Lilly’s oral GLP-1 orforglipron met the cardiovascular safety goal in ACHIEVE-4 while reducing A1C and body weight versus insulin glargine.
Written By: Neha Vishwakarma, PharmD
Reviewed By: Pharmacally Editorial Team
Eli Lilly’s once-daily oral GLP-1 receptor agonist Foundayo (orforglipron) met the primary cardiovascular safety objective in ACHIEVE-4, while delivering sustained reductions in A1C and body weight versus insulin glargine in adults with type 2 diabetes and elevated cardiovascular risk.
Cardiovascular Non-Inferiority Established
In the Phase 3 ACHIEVE-4 trial, orforglipron produced a 16% lower risk of four-component major adverse cardiovascular events (MACE-4) compared with insulin glargine. The hazard ratio was 0.84, with a 95% CI of 0.59 to 1.20. The upper confidence limit remained below the prespecified non-inferiority margin of 1.8, establishing cardiovascular non-inferiority.
For MACE-3, defined as cardiovascular death, myocardial infarction or stroke, the hazard ratio was 0.77 (95% CI, 0.52-1.13), corresponding to a 23% lower observed risk with orforglipron.
Pre-planned analyses also reported lower risks of cardiovascular and all-cause death, with hazard ratios of 0.47 and 0.43, respectively. However, these analyses were not controlled for family-wise type I error, so the findings should be interpreted as additional analyses rather than confirmatory efficacy outcomes.
A1C and Weight Benefits Sustained
ACHIEVE-4 randomized 2,749 adults with type 2 diabetes, overweight or obesity, and increased cardiovascular risk across multiple countries, including India. Participants had baseline A1C levels of 7.0% to 10.5% and received either escalating doses of orforglipron or titrated insulin glargine. Lilly’s oral GLP-1,
At 52 weeks, A1C declined by 1.6 percentage points with orforglipron compared with 1.0 percentage point with insulin glargine. The estimated treatment difference was -0.66 percentage points (95% CI, -0.74 to -0.58; P<0.001).
Body weight fell 8.8%, or 8.1 kg, with orforglipron, while the insulin glargine group gained 1.7%, or 1.4 kg. The estimated treatment difference was -10.42% (95% CI, -10.92 to -9.93; P<0.001). At 104 weeks, 54.6% of participants receiving orforglipron achieved an A1C of 6.5% or lower, compared with 23.8% with insulin glargine.
Cardiometabolic and Renal Measures Improve
The trial also showed improvements in several cardiovascular risk markers. At week 52, orforglipron reduced waist circumference by 7.0 cm, systolic blood pressure by 4.4 mmHg, triglycerides by 18.9%, non-HDL cholesterol by 6.6% and hsCRP by 38.9%.
Kidney-related measures also favored orforglipron, including a 2.8 mL/min/1.73 m² smaller decline in eGFR and a 27.1% greater reduction in albuminuria compared with insulin glargine. These endpoints were not controlled for family-wise type I error.
Safety Profile and Oral Administration
The overall safety profile was consistent with earlier orforglipron studies and other incretin therapies. Common adverse events included nausea, vomiting, diarrhea, decreased appetite and constipation. During the minimum 52-week treatment period, 10.6% of participants discontinued orforglipron because of adverse events. Lilly’s oral GLP-1, Foundayo (o…
Orforglipron is a once-daily, non-peptide oral GLP-1 receptor agonist that can be taken without restrictions around food or water. In ACHIEVE-4, participants started at 0.8 mg once daily, with dose increases every four weeks to a maximum tolerated dose of up to 17.2 mg.
Next Development Milestones
Lilly said the ACHIEVE-4 findings reinforce the efficacy and safety profile observed across the Phase 3 ACHIEVE program, which has enrolled more than 6,000 people with type 2 diabetes. 680300
The company is continuing cardiovascular outcomes research through the Phase 3 ATTAIN-OUTCOMES trial in adults with established cardiovascular or kidney disease. Orforglipron is also being studied in several additional conditions, including obstructive sleep apnea, osteoarthritis knee pain, hypertension, peripheral artery disease and stress urinary incontinence.
Reference
Lilly’s oral GLP-1, Foundayo (orforglipron), demonstrated cardiovascular safety alongside sustained A1C reduction and weight loss in its largest and longest type 2 diabetes study, Eli Lilly, 30 September 2026
A Study of Daily Oral Orforglipron (LY3502970) Compared With Insulin Glargine in Participants With Type 2 Diabetes and Obesity or Overweight at Increased Cardiovascular Risk (ACHIEVE-4), ClinicalTrials.gov ID NCT05803421
About the Writer
Neha Vishwakarma (Linkedin) is a Pharm.D professional with experience in clinical pharmacy, pharmacovigilance, and clinical research. She has hands-on experience in ADR assessment, ICSR processing, medication safety, and clinical data evaluation. Her research background in surgical site infections and antibiotic use supports her focus on evidence-based healthcare writing.