Lilly’s Foundayo orforglipron has reached a major clinical milestone with the announcement of topline results from the ACHIEVE-4 trial. This study, the longest and largest Phase 3 investigation of the oral medication to date, confirms the drug’s potential as a foundational treatment for adults living with type 2 diabetes (T2D) who also face obesity or overweight and elevated cardiovascular risk.
ACHIEVE-4 Study: Comparing Lilly’s Foundayo orforglipron to Insulin
The ACHIEVE-4 trial was designed to evaluate the cardiovascular safety and efficacy of Lilly’s Foundayo orforglipron against insulin glargine. Enrolling over 2,700 participants across 15 countries, the study focused on those at high risk for major adverse cardiovascular events (MACE).
Unlike many injectable treatments, this once-daily small molecule (non-peptide) pill can be taken at any time of day without food or water restrictions. This provides a level of convenience that could significantly improve patient adherence compared to traditional injectable GLP-1 therapies or daily insulin injections.
Primary Endpoint: Cardiovascular Safety and MACE Reduction
The primary objective was to demonstrate that Lilly’s Foundayo orforglipron is non-inferior to insulin glargine regarding cardiovascular safety. The results surpassed expectations, showing a 16% lower observed risk of MACE-4 (a composite of cardiovascular death, myocardial infarction, stroke, and hospitalisation for unstable angina).
Clinical Efficacy: A1C and Weight Reduction Results
In addition to safety, the trial highlighted the superior efficacy of Lilly’s Foundayo orforglipron in managing blood sugar and body weight. At the 52-week mark, patients taking the oral medication saw an 8.8% reduction in body weight, whereas those on insulin glargine experienced a 1.7% increase.
Learn More: Foundayo FDA Approval: Eli Lilly’s New Once-Daily Pill for Chronic Weight Management
| Measure (at 52 Weeks) | Foundayo (orforglipron) | Insulin Glargine | Difference/Hazard Ratio |
| Body Weight Change | -8.8% (-8.1 kg) | +1.7% (+1.4 kg) | -10.4% (p < 0.001) |
| MACE-4 Risk (HR) | — | — | 0.84 (95% CI: 0.59-1.20) |
| All-Cause Death (HR) | — | — | 0.43 (nominal p = 0.002) |
| Discontinuation Rate | 10.6% | — | Consistent with GLP-1 class |
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Safety Profile of Lilly’s Foundayo orforglipron
The safety and tolerability of Lilly’s Foundayo orforglipron were consistent with the broader GLP-1 receptor agonist class. The most common adverse events reported were gastrointestinal in nature, such as nausea and vomiting, which were generally mild-to-moderate and occurred during the dose-escalation phase.
Notably, the study found no signals of drug-induced liver injury, addressing a key area of interest for regulatory agencies. Lilly plans to submit these results to the U.S. Food and Drug Administration (FDA) by the end of Q2 2026.
