DrugClassOverview
Glucagon-like Peptide-1 (GLP-1) Receptor Agonists and Dual Agonists
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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]
Type 2 Diabetes Mellitus
Obesity, Weight Loss, and Chronic Weight Management
Oral GLP-1 receptor agonists
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) |
| 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 kgAdverse 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.
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]
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]
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]
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]
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]
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]
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]
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]
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 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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[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 - 2024. Diabetes Care. 2024; 47(Suppl 1):S1-S321. Available at: https://diabetesjournals.org/care/issue/47/Supplement_1
[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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