Spotlight on new drug candidates

Three recently published studies reported on industry-funded trials of potential medications for type 2 diabetes and weight loss.

The first trial, published by the New England Journal of Medicine (NEJM) on June 21 and supported by Eli Lilly, assessed orforglipron, a small-molecule, nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist. The phase 3 trial tested three doses of the drug (3 mg, 12 mg, or 36 mg) against placebo for 40 weeks in 559 patients with type 2 diabetes treated only with diet and exercise, an HbA1c level of 7.0% to 9.5%, and a body mass index (BMI) of at least 23 kg/m². All three doses reduced HbA1c levels more than placebo (estimated mean differences of 0.83, 1.06, and 1.07 percentage points, respectively; P<0.001 for all comparisons). The average percent decrease in body weight was 4.5% with 3 mg of orforglipron, 5.8% with 12 mg, 7.6% with 36 mg, and 1.7% with placebo. The most common adverse events were gastrointestinal, and no episodes of severe hypoglycemia were reported. The observed reductions in HbA1c levels compared to placebo are consistent with those seen in previous trials of oral and injectable GLP-1 receptor agonists in similar populations, according to the study authors. They noted that orforglipron is being compared with oral semaglutide in a trial that's currently underway.

The second trial, published by NEJM on June 22 and funded by Novo Nordisk, assessed the combination of cagrilintide (a long-acting amylin analogue) and semaglutide (a GLP-1 receptor agonist). The phase 3a trial randomized 1,206 patients with type 2 diabetes, a BMI of at least 27 kg/m², and an HbA1c level of 7% to 10% to once-weekly cagrilintide-semaglutide (2.4 mg each) or placebo, along with lifestyle intervention, for 68 weeks. The estimated mean decrease in body weight was 13.7% in the cagrilintide-semaglutide group compared to 3.4% in the placebo group (P<0.001), and the percentage of patients who had an HbA1c level of 6.5% or less was 73.5% in the cagrilintide-semaglutide group versus 15.9% in the placebo group. Gastrointestinal adverse events were reported by 72.5% of the patients in the cagrilintide-semaglutide group and 34.4% in the placebo group. The study authors noted that the magnitude of weight loss with cagrilintide-semaglutide was similar to that seen in trials of tirzepatide, and they concluded that the combination drug is “a promising treatment option in this population.”

The third study, published by The Lancet Diabetes & Endocrinology on June 30 and funded by Eli Lilly, looked at retatrutide, a triple GLP-1 receptor agonist, glucose-dependent insulinotropic polypeptide, and glucagon receptor agonist. This substudy of a phase 2 trial included 189 patients with type 2 diabetes, an HbA1c level of 7% to 10.5%, and a BMI of 25 to 50 kg/m² who were randomized to a placebo, 1.5 mg of dulaglutide (a GLP-1 receptor agonist), or a varying dose of retatrutide once a week. The prespecified endpoint was percent change from baseline to week 36 in total fat mass, as measured by dual-energy X-ray absorptiometry. Average declines were 4.9% with retatrutide, 0.5 mg; 15.2% with retatrutide, 4 mg; 26.1% with retatrutide, 8 mg; 23.2% with retatrutide, 12 mg; 2.6% with dulaglutide; and 4.5% with placebo. Adverse events were similar between groups and were most frequently gastrointestinal. The study authors concluded that the findings “warrant continued investigation of the effects of retatrutide on body composition in phase 3 trials.”

An editorial accompanying this study noted that the rise of GLP-1 receptor agonists “has raised concerns about the risk of an unproportional loss of lean mass, particularly skeletal muscle which constitutes about 55% of the lean mass, which could reduce the long-term benefit of weight loss.” The editorialist highlighted the finding that in this study, lean mass represented about 38% of the total weight loss and called for “therapeutic strategies for preservation of muscle mass,” including resistance training and dietary counseling, especially about protein intake.