Lilly's Foundayo meets heart safety goal in longest type 2 diabetes trial

Eli Lilly said April 16 that its once-daily GLP-1 pill Foundayo (orforglipron) met the main goal of the Phase 3 ACHIEVE-4 trial, carrying no higher risk of major cardiovascular events than insulin glargine in adults with type 2 diabetes and obesity or overweight who are at increased cardiovascular risk ^[3].

ACHIEVE-4 is the largest and longest study of Foundayo in type 2 diabetes to date, with 2,749 participants ^[3]. It compared escalating doses of Foundayo, starting at 1 mg capsule (equal to 0.8 mg tablets) and rising every four weeks to a maximum tolerated dose of up to 36 mg capsule or 17.2 mg tablet, against insulin glargine ^[3]. Participants entered with an A1C between 7.0% and 10.5% and a body mass index of at least 25 ^[3].

On the primary measure — time to a first major adverse cardiovascular event, defined as cardiovascular death, heart attack, stroke or hospitalization for unstable, sudden chest pain, known as MACE-4 — the hazard ratio was 0.84, with a 95% confidence interval of 0.59 to 1.20 ^[3]. That met the trial's preset rule for non-inferiority, which required the top of the confidence interval to fall below 1.8 ^[3]. Non-inferiority means Foundayo was not shown to be worse than insulin glargine on this measure. It was not a demonstration that Foundayo is better, and the confidence interval crossed 1.0 ^[3]. A key secondary measure, MACE-3, had a hazard ratio of 0.77 (95% CI 0.52 to 1.13) ^[3].

In a pre-planned analysis, the risk of death from any cause was 57% lower with Foundayo than with insulin glargine (hazard ratio 0.43; 95% CI 0.25 to 0.75; nominal p = 0.002) ^[3]. Lilly said this analysis was not controlled for family-wise type 1 error, meaning the result is a signal that would need confirmation rather than a proven effect ^[3].

Foundayo also lowered A1C by 1.6% at 52 weeks, compared with 1.0% for insulin glargine, from a mean baseline of 8.22% ^[3]. Body weight fell 8.8% (about 8.1 kg, or 17.9 pounds) with Foundayo and rose 1.7% (about 1.4 kg, or 3.1 pounds) with insulin glargine ^[3]. Lilly reported improvements from baseline in non-HDL cholesterol, systolic blood pressure, triglycerides and hsCRP ^[3].

The most common side effects in the trial were nausea, vomiting, diarrhea, decreased appetite and constipation, consistent with earlier studies and with the GLP-1 drug class, Lilly said ^[3]. During the 52-week minimum treatment period, 10.6% of patients taking Foundayo stopped treatment because of side effects ^[3]. The trial included a thorough analysis of potential drug-induced liver injury, and Lilly said it found no liver safety signal, matching earlier ACHIEVE and ATTAIN studies ^[3].

Why it matters for patients

Foundayo is currently FDA-approved for adults with obesity, or some adults with overweight who also have a weight-related medical problem — not for type 2 diabetes ^[1][2]. The ACHIEVE-4 results are part of Lilly's case for adding that use ^[3]. Foundayo is a small-molecule, non-peptide GLP-1 taken as a once-daily tablet with no restrictions on food or water ^[1][2]. It carries a boxed warning for thyroid C-cell tumors, and warnings for pancreatitis, severe stomach problems, kidney injury from dehydration, low blood sugar, serious allergic reactions, vision changes in people with type 2 diabetes, gallbladder disease and aspiration during anesthesia ^[1][2].

For people with type 2 diabetes and high cardiovascular risk, ACHIEVE-4 addresses a question that had not been tested for this oral pill: whether it is at least as safe as insulin on heart outcomes. Injectable GLP-1 drugs have their own cardiovascular data, but those results do not automatically transfer to a different molecule taken as a pill ^[3].

Cost information Lilly released at approval said eligible patients with commercial insurance may pay as little as $25 per month with a savings card, self-pay starts at $149 per month for the lowest dose, and eligible Medicare Part D patients may be able to get Foundayo for $50 per month beginning as soon as July 1, 2026 ^[2].

What happens next

Lilly said it plans to submit Foundayo for the treatment of type 2 diabetes to the FDA by the end of the second quarter of 2026, using the Commissioner's National Priority Review Voucher ^[3]. Whether the FDA will approve that new use, and when a decision would come, has not been disclosed ^[3]. The ACHIEVE program has enrolled more than 6,000 people with type 2 diabetes across five registrational trials ^[3].