SEMAGLUTIDE

Semaglutide is a synthetic glucagon-like peptide-1 receptor agonist (GLP-1 RA) that belongs to a class of antidiabetic agents called incretin mimetics. Incretins are endogenous compounds, including glucagon-like peptide-1 (GLP-1), that improve glycemic control once released into the circulation via the gut. Semaglutide subcutaneous injection and oral tablets are used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). Semaglutide oral tablets demonstrated CV safety by meeting the primary endpoint of non-inferiority for the composite MACE endpoint; the proportion of patients who experienced at least one MACE was 3.8% with semaglutide oral tablets and 4.8% with placebo.^[1] However, semaglutide oral tablets are not approved for the reduction of CV events. As with other agents in this class, semaglutide has a boxed warning regarding rodent thyroid C-cell tumor findings and the uncertain relevance to humans. First-line T2DM therapy depends on comorbidities, patient-centered treatment factors, and management needs and generally includes metformin and comprehensive lifestyle modification. Therapy with a GLP-1 RA or sodium-glucose cotransporter 2 inhibitor (SGLT2 inhibitor) that has proven CV benefit is recommended for initial therapy, with or without metformin based on glycemic needs, in patients with indicators of high-risk or established CV disease. Among the GLP-1 RAs, evidence of CV benefit is strongest for liraglutide, favorable for semaglutide, and less certain for exenatide; there is no evidence of CV benefit with lixisenatide. GLP-1 RAs have high glucose-lowering efficacy, but with variation within the drug class. Evidence suggests that the 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. GLP-1 RAs improve CV outcomes, as well as secondary outcomes such as progression of renal disease, in patients with established CV disease or chronic kidney disease (CKD); these factors make GLP-1 RAs an alternative initial treatment option, with or without metformin based on glycemic needs, in T2DM patients with indicators of high-risk or established heart failure (HF) or CKD who cannot tolerate an SGLT2 inhibitor. In patients with T2DM who do not have atherosclerotic cardiovascular disease (ASCVD)/indicators of high-risk, HF, or CKD and who need to minimize hypoglycemia and/or promote weight loss, GLP-1 RAs are generally recommended as a second or third-line option as add-on to metformin therapy. For patients requiring an injectable medication, GLP-1 RAs are preferred to insulin due to similar or even better efficacy in A1C reduction, lower risk of hypoglycemia, and reductions in body weight.^[2][3][4][5] A separate product, semaglutide subcutaneous injection, is indicated as an adjunct to lifestyle modifications for weight loss and chronic weight management in obese (BMI 30 kg/m2 or greater) or overweight adults (BMI 27 kg/m2 or greater) with at least 1 weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Four clinical trials for weight management were conducted pre-approval. Depending on the clinical trial, more treated participants lost 5% up to 15% of their initial body weight vs. those taking placebo. According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, weight loss medications should be offered as chronic treatment along with lifestyle modifications to patients with obesity when the potential benefits outweigh the risks. Short-term pharmacotherapy has not been shown to produce longer-term health benefits and cannot be generally recommended. A generalized hierarchy for medication preferences that would apply to all overweight patients cannot currently be scientifically justified. Individualized weight loss pharmacotherapy is recommended, based upon factors such as the specific characteristics of each weight loss medication, the presence of weight-related complications, and the medical history of the patient.^[6]