Single, dual, and triple incretin agonists

What "agonism" actually means

Receptor agonism refers to a drug binding and activating a specific receptor. The incretin family contains three receptors of clinical interest: GLP-1 (the workhorse for appetite suppression and glucose-dependent insulin release), GIP (glucose-dependent insulinotropic polypeptide, with effects on adipose tissue and central appetite signaling), and the glucagon receptor (which raises basal energy expenditure when activated and mobilizes hepatic glycogen / lipid).

The simplest molecules in this class, semaglutide and liraglutide, activate only the GLP-1 receptor. Each step up adds another receptor.

Single agonism, GLP-1 alone

Examples: semaglutide (Ozempic / Wegovy), liraglutide (Victoza / Saxenda), dulaglutide (Trulicity).

Single GLP-1 agonists drive appetite suppression, slowed gastric emptying, and glucose-dependent insulin release. Phase 3 weight loss in obesity at semaglutide 2.4 mg averages ~15% over 68–72 weeks. The cardiovascular outcomes data is the strongest in the class, SELECT in particular establishing semaglutide as having a 20% MACE reduction in obesity with established CV disease.

Dual agonism, GLP-1 + GIP

Example: tirzepatide (Mounjaro / Zepbound).

Adding GIP receptor agonism to GLP-1 agonism produced an unexpectedly large step up. SURMOUNT-1 reported ~21% weight loss at 72 weeks at the 15 mg dose, meaningfully greater than semaglutide 2.4 mg in head-to-head comparison.

The mechanistic story for why GIP addition helps is still being characterized. The historical assumption was that GIP agonism contributes additional appetite suppression and adipose-tissue effects. Recent work (most strikingly from the MariTide program) has questioned that assumption, suggesting GIP antagonism may be doing some of the work, meaning the field's understanding of dual receptor strategies remains open.

Triple agonism, GLP-1 + GIP + glucagon

Example: retatrutide (TRIUMPH program).

Adding glucagon receptor agonism to the GLP-1/GIP combination contributed an additional energy-expenditure mechanism. The Phase 2 TRIUMPH-1 result, ~24% weight loss at 48 weeks, extended the trajectory.

The challenge with glucagon-receptor activation is balancing the energy-expenditure benefit against glucagon's glucose-raising and heart-rate effects. The molecular tuning of receptor affinity ratios is what makes the triple-agonist concept clinically viable.

The dual GLP-1/glucagon path

An alternative configuration, skipping GIP and combining GLP-1 with glucagon, is represented by survodutide, mazdutide, and pemvidutide. These programs prioritize hepatic effects (relevant for MASH) and can compete on weight loss with the dual GIP/GLP-1 strategy.

The inverse, GLP-1 + GIP-receptor antagonism

MariTide (maridebart cafraglutide) takes a striking direction: GLP-1 agonism combined with GIP receptor antagonism. The rationale is that GIP antagonism, not agonism, may be the mechanism that drives the additive weight loss seen when modulating both receptors. Phase 3 will adjudicate the hypothesis at scale.

What this means in practice

• Magnitude of weight loss generally rises with receptor count, though differences narrow at the upper end.
• Cardiovascular outcomes data is most established for semaglutide (SELECT) and accruing for the broader class.
• Tolerability profiles are similar in shape across the class but vary in detail (heart rate effects, GI signature, glucose tolerability with glucagon-arm drugs).
• Indication tuning is increasingly important, MASH-focused programs (pemvidutide, survodutide) are not simply weight-loss-stronger drugs; they are designed for liver-disease endpoints.

Bottom line

The single → dual → triple progression has driven the field's weight-loss ceiling from ~15% with semaglutide toward ~24% with retatrutide in Phase 2, with monthly antibody-conjugate strategies (MariTide) and multi-receptor balances (survodutide, pemvidutide) now competing for indication-specific advantages. The next several years will sort how much further receptor stacking can push outcomes, and where indication-specific molecular design matters more than receptor count.