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

Two days ago, we covered the FDA’s request for additional safety data on Foundayo. Today, the data the FDA wanted is public. The ACHIEVE-4 trial results answer the cardiovascular and liver safety questions directly, and the numbers are reassuring.

The study ran for over two years, making it the longest Phase 3 trial of Foundayo (orforglipron) to date. The primary finding: Foundayo was non-inferior to insulin glargine for major adverse cardiovascular events (MACE). That means it’s at least as safe as insulin, which has decades of cardiovascular safety data behind it. But the secondary findings are what caught attention. Foundayo showed a 16% lower risk of four-component MACE (heart attack, stroke, cardiovascular death, and hospitalization for unstable angina) with a hazard ratio of 0.84. And the all-cause mortality finding was striking: 57% lower risk of death from any cause (HR 0.43, nominal p = 0.002), though this endpoint was not adjusted for multiple comparisons, so it’s considered exploratory rather than confirmatory.

On liver safety, which was the FDA’s other concern, ACHIEVE-4 showed no drug-induced liver injury signal. The GI side effects (nausea, diarrhea, vomiting) were consistent with what you’d expect from any GLP-1 medication and generally resolved during titration. Blood sugar control was superior to insulin at both 52 and 104 weeks, with better HbA1c reductions and meaningful weight loss, two things insulin doesn’t typically deliver together.

What this means going forward: Lilly plans to file for a type 2 diabetes indication by the end of Q2 2026, based on these results. That’s a big deal for access. Right now, Foundayo is approved only for weight management, and some insurers limit GLP-1 coverage to obesity indications. A diabetes indication would open up prescribing to endocrinologists and primary care doctors treating diabetes, and insurance coverage for type 2 diabetes medications is much broader than for weight loss drugs. If you have type 2 diabetes and obesity, a single $149/month pill that addresses both is a meaningful option. Providers like Calibrate and Found already work with patients who have overlapping conditions like these.

Source: Eli Lilly Press Releases

Frequently asked questions

Does the 57% lower death risk mean Foundayo prevents heart disease?

Not quite. The all-cause mortality finding (HR 0.43) is an exploratory endpoint, meaning it wasn’t the primary thing the study was designed to prove. Because it wasn’t adjusted for multiple statistical comparisons, the result could be influenced by chance. It’s a promising signal that needs confirmation in a dedicated cardiovascular outcomes trial. What the study does confirm is that Foundayo is at least as safe as insulin for heart events, and possibly better. That’s reassuring for patients who were concerned after the FDA’s safety data request.

Will the type 2 diabetes filing change insurance coverage?

Likely yes, and in a meaningful way. Insurance plans generally cover diabetes medications more readily than weight-loss drugs. If the FDA approves Foundayo for type 2 diabetes (expected later in 2026), your endocrinologist or primary care doctor could prescribe it under a diabetes diagnosis, which opens access through most commercial and Medicare Part D formularies. This wouldn’t affect the $149/month self-pay price, but it could mean lower copays for insured patients beyond the current $25/month savings card.

How do ACHIEVE-4 results compare to cardiovascular data for other GLP-1 drugs?

The ACHIEVE-4 non-inferiority result for MACE is consistent with what other GLP-1 medications have shown. Wegovy’s SELECT trial demonstrated a 20% reduction in MACE events. The ACHIEVE-4 MACE-4 result (16% reduction) is in a similar range. The key difference is that Foundayo showed these results as an oral medication at a fraction of the cost. The cardiovascular safety profile appears comparable to injectable GLP-1 drugs, which is exactly what the FDA and patients needed to see.

Keep reading

• Foundayo: Full medication profile
• Calibrate: Provider profile and pricing
• Foundayo vs Wegovy: Oral vs injectable
• GLP-1 cost calculator