Semaglutide Alternatives & Comparison

Adds GIP to the GLP-1 action, and head-to-head trials generally show more average weight loss

Tirzepatide is a "twincretin". Two incretin receptors switch on together under it: GLP-1, and GIP — glucose-dependent insulinotropic polypeptide.

In the SURMOUNT-1 trial (N=2,539), tirzepatide at the 15mg dose achieved an average weight loss of 22.5% over 72 weeks — nearly double the results seen with semaglutide.

A daily GLP-1 injection that has been around longer, if track record is what you weigh

Liraglutide is an acylated, 97%-homologous analog of native human GLP-1, modified with a fatty-acid side chain that lets it bind albumin and resist DPP-4 degradation — extending its half-life from minutes to about 13 hours.

The pivotal trial was SCALE Obesity and Prediabetes (N=3,731 adults, none diabetic; Pi-Sunyer et al. NEJM 2015, PMID 26132939).

Daily pill, different molecule, and nothing to inject

Orforglipron is not built as a peptide. It is a small organic molecule that binds the GLP-1 receptor and switches it on directly.

ATTAIN-1 (NCT05869903) ran its full 72-week course across 10 countries: phase 3, randomized, placebo-controlled, 3,127 adults, all of them obese or overweight carrying a weight-related comorbidity, none of them diabetic.

An oral drug outside the GLP-1 class, which matters if incretin GI effects are the problem

Bupropion stimulates hypothalamic pro-opiomelanocortin (POMC) neurons, which release alpha-MSH to reduce appetite, but POMC neurons also release beta-endorphin, which feeds back onto mu-opioid receptors on the POMC neurons themselves and shuts them off — limiting the appetite-suppressing effect.

Contrave's FDA approval was supported by four pivotal 56-week phase 3 trials in the Contrave Obesity Research (COR) program.