ACHIEVE-4: Orforglipron Non-Inferior to Insulin Glargine for Cardiovascular Protection in T2D

Eli Lilly’s orforglipron (Foundayo) has proven its noninferiority to insulin glargine in adults with type 2 diabetes (T2D) and obesity or overweight at increased cardiovascular risk, according to topline results from the ACHIEVE-4 trial.1

Orforglipron, a once-daily small molecule non-peptide oral GLP-1 receptor agonist, is able to be taken at any time of day without any restriction on food or water intake. It was first approved by the US Food and Drug Administration (FDA) on April 1, 2026, receiving an indication for adults with overweight or obesity and related conditions.1,2

“Across 7 phase 3 studies enrolling more than 11,000 patients, Foundayo has demonstrated a consistent safety and efficacy profile,” Thomas Seck, MD, senior vice president of product development at Lilly Cardiometabolic Health, said in a statement. “ACHIEVE-4 adds a new dimension to that evidence – cardiovascular safety and a lower observed risk of all-cause death in patients who carry elevated cardiovascular risk.”1

ACHIEVE-4 was the largest and longest study of orforglipron in T2D to date, including >2700 patients across 15 countries. Patients were eligible for inclusion if they presented with a diagnosis of T2D and an increased risk of cardiovascular disease events due to coronary heart disease, cerebrovascular disease, or congestive heart failure, among other criteria. Patients were excluded from the trial if they had type 1 diabetes mellitus, chronic or acute pancreatitis prior to screening, a known clinically significant gastric emptying abnormality, acute or chronic hepatitis, or any other liver disease, among other criteria.3

Eligible patients were randomly assigned to receive either orforglipron or insulin glargine. Orforglipron was administered in escalated oral doses, while insulin glargine was administered subcutaneously in individualized doses which were titrated according to a treat-to-target algorithm. The study’s primary outcome was time to first occurrence of any major adverse cardiovascular event (MACE), including myocardial infarction, stroke, hospitalization for unstable angina, and cardiovascular death. Secondary outcomes included change from baseline in HbA1c, fasting serum glucose, and body weight, among others.3

Ultimately, orforglipron met its primary endpoint, demonstrating a 16% lower risk of the primary MACE endpoint compared to insulin glargine (HR, 0.84; 95% CI, 0.59-1.2), meeting the prespecified criteria for non-inferiority (upper limit of 95% CI of the HR <1.8). Additionally, all-cause death risk was 57% lower with orforglipron (HR, 0.43; 95% CI, 0.25-0.75; nominal P = .002). Orforglipron also demonstrated clinically meaningful improvements from baseline in non-HDL-C, systolic blood pressure, triglycerides, and hsCRP.1

Investigators also noted a safety and tolerability profile consistent with that of previous trials and with the GLP-1 class as a whole. The most common adverse events were nausea, vomiting, diarrhea, constipation, and decreased appetite. 10.6% of patients in the orforglipron arm discontinued treatment during the 52-week minimum treatment period.1

“Together with the simplicity of a once-daily pill that requires no food or water restrictions, we believe Foundayo could be an important new treatment option for people with type 2 diabetes,” Seck said.1

In the release, Lilly announced its plan to submit orforglipron for the treatment of T2D to the FDA by the end of Q2 2026, using the Commissioner’s National Priority Review Voucher.1

References

1. Eli Lilly. ACHIEVE-4, the longest Phase 3 study of Lilly’s Foundayo (orforglipron) to date, reaffirmed its cardiovascular and overall safety profile as well as consistent improvements across key measures of cardiometabolic health. April 16, 2026. Accessed April 16, 2026. https://investor.lilly.com/news-releases/news-release-details/achieve-4-longest-phase-3-study-lillys-foundayo-orforglipron

2. Eli Lilly. FDA approves Lilly’s Foundayo (orforglipron), the only GLP-1 pill for weight loss that can be taken any time of day without food or water restrictions. April 1, 2026. Accessed April 16, 2026. https://investor.lilly.com/news-releases/news-release-details/fda-approves-lillys-foundayotm-orforglipron-only-glp-1-pill

3. Eli Lilly and Company. A Study of Daily Oral Orforglipron (LY3502970) Compared With Insulin Glargine in Participants With Type 2 Diabetes and Obesity or Overweight at Increased Cardiovascular Risk (ACHIEVE-4). ClinicalTrials.gov Identifier: NCT05803421. Updated January 21, 2026. Accessed April 16, 2026. https://clinicaltrials.gov/study/NCT05803421