Early treatment strategies that improve both glycemic control and body weight remain an important focus in type 2 diabetes mellitus (T2DM) management. A study published in The Lancet evaluated the efficacy and safety of retatrutide, a glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptor triple agonist, as monotherapy in adults with T2DM inadequately controlled with diet and exercise alone.

This phase 3, randomized, double-blind, placebo-controlled trial was conducted across 48 sites in the United States, Mexico, and India. Adults aged 18 years or older with HbA1c levels between 7.0% and 9.5% and body mass index (BMI) of at least 23 kg/m² were randomized in a 1:1:1:1 ratio to once-weekly subcutaneous retatrutide 4 mg, 9 mg, 12 mg, or placebo for 40 weeks. The primary endpoint was change in HbA1c from baseline to week 40, while a key secondary endpoint assessed percentage change in body weight.

Findings

• Among 930 screened individuals, 537 participants were randomized, including 296 women (55%) and 241 men (45%).
• Mean baseline HbA1c was 7.9%, mean diabetes duration was 2.5 years, and mean BMI was 35.8 kg/m².
• Mean HbA1c reductions at week 40 were −1.69%, −1.86%, and −1.94% with retatrutide 4 mg, 9 mg, and 12 mg, respectively, versus −0.81% with placebo. Estimated treatment differences versus placebo ranged from −0.88% to −1.12% (all P<0.0001).
• Mean body weight reductions were −11.5%, −13.9%, and −15.3% across retatrutide dose groups compared with −2.6% with placebo.
• Gastrointestinal adverse events were the most commonly reported events and were generally mild to moderate, with symptoms decreasing over time.
• Adverse event-related discontinuation rates ranged from 2% to 5% with retatrutide, while no severe hypoglycemia was reported. Two deaths occurred during the study and were considered unrelated to treatment.

This phase 3 trial showed that retatrutide improved glycemic control and produced substantial body weight reduction in adults with T2DM inadequately controlled with diet and exercise alone. The safety profile was generally consistent with incretin-based therapies, with gastrointestinal events representing the most frequent adverse events.