MILAN — The once-daily nonpeptide small molecule GLP-1 receptor agonist orforglipron (Foundayo, Eli Lilly) was noninferior to insulin glargine for cardiovascular (CV) outcomes in people with type 2 diabetes (T2D) at increased CV risk, according to results from a phase 3 trial. 

It also "showed clinically relevant improvements in glycemia and bodyweight," said study investigator Klara Klein, MD, PhD, assistant professor in the Division of Endocrinology and Metabolism at the University of North Carolina, Chapel Hill, at a press briefing here at the European Association for the Study of Diabetes (EASD) 2026 Annual Meeting.

The results of the ACHIEVE-4 trial were presented at the meeting and simultaneously published in The Lancet. 

Topline results from ACHIEVE-4 were released in April 2026, and the drug was approved in the US later that month for weight management; it is currently under review for T2D treatment. Orforglipron was approved for both weight loss and T2D in the UK in August 2026, but not yet for either indication in the European Union. 

Although superiority was not shown for CV outcomes (the investigators noted that the trial wasn't powered for superiority), there was an association of lower risk for major CV events and death with orforglipron.

"I personally believe that the cardiovascular benefit is a class effect," Klein said during the briefing in response to a question from Medscape Medical News. "This is a new small molecule, and so we really can't say until we have a trial that demonstrates this, and that's coming. But I think these are very encouraging data that this will be in line with the class," she added. 

An upcoming trial, ATTAIN-OUTCOMES, will be powered for CV outcomes. 

Noninferior for MACE, Superior for Other Outcomes 

The 2749 participants all had baseline A1c levels of 7-10.5 and a BMI of 25 or greater while treated with metformin, a sulfonylurea, and/or an SGLT2 inhibitor; 85.9% of patients had established CV disease, and 37.6 had chronic kidney disease. They were randomized to receive either orforglipron maximum tolerated dose (up to 36 mg capsule) daily or daily injected titrated insulin glargine. 

Insulin glargine was chosen as the active comparator because it is effective in glucose-lowering, has a documented long-term safety profile in patients with T2D, and has a neutral effect on CV risk and overall mortality, Klein explained. 

The primary outcome was time to occurrence of four-component major adverse CV events (MACE-4), including CV death, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for unstable angina.

Over a median follow-up of 104 weeks, the primary endpoint occurred in 4.2% of patients in the orforglipron group vs 5.0% in the insulin glargine group (hazard ratio [HR], 0.84; P < .0001), meeting noninferiority criteria (upper limit of the two-sided 95% CI for the HR < 1.8).

However, a key secondary efficacy endpoint, superiority over glargine for MACE-3 (CV death, nonfatal MI, or nonfatal stroke) was not met (HR 0.77; P = .18). 

Subgroup analyses by baseline characteristics, including baseline SGLT2 inhibitor use, showed consistent results. 

Orforglipron was noninferior (margin 0.3%) in other key secondary endpoints, with superiority over insulin glargine for A1c reduction, -1.46 vs -0.96 percentage points, estimated treatment difference 0.50%; and for body weight reduction, -7.79% vs +1.12%, estimated treatment difference of 8.9%. 

The mean A1c and body weight decreases with orforglipron vs titrated glargine were sustained through 104 weeks of treatment. 

Adverse Events 

Discontinuation of study treatment due to adverse events including deaths occurred in 15.4% with orforglipron vs 5.4% assigned to insulin glargine. 

Treatment-emergent adverse events occurred in 82.3% with orforglipron vs 68.0% with glargine, mostly driven by gastrointestinal events (62.1% vs 14.2%), including nausea (31.9% vs 1.4%), vomiting (21.0% vs 1.6%), and diarrhea (20.4% vs 4.9%). Most of these were reported as mild to moderate, occurred early in the study, and diminished over time, Klein noted. 

Serious adverse events occurred 16.2% and 18.8% with orforglipron and insulin glargine, respectively. Clinically significant or severe hypoglycemia (level 2 or 3) occurred in 6.8% with orforglipron vs 19.2% with insulin glargine. Severe (level 3) hypoglycemia was reported in one individual on orforglipron who was also taking metformin and a sulfonylurea, vs 12 taking glargine. 

The safety profile was consistent with that seen for orforglipron in the previously-reported ACHIEVE-1 and ATTAIN-1 studies for glycemic control and weight management, respectively, Klein said. 

Points to Consider in Data Interpretation 

Independent commentator Gian Paolo Fadini, MD, PhD, professor of endocrinology and metabolism at the University of Padova, Italy, presented the following six points to keep in mind when interpreting the trial data:

• Glargine is "a valid but asymmetric comparator": Comparing orforglipron to glargine, which has neutral CV effects, is different from other CV outcomes trials of glucose-lowering drugs comparing them against agents with established CV benefit. Thus, the findings are "strong for safety, weaker for comparative CV efficacy," noted Fadini, who is also director of the Division of Metabolic Diseases and Diabetology at his institution.
• MACE-4 contains a "soft" component: Hospitalization for unstable angina is less objective than death, MI, or stroke, and is the only component that trended in the opposite direction (HRs were 0.47, 0.85, and 0.98 for CV death, MI, and nonfatal stroke, respectively, vs 1.55 for unstable angina hospitalization, all nonsignificant). "Open-label treatment makes this worth scrutiny," Fadini said.
• The mortality signal is "striking but numerically fragile": There appears to be a trend, but only 62 deaths occurred overall, 43 (3.2%) with glargine vs 19 (1.4%) with orforglipron.
• What explains the fewer CV deaths with orforglipron (HR, 0.47), without fewer MI (HR, 0.85) or stroke (HR, 0.98)? "A detailed breakdown of fatal events would be needed to understand what is actually being prevented," he said.
• Competing risk deserves attention: "This is especially relevant when the mortality curves separate. More deaths with glargine means less subsequent time at risk for nonfatal events. Cumulative incidence and competing risk analysis would strengthen interpretation of component endpoints."
• Efficacy vs effectiveness: Regarding the difference in treatment discontinuation (15.4% vs 5.4%), "differential tolerability and treatment persistence matter in practice. The metabolic effect is compelling, but long-term benefit depends on patients remaining on therapy."

Nonetheless, Fadini concluded, "these points do not invalidate ACHIEVE-4. They define the limits of what the trial can tell us." 

Klein has consulted for Antag Therapeutics, Corxel, Eli Lilly, Novo, Pfizer, Roche, and vTv Therapeutics. She has received research-related contracts paid to her institution from Bayer, Boehringer-Ingelheim, Carmot, Diasome, GentiBio, Lilly, Novo, Rhythm Pharmaceuticals, Roche, and vTv. Fadini has received honoraria for advisory board or lecture fees from AstraZeneca, Boehringer, Lilly, Novo, Sanofi, Guidotti, MSD, Novartis, and Bayer. 

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR's Shots blog, and Diatribe. She is on X (formerly Twitter) @MiriamETucker and BlueSky @miriametucker.bsky.social