English
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 therapies help restore insulin secretory functions, thus improving glycemic control and reducing body weight in patients with T2DM.[63167]
Type 2 Diabetes Mellitus
Obesity and for chronic weight management
Oral GLP-1 receptor agonists
Injectable 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 | 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) |
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 noninferiority) 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 noninferiority 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. |
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. |
Abbreviations: CI, confidence interval; CV, cardiovascular; DM, diabetes mellitus; GI, gastrointestinal; HR, hazard ratio; MI, myocardial infarction; WMD, weighted mean differences.
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.
GLP-1 receptor agonists are considered to have a low risk of hypoglycemia. There is no clinically significant difference in hypoglycemic incidence among the agents within the class.[63171] 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]
GLP-1 receptor agonists have been shown to aid in weight loss in type 2 diabetes mellitus (T2DM) patients. 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. They appear at least to be weight neutral, helping to prevent weight gain in T2DM patients. There is no clinically meaningful difference in weight loss effects among the agents within the class.[63167][63171][63173]
In general, the propensity of the GLP-1 receptor agonists to exhibit pharmacokinetic drug-drug interactions is low as these drugs are not reported to induce or inhibit the hepatic cytochrome P450 (CYP450) enzyme system.[57014][57946][48491][38653][61024][58673][62656]
GLP-1 receptor agonists delay gastric emptying time and could 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][48491][38653][61024][58673][62656]
Acute pancreatitis has occurred in patients prescribed GLP-1 receptor agonists in clinical and postmarketing data. In February 2014, the FDA and EMA stated that after reviewing a number of clinical trials and animal studies, the current data does 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, although they have expressed that the totality of the data that have been reviewed provides reassurance. Recommendations will be communicated once the review is complete; continue to consider precautions related to pancreatic risk until more data are available.[56778] Patients with a history of pancreatitis or who develop pancreatitis should be prescribed alternative antidiabetic therapy. After initiation of a GLP-1 receptor agonists, patients should be observed for signs and symptoms of pancreatitis.[53573]
GLP-1 receptor 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). GLP-1 receptor agonists 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 cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. Although routine monitoring of serum calcitonin is of uncertain value in patients treated with GLP-1 receptor agonists, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation.[57014][57946][48491][38653][61024][58673][62656]
GLP-1 receptor agonists may delay gastric emptying. GLP-1 receptor agonists 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 GLP-1 receptor agonists with caution in patients 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 this class of medications. If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated.[57014][57946][48491][38653][61024][58673][62656]
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[53573]Food and Drug Administration (US FDA) Drug Medwatch-FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes. Retrieved Mar. 14, 2013. Available on the World Wide Web at http://www.fda.gov/Drugs/DrugSafety/ucm343187.htm.
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[61921]Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016;375:311-22.
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[63167]Garber AJ. Long-acting glucagon-like peptide 1 receptor agonists. Diabetes Care. 2011; 34(Supplement 2):S279-S284.
[63170]Andreadis P, Karagiannis T, et al. Semaglutide for type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Obes Metab. 2018; epub.
[63171]Htike ZZ, Zaccardi, et al. Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a systematic review and mixed-treatment comparison analysis. Diabetes Obes Metab. 2017; 19(4):524-36.
[63172]Pi-Sunyer X, Astrup A, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015; 373:11-22.
[63173]Uccellatore A, Genovese S, et al. Comparison review of short-acting and long-acting glucagon-like peptide-1 receptor agonists. Diabetes Ther. 2015; 6(3):239-56.
[63176]Kayaniyil S, Lozano-Ortega G, et al. A network meta-analysis comparing exenatide once weekly with other GLP-1 receptor agonists for the treatment of type 2 diabetes mellitus. Diabetes Ther. 2016; 7(1):27-43.
[63241]Horowitz M, Aroda VR, Han J, et al. Upper and/or lower gastrointestinal adverse events with glucagon-like peptide-1 receptor agonists: Incidence and consequences. Diabetes Obes Metab 2017;19:672-681.
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[64926]American Diabetes Association. Standards of Medical Care in Diabetes - 2022. Diabetes Care. 2022; 45(Suppl 1):S1-S270. Available at: https://diabetesjournals.org/care/issue/45/Supplement_1
[64933]Buse JB, Wexler DJ, Tsapas A, et al. 2019 Update to: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2019. Epub ahead of print, doi: 10.2337/dci19-0066.
[64937]Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016;375:1834-1844.
[65018]Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomized placebo-controlled trial. Lancet. 2019; 394:121-130.
[66713]Wegovy (semaglutide) injection package insert. Plainsboro, NJ: Novo Nordisk Inc.; 2022 Dec.
[66723]Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021;384:989-1002.
[66724]Davies M, Faerch L, Kleist Jeppesen O, et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomized, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 2021;397:971-84.
[66725]Wadden TA, Bailey TS, Billings LK, et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial. JAMA 2021;325:1403-1413.
[66729]Rubino D, Abrahamsson N, Davies, M et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA 2021;325:1414-1425.