Metabolic & Body-Composition Research

Result. Mean change in body weight was −14.9% with semaglutide versus −2.4% with placebo at week 68.

Adverse events. Nausea and diarrhoea were the most common events, typically transient and dose-escalation related; more discontinuations for gastrointestinal events than placebo.

Limitations. Participants without diabetes only; all participants received lifestyle intervention; 68-week duration does not address longer-term maintenance or discontinuation effects.

Result. Mean percentage weight change was −15.0%, −19.5%, and −20.9% at 5 mg, 10 mg, and 15 mg respectively, versus −3.1% with placebo.

Adverse events. Predominantly gastrointestinal (nausea, diarrhoea, constipation, vomiting), mostly mild to moderate and occurring during escalation.

Limitations. Excluded participants with diabetes; lifestyle intervention in all arms; does not establish durability after discontinuation.

Result. Reported substantially lower progression to type 2 diabetes versus placebo with sustained weight reduction over the treatment period; weight regain was observed after treatment withdrawal.

Adverse events. Consistent with the established gastrointestinal profile of the class.

Limitations. Prediabetes population only; the post-withdrawal regain finding is directly relevant to any assumption that effects persist after stopping.

Result. Reported substantially lower progression to type 2 diabetes versus placebo with sustained weight reduction over the treatment period; weight regain was observed after treatment withdrawal.

Adverse events. Consistent with the established gastrointestinal profile of the class.

Limitations. Prediabetes population only; the post-withdrawal regain finding is directly relevant to any assumption that effects persist after stopping.

Result. Mean change in body weight was −14.9% with semaglutide versus −2.4% with placebo at week 68.

Adverse events. Nausea and diarrhoea were the most common events, typically transient and dose-escalation related; more discontinuations for gastrointestinal events than placebo.

Limitations. Participants without diabetes only; all participants received lifestyle intervention; 68-week duration does not address longer-term maintenance or discontinuation effects.

Result. Reported substantially lower progression to type 2 diabetes versus placebo with sustained weight reduction over the treatment period; weight regain was observed after treatment withdrawal.

Adverse events. Consistent with the established gastrointestinal profile of the class.

Limitations. Prediabetes population only; the post-withdrawal regain finding is directly relevant to any assumption that effects persist after stopping.

Result. The human programme did not demonstrate a statistically significant weight reduction versus placebo at the primary endpoint, and development for that indication did not proceed.

Adverse events. Generally well tolerated in the trials.

Limitations. This is a negative-result record and is retained deliberately. Marketing material for this compound frequently omits it.

Result. Mean weight reduction at 48 weeks reached −24.2% in the highest-dose group versus −2.1% with placebo.

Adverse events. Dose-dependent gastrointestinal events; dose-dependent increases in heart rate were reported that peaked and then declined.

Limitations. Phase 2, 338 participants, 48 weeks. Not a phase 3 outcome trial; long-term safety and cardiovascular outcomes are not established.

Result. Pooled analysis reported significant weight and metabolic marker changes versus comparator.

Adverse events. Pooled gastrointestinal event rates consistent with the individual trials.

Limitations. Small number of constituent trials; heterogeneity in dose and duration; dominated by a single phase 2 programme.

Result. Body weight changed by −20.4% with the combination versus −3.0% with placebo on the treatment-policy estimand, a difference of −17.3 percentage points. Semaglutide alone reached −14.9% and cagrilintide alone −11.5% in the same trial.

Adverse events. Gastrointestinal events predominated and were most frequent during escalation, consistent with both drug classes.

Limitations. Excluded type 2 diabetes. The widely quoted −22.7% figure is the trial-product estimand, which models full adherence, and is not the primary result. Sixty-eight weeks says nothing about what happens on discontinuation.

Result. Body weight changed by −13.7% versus −3.4% with placebo, a difference of −10.4 percentage points. The effect is materially smaller than in the population without diabetes.

Adverse events. Gastrointestinal events consistent with the incretin and amylin classes.

Limitations. The gap between this result and REDEFINE 1 is the finding worth carrying: the same schedule in a diabetic population produced roughly two-thirds of the weight change.

Result. HbA1c fell 2.2 percentage points with the combination versus 1.8 with semaglutide alone, which did not reach significance. Body weight fell 15.6% versus 5.1% and 8.1%, which did.

Adverse events. Gastrointestinal, dose-escalation related.

Limitations. Ninety-two participants across three arms. This is the dose-ranging ancestor of the phase 3 programme, not a basis for practice.

Result. Weight change ranged from −6.0% at 0.3 mg to −10.8% at 4.5 mg, against −3.0% for placebo. The 4.5 mg arm beat liraglutide 3.0 mg at −9.0%.

Adverse events. Gastrointestinal events, dose related.

Limitations. This is the only trial that establishes what cagrilintide does on its own. Note that the amount taken forward into the combination programme was 2.4 mg, not the 4.5 mg that performed best here.

Result. The amylin analogue alone and in combination with semaglutide reported greater weight reduction than semaglutide alone in the programmes reported.

Adverse events. Gastrointestinal events consistent with the incretin/amylin classes.

Limitations. Verify the specific trial and arm before citing a figure. Combination programmes are ongoing and readouts continue to change.

Result. Reported reduction in adipose mass in the mouse models studied.

Adverse events. Not characterised in humans.

Limitations. Entirely preclinical. No published human efficacy or safety trials.