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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.
Type 2 Diabetes Mellitus
Oral GLP-1 receptor agonists
Injectable GLP-1 receptor agonists
Avoid if eGFR less than 45 mL/min/1.73 m2
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)
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)
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.
Change in A1C
No significant difference in comparisons for weight loss, systolic blood pressure, risk of nausea, or treatment discontinuation.
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)
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.
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)
Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal.
Gerstein HC, et al. Lancet. 2019; 394:121-130.
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)
Dulaglutide vs. placebo: 0.90 HR (95% CI 0.80 to 1.01; p = 0.067)
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).
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)
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. 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 patients (25%) experienced GI adverse events compared to liraglutide (once daily)-treated patients (41%). Patients with gastroparesis or other GI issues are more likely to experience these adverse reactions. If patient experiences severe nausea, vomiting, or GI upset, alternative diabetic therapy should be considered.
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. 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.
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.
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.
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.
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. 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.
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.
GLP-1 receptor agonists may delay gastric emptying. GLP-1 receptor agonists have not been studied in patients with severe gastrointestinal (GI) disease, including gastroparesis. 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 (e.g., Crohn's disease, gastroparesis, inflammatory bowel disease, ulcerative colitis). Patients who develop severe abdominal pain while receiving GLP-1 receptor agonists should be evaluated as this could be a warning sign for a serious condition.
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Bydureon (exenatide extended-release) package insert. West Chester, OH: Amylin Ohio, LLC.; 2020 Feb.
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Tanzeum (albiglutide) injection package insert. Wilmington, DE: GlaxoSmithKline LLC; 2017 Dec.
Trulicity (dulaglutide) package insert. Indianapolis, IN: Eli Lilly and Company; 2020 Sept.
Saxenda (liraglutide) injection package insert. Plainsboro, NJ: Novo Nordisk Inc; 2020 Dec.
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Lixisenatide (Adlyxin) package insert. Bridgewater, NJ: Sanofi-aventis U.S. LLC; 2016 July.
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Ozempic (semaglutide solution for injection) package insert. Plainsboro, NJ: Novo Nordisk Inc.; 2021 April.
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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.
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