ACHIEVE-4 cut the risk of major cardiovascular events by 16%.

Topline results and trial scope

Eli Lilly's Phase 3 ACHIEVE-4 trial found that Foundayo (orforglipron) produced a 16% lower risk of major adverse cardiovascular events (MACE‑4) versus insulin glargine, meeting the study's prespecified non‑inferiority threshold. The trial enrolled more than 2,700 adults with type 2 diabetes and overweight or obesity across 15 countries and ran through 104 weeks.

The primary MACE‑4 endpoint combined cardiovascular death, heart attack, stroke and hospitalization for unstable or sudden chest pain. The reported hazard ratio for the primary endpoint was 0.84 with a 95.0% confidence interval of 0.59 to 1.20 and a p‑value of 0.336 for superiority testing. This trial also showed a 23% lower risk for MACE‑3, which excludes hospitalization for unstable chest pain from the composite.

Foundayo demonstrated persistent improvements in glycemic control and weight. Lilly reported superior reductions in A1C and body weight at 52 weeks compared with insulin glargine, and those benefits persisted through the 104‑week treatment period.

Mortality, safety signals and statistical notes

In a preplanned analysis, the risk of all‑cause death was 57% lower with Foundayo compared with insulin glargine. The hazard ratio for all‑cause mortality was 0.43 (95.0% CI: 0.25 to 0.75) with a nominal p = 0.002. Lilly cautioned that the trial didn't control for multiplicity on that endpoint; the company nonetheless characterized the difference as notable in higher‑risk patients.

The company reported clinically meaningful improvements from baseline across several cardiovascular risk factors, including non‑HDL cholesterol, systolic blood pressure, triglycerides and high‑sensitivity C‑reactive protein (hsCRP). Lilly said its analyses included a thorough review for drug‑induced liver injury and found no hepatic safety signal in ACHIEVE‑4, consistent with prior studies in its ACHIEVE and ATTAIN programs.

Regulatory backdrop and FDA follow‑up

The ACHIEVE‑4 findings arrive as Lilly prepares a submission to the U.S. Food and Drug Administration seeking approval of Foundayo for the treatment of type 2 diabetes. Lilly told investors it plans to file with the FDA by the end of the second quarter of 2026.

The FDA recently approved Foundayo for weight management but requested additional post‑approval safety studies. The agency asked Lilly to collect long‑term data on potential liver injury, cardiovascular events, and delayed gastric emptying. It also requested at least 15 years of data on thyroid cancer risk and asked Lilly to establish registries to monitor outcomes in children with obesity who take weight‑loss medicines and in pregnant women exposed to Foundayo.

The regulator singled out ACHIEVE‑4 as an appropriate vehicle to furnish MACE data. ACHIEVE‑4's size and duration address the agency's call for longer follow‑up in a population at elevated cardiovascular risk, and the trial's design compares the oral GLP‑1 candidate directly with insulin glargine rather than placebo.

Company perspective and clinical context

Thomas Seck, M.D., senior vice president of product development for Lilly Cardiometabolic Health, said the body of evidence from the Phase 3 program supports a consistent safety and efficacy profile for Foundayo across more than 11,000 patients enrolled in Lilly's late‑stage studies. He framed ACHIEVE‑4 as adding cardiovascular safety data and an observed lower risk of all‑cause death in patients with elevated cardiovascular risk.

Foundayo is an oral GLP‑1 receptor agonist with a new active ingredient, orforglipron, and is dosed once daily. Lilly highlights the pill's dosing simplicity—no food or water restrictions—as a potential advantage over injectables and some oral competitors.

How ACHIEVE‑4 fits into the competitive field

Foundayo enters a market already populated by injectable and oral GLP‑1 therapies.

Regulators have treated new active ingredients with caution. When the FDA authorized an oral formulation of semaglutide for weight management in the past, the agency relied on an extensive safety record for semaglutide stretching back to its first approvals in 2017 and didn't require the same breadth of post‑approval safety data that it's now seeking for orforglipron.

Because orforglipron is a newer molecule, the FDA has requested additional safety surveillance. Those requests include targeted safety endpoints and long‑term follow‑up on cancer risk and liver injury. The scope of post‑approval measures could shape prescribing practices, label language and future trial designs for oral GLP‑1 agents.

Business and market implications

For Lilly, ACHIEVE‑4 serves two commercial and regulatory purposes. First, the trial provides direct cardiovascular safety data in a population with type 2 diabetes and overweight or obesity—patients who represent an important portion of the diabetes market. Second, the study addresses specific FDA concerns that accompanied Foundayo's obesity approval and reinforces Lilly's case in the planned diabetes filing.

The company said it will pursue approval for type 2 diabetes by the end of Q2 2026 and intends to use available regulatory tools to expedite review where applicable. Lilly also flagged plans to leverage priority review mechanisms when seeking new indications, underscoring the programmatic push to move Foundayo into diabetes treatment as quickly as regulators permit.

How payers and prescribers weigh Foundayo's oral dosing convenience, cardiovascular findings and the FDA's post‑approval commitments will determine uptake. Payers have increasingly scrutinized long‑term safety and comparative effectiveness when setting coverage for GLP‑1 therapies, and ACHIEVE‑4 provides head‑to‑head data against a widely used basal insulin comparator that could factor into those assessments.

What remains on the agenda

Regulators will review the ACHIEVE‑4 dataset in the context of Lilly's full Phase 3 program and its post‑approval commitments. The FDA's conditions include ongoing safety monitoring and registries that extend for years, particularly around thyroid cancer risk and special populations such as children and pregnant women.

Clinicians and policymakers will watch how the mortality signal in ACHIEVE‑4 is presented in regulatory filings and labeling. The trial's lack of multiplicity control on the all‑cause death endpoint will likely prompt scrutiny during review and in advisory settings.

For investors, ACHIEVE‑4 reduces a material regulatory uncertainty by providing cardiovascular outcome data; but the long‑term safety commitments may extend the timeline and costs associated with monitoring and risk management.

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Lilly said it will submit Foundayo for the treatment of type 2 diabetes to the U.S. Food and Drug Administration by the end of Q2 2026.