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semaglutide (Ozempic, Rybelsus, Wegovy)

Indications: - treatment of diabetes mellitus type-2 (Ozempic FDA-approved Dec 2017) [3] - add on to metformin [4] - 2.4 mg/week subcutaneous dose FDA-approved for weight reduction [15,20] - Wegovy FDA-approved, age >= 12 years [20] - hypoglycemic agent of choice (if not insulin) in patients with CKD4 - benefits obese patients with HFpEF [26] - benefits obese patients with HFpEF & diabetes mellitus type-2 [36] - benefits obese patients with HFrEF [47] - secondary prevention of cardiovascular disease - reduces cardiovascular events in overweight or obese patients with cardiovascular disease (heart attack, stroke) but without diabetes mellitus (6.5% vs 8.0% over 40 months) [28,75] (FDA-approved [34]) - regardless of Hgb A1c [42] - reduces Hgb A1c at 20 months [43] - reduces second major cardiovascular event after myocardial infarction in obese patients without diabetes mellitus [33] - in obese patients with HFpEF, semaglutide 2.4 mg improves symptoms, physical limitations, & exercise, NYHA functional class & reduces inflammation & body weight across LVEF [29,31,37,40] - oral semaglutide reduces heart failure events in patients with type 2 diabetes [81] - reduces risk of renal complications & cardiovascular mortality in patients with type 2 diabetes & chronic kidney disease [38] - in patients with type2 2 diabetes & chronic kidney disease, semaglutide reduces major kidney disease events at a median 3 years. regardless of baseline mineralocorticoid receptor antagonist use [68] - reduces the risk of cardiovascular events (death, myocardial infarction, stroke) regardless of baseline chronic kidney disease severity in patients with type 2 diabetes [51] - oral semaglutide reduces 4 year risk of cardiovascular events by 1.8% (12% vs 13.8% for placebo) [63] - semaglutide 1.0 mg weekly improves lower limb peripheral arterial disease (PAD) [62] - increases walking ability of people with type 2 diabetes lower limb PAD by 21% - 2.4 mg dose of semaglutide reduces mortality from infectious disease, including Covid-19 [46] - semaglutide 2.4 mg weekly reduces all-cause hospital admissions [52] - semaglutide reduces pain, improves physical function in patients with obesity & knee osteoarthritis [50] - may reduce risk of Alzheimer's disease (RR=0.3-0.6) [49] - may decrease risk of hospitalization due to alcohol abuse [14] - can reduce craving & some drinking outcomes - may be useful for alcohol use disorder [58] - once-weekly semaglutide 2.4 mg reduces steatohepatitis & liver fibrosis in adults with NASH & moderate or advanced liver fibrosis [64] - may increase likelihood of NASH (stage F2 or F3 fibrosis) resolution, but does not inmprove fibrosis stage [10] - FDA-approved for treatment of MASH - provides protective effects on osteoporosis & gout in obese type 2 diabetics [66] * > 1/2 of all adults in the U.S. are eligible for semaglutide [54] * semaglutide improves HgbA1c more than canagliflozin 1.5 vs 1.0% [8] - semaglutide also associated with more weight reduction (5.3 vs 4.2 kg) - may be useful as an adjunct to diet & exercise for weight reduction in non-diabetic overweight or obese adults [11] & adolescents [18] - in conjunction with an intensive dietary-behavioral intervention, semaglutide more than doubles weight reduction [12] - continuing weekly semaglutide after 20 weeks in young obese adults results in continued weight reduction vs weight gain if discontinued [14,48] - 2.4 mg SC weekly normalizes glycemic control in most obese patients with prediabetes [17] Contraindications: - pancreatitis - history of pancreatitis is relative contraindication - family history of medullary thyroid carcinoma or patients with Multiple Endocrine Neoplasia-2 (MEN2) [22] - gastroparesis [23] - does not reduce hospitalization due to heart failure [21] - not associated with greater weight loss when used before bariatric surgery [60] Dosage: - 0.25 mg SC once weekly for 4 weeks, then increase to 0.5 mg once weekly - if glycemic control is not achieved after at least 4 weeks on 0.5-mg dose, the dose may be increased to 1 mg once weekly - 2.4-mg dose weekly induces weight reduction of 10% of body weight in patients with type-2 diabetes [13] - 7.2 mg superior to 2·4 mg for bodyweight reduction in adults with obesity [74] - oral semaglutide (Rybelsus) 7 mg & 14 mg (FDA-approved Sept 2019) [6,9] - 25 mg semaglutide (oral) effective for weight loss (11-14%) in obese [71] - doses as high as 50 mg safe & effective [24] * no weaning indicated for discontinuation [28,78,79] * weight, health benefits disappear within 2 years after discontinuation [80] Dosage adjustment with renal failure: - no adjustment needed for once weekly injection Adverse effects: - gastrointestinal disorders - GI distress, nausea (44%) [25], gastroparesis [25] - pancreatitis [27] - ileus [27] - xerostomia (dry mouth) [77] - dysesthesia [74] - hypoglycemia [65] - increased incidence of diabetic retinopathy complications, including blindness [1,22] - increased risk of non-arteritic anterior ischemic optic neuropathy (NAION) [39,55,59] - increased risk of neovascular age-related macular degeneration [67] - absolute risk is small 0.2% at 3 years vs 0.1% in non-users [67] - may increase likelihood of neoplasms (no organ-specific pattern identified) [10] - increased risk of suicidal ideation ? - semaglutide is not associated with an increased risk of suicidal ideation [30] - a WHO database found a suggestion of semaglutide-associated suicidal ideation*, which warrants urgent clarification [44] * not such association was found with liraglutide [44] Mechanism of action: - glucagon-like peptide-1 receptor agonist [1] - may reduce cardiovascular events (mostly stroke) in type 2 diabetics with increased cardiovascular risk in industry-conducted trial [1] - may be beneficial for weight reduction; 3 kg vs placebo [2] - may reduce incidence of diabetic nephropathy - may reduce HgbA1c [1]; 1.55% vs placebo [2] Clinical trials: - 6 months, almost all participants achieved 5% weight loss, 1/2 lost >10%, & a 1/4 lost >15% of their body weight [16] - STEP 1 & STEP 4 trials: [14,48] - 1 year after withdrawal of once-weekly subcutaneous semaglutide 2.4 mg & lifestyle intervention, participants regained 2/3 of their prior weight loss, with similar changes in cardiometabolic measures [48] 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 - weight reductions in obese adults > with tirzepatide vs semaglutide (15% vs 8% at 12 months) [41] - may diminish HgbA1c as add on to metformin > dulaglutide by 0.4% [4] - may diminish HgbA1c as add on to metformin > sitagliptin by 0.3-0.5% [5] - oral semaglutide compares favorably with subcutaneous liraglutide for glycemic control & weight reduction [7] - Medicare will cover semaglutide (Wegovy) under Part D for overweight or obese patients with preexisting cardiovascular disease to prevent heart attack or stroke [35] - this could lead to unmanageable costs [45] - cost $10,000 annually (2019) - cost for Wegovy (weight loss) is $1349 for 4 weekly injections [19] - Novo Nordisk has not announced pricing on oral semiglutide - the price of Wegovy would need to be cut by over 80% to $127/month to become costs effective [61]

Interactions

drug adverse effects of hypoglycemic agents

General

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

Database Correlations

PUBCHEM cid=56843331

References

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Component-of

cagrilintide/semaglutide