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glucagon-like peptide 1 (GLP-1) receptor agonist; incretin mimetic; GLP-1 mimetic; GLP-1 agonist; glutide; GLP-1RA

Indications: - treatment of diabetes mellitus type-2 - overall reduction in HgbA1c of 0.72% [41] - associated with cardiovascular, renal, & metabolic benefits in type 2 diabetes [57] - no increased cancer risk [57] - treatment of intracranial hypertension [55] - GLP-1 agonists promote weight reduction in patients with or without diabetes mellitus [1] - risk reduction for cardiovascular disease in patients with diabetes mellitus type 2 (ACC recommendation) [13] - GLP-1 receptor agonists reduce renal failure & cardiovascular events [38] regardless of SGLT2-inhibitor use [39] - GLP-1 receptor agonists reduce major cardiovascular events & mortality in high-risk patients [53] - in patients with diabetes mellitus type-2 & asthma, metformin cuts odds of asthma attacks by 30%; adding a GLP-1 receptor agonist reduces odds by another 40% [36] - useful for weight loss in patients without diabetes mellitus - may lower risk for alcohol use disorder hospitalization [37] - reduced risk for - substance use & psychotic disorders including schizophrenia [42] - seizures [42] - neurodegenerative disorders (including Alzheimer's disease & related dementias) - age-related macular degeneration, glaucoma [48] & cataracts [58] - coagulation disorders [42] - infectious disease [42] - respiratory failure & pneumonia - heart failure cardiac arrest (RR=0.8-0.9) [42] - chronic limb-threatening ischemia in diabetics [64] - all-cause mortality, all-cause hospitalization in patients with cancer [62] Contraindications: - pancreatitis - history of pancreatitis is relative contraindication - family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia-2 (MEN2) - gastroparesis [20] - does not reduce hospitalization due to heart failure [19] - NLY01 investigational for treatment of Parkinson's disease (see Mechanism of action below) failed to reach primary efficacy endpoint [26] Benefits: - people more likely to purchase healthy food after initiating GLP-1 therapy [66] Dosage: SC weekly * oral semaglutide (Rybelsus) [15] * no weaning indicated for discontinuation (see Wegovy & Zepbound Dosage:) * weight, health benefits disappear within 2 years after discontinuation [61] Dosage adjustment with renal failure: - no adjustment needed for once weekly injection Adverse effects: - nausea/vomiting, diarrhea, constipation most common [7,40] - increased risk for pancreatitis? [3]; no [4,5] - probably no increased risk for pancreatitis [4,5] - increased risk of pancreatitis when used for weight loss [22] - no increased risk of pancreatic cancer [8] - xerostomia (dry mouth) [60] - increased risk of chronic cough independent of prior history of GERD [56] - delayed gastric emptying, gastroparesis* - risk of residual gastric contents on day of elective surgery [31] - risk of gastric food retention 17% with EGD alone but none when EGD combined with colonoscopy [34] - increased risk of gastroparesis when used for weight loss [22] - increased risk of GERD [52,63] - cases of postmarketing acute cholecystitis with GLP-1 mimetics [18] - increased risk of gallbladder disease & disorder of the bile ducts [10] - may increase risk for cholangiocarcinoma [14] - increased risk of gallbladder or biliary diseases, especially when used at higher doses, for longer durations, & for weight loss [17] - increase risk for cholelithiasis [63] but not other biliary adverse events - inadequate bowel preparation for colonoscopy, 11% vs 5% of controls [46] - increased risk of bowel obstruction when used for weight loss [22] - increased risk of chronic renal failure [7] - increased risk of overall thyroid cancer (RR=1.52) but not papillary thyroid cancer or medullary thyroid cancer [23] - no increase in risk of thyroid cancer [28,43] - increased risk of thyroid cancer (RR=1.8) within 1st year of starting GLP-1 receptor agonist likely due to increased surveilliance [43] - no increased risk of thyroid neoplasms in patients with type-2 diabetes [49] - no increased risk for breast cancer [11] - little or no effect on risk for obesity-related cancers [59] - no increased risk of mortality [12] - alopecia, pulmonary aspiration, suicidal ideation (potential) [24] - FDA clears GLP-1 receptor agonists of suicidal risk, but continues review [24] - pulmonary aspiration during general anesthesia or deep sedation [35] - no increased risk of suicide in patients without mental illness [32] - questions remain regarding use in patient with depression [32] - slightly increased risk of developing incident diabetic retinopathy but similar incidence of NAION but fewer serious diabetic retinopathy-associated complications, including new-onset blindness [51] - twofold higher risk for neovascular (wet) age-related macular degeneration in patients with diabetes [54] - no increased risk for optic nerve or vision-threatening serious adverse events [65] - increased risks for - hypotension [42] - syncope [42] - arthritis [42] - nephrolithiasis [42] (RR=1.1-1.2) - delirium risk initially decreases but eventually increases among patients with type 2 diabetes using GLP-1 agonists [47] - not associated with increased risk for hospitalization due to heart failure [9] * Black box warning of contraindication for personal of family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia-2 (MEN2) (based on rodent studies where GLP-1 receptors on parfollicular cells induced C-cell proliferation & develpment of C-cell tumors) [20] * prone to retained gastric contents on upper GI endoscopy [21] - 8-hour solid-food fast & 2-hour liquid fast prior to the procedure, - delay procedure if nausea, vomiting, or abdominal distension [29] - 9% with gastric retention, nearly all with diabetes - higher incidence with higher HgbA1c [45] - 2% of upper endoscopies aborted due to gastric retention [45] - no cases of pulmonary aspiration [45] Drug interactions: - hypoglycemia when used in combination with sulfonylurea [7] - GLP-1 agonists (incretin mimetics) delay gastric emptying time which can decrease level & affect of concomitantly administered oral medications including acetaminophen [16] Laboratory: - a commercially available test for 40 genetic variants identifies people with the "hungry gut" obesity phenotype who will respond best to GLP-1 receptor agonists for weight management [30] Mechanism of action: - glucagon-like peptide 1 receptor agonist - mimicks action of incretin (gliptins also act through incretin effects) - stimulates glucose-related insulin secretion - inhibits glucagon secretion - slows gastric emptying - diminishes appetite in patients with type 2 diabetes - increases satiety - can lower Hgb A1c about 1.5% [2] - increases activity of cholangiocytes [10] - anti-inflammatory [25] - a brain-penetrant, pegylated, long-lasting version of exenatide (NLY01) reduces microglia activation [26] Clinical trials: - randomized controlled trial - persons receiving a GLP-1 drug had a mean 8.1 kg body weight reduction vs a 1.2 kg weight loss for those receiving placebo - using a GLP-1 drug resulted in a 5.4 kg decrease in fat mass % a 2.5 kg loss in lean mass [44] Notes: - tirzepatide is most effective GLP-1 agonist for both glycemic control & weight loss - semaglutide is second most effective GLP-1 agonist for both indications - dulaglutide (1.5 mg) associated with greatest decrease in HgbA1c relative to placebo (1.4%), followed by once-weekly exenatide, & taspoglutide [6] - taspoglutide associated with largest weight loss (1.3 kg), followed by exenatide & dulaglutide - dulaglutide & exenatide were associated with highest risk for symptomatic hypoglycemia [6] - once weekly semaglutide lowers A1c more than flozin as add on to metformin - oral semaglutide compares favorably with subcutaneous liraglutide for glycemic control & weight loss [15]

Interactions

drug interactions drug adverse effects (more general classes)

Related

gliptin; dipeptidyl peptidase-4 inhibitor; DPP-4 inhibitor glucagon-like peptide 1 receptor; GLP-1 receptor; GLP-1-R; GLP-1R (GLP1R) incretin

Specific

albiglutide (Tanzeum) dulaglutide (Trulicity) efpeglenatide exenatide (Byetta, AC2993, extendin-4, Gilly, Lizzie, Bydureon) liraglutide (Victoza, Saxenda) lixisenatide (Adlyxin, Lyxumia) maridebart cafraglutide (MariTide) orforglipron retatrutide semaglutide (Ozempic, Rybelsus, Wegovy) tirzepatide (Mounjaro, Zepbound)

General

parenteral hypoglycemic agent

References

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