Orforglipron Demonstrates Cardiovascular Benefits for Type 2 Diabetes

ACHIEVE-4 (NCT05803421), the longest phase 3 study of Lilly's orforglipron (Foundayo) to date, reaffirmed its cardiovascular and overall safety profile as well as consistent improvements across key measures of cardiometabolic health. Eli Lilly and Company recently announced these positive topline results from the trial, which specifically evaluated the efficacy and safety of the oral drug in adults with type 2 diabetes and obesity or overweight who were at an increased risk for cardiovascular events.¹

"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 news release. "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."

This study, which enrolled more than participants across 15 countries, met its primary objective by demonstrating that orforglipron is noninferior to insulin glargine in the risk of major adverse cardiovascular events (MACE-4).

The cardiovascular findings are particularly significant for clinical practice, as data from the trial showed a 16% lower risk for MACE-4 events, which include cardiovascular death, heart attack, stroke, and hospitalization for unstable chest pain. In a pre-planned analysis that was not controlled for multiplicity, the risk of all-cause death was found to be 57% lower for patients taking orforglipron compared with those receiving insulin glargine. Beyond these primary outcomes, the trial recorded clinically meaningful improvements from baseline across several other cardiovascular risk factors, including systolic blood pressure, triglycerides, nonhigh-density lipoprotein cholesterol, and high-sensitivity C-reactive protein.

For pharmacists, the unique pharmacokinetic profile of orforglipron represents a notable shift in the management of metabolic diseases. Unlike current oral glucagon-like peptide-1 (GLP-1) therapies that require strict fasting and water intake protocols, orforglipron is a nonpeptide small molecule that can be administered at any time of day without food or water restrictions. This simplified dosing regimen is expected to potentially enhance patient adherence by removing the dietary constraints that often complicate the use of existing oral GLP-1 receptor agonists.^2,3

In addition to its cardiovascular profile, ACHIEVE-4 demonstrated that orforglipron provided superior improvements in both A_1C and body weight compared to insulin glargine. At the 52-week mark, patients taking the drug saw a 1.6% reduction in A_1C and an 8.8% reduction in body weight, improvements that persisted through 104 weeks of therapy. These results align with broader data from the ACHIEVE clinical program, which has shown orforglipron to be superior to other active comparators such as dapagliflozin and oral semaglutide in managing glycemic control and weight loss.^1,3,4

From a safety and counseling perspective, pharmacists should note that the tolerability of orforglipron is generally consistent with the established GLP-1 receptor agonist class. The most frequent adverse events reported were gastrointestinal in nature, including nausea, vomiting, diarrhea, and constipation. To mitigate these effects, the drug utilizes a stepwise titration approach, typically starting at a 0.8 mg dose and increasing at intervals of at least 30 days until reaching the maintenance dose.^1,3

Pharmacists must also remain vigilant regarding the medication's boxed warning and use limitations. Orforglipron carries a boxed warning for thyroid C-cell tumors and is strictly contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2. Furthermore, clinical guidelines specify that orforglipron should not be used in combination with any other GLP-1 receptor agonist.

As Lilly plans to submit orforglipron for the treatment of type 2 diabetes to the FDA by the end of the second quarter of 2026, these long-term safety and efficacy data solidify its potential role as a foundational treatment in cardiometabolic health.

READ MORE: Diabetes Resource Center

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REFERENCES

1. 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. News release. Eli Lilly. April 16, 2026. Accessed April 17, 2026. https://investor.lilly.com/news-releases/news-release-details/achieve-4-longest-phase-3-study-lillys-foundayo-orforglipron

2. Gallagher A. Orforglipron demonstrates superior blood sugar control compared with oral semaglutide. Drug Topics. February 26, 2026. Accessed April 17, 2026. https://www.drugtopics.com/view/orforglipron-demonstrates-superior-blood-sugar-control-compared-with-oral-semaglutide

3. Gallagher A. FDA approves Orforglipron for chronic weight management. Drug Topics. April 1, 2026. Accessed April 17, 2026. https://www.drugtopics.com/view/fda-approves-orforglipron-for-chronic-weight-management

4. Gallagher A. Orforglipron demonstrates superior glycemic control for type 2 diabetes. Drug Topics. October 16, 2025. Accessed April 17, 2026. https://www.drugtopics.com/view/orforglipron-demonstrates-superior-glycemic-control-for-type-2-diabetes