DrugClassOverview

Glucagon-like Peptide-1 (GLP-1) Receptor Agonists and Dual Agonists

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Jan.15.2025

Glucagon-like Peptide-1 (GLP-1) Receptor Agonists and Dual Agonists

Summary

Glucagon-like peptide-1 (GLP-1) receptor agonists bind to and activate the GLP-1 receptor, enhancing insulin secretion and slowing gastric emptying. Dual Agonists (tirzepatide) selectively bind to and activate both the Glucose-dependent Insulinotropic polypeptide (GIP) and GLP-1 receptors, the targets for native GIP and GLP-1.
The GLP-1 receptor agonists, with or without metformin based on glycemic needs, are appropriate initial therapy for patients with type 2 diabetes mellitus (T2DM) with or at high risk for atherosclerotic cardiovascular disease (ASCVD)/indicators of high-risk, heart failure (HF), or chronic kidney disease (CKD).
The GLP-1 receptor agonists and GIP/ GLP-1 dual agonists are generally recommended as a second or third-line option as add-on to metformin therapy in patients with T2DM who do not have ASCVD/indicators of high-risk for ASCVD, HF, or CKD and who need to minimize hypoglycemia and/or promote weight loss.
In those with T2DM who continue to have an A1C above target despite dual/triple therapy with metformin and other antidiabetic agents, the GLP-1 receptor agonists and dual agonists are preferred injectable medications to insulin due to similar or even better efficacy in A1C reduction, minimal risk of hypoglycemia, and because they do not cause weight gain; these agents help promote weight loss.
Efficacy and safety of the medications in these classes appear similar for T2DM management, and the individual agents primarily differ by their frequency of administration.
Gastrointestinal side effects are the most common adverse reactions leading to discontinuation of these medications.
Tirzepatide is the only dual GIP/ GLP-1 agonist that is FDA approved; in clinical trials it has shown to be more effective at lowering A1C and decreasing body weight compared to other diabetes and weight loss medications. Trials to evaluate ASCVD benefit are ongoing.
Liraglutide, semaglutide, and dulaglutide injection are GLP-1 receptor agonists indicated for the treatment of T2DM and for cardiovascular (CV) risk reduction; these drugs reduce major adverse cardiovascular events (MACE; e.g., non-fatal myocardial infarction or non-fatal stroke, CV mortality) in type 2 DM patients who also have established CV disease. Dulaglutide is also indicated for the reduction of CV mortality in type 2 DM patients with multiple CV disease risk factors.
Semaglutide is the only GLP-1 receptor agonist that is commercially available as oral and injectable dosage forms.
Both GLP-1 receptor agonists and GIP/ GLP-1 dual agonists promote weight loss; however, liraglutide (Saxenda), semaglutide (Wegovy), and tirzepatide (Zepbound) are the only products in these classes that are FDA-approved for weight loss and weight management in patients with obesity. Semaglutide (Wegovy) is also indicated for the reduction of the risk of MACE in adults with established cardiovascular disease and obesity or who are overweight.

Pharmacology/Mechanism of Action

The Glucagon-like peptide-1 (GLP-1) receptor agonists bind and activate the GLP-1 receptor in a manner similar to endogenous GLP-1. GLP-1 is an important, gut-derived, incretin hormone; this glucose homeostasis regulator is released after the oral ingestion of carbohydrates or fats. In patients with type 2 diabetes mellitus (T2DM), GLP-1 concentrations are decreased in response to an oral glucose load. GLP-1 enhances insulin secretion; it increases glucose-dependent insulin synthesis and the in vivo secretion of insulin from pancreatic beta cells in the presence of elevated glucose. In addition to increasing insulin secretion and synthesis, GLP-1 suppresses glucagon secretion, slows gastric emptying, reduces food intake via the reduction of appetite, and promotes beta cell proliferation. Clinical data have demonstrated that GLP-1 receptor agonists help restore insulin secretory functions, thus improving glycemic control and reducing body weight in patients with T2DM.[63167]

Dual glucose-dependent insulinotropic polypeptide (GIP)/ GLP-1 agonists bind to both the GIP and GLP-1 receptors but favor GIP receptor agonism over GLP-1. GIP inhibits gastric secretion activity, stimulates insulin secretion, and has insulin-like action on adipose tissue inhibiting lipolysis and promoting lipogenesis. Dual agonism adds to the effect of GLP-1 glucose-dependent insulin secretion to stimulate glucagon production during fasting and hypoglycemic states. Collectively, GLP-1 and GIP seem to work in tandem with GLP-1 inhibiting glucagon secretion when the plasma glucose concentration is high, while GIP acts at lower glucose levels. In addition to the satiating effects of GLP-1, because GIP plays a role in lipid homeostasis, this further improves the weight-loss promoting factor of GIP/ GLP-1 agonists beyond just that of GLP-1 receptor agonists.[69947][69948][69949]

Therapeutic Use

Type 2 Diabetes Mellitus

GLP-1 receptor agonists that have proven cardiovascular (CV) benefit are recommended for initial therapy, with or without metformin based on glycemic needs, in patients with type 2 diabetes mellitus (T2DM) and indicators of high-risk or established CV disease.
GLP-1 receptor agonists that improve secondary outcomes such as progression of renal disease, in patients with established CV disease or chronic kidney disease (CKD) are an alternative initial treatment option, with or without metformin based on glycemic needs, in patients with indicators of high-risk or established heart failure (HF) or CKD who cannot tolerate a sodium-glucose cotransporter 2 inhibitor (SGLT2 inhibitor).
GLP-1 receptor agonists and dual GIP/ GLP-1 agonists are generally recommended as a second or third-line option as add-on to metformin therapy in patients with T2DM who do not have atherosclerotic cardiovascular disease (ASCVD)/indicators of high-risk, HF, or CKD and who need to minimize hypoglycemia and/or promote weight loss.[50321][64926][60608]
Tirzepatide, a dual GIP/ GLP-1 agonist has been shown to be effective at improving blood sugar more effectively than other diabetes treatments. The SURPASS trials showed positive results with tirzepatide in various patient populations, and as either a stand-alone therapy or as an add-on to other medications.[69951]
Evidence of CV benefit is strongest for liraglutide (Victoza), semaglutide (Ozempic), and dulaglutide (Trulicity) injections and less certain for exenatide. In studies there was no evidence of CV benefit with lixisenatide (Adlyxin).[50321][64926][60608][65018] The manufacturer discontinued lixisenatide from the U.S. market in 2023 for business reasons.
Tirzepatide has been shown to improve lipid profiles, reduce blood pressure, and have favorable effects on inflammatory markers in clinical studies.[69949] Several studies have shown that tirzepatide does not increase the risk of CV events.[69943][69950] In a clinical study of tirzepatide for diabetes, improvements in all prespecified cardiometabolic measures were observed; however, studies to determine whether tirzepatide decreases the risk of major adverse cardiovascular events (MACE) are ongoing.[69949][69945][69951]
These drugs are effective in lowering fasting plasma glucose (FPG) and A1C in T2DM patients. Evidence suggests that the glucose-lowering effect may be greatest for tirzepatide, followed by semaglutide once weekly, dulaglutide and liraglutide, closely followed by exenatide once weekly, and then exenatide twice daily and lixisenatide.[50321][64926][60608][69951]
Short-acting GLP-1 receptor agonists are more suitable for patients with predominantly postprandial hyperglycemia, and long-acting GLP-1 receptor agonists (which have a duration of 24 hours or more) are more suitable for patients with fasting hyperglycemia.[63173]
GLP-1 receptor agonists have shown efficacy in clinical trials to promote weight loss in those with T2DM by delaying gastric emptying and increasing satiety. Various studies report a mean weight loss of -1 kg to -4.4 kg after 3 to 4 months of treatment in overweight T2DM patients.[63167][63171][63173]
Tirzepatide may cause greater weight loss than other diabetes treatments because of its dual mechanism of action reducing body weight, food consumption, and fat mass. In a study for T2DM, tirzepatide-treated patients lost 7.6 kg with tirzepatide 5 mg, 9.3 kg with tirzepatide 10 mg, and 11.2 kg with tirzepatide 15 mg over 40 weeks.[69942][69949][69943][69950][69951]
Liraglutide and exenatide extended-release injections are the only GLP-1 receptor agonists approved for use in pediatric patients with T2DM who are 10 years and older.[38653][62560]

Obesity, Weight Loss, and Chronic Weight Management

Manufacturers of drugs in these classes market these drugs for weight loss and management under different brand names from the products that are indicated for T2DM treatment.
Liraglutide (Saxenda) and semaglutide (Wegovy) are the GLP-1 receptor agonist injection products with an FDA-approved indication for weight loss and weight management in individuals with obesity. These products are indicated for those with an initial body mass index (BMI) of at least 30 kg/m² or with a BMI of 27 kg/m² or more with at least 1 weight-related comorbid condition (i.e., hypertension, T2DM, or dyslipidemia).[58673][66713]
Semaglutide (Wegovy) is additionally indicated for the reduction of the risk of MACE, including reduction of cardiovascular mortality, non-fatal myocardial infarction, or non-fatal stroke, in adults with established cardiovascular disease and obesity or who are overweight. In a cardiovascular outcomes trial in adults who were obese or overweight and without type 2 diabetes mellitus, semaglutide reduced the risk for first occurrence of MACE (hazard ratio 0.8 [95% CI: 0.72 to 0.9]; p less than 0.001).[66713]
Tirzepatide (Zepbound) is indicated for patients with an initial BMI of at least 30 kg/m² or with a BMI of 27 kg/m² or more with at least 1 weight-related comorbid condition (i.e., hypertension, T2DM, dyslipidemia, obstructive sleep apnea, or CV disease). In the study for weight loss in patients without type 2 DM who were obese (BMI 30 kg/m² or greater) or overweight (BMI 27 to less than 30 kg/m²) with at least 1 weight-related comorbid condition, those randomized to receive tirzepatide 15 mg once weekly lost on average 18% of their body weight compared to those randomized to placebo. In the study of patients with a BMI 27 kg/m² or greater and Type 2 DM, those randomized to receive tirzepatide 15 mg once weekly lost on average 12% of their body weight compared to those randomized to placebo.[69945][69945][69808]

Metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic dysfunction-associated steatohepatitis (MASH)

In adults with type 2 DM and MASLD or MASH, GLP-1 receptor agonists and dual GIP/ GLP-1 agonists are recommended for glycemic management either alone or in combination with pioglitazone; however, these agents are not FDA approved for these indications.[64926] Liraglutide and semaglutide have been shown to be safe and well-tolerated in patients with MASLD or MASH.[68793][71760][71770][71771]

Oral GLP-1 receptor agonists

Semaglutide is the only GLP-1 receptor agonist that is available as a once daily oral tablet (Rybelsus). Unlike semaglutide injection, the evidence of CV benefit using the oral route has not been definitively established.[64637]

Injectable GLP-1 receptor agonists/Dual GIP/GLP-1 receptor agonists

Drug	Injection Frequency	Duration of Action	Appropriate in Renal Impairment	Appropriate in Hepatic Impairment
Albiglutide	Once weekly	Long-acting	Yes (no dose adjustment needed)	Yes (no dose adjustment needed)
Dulaglutide	Once weekly	Long-acting	Yes (no dose adjustment needed)	Yes (no dose adjustment needed)
Exenatide	Twice daily	Short-acting	Avoid if eGFR less than 30 mL/min/1.73 m²	Yes (no dose adjustment needed)
Exenatide extended-release (ER)	Once weekly	Long-acting	Avoid if eGFR less than 45 mL/min/1.73 m²	Yes (no dose adjustment needed)
Liraglutide	Once daily	Long-acting	Yes (no dose adjustment needed)	Yes (no dose adjustment needed)
Lixisenatide (off-market)	Once daily	Short-acting	Do not use if eGFR less than 15 mL/min/1.73 m²	Yes (no dose adjustment needed)
Semaglutide	Once weekly	Long-acting	Yes (no dose adjustment needed)	Yes (no dose adjustment needed)
Tirzepatide	Once weekly	Long-acting	Yes (no dose adjustment needed)	Yes (no dose adjustment needed)

Comparative Efficacy

Citation	Design/Regimen	Results	Conclusion
Type 2 Diabetes Mellitus (T2DM)
Andreadis P, et al. Diabetes Obes Metab. 2018; epub.[63170]	Systematic review and meta-analysis of 6 placebo-controlled trials and 7 active-controlled trials with subcutaneous semaglutide.	A1C reduction Semaglutide 0.5 mg vs. placebo, A1C reduction 1.01% (95% CI 0.56 to 1.47) Semaglutide 1 mg vs. placebo, A1C reduction 1.38% (95% CI 1.05 to 1.70) Semaglutide vs. liraglutide, exenatide ER, dulaglutide: WMD -0.37% (95% CI -0.69 to -0.05, 3 studies) Semaglutide vs. sitagliptin: WMD -0.98% (95% CI -1.37 to -0.59, 2 studies) Weight reduction Semaglutide 0.5 mg vs. placebo, WMD -2.32 kg (95% CI -3.19 to -1.46, 4 studies) Semaglutide 1 mg vs. placebo, WMD -4.11 kg (95% CI -4.85 to -3.37, 61%, 6 studies) Semaglutide 0.5 mg vs. liraglutide, exenatide ER, dulaglutide: WMD -2.28 kg (95% CI -3.42 to -1.14, 6 studies) Semaglutide 1 mg vs. liraglutide, exenatide ER, dulaglutide: WMD -3.78 kg (95% CI -4.9 to -2.66, 93%, 7 studies) Adverse Reactions Nausea Semaglutide vs. liraglutide, exenatide ER, dulaglutide: OR 1.72 (95% CI 1.38 to 2.14) Vomiting Semaglutide vs. liraglutide, exenatide ER, dulaglutide: OR 1.52 (95% CI 1.12 to 2.07)	Semaglutide significantly decreased A1C compared to sitagliptin, liraglutide, exenatide ER, and dulaglutide; however, adverse reactions (nausea, vomiting) were more likely to occur with the use of semaglutide.
Htike ZZ, et al. Diabetes Obes Metab. 2017; 19:524-36.[63171]	Systematic review of 34 clinical trials (n = 14,464) of GLP-1 agonists for T2DM. Drugs studied included albiglutide, dulaglutide, twice-daily exenatide, once-weekly exenatide, liraglutide, lixisenatide, and semaglutide.	A1C reduction There were no differences within short-acting or long-acting groups. Dulaglutide, liraglutide, and exenatide ER all had a significantly greater decrease in A1C compared to twice daily exenatide and lixisenatide. Dulaglutide vs. placebo: 1.21% (95% CI 1.05 to 1.36) Weight loss (vs. placebo) Liraglutide: 1.96 kg (95% CI 1.25 to 2.67) Exenatide: 1.67 kg (95% CI 1.05 to 2.29) Dulaglutide: 1.57 kg (95% CI 0.66 to 2.48) Exenatide ER: 1.49 kg (95% CI 0.4 to 2.58) Lixisenatide: 0.78 kg (95% CI 0.09 to 1.48)	Dulaglutide, liraglutide, and exenatide were more effective at lower A1C compared to short-acting GLP-1 receptor agonists (twice daily exenatide and lixisenatide). Compared to placebo, dulaglutide showed the largest reduction in A1C. Compared to placebo, all agents, except albiglutide, significantly reduced weight and increased the risk of hypoglycemia and GI side effects. There were no clinically meaningful differences in weight loss effects, blood pressure reduction, or hypoglycemia risk among the drugs.
Kayaniyil S, et al. Diabetes Ther. 2016; 7:27-43.[63176]	A meta-analysis of randomized controlled trials comparing exenatide ER (once weekly) to albiglutide, dulaglutide, exenatide, liraglutide, and lixisenatide (14 trials).	Change in A1C Exenatide ER vs. lixisenatide: -0.59 (95% CI -1.15 to -0.03) No significant difference in comparisons for weight loss, systolic blood pressure, risk of nausea, or treatment discontinuation.	Exenatide ER significantly reduced A1C compared to lixisenatide. There were no significant differences when compared to albiglutide, dulaglutide, exenatide, or liraglutide.
Marso SP, et al. N Engl J Med. 2016; 375:311-322.[61921]	Double-blind, randomized control trial comparing the effects of liraglutide vs. placebo on cardiovascular outcomes in T2DM (n = 9,340).	Death from CV causes, nonfatal MI, or nonfatal stroke Liraglutide vs. placebo: 0.87 HR (95% CI 0.78 to 0.97, p = 0.01) Death from any cause Liraglutide vs. placebo: 0.85 HR (95% CI 0.74 to 0.97, p = 0.02) Rate of Nephropathy Liraglutide vs. placebo: 0.84 HR (95% CI 0.73 to 0.97, p = 0.02) Adverse Reactions No significant difference in acute pancreatitis occurrence. Gastrointestinal adverse reactions were significantly higher in patients taking liraglutide.	Patients in the liraglutide group had a lower risk of the primary composite outcome-first occurrence of CV death, nonfatal MI, or non-fatal stroke. Liraglutide significantly decreased the occurrence of death from CV causes, death from any cause, and nephropathy compared to placebo. The most common adverse reaction among liraglutide patients was GI upset; no significant differences in acute pancreatitis were observed. This study shows the potential benefit of GLP-1 receptor agonists reducing the risk of CV death in patients with T2DM. Systematic reviews are needed to analyze if this is a class effect.
Marso SP, et al. N Engl J Med. 2016; 375:1834-1844.[64937]	Double-blind, randomized control trial comparing the effects of semaglutide vs. placebo on CV outcomes in T2DM patients with established CV disease (n = 3,297).	Death from CV causes, nonfatal MI, or nonfatal stroke Semaglutide vs. placebo: 0.89 HR (95% CI 0.58 to 0.95; p less than 0.001 for non-inferiority) Rate of New or Worsening Nephropathy Semaglutide vs. placebo: 0.64 HR (95% CI 0.46 to 0.88, p = 0.005) Rate of Retinopathy Complications Semaglutide vs. placebo: 1.76 HR (95% CI 1.11 to 2.78, p = 0.02) Adverse Reactions Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal.	In patients with T2DM who were at high CV risk, the rate of CV death, nonfatal MI, or non-fatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the non-inferiority of semaglutide.
Gerstein HC, et al. Lancet. 2019; 394:121-130.[65018]	Double-blind, randomized control trial comparing the effects of dulaglutide vs. placebo on CV outcomes in T2DM patients with and without established CV disease (n = 9,901).	First occurrence of the composite endpoint of non-fatal MI, non-fatal stroke, or death from CV causes Dulaglutide vs. placebo: 0.88 HR (95% CI 0.79 to 0.99; p = 0.026) All-cause Mortality Dulaglutide vs. placebo: 0.90 HR (95% CI 0.80 to 1.01; p = 0.067) Adverse Reactions Gastrointestinal adverse events were reported in 2,347 (47.4%) of patients assigned to dulaglutide vs. 1,687 (34.1%) of participants assigned to placebo (p is less than 0.0001).	Dulaglutide could be considered for the management of glycemic control in middle-aged and older people with T2DM with either previous CV disease or CV risk factors.
Frias JP, et al. N Engl J Med. 2021; 385:503-515.[69942]	Open-label, parallel-group, randomized, active-controlled, phase 3 trial comparing the efficacy and safety of tirzepatide to semaglutide in patients with type 2 DM that had been inadequately controlled with metformin monotherapy (n = 1,879).	Change in A1C Tirzepatide 5 mg: -2.01% Tirzepatide 10 mg: -2.24% Tirzepatide 15 mg: -2.30% Semaglutide 1 mg: -1.86% Change in body weight Tirzepatide 5 mg: -7.6 kg Tirzepatide 10 mg: -9.3 kg Tirzepatide 15 mg: -11.2 kg Semaglutide 1 mg: -5.7 kg A1C less than 7 Tirzepatide: 82% to 86% Semaglutide: 79% Adverse Reactions The most common adverse events were GI and were primarily mild to moderate in severity in the tirzepatide and semaglutide groups (nausea, 17% to 22% and 18%; diarrhea, 13% to 16% and 12%; and vomiting, 6% to 10% and 8%, respectively).	In patients with type 2DM, tirzepatide at all doses was non-inferior and superior to semaglutide with respect to the mean change in A1C from baseline to 40 weeks. Reductions in body weight were greater with tirzepatide than with semaglutide. It should be noted that the dose of semaglutide is not the recommended dose for obesity. Gastrointestinal adverse events reported with both drugs were consistent with those that would be expected with the GLP-1 receptor agonist class and were mostly mild to moderate and occurred during the escalation period with both trial drugs.
Inagaki N, et al. Lancet Diabetes Endocrinol. 2022; 10:623-633.[69944]	Multicenter, randomized, double-blind, parallel, active-controlled, phase 3 trial to assess efficacy and safety of tirzepatide compared to dulaglutide in Japanese patients with type 2 DM who had discontinued oral antihyperglycemic monotherapy or were treatment naive (n = 636).	Mean change in A1C Tirzepatide 5 mg: -2.4% Tirzepatide 10 mg: -2.6% Tirzepatide 15 mg: -2.8% Dulaglutide 0.75 mg: -1.3% Change in body weight Tirzepatide 5 mg: -5.8 kg Tirzepatide 10 mg: -8.5 kg Tirzepatide 15 mg: -10.7 kg Dulaglutide 0.75 mg: -0.5 kg Adverse Reactions The most common adverse reactions were nausea (12% to 20% vs. 8%), constipation (14% to 18% vs. 11%), and nasopharyngitis (14% to 18% vs. 16%) in subjects taking tirzepatide and dulaglutide, respectively.	Tirzepatide was superior compared with dulaglutide for glycemic control and reduction in bodyweight at 52 weeks. The safety profile of tirzepatide was consistent with that of GLP-1 receptor agonists, indicating a potential therapeutic use in Japanese patients with type 2 DM.
Weight Loss/Management
Pi-Sunyer X, et al. N Engl J Med. 2015; 373:11-22.[63172]	A 56-week, double-blind trial comparing efficacy and safety of liraglutide 3 mg for weight management in patients with a BMI of at least 30 without type 2 DM or a BMI of 27 or more if they had treated or untreated dyslipidemia or hypertension (n = 3,731).	Mean weight loss Liraglutide: -5.6 kg (95% CI -6 to -5.1) (p less than 0.001) Percentage of patients that lost at least 5% of body weight Liraglutide vs. placebo: 63.2% vs. 27.1% (p less than 0.001)	Compared to placebo, liraglutide significantly reduced overall body weight, with weight loss of at least 5% and up to 10% or more of initial weight. The most common adverse events with liraglutide were mild or moderate nausea, diarrhea and vomiting; a dose escalation period is required. Serious events occurred in 6.2% of the patients in the liraglutide group vs. 5% in the placebo group.
Wilding JPH, et al. N Engl J Med. 2021; 384:989-1002.[66723] Davies M, et al. Lancet. 2021; 397:971-84.[66724] Wadden TA, et al. JAMA. 2021; 325:1403-1413.[66725] Rubino D, et al. JAMA. 2021; 325:1414-1425.[66729]	Four 68-week randomized, double-blind control trials comparing efficacy and safety of semaglutide 2.4 mg for weight management in patients with a BMI of at least 30 without type 2 DM, a BMI 27 or more without type 2 DM with at least 1 weight-related comorbidity, or a BMI 27 or more with type 2 DM.	Mean change in body weight Semaglutide vs. placebo: -9.6% to -17.4% vs. -2.4% to -5.9% Percentage of patients that lost at least 5% of body weight Semaglutide vs. placebo: 68.8% to 88.7% vs. 28.5% to 47.6%	Compared to placebo, semaglutide significantly reduced overall body weight, with weight loss of at least 5% and up to 15% of initial weight. The most common adverse events with semaglutide were nausea and vomiting; a dose escalation period is required.
Jastreboff AM, et al. N Engl J Med. 2022; 387:205-216.[69945]	Phase 3 randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of tirzepatide in adults without type 2 DM who were obese (BMI 30 kg/m² or greater) or overweight (BMI 27 to less than 30 kg/m²) with at least 1 weight-related comorbid condition (n = 2,539).	Change in body weight Tirzepatide 5 mg: -15% (95% CI, -15.9 to -14.2) Tirzepatide 10 mg: -19.5% (95% CI, -20.4 to -18.5) Tirzepatide 15 mg: -20.9% (95% CI, -21.8 to -19.9) Placebo: -3.1% (95% CI, -4.3 to -1.9) (p less than 0.001 for all comparisons with placebo) Percentage of patients that lost at least 5% of body weight Tirzepatide 5 mg: 85% (95% CI, 82 to 89) Tirzepatide 10 mg: 89% (95% CI, 86 to 92) Tirzepatide 15 mg: 91% (95% CI, 88 to 94) Placebo: 35% (95% CI, 30 to 39) (p less than 0.001 for all comparisons with placebo)	Tirzepatide 5 mg, 10 mg, or 15 mg once weekly provided substantial reductions in body weight over 72 weeks in adults with obesity.
Garvey WT, et al. Lancet. 2023; 402:613-626.[69946]	Phase 3 randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of tirzepatide once weekly for chronic weight management in adults with a BMI of 27 kg/m² of higher who have type 2 DM (n = 938).	Change in body weight Tirzepatide 10 mg: -12.8% (-12.9 kg) Tirzepatide 15 mg: -14.7% (-14.8 kg) Placebo: -3.2% (-3.2 kg) (p less than 0.0001 for all comparisons with placebo) Percentage of patients that lost at least 5% of body weight Tirzepatide 10 mg: 79% Tirzepatide 15 mg: 83% Placebo: 32% (p less than 0.0001 for all comparisons with placebo)	Tirzepatide 10 mg, or 15 mg once weekly provided substantial and clinically meaningful reductions in body weight over 72 weeks in adults with obesity and type 2 DM, with a safety profile that was similar to other incretin-based therapies for weight management.

Abbreviations: CI, confidence interval; CV, cardiovascular; DM, diabetes mellitus; GI, gastrointestinal; HR, hazard ratio; MI, myocardial infarction; WMD, weighted mean differences.

Adverse Reactions/Toxicities

Gastrointestinal Adverse Reactions

Nausea/vomiting and gastrointestinal (GI) upset are common adverse reactions of the GLP-1 receptor agonists. These side effects occur early on in treatment, but tend to be transient and rarely result in discontinuation of therapy.[63167] Dose titration regimens for initial short-acting therapy are intended to reduce the incidence of troublesome GI effects. In general, patients on long-acting therapy experience lower rates of GI complaints than those on short-acting therapy. In one safety study comparing GI adverse events, fewer exenatide ER (once-weekly)-treated patients (34%) experienced GI adverse events compared to exenatide (twice daily)-treated patients (45%), a difference that was statistically significant. In addition, significantly fewer exenatide ER (once weekly)-treated patients (25%) experienced GI adverse events compared to liraglutide (once daily)-treated patients (41%).[63241] Patients with gastroparesis or other GI issues are more likely to experience these adverse reactions.

The side effect profile of tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP)/ GLP-1 agonist is comparable to that of GLP-1 receptor agonists. The most frequently observed side effects were related to the GI system and included nausea, diarrhea and vomiting.[69951] In a trial of tirzepatide versus semaglutide for diabetes, nausea (17% to 22%), diarrhea (13% to 16%), and vomiting (6% to 10%) were among the most common adverse reactions; most cases of nausea, vomiting, and diarrhea were mild to moderate in severity and transient and occurred during the dose-escalation period in all groups.[69942] Nausea (12% to 18%), diarrhea (12% to 17%), and vomiting (5% to 9%) were also reported as common adverse reactions in the pool of placebo-controlled trials of tirzepatide for diabetes.[67631] In clinical trials of tirzepatide for weight management, GI adverse reactions occurred more frequently among patients receiving tirzepatide than placebo. More patients receiving tirzepatide discontinued treatment due to GI adverse reactions than patients receiving placebo. Nausea (25% to 29%), vomiting (8% to 13%), and diarrhea (19% to 23%) occurred during dose escalation and decreased over time.[69945][69946]

Hypoglycemia

GLP-1 receptor agonists and GIP/ GLP-1 dual agonists are considered to have a low risk of hypoglycemia. There is no clinically significant difference in hypoglycemic incidence among the agents.[63171][67631][69808] Administration with insulin or insulin secretagogues (i.e., sulfonylureas) increases the risk of hypoglycemia. Consider reducing the dosage of concomitantly administered insulin secretagogues or insulin.[63167][67631][69808]

Drug Interactions

In general, the propensity of the GLP-1 receptor agonists and GIP/GLP-1 dual agonists to exhibit pharmacokinetic drug-drug interactions is low as these medications do not induce or inhibit the hepatic cytochrome P450 (CYP450) enzyme system.[57014][57946][38653][61024][58673][62656][66713][67631][69808]

Oral Medications

GLP-1 receptor agonists and GIP/ GLP-1 dual agonists delay gastric emptying time and have the potential to impact absorption of oral medications. Studies have shown little clinical significance, but patients should be monitored when starting therapy.[57014][57946][38653][61024][58673][62656][66713][67631][69808]

Safety Issues

Counterfeit Products

In December 2023, the FDA warned consumers not to use counterfeit semaglutide (Ozempic or Wegovy). Wholesalers, retail pharmacies, health care practitioners and patients are advised to check the products they have received and not distribute, use, or sell Ozempic products labeled with lot number NAR0074 and serial number 430834149057. The FDA and Novo Nordisk are testing the seized products and do not yet have information about the drugs' identity, quality, or safety. Analysis found the needles from the samples are counterfeit and therefore, the sterility of the needles cannot be confirmed, which presents an increased risk of infection. Other confirmed counterfeit components within the seized products are the pen label, accompanying health care professional and patient information, and carton. The FDA is aware of 5 adverse events from this lot, none of which are serious and are consistent with known common adverse reactions to authentic semaglutide. FDA recommends retail pharmacies only purchase authentic products through authorized distributors and review the photographs and information to confirm the legitimacy of their shipments. Patients should only obtain semaglutide products with a valid prescription through state-licensed pharmacies and check the product before using for any signs of counterfeiting. Health care professionals and consumers should report adverse events related to the use of this product to FDA's MedWatch Safety Information and Adverse Event Reporting Program. Retailers and patients may also contact Novo Nordisk customer care at 1-800-727-6500 with questions or concerns.[70063]

Micro-dosing

There are reports of patients micro-dosing certain GLP-1 receptor agonists. Micro-dosing, also known as "click-counting", is the practice of using very small doses of medication, outside the FDA-approved dosing schedule, to achieve desired outcomes or results. This practice is the method by which audible clicks are used to count doses to achieve the prescribed dose. Semaglutide (Ozempic), and liraglutide (Saxenda and Victoza) multi-dose pens have been used for micro-dosing. This practice has been used to reduce cost, assist with shortage issues, minimize adverse effects (e.g., nausea, vomiting), and maintain weight loss. The risk of micro-dosing is that errors could result in overdosing by using the incorrect number of clicks. Each strength of the pen requires a different number of clicks per desired dose. Dialing and counting to the correct number of clicks may be difficult for some individuals with dexterity or auditory issues. A patient may not have enough pen needles to last beyond the expected days' supply and may be tempted to reuse pen needles resulting in possible infection. Additionally, despite directing the patient to use click counting for an unlabeled dose, providers are writing prescriptions for these products using FDA-approved doses, which results in mismatched directions. Patients should be informed that the practice of micro-dosing is not approved by the FDA or the manufacturers of GLP-1 receptor agonists.

However, a large body of clinical evidence shows GLP-1 receptor agonists are safe and effective even at submaximal doses within the recommended dose ranges listed in the medication labeling. Providers who are prescribing micro-dosing regimens should assess the patient's ability to count the prescribed number of clicks accurately and consistently. The patient should receive clear verbal and written instructions for their micro-dose regimen. The patient's micro-dose and prescribed number of clicks should be fully documented in the medical record. Providers should also share the prescribed micro-dose and number of clicks with the dispensing pharmacy to enable them to support the patient's accurate dose measurement. Pharmacists should verify with the patient their current stage of the dose escalation schedule during counseling; they should ask the patient the dose that they are taking or have been directed to take by their prescriber. Pharmacy staff should be made aware of GLP-1 receptor agonist micro-dosing and that prescription directions may differ.[71597]

Pancreatitis

Acute pancreatitis has occurred in patients prescribed GLP-1 receptor agonists and GIP/ GLP-1 dual agonists.[57014][57946][38653][61024][58673][62656][66713][67631][69808] The FDA and EMA has previously stated that after reviewing a number of clinical trials and animal studies, the current data does not support an increased risk of pancreatitis or pancreatic cancer in patients receiving incretin mimetics. The totality of the data that have been reviewed provides reassurance. However, clinicians should continue to consider precautions related to pancreatic risk until more data are available. Patients with a history of pancreatitis or who develop pancreatitis should be prescribed alternative antidiabetic therapy. After initiation of a GLP-1 receptor agonists or GIP/ GLP-1 dual agonists, patients should be observed for signs and symptoms of pancreatitis.[56778]

Thyroid Cancer

GLP-1 receptor agonists and GIP/ GLP-1 dual agonists are 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). These medications have been shown to cause dose-dependent and treatment duration-dependent malignant thyroid C-cell tumors at clinically relevant exposures in both genders of rats. It is unknown whether GLP-1 receptor agonists and GIP/ GLP-1 dual agonists cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. Although routine monitoring of serum calcitonin is of uncertain value in treated patients, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation.[57014][57946][38653][61024][58673][62656][66713][67631][69808]

Gastrointestinal Safety

The GLP-1 receptor agonists and GIP/ GLP-1 dual agonists may delay gastric emptying. These medications are commonly associated with GI adverse effects, including nausea, vomiting, and diarrhea. They are not recommended in patients with severe GI disease, such as severe gastroparesis. Also, use these medications with caution in those with known gallbladder disease or a history of cholelithiasis. Acute gallbladder disease events, such as cholecystitis or cholelithiasis, have been reported in clinical studies with these classes of medications. If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated.[57014][57946][38653][61024][58673][62656][66713][67631][69808]

Depression and Suicidal Thoughts or Behaviors

Suicidal behavior and ideation have been reported in clinical trials with incretin mimetics that are indicated for weight management. Therefore, administer with caution in patients with depression and avoid use in patients with a history of suicide attempts or active suicidal ideation; monitor patients for the emergence or worsening of depression, suicidal thoughts or behavior, and any unusual changes in moods or behaviors. 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]

Perioperative pulmonary aspiration

Perioperative pulmonary aspiration has been reported in patients receiving GLP-1 receptor agonists who underwent elective surgery or procedures requiring general anesthesia or deep sedation. GLP-1 receptor agonists and GIP/ GLP-1 dual agonists delay gastric emptying. 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 GLP-1 receptor agonists and GIP/ GLP-1 dual agonists, including whether to modify preoperative fasting recommendations or temporarily discontinue therapy.[57014][57946][38653][61024][58673][62656][66713][67631][69808]

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