Lilly’s orforglipron outperforms oral semaglutide in Phase 3 diabetes trial

Eli Lilly and Company has announced detailed results from three Phase 3 trials in the ACHIEVE programme evaluating orforglipron, a small molecule oral GLP-1, in adults with type 2 diabetes. According to the company, the therapy is taken without food or water restrictions.

In the ACHIEVE-3 trial, orforglipron outperformed oral semaglutide across the primary endpoint and all key secondary endpoints. In ACHIEVE-2 and ACHIEVE-5, orforglipron met the primary endpoint and key secondary endpoints, delivering A1C reduction and weight loss compared with dapagliflozin and placebo added to insulin glargine, respectively. Results from ACHIEVE-3, ACHIEVE-2 and ACHIEVE-5 were presented at the American Diabetes Association (ADA) 86th Scientific Sessions. ACHIEVE-3 was published in The Lancet, while ACHIEVE-2 and ACHIEVE-5 were published in The Lancet and JAMA, respectively.

“ACHIEVE-3 provides the first head-to-head data on oral GLP-1s in type 2 diabetes, with orforglipron showing greater A1C and weight reductions than oral semaglutide, which was tested at approved diabetes doses,” said Dr. Julio Rosenstock, clinical professor of medicine at the University of Texas Southwestern Medical Center and ACHIEVE-3 lead investigator. “That level of efficacy is reinforced in ACHIEVE-2 and ACHIEVE-5, demonstrating a consistent and robust treatment effect across a wide spectrum of patient populations. These results support a potential shift toward using oral GLP-1 receptor agonist therapies like orforglipron earlier as a foundation of type 2 diabetes care.”

According to Lilly, ACHIEVE-3 compared orforglipron 9 mg and 17.2 mg with oral semaglutide 7 mg and 14 mg in a Phase 3 head-to-head trial of two oral GLP-1 receptor agonists for type 2 diabetes. At 52 weeks, orforglipron lowered A1C by an average of 1.9 per cent (9 mg) and 2.2 per cent (17.2 mg), compared with 1.1 per cent (7 mg) and 1.4 per cent (14 mg) for oral semaglutide. Lilly stated that this represented a 57.1 per cent greater relative reduction at the highest dose comparison.

The company also reported that 37.1 per cent of patients receiving the highest dose of orforglipron achieved an A1C level below 5.7 per cent, compared with 12.5 per cent of patients receiving the highest dose of oral semaglutide. Weight loss averaged 6.6 kg (6.7 per cent; 9 mg) and 8.9 kg (9.2 per cent; 17.2 mg) with orforglipron, compared with 3.6 kg (3.7 per cent; 7 mg) and 5.0 kg (5.3 per cent; 14 mg) with oral semaglutide. Lilly reported a 73.6 per cent greater relative weight loss at the highest dose comparison.

In ACHIEVE-2, orforglipron reduced A1C by up to an average of 1.7 per cent at 40 weeks from a baseline of 8.1 per cent, compared with 0.8 per cent for dapagliflozin. Up to 68.6 per cent of patients receiving the highest dose of orforglipron achieved an A1C level of 6.5 per cent or below, compared with 21.6 per cent for dapagliflozin.

Patients receiving orforglipron lost an average of 3.2 kg (3.5 per cent; 2.5 mg), 5.8 kg (6.3 per cent; 9 mg) and 6.8 kg (7.3 per cent; 17.2 mg), compared with 2.7 kg (3.0 per cent) for dapagliflozin.

In ACHIEVE-5, which evaluated orforglipron alongside titrated insulin glargine, the therapy reduced A1C by up to an average of 2.1 per cent at 40 weeks from a baseline of 8.5 per cent, compared with 0.8 per cent for placebo. Up to 69.1 per cent of patients receiving orforglipron 9 mg achieved an A1C level of 6.5 per cent or below, compared with 11.1 per cent for placebo.

Participants receiving orforglipron lost an average of 2.2 kg (2.7 per cent; 2.5 mg), 5.0 kg (5.8 per cent; 9 mg) and 5.2 kg (6.1 per cent; 17.2 mg), compared with a 0.5 kg (0.6 per cent) weight gain in the placebo group.

“When we look across the ACHIEVE program, orforglipron consistently demonstrated superior A1C control and weight loss, giving us real confidence in what it could deliver for patients,” said Thomas Seck, M.D., senior vice president of product development, Lilly Cardiometabolic Health. “ACHIEVE-3 marks the first time two oral GLP-1 therapies have been tested head-to-head in a Phase 3 study, and orforglipron clearly outperformed oral semaglutide on the outcomes that matter most to patients with type 2 diabetes. For the millions of people with type 2 diabetes who want an oral treatment they can take any time of day, orforglipron has the potential to be an attractive first-line therapy option in primary care.”

Lilly stated that across all three trials, orforglipron demonstrated improvements from baseline in cardiovascular risk factors including non-HDL cholesterol, HDL cholesterol, VLDL cholesterol, total cholesterol, systolic blood pressure and triglycerides.

The company reported that the safety and tolerability profile of orforglipron, including treatment discontinuation rates, was consistent with previous studies. The most common adverse events across the three studies were gastrointestinal, including nausea, diarrhoea, vomiting, dyspepsia and decreased appetite.

Treatment discontinuation rates due to adverse events in ACHIEVE-3 were 8.7 per cent and 9.7 per cent with orforglipron 9 mg and 17.2 mg, respectively, compared with 4.5 per cent and 4.9 per cent for oral semaglutide. In ACHIEVE-2, discontinuation rates were 9.2 per cent, 10.8 per cent and 12.4 per cent for orforglipron 2.5 mg, 9 mg and 17.2 mg, respectively, compared with 1.2 per cent for dapagliflozin. In ACHIEVE-5, discontinuation rates were 3.6 per cent, 7.6 per cent and 9.6 per cent for orforglipron 2.5 mg, 9 mg and 17.2 mg, respectively, compared with 3.6 per cent for placebo.

Lilly said that based on findings from ACHIEVE-1, ACHIEVE-3, ACHIEVE-2, ACHIEVE-4 and ACHIEVE-5, it plans to submit orforglipron for the treatment of type 2 diabetes to the US FDA by the end of the second quarter under the Commissioner’s National Priority Review Voucher.