ACHIEVE-5: Orforglipron Improves Glycemic Control, Weight in T2D on Basal Insulin

New phase 3 data show orforglipron (Foundayo) added to titrated insulin glargine produced superior reductions in HbA1c across all tested doses compared with placebo in adults with long-standing type 2 diabetes (T2D), according to results from the ACHIEVE-5 trial presented at the American Diabetes Association (ADA) Scientific Sessions 2026 by Francesco Giorgino, MD, PhD, University of Bari Aldo Moro.¹

The findings add to a growing body of evidence from the ACHIEVE clinical program supporting orforglipron as a potential foundational oral treatment across multiple T2D treatment backgrounds. Orforglipron, a once-daily oral non-peptide glucagon-like peptide-1 receptor agonist (GLP-1 RA) developed by Eli Lilly, received US Food and Drug Administration approval in April 2026 for adults with obesity or overweight with at least one weight-related comorbidity, with regulatory submissions for the T2D indication anticipated later this year.²

ACHIEVE-5 Trial Design, Primary Glycemic Outcomes

ACHIEVE-5 was a 40-week, double-blind, randomized, placebo-controlled phase 3 study enrolling 546 adults with T2D and inadequate glycemic control on background basal insulin therapy. Participants were randomly assigned in a 1:1:1:1 ratio to orforglipron 3 mg, 12 mg, or 36 mg once daily, or placebo, with background regimens of titrated insulin glargine with or without metformin and/or an SGLT-2 inhibitor.

The primary endpoint was change from baseline in HbA1c at week 40, with superiority prespecified for the 12 mg and/or 36 mg doses.

Among the cohort, the mean age was 60.2 years, mean T2D duration was 15.0 years, baseline HbA1c was 8.5% (69.4 mmol/mol), and mean BMI was 30.8 kg/m².¹

Results showed all 3 orforglipron doses met superiority versus placebo on the primary endpoint (all P < .001). Mean HbA1c decreased by 1.54% to 2.05% across orforglipron groups, compared with a reduction of 0.77% in the placebo group.¹ Superiority over placebo was also established across all key secondary endpoints.

Orforglipron Safety and Weight Outcomes in ACHIEVE-5

Beyond glycemic efficacy, orforglipron also demonstrated clinically meaningful reductions in body weight across all dose levels. Body weight change ranged from -2.7% to -6.1% with orforglipron, compared with a gain of 0.6% in the placebo group.¹ These weight effects are especially notable given the insulin background, in which weight gain and hypoglycemia are longstanding clinical concerns.

Rates of Level 2 hypoglycemia were similar between orforglipron and placebo groups. Severe hypoglycemia was reported in 2 participants in the 12 mg group and 1 in the 36 mg group, with no events reported in the placebo arm. The most frequently reported adverse events were gastrointestinal in nature and occurred predominantly during the dose escalation phase, consistent with the known class profile of GLP-1 RAs.¹

Contextualization Across The ACHIEVE Program

The safety and tolerability findings from ACHIEVE-5 are broadly consistent with prior ACHIEVE program data. In ACHIEVE-3, a 52-week head-to-head trial versus oral semaglutide published in The Lancet in 2026, orforglipron 12 mg and 36 mg produced superior HbA1c reductions and greater weight loss than oral semaglutide, with GI adverse events and discontinuation rates similarly concentrated during titration.³

ACHIEVE-4, the largest and longest study in the program to date enrolling > 2700 participants, confirmed orforglipron's non-inferior cardiovascular safety versus insulin glargine and established superior HbA1c and body weight reductions through 104 weeks, with no hepatic safety signal identified.²

Taken together, the ACHIEVE-5 results support orforglipron as an add-on option capable of improving both glycemic and weight outcomes in a population with longstanding, insulin-requiring T2D, a setting in which injectable GLP-1 RAs have historically been underutilized due to injection burden and adherence barriers.

Lilly has submitted orforglipron for regulatory approval in more than 40 countries and expects to submit for the T2D indication in the US in 2026.²

References

1. Giorgino F, Dsouza S, Ludwig L, et al. Efficacy and Safety of Orforglipron vs. Placebo Added to Titrated Insulin Glargine in Adults with Long-Standing Type 2 Diabetes: ACHIEVE-5. Presented at: American Diabetes Association 2026 Scientific Sessions; June 6, 2026; New Orleans, LA.

2. Eli Lilly and Company. 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. Published April 16, 2026. Accessed June 7, 2026. https://www.prnewswire.com/news-releases/achieve-4-the-longest-phase-3-study-of-lillys-foundayo-orforglipron-to-date-reaffirmed-its-cardiovascular-and-overall-safety-profile-as-well-as-consistent-improvements-across-key-measures-of-cardiometabolic-health-302744289.html

3. Eli Lilly and Company. Lilly's oral GLP-1, orforglipron, delivered superior blood sugar control and weight loss compared to oral semaglutide in head-to-head type 2 diabetes trial published in The Lancet. Published February 26, 2026. Accessed June 7, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-delivered-superior-blood-sugar