Semaglutide

A 31-amino-acid GLP-1 receptor agonist with 94% homology to native human GLP-1. Semaglutide is engineered with an Aib substitution at position 8 for DPP-4 resistance and a C-18 fatty diacid at Lys26 via a γ-Glu + mini-PEG linker enabling >99% albumin binding and a ~1-week half-life. FDA-approved for the treatment of type 2 diabetes (Ozempic, 2017), chronic weight management (Wegovy, 2021), and type 2 diabetes via oral formulation (Rybelsus, 2019).

Also approved to reduce major adverse cardiovascular events (MACE) in adults with T2DM and established CVD, and to reduce risk of sustained eGFR decline, end-stage kidney disease, or cardiovascular death in adults with T2DM and CKD. The STEP 1 trial demonstrated mean weight loss of −14.9% vs −2.4% placebo over 68 weeks.

Semaglutide has been evaluated in extensive phase 3 programs. The SUSTAIN trials (1–10) established efficacy for glycemic control in T2DM, with SUSTAIN 6 demonstrating a 26% reduction in MACE (HR 0.74). The STEP trials (1–5) established efficacy for chronic weight management, with STEP 1 showing −14.9% mean body weight reduction.

SELECT demonstrated CV benefit in obesity without diabetes. Active investigation continues in MASH/NASH (phase 2 showed 59% resolution; phase 3 ESSENCE trial ongoing), addiction and substance use disorders, PCOS, obstructive sleep apnea, and neurodegenerative diseases including Alzheimer's and Parkinson's. Off-label uses are not FDA-approved and are under clinical investigation.