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Feb.25.2020

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

Summary

  • Glucagon-like peptide-1 (GLP-1) receptor agonists bind and activate the GLP-1 receptor, enhancing insulin secretion and slowing gastric emptying.
  • GLP-1 receptor agonists are generally recommended as second and third-line therapy for type 2 diabetes mellitus (T2DM).
  • In patients who continue to have an A1C above target despite dual/triple therapy with metformin and other antidiabetic agents, GLP-1 receptor agonists are the preferred injectable medication 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 drugs in the class appear similar and agents primarily differ by their frequency of administration.
  • Gastrointestinal side effects are the most common adverse reactions leading to discontinuation of these medications.
  • Liraglutide, semaglutide, and dulaglutide injection are 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.

Pharmacology/Mechanism of Action

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]

Therapeutic Use

Type 2 Diabetes Mellitus

  • GLP-1 receptor agonists, in general, are recommended as second and third-line therapy for type 2 diabetes mellitus (T2DM).[64926]
  • Therapy with a GLP-1 receptor agonist that has proven CV benefit should be considered in patients with indicators of high-risk or established CV disease, independent of baseline A1C or individualized A1C target.[50321][64933][64926][60608]
  • Evidence of CV benefit is strongest for liraglutide (Victoza), semaglutide (Ozempic), and dulaglutide (Trulicity) injections and less certain for exenatide; there is no evidence of CV benefit with lixisenatide.[50321][64933][64926][60608][65018]
  • 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 semaglutide once weekly, followed by dulaglutide and liraglutide, closely followed by exenatide once weekly, and then exenatide twice daily and lixisenatide.[50321][64933][64926][60608]
  • 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 by delaying gastric emptying and increasing satiety. There is no significant difference in weight loss effect among the agents in the class.[63171]
  • Liraglutide (Saxenda) is the only GLP-1 receptor agonist product with an FDA-approved indication for weight loss in patients with obesity.[58673]

 

Oral GLP-1 receptor agonists

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

 

Injectable GLP-1 receptor agonists

DrugInjection FrequencyDuration of ActionAppropriate in Renal ImpairmentAppropriate in Hepatic Impairment
AlbiglutideOnce weeklyLong-actingYes (no dose adjustment needed)Yes (no dose adjustment needed)
DulaglutideOnce weeklyLong-actingYes (no dose adjustment needed)Yes (no dose adjustment needed)
ExenatideTwice dailyShort-actingAvoid if eGFR less than 30 mL/min/1.73 m2Yes (no dose adjustment needed)
Exenatide extended-release (ER)Once weeklyLong-acting

Avoid if eGFR less than 45 mL/min/1.73 m2

Yes (no dose adjustment needed)
LiraglutideOnce dailyLong-actingYes (no dose adjustment needed)Yes (no dose adjustment needed)
LixisenatideOnce dailyShort-actingDo not use if eGFR less than 15 mL/min/1.73 m2Yes (no dose adjustment needed)
SemaglutideOnce weeklyLong-actingYes (no dose adjustment needed)Yes (no dose adjustment needed)

Comparative Efficacy

CitationDesign/RegimenResultsConclusion
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 greater than 30 without type 2 DM (n = 3,731).

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. The most common adverse events with liraglutide were mild or moderate nausea and diarrhea. Serious events occurred in 6.2% of the patients in the liraglutide group vs. 5% in the placebo group.

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] 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%).[63241] 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.

Hypoglycemia

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]

Weight Loss

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]

Drug Interactions

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]

Oral Medications

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]

Safety Issues

Pancreatitis

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]

Thyroid Cancer

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]

Gastrointestinal Safety

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.[57014][57946][48491][38653][61024][58673][62656]

[38653]Victoza (liraglutide) package insert. Princeton, NJ: Novo Nordisk Inc; 2020 Nov.

[48491]Bydureon (exenatide extended-release) package insert. West Chester, OH: Amylin Ohio, LLC.; 2020 Feb.

[50321]Davies MJ, D'Alessio DA, Fradkin J, et al. 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 2018;41:2669-2701.

[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.

[56778]Egan AG, Blind E, Dunder K, , et al. Pancreatic safety of incretin-based drugs-FDA and EMA assessment. N Engl J Med 2014;370:794—7.

[57014]Tanzeum (albiglutide) injection package insert. Wilmington, DE: GlaxoSmithKline LLC; 2017 Dec.

[57946]Trulicity (dulaglutide) package insert. Indianapolis, IN: Eli Lilly and Company; 2020 Sept.

[58673]Saxenda (liraglutide) injection package insert. Plainsboro, NJ: Novo Nordisk Inc; 2020 Dec.

[60608]Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by The American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm 2019 Executive Summary. Endocrine Pract 2019;25:69-100.

[61024]Lixisenatide (Adlyxin) package insert. Bridgewater, NJ: Sanofi-aventis U.S. LLC; 2016 July.

[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.

[62656]Ozempic (semaglutide solution for injection) package insert. Plainsboro, NJ: Novo Nordisk Inc.; 2021 April.

[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.

[64637]Rybelsus (semaglutide tablets) package insert. Plainsboro, NJ: Novo Nordisk Inc.; 2021 April.

[64926]American Diabetes Association. Standards of Medical Care in Diabetes - 2021. Diabetes Care. 2021; 44(Suppl 1):S1-S232. Available at: https://care.diabetesjournals.org/content/44/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.

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