Retatrutide

Mechanism (as reported)

Research descriptions characterize retatrutide as an agonist of GIP, GLP-1, and glucagon receptors. (PMIDs: 37366315, 37385280, 41090431)

Key findings (each cites a source)

• A phase 2, double-blind, randomized, placebo-controlled trial in adults with obesity reported dose-dependent reductions in body weight at 24 and 48 weeks, with the placebo group showing smaller changes. (PMIDs: 37366315) [PMID 37366315]
• In the same obesity phase 2 trial, gastrointestinal adverse events were reported as the most common events in retatrutide groups; the source describes them as dose-related, mostly mild to moderate, and partially mitigated with a lower starting dose; dose-dependent heart rate increases were described as peaking at 24 weeks and declining thereafter. (PMIDs: 37366315) [PMID 37366315]
• A phase 2 trial in people with type 2 diabetes reported changes in HbA1c at 24 weeks that were greater than placebo for most retatrutide doses, with findings described as consistent at 36 weeks. (PMIDs: 37385280) [PMID 37385280]
• In the phase 2 type 2 diabetes trial, body weight decreased in a dose-dependent manner at 36 weeks versus placebo and versus a comparator (dulaglutide), with greater decreases reported for retatrutide doses 4 mg and above. (PMIDs: 37385280) [PMID 37385280]
• In the phase 2 type 2 diabetes trial, mild-to-moderate gastrointestinal adverse events were reported in a proportion of participants receiving retatrutide; the source reports no severe hypoglycemia and no deaths during the study. (PMIDs: 37385280) [PMID 37385280]
• A randomized, double-blind, placebo-controlled phase 2a trial described reductions in liver fat at 24 weeks in participants with metabolic dysfunction-associated steatotic liver disease, with mean relative liver-fat change reported as more negative in retatrutide groups than placebo, and with higher proportions achieving normal liver fat (<5%) in retatrutide groups versus placebo. (PMIDs: 38858523) [PMID 38858523]
• The TRIUMPH phase 3 clinical development program is described as evaluating retatrutide for obesity and two complications (obstructive sleep apnea and knee osteoarthritis), using four phase 3 randomized, double-blind studies (including weight-management basket trials and additional OA and CVD-related components) with specified primary endpoints for weight management, OSA, and knee OA. (PMIDs: 41090431) [PMID 41090431]
• Systematic review and network meta-analysis evidence (including RCTs of GLP-1 receptor agonists and polyagonists) reported retatrutide (12 mg and 8 mg) among the top efficacious treatments versus placebo for reducing body weight and waist circumference in patients with obesity or overweight, and described subgroup differences related to type 2 diabetes status and other factors; it also reported safety outcomes without a significant increase in serious adverse or hypoglycemic events across interventions in the analysis framework. (PMIDs: 39305981) [PMID 39305981]
• A systematic review of RCTs in adults without diabetes reported that retatrutide (12 mg once weekly) produced weight loss of up to 22.1% after 48 weeks and that gastrointestinal adverse events were common, with discontinuations due to adverse events described as rare and serious adverse events also described as rare. (PMIDs: 39761578) [PMID 39761578]