measured. Among liraglutide-treated patients, 7.9% had a lipase value at any time during treatment of greater than or equal to 3 times the ULN compared with 4.5% of placebo-treated patients, and 1% of liraglutide-treated patients had an amylase value at any time during treatment of greater than or equal to 3 times the ULN versus 0.7% of placebo-treated patients.[61921] The clinical significance of elevations in lipase or amylase with liraglutide is unknown in the absence of other signs and symptoms of pancreatitis.[38653] [58673] The FDA has evaluated unpublished findings that suggest an increased risk of pancreatitis and pre-cancerous cellular changes called pancreatic duct metaplasia in patients treated with incretin mimetics. These findings were based on examination of a small number of pancreatic tissue specimens taken from patients after they died from unspecified causes.[53573] The FDA and the EMA have stated that after review, 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. Pancreatitis will continue to be a risk associated with incretin mimetics until more data are available; recommendations will be communicated once the review is complete.[56778] Patients should be instructed to seek prompt medical attention if they experience unexplained persistent severe abdominal pain, which may or may not be accompanied by vomiting. If pancreatitis is suspected, liraglutide should be discontinued. If pancreatitis is confirmed, liraglutide should not be restarted.[38653]

In adult patients receiving liraglutide for weight management, mean increases in resting heart rate of 2 to 3 beats per minute (bpm) were observed during routine clinical monitoring. More patients treated with liraglutide, compared with placebo, had changes from baseline at 2 consecutive visits of more than 10 bpm (34% versus 19%, respectively) and 20 bpm (5% versus 2%, respectively). In 6% of patients receiving liraglutide, at least 1 resting heart rate greater than 100 bpm was recorded compared with 4% of placebo-treated patients; this occurred at 2 consecutive study visits for 0.9% of liraglutide-treated patients and 0.3% of patients receiving placebo. Sinus tachycardia was reported in 0.6% of patients receiving liraglutide and in 0.1% of patients receiving placebo. In a clinical pharmacology trial that monitored heart rate continuously for 24 hours, liraglutide treatment was associated with a heart rate that was 4 to 9 bpm higher than that observed with placebo; the clinical significance is unclear, especially for patients with cardiac and cerebrovascular disease as a result of limited exposure in these patients in clinical trials. In a pediatric clinical trial for weight management, mean increases from baseline in resting heart rate of 3 to 7 bpm were observed in liraglutide-treated patients. In clinical trials, 11 (0.3%) of 3,384 liraglutide-treated adult patients compared with none of the 1,941 placebo-treated patients had a cardiac conduction disorder, reported as first degree atrioventricular block (AV block), right bundle-branch block, or left bundle-branch block. Adverse reactions related to hypotension (that is, reports of hypotension, orthostatic hypotension, circulatory collapse, and decreased blood pressure) were reported more frequently with liraglutide (1.1%) compared with placebo (0.5%). Systolic blood pressure decreases to less than 80 mmHg were observed in 4 (0.1%) liraglutide-treated patients compared with no placebo-treated patients. One patient receiving liraglutide had hypotension associated with gastrointestinal adverse reactions and renal failure. In addition, hypotension and palpitations have been associated with anaphylactic reactions in patients receiving liraglutide. Heart rate should be monitored at regular intervals consistent with usual clinical practice. Patients receiving liraglutide should inform health care providers of palpitations or feelings of a racing heartbeat while at rest. For patients who experience a sustained increase in resting heart rate, discontinue treatment with liraglutide.[58673]

Anti-liraglutide antibodies were detected in 42 (2.8%) of 1,505 adult patients receiving liraglutide for weight management. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 18 (1.2%) of 1,505 patients receiving liraglutide for weight loss. In a pediatric trial, anti-liraglutide antibodies were detected in 14 (12%) of 117 patients receiving liraglutide for weight management; 5 patients (4.3%) had persistent antibodies as defined by more than 2 antibody visits at least 16 weeks apart. Two patients (1.7%) remained positive throughout the follow-up period, 1 patient (0.9%) had antibodies cross-reactive to native GLP-1, and no patients had neutralizing antibodies.[58673] Anti-liraglutide antibodies were detected in 102 (9%) of 1,104 adult patients with type 2 diabetes mellitus receiving liraglutide during clinical trials. Antibodies that cross-reacted with native GLP-1 were detected in 56 (5%) of the 102 patients that developed anti-liraglutide antibodies. The cross-reacting antibodies were not tested for neutralizing effect, and their effect against native GLP-1 is unknown. In vitro, antibodies with a neutralizing effect on liraglutide were seen in 12 (1%) of patients. There was no identified clinically significant effect of anti-liraglutide antibodies on effectiveness of liraglutide.[38653] Infection was the most common adverse event in patients with diabetes who developed anti-liraglutide antibodies (40% compared to 36%, 34%, and 35% of antibody-negative liraglutide-treated, placebo-treated, and active-control-treated patients, respectively). The specific infections which occurred with greater frequency among liraglutide-treated antibody-positive patients were primarily nonserious upper respiratory tract infections (11% antibody-positive patients and among 7%, 7%, and 5% of antibody-negative liraglutide-treated, placebo-treated, and active-control-treated patients, respectively). Among liraglutide-treated antibody-negative patients with diabetes, the most common category of adverse events was that of gastrointestinal (GI) events, which occurred in 43%, 18%, and 19% of antibody-negative liraglutide-treated, placebo-treated, and active-control-treated patients, respectively. When comparing mean A1C of all antibody-positive and antibody-negative patients, the results indicate that antibody formation was not associated with reduced efficacy of liraglutide; however, the 3 patients with the highest titers of anti-liraglutide antibodies had no reduction in A1C with liraglutide treatment. In the LEADER trial, anti-liraglutide antibodies were detected in 11 out of the 1,247 (0.9%) liraglutide-treated patients with antibody measurements. Of the 11 liraglutide-treated patients who developed anti-liraglutide antibodies, none were observed to develop neutralizing antibodies to liraglutide, and 5 patients (0.4%) developed cross-reacting antibodies against native GLP-1.[38653] [61921] In clinical trials of liraglutide in patients with diabetes, events from an aggregate of adverse events potentially related to immunogenicity (e.g., urticaria, angioedema) occurred among 0.8% of the entire cohort of liraglutide-treated patients and among 0.4% of comparator-treated patients. About one-half of the events in this composite for liraglutide-treated patients were reported as urticaria. It should be noted that patients with anti-liraglutide antibodies were not more likely to develop this type of adverse reaction compared to patients who did not develop anti-liraglutide antibodies. Postmarketing reports of serious hypersensitivity reactions, including anaphylactoid reactions, rash, pruritus, and angioedema have been reported in patients receiving liraglutide for diabetes.[38653] Urticaria was reported in 0.7% of patients receiving liraglutide for weight loss. In a pediatric clinical trial for weight management, rash was reported in 3.2% of patients receiving liraglutide. Asthma, bronchial hyperreactivity, bronchospasm, oropharyngeal swelling, facial swelling, pharyngeal edema, and type IV hypersensitivity reactions have been reported in patients treated with liraglutide in clinical trials. Cases of anaphylactic reactions with additional symptoms such as hypotension, palpitations, dyspnea, and edema have been reported with marketed use of liraglutide.[58673]

In premarketing trials of at least 26 weeks duration in patients with diabetes, the incidence of injection site reaction (e.g., injection site rash, erythema) in patients treated with liraglutide was approximately 2%; withdrawal rates due to injection site reactions were less than 0.2% in liraglutide-treated patients.[38653] In adult patients receiving liraglutide for weight management, injection site erythema (2.5%) and injection site reaction (2.5% to 13.9%) were reported. The most common reactions, each reported by 1% to 2.5% of liraglutide-treated patients and more commonly than by placebo-treated patients, included erythema, pruritus, and rash at the injection site. Injection site reaction was the cause for discontinuation of treatment in 0.6% of liraglutide-treated patients and 0.5% of placebo-treated patients. In a pediatric clinical trial for weight management, pain in extremity (4%) and injection site pain (3.2%) were reported in patients receiving liraglutide. Presence of antibodies may be associated with a higher incidence of injection site reactions. In clinical trials, these events were usually classified as mild and resolved while patients continued on treatment.[58673]

In the controlled clinical trials of at least 26 weeks duration in patients with diabetes, infection was the most common adverse event in patients who developed anti-liraglutide antibodies (40% compared to 36%, 34% and 35% of antibody-negative liraglutide-treated, placebo-treated and active-control-treated patients, respectively); the most common infection in these patients was non-serious upper respiratory infections. In the entire cohort of patients receiving liraglutide for weight management, influenza (7.4% vs. 3.6% glimepiride), sinusitis (5.6% vs. 6% glimepiride), and nasopharyngitis (5.2% vs. 5.2% glimepiride) were reported. Urinary tract infection was also reported in 4.3% to 6% of patients taking liraglutide.[38653] [58673] In patients receiving liraglutide for weight management, gastroenteritis (4.7%) and viral gastroenteritis (2.8%) were reported.[58673]

Other notable adverse events that occurred in patients with diabetes receiving liraglutide were headache (9.1% vs. 9.3% glimepiride), dizziness (5.8% vs. 5.2% glimepiride), back pain (5% vs. 4.4% glimepiride), and hypertension (3% vs. 6% glimepiride).[38653] In a 52 week trial for diabetes, headache (21.2% vs. 19.1% placebo) and dizziness (12.1% vs. 2.9% placebo) were reported in pediatric patients ages 10 to 17 years treated with liraglutide.[64323] In patients receiving liraglutide for weight management, asthenia (2.1%), fatigue (7.5%), malaise, and dizziness (6%) were mainly reported within the first 12 weeks of treatment and were often co-reported with gastrointestinal events such as nausea, vomiting, and diarrhea. Headache was reported in 13.6% of patients receiving liraglutide for weight management. In a pediatric clinical trial for weight management, dizziness (10.4%) and fatigue (4.8%) were reported in patients receiving liraglutide.[58673]

New primary malignancy has been reported in patients receiving liraglutide; however, causality has not been established.[38653] [58673] In clinical trials of patients receiving liraglutide for diabetes mellitus, there were 7 reported cases of papillary thyroid carcinoma in liraglutide-treated patients; there was 1 case in patients treated with placebo (1.5 vs 0.5 cases per 1,000 patient-years). Most were less than 1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol specified screening with serum calcitonin or thyroid ultrasound. In a pooled analysis of clinical trials, the incidence rate (per 1,000 patient-years) for new primary malignancy was 10.9 for liraglutide, 6.3 for placebo, and 7.2 for active comparator. No particular cancer cell type predominated after excluding papillary thyroid carcinoma events. Seven malignant neoplasm events were reported beyond 1 year of exposure to study medication; 6 events among liraglutide-treated patients (4 colon, 1 prostate and 1 nasopharyngeal), no events with placebo, and 1 event with active comparator (colon). Causality has not been established.[38653] In patients receiving liraglutide for weight management, papillary thyroid carcinoma confirmed by adjudication was reported in 7 (0.2%) of 3,291 patients compared with no cases among 1843 placebo-treated patients. Four of these papillary thyroid carcinomas were less than 1 cm in greatest diameter and four patients were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings identified prior to treatment. Calcitonin, a biological marker of medullary thyroid carcinoma (MTC), was measured throughout the clinical development program. More patients treated with liraglutide in the clinical trials were observed to have high calcitonin values during treatment, compared with placebo. The proportion of patients with calcitonin 2 times or greater the upper limit of normal (ULN) at the end of the trial was 1.2% in liraglutide-treated patients and 0.6% in placebo-treated patients. Calcitonin values greater than 20 ng/L at the end of the trial occurred in 0.5% of liraglutide-treated patients and 0.2% of placebo-treated patients; among patients with pre-treatment serum calcitonin less than 20 ng/L, none had calcitonin elevations to more than 50 ng/L at the end of the trial. In clinical trials of patients receiving liraglutide for weight management, benign colorectal neoplasms (mostly colon adenomas) confirmed by adjudication were reported in 17 (0.5%) of 3,291 patients compared with 4 (0.2%) of 1,843 placebo-treated patients. Two positively adjudicated cases of malignant colorectal carcinoma were reported in liraglutide-treated patients (0.1%) and none in placebo-treated patients. In clinical trials of patients receiving liraglutide for weight management, breast cancer confirmed by adjudication was reported in 14 (0.6%) of 2379 women compared with 3 (0.2%) of 1300 placebo-treated women, including invasive cancer (11 liraglutide- and 2 placebo-treated women) and ductal carcinoma in situ (3 liraglutide- and 1 placebo-treated woman). The majority of cancers were estrogen- and progesterone-receptor positive. There were too few cases to determine whether these cases were related to liraglutide. In addition, there are insufficient data to determine whether liraglutide has an effect on pre-existing breast neoplasia.[58673]

Acute renal failure (unspecified) and worsening of chronic renal failure, sometimes leading to required hemodialysis, have been reported in patients taking liraglutide. Some of these events were reported in patients without known underlying renal disease; a majority of the events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. In addition, some of the affected patients were receiving 1 or more medications known to affect renal function or hydration status. Renal function was reversible in many of the cases with supportive treatment and discontinuation of potentially causative agents, including liraglutide. In a pediatric clinical trial for weight management, increased blood creatine kinase was reported in 3.2% of patients receiving liraglutide.[38653] [58673]

In clinical trials of liraglutide for weight management in adults, 0.3% of patients receiving liraglutide reported suicidal ideation compared to 0.1% of the patients receiving placebo; 1 of the liraglutide-treated patients attempted suicide. In a pediatric clinical trial of liraglutide for weight management, 1 (0.8%) of the 125 patients receiving liraglutide died by suicide. Depression was reported in 4% of pediatric patients receiving liraglutide. Monitor patients receiving liraglutide for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue liraglutide in patients who develop suicidal thoughts or behaviors. Other psychiatric adverse reactions reported in clinical trials of patients receiving liraglutide for the treatment of obesity included insomnia (2.4%) and anxiety (2%).[58673] In January 2024, the FDA announced that they have not found evidence that use of GLP-1 RAs for type 2 diabetes or weight management causes suicidal thoughts or actions. During their preliminary evaluation, they conducted detailed reviews of reports of suicidal thoughts or actions received in the FDA Adverse Event Reporting System (FAERS) and reviews of clinical trials, including large outcome studies and observational studies. However, because of the small number of suicidal thoughts or actions observed in both people using GLP-1 RAs and in the comparative control groups, they cannot definitively rule out that a small risk may exist; therefore, FDA is continuing to look into this issue. Further evaluations include a meta-analysis of clinical trials across all GLP-1 RA products and an analysis of postmarketing data in the Sentinel System; final conclusions and recommendations will be communicated once more information is known.[70130]

In a pediatric clinical trial for weight management, fever (8%), dyslipidemia (4.8%), and cough (4%) were reported in patients receiving liraglutide.[58673]

There have been postmarketing reports of perioperative pulmonary aspiration in patients receiving GLP-1 receptor agonists who underwent elective surgery or procedures requiring general anesthesia or deep sedation. Despite adherence to preoperative fasting guidelines, these patients were found to have residual gastric contents. The available data is insufficient to give recommendations on mitigating the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking liraglutide, including whether to modify preoperative fasting recommendations or temporarily discontinue liraglutide.[38653]

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.[38653] [58673]

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.[38653]

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.[38653]

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.[58673] 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]

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]

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]

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] [58673] 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] [58673] 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.[62881]

Use liraglutide with caution in patients with hepatic disease. There is limited experience in patients with mild, moderate, or severe hepatic impairment.[38653] [58673] 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).[62881]

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.[58673] [38653] 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]

Administer liraglutide 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] In January 2024, the FDA announced that they have not found evidence that use of GLP-1 RAs for type 2 diabetes or weight management causes suicidal thoughts or actions. During their preliminary evaluation, they conducted detailed reviews of reports of suicidal thoughts or actions received in the FDA Adverse Event Reporting System (FAERS) and reviews of clinical trials, including large outcome studies and observational studies. However, because of the small number of suicidal thoughts or actions observed in both people using GLP-1 RAs and in the comparative control groups, they cannot definitively rule out that a small risk may exist; therefore, FDA is continuing to look into this issue. Further evaluations include a meta-analysis of clinical trials across all GLP-1 RA products and an analysis of postmarketing data in the Sentinel System; final conclusions and recommendations will be communicated once more information is known.[70130] 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]

Liraglutide may slow gastric emptying. Liraglutide has not been studied in patients with pre-existing gastroparesis.[38653]

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.[64926] 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]

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]

Use liraglutide with caution during breast-feeding. Liraglutide excretion into human milk is unknown; however, because it has a high molecular weight the amount in breast milk is likely to be very low and absorption is unlikely because the medication is most likely destroyed in the infant's gastrointestinal tract.[70364] [70365] 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. 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 an individual with type 2 diabetes mellitus (T2DM) and blood glucose is not controlled on diet and exercise alone, insulin therapy may be considered. Oral hypoglycemics may also be considered. Metformin monotherapy may be appropriate for some patients as available studies indicate low excretion in milk and that maternal use during breast-feeding is not expected to result in side effects to a healthy nursing infant. Some experts recommend using metformin with caution if the patient is breastfeeding a newborn or a premature neonate with reduced renal function.[31407] [31408] [31409] [32459] [70364] Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected; therefore, this agent may be an alternative if postprandial glucose control is needed.[46303] 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]

Liraglutide should be used with caution in patients who will undergo elective surgery or procedures requiring general anesthesia or deep sedation. Liraglutide delays gastric emptying. There have been postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists who underwent elective surgery or procedures requiring general anesthesia or deep sedation. Despite adherence to preoperative fasting guidelines, these patients were found to have residual gastric contents. The available data is insufficient to give recommendations on mitigating the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking liraglutide, including whether to modify preoperative fasting recommendations or temporarily discontinue liraglutide.[38653]