Semaglutide Alternatives & Comparison

Dual GIP/GLP-1 mechanism, generally greater average weight loss in head-to-head trials

Tirzepatide is a "twincretin" that activates both GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 receptors.

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.

Older once-daily GLP-1 injection for patients who prefer a longer track record

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.

In the pivotal SCALE Obesity and Prediabetes trial (Pi-Sunyer et al.

Once-daily oral GLP-1 pill — no injection, different molecule class

Orforglipron is a non-peptide small molecule that binds and activates the GLP-1 receptor directly.

ATTAIN-1 (NCT05869903) was a 72-week phase 3 randomized placebo-controlled trial of 3,127 adults with obesity or overweight plus a weight-related comorbidity (no diabetes), conducted across 10 countries.

Non-GLP-1 oral option for patients who can't tolerate incretin-class GI side effects

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.