Lilly’s Orforglipron Meets CV Safety Endpoint, Shows Reduced Mortality Risk in Phase 3 ACHIEVE-4 Trial

Eli Lilly and Company reported positive topline results from the Phase 3 ACHIEVE-4 trial evaluating its oral GLP-1 receptor agonist, orforglipron (brand name Foundayo) in adults with type 2 diabetes and obesity or overweight at elevated cardiovascular risk.¹ The study met its primary endpoint, demonstrating non-inferiority to insulin glargine in the risk of major adverse cardiovascular events (MACE-4), with a hazard ratio of 0.84 (hazard ratio [HR]: 0.84; 95% CI: 0.59–1.20).

Additional analyses showed a 23% lower risk of MACE-3 events (HR: 0.77; 95% CI: 0.52–1.13), although the study was not powered for superiority. In a pre-planned analysis, the risk of all-cause death was 57% lower with orforglipron compared with insulin glargine (HR: 0.43; 95% CI: 0.25–0.75; nominal p = 0.002), suggesting a potential broader cardiometabolic benefit.

What were the metabolic efficacy outcomes?

Orforglipron demonstrated superior glycemic and weight outcomes compared with insulin glargine. At 52 weeks, patients receiving orforglipron achieved a mean reduction in A1C of 1.6% from a baseline of 8.22%, compared with a

1.0% reduction for insulin glargine, resulting in an estimated treatment difference of –0.66 percentage points (p < 0.001).

Weight reduction was also more pronounced with orforglipron, with an average decrease of 8.8% (–8.1 kg) compared with a 1.7% increase (+1.4 kg) in the insulin group, corresponding to an estimated treatment difference of –10.42% (p < 0.001). Improvements were also observed across additional cardiometabolic risk markers, including non-HDL cholesterol, systolic blood pressure, triglycerides, and high-sensitivity C-reactive protein.

How does the safety profile compare?

The safety and tolerability profile of orforglipron in ACHIEVE-4 was consistent with prior studies and with the GLP-1 receptor agonist class. The most commonly reported adverse events (AEs) included gastrointestinal effects such as nausea, vomiting, diarrhea, decreased appetite, and constipation.

During the 52-week minimum treatment period, 10.6% of patients discontinued treatment due to AEs. Notably, a comprehensive evaluation of potential drug-induced liver injury found no hepatic safety signal, consistent with findings from earlier studies in the ACHIEVE and ATTAIN clinical programs.

What differentiates orforglipron in the GLP-1 landscape?

The ACHIEVE-4 trial represents the largest and longest study of orforglipron in type 2 diabetes to date, enrolling more than 2,700 participants across 15 countries and extending treatment out to 104 weeks. The broader ACHIEVE Phase 3 program has enrolled more than 6,000 patients globally.

What are the regulatory and development implications?

Lilly announced the FDA’s approval of Foundayo earlier this month. Beyond diabetes, orforglipron is being evaluated across multiple indications, including obesity, obstructive sleep apnea, osteoarthritis, hypertension, peripheral artery disease, and stress urinary incontinence, reflecting a broader lifecycle strategy for the asset.

The ACHIEVE-4 results add to the expanding evidence base supporting GLP-1 receptor agonists as cardiometabolic therapies with benefits extending beyond glycemic control. The observed reductions in cardiovascular risk and all-cause mortality—while requiring further confirmation—highlight the potential for oral GLP-1 agents to play a larger role in managing complex, high-risk patient populations.

If confirmed in future analyses, these findings could further shift treatment paradigms toward earlier and more widespread use of GLP-1–based therapies in type 2 diabetes and related conditions.

References

1. Horn, D. (2025, December 20). Orforglipron, an oral small-molecule GLP-1 receptor agonist, for the treatment of obesity in people with type 2 diabetes (ATTAIN-2): a phase 3, double-blind, randomised, multicentre, placebo-controlled trial. The Lancet. https://www.thelancet.com/journals/lancet/article/PIIS0140673625021658/abstract