New daily orforglipron pill demonstrated cardiovascular safety in its largest and longest study of type 2 diabetes (ACHIEVE-4 study)

New research presented at the Annual Meeting of The European Association for the Study of Diabetes (EASD) in Milan, Italy (Sept 28 – Oct 2) and published in The Lancet shows that, for people living with type 2 diabetes at increased cardiovascular risk, the new daily orforglipron pill had comparable cardiovascular safety to insulin glargine daily injections while providing superior improvements in weight reductions and blood sugar control. However, the rate of gastrointestinal (GI) adverse events was higher for orforglipron daily pills than for daily insulin glargine injections, which led to more discontinuation of orforglipron compared to insulin glargine. The study is sponsored by Eli Lilly, the manufacturer of orforglipron.

The authors, including Dr Klara Klein, Director, Endocrine Diabetes and Obesity Clinical Research Unit University of North Carolina at Chapel Hill, NC, USA, and colleagues, say the study shows daily oral orforglipron pills could be an alternative treatment to daily insulin glargine injections for these patients.

Orforglipron is an oral, non-peptide GLP-1 receptor agonist, approved for treatment of obesity in both the USA (April 2026) and recently the UK (August 2026). While some peptide GLP-1 receptor agonists have established cardiovascular benefit, the cardiovascular safety of non-peptide GLP-1 receptor agonists has not been studied. Insulin glargine is a long-acting, man-made form of insulin used once a day to control blood sugar. In people with type 2 diabetes, it is used at a more advanced stages of the condition when other medications can no longer control blood sugar adequately. Insulin glargine provides a steady baseline level of insulin for approximately 24 hours.

This study aimed to compare the effect of orforglipron with insulin glargine on the incidence of major adverse cardiovascular events in adults with type 2 diabetes and obesity or overweight who are at increased risk for cardiovascular events.

Participants with type 2 diabetes at increased cardiovascular risk and having glycated haemoglobin (a measure of blood sugar control - HbA1c) between 7·0-10·5%, BMI of at least 25 kg/m2 and treated with up to 3 glucose lowering medications (metformin, sulfonylurea, and/or an SGLT2i) were randomised 1:1 to open-label oral daily orforglipron maximum tolerated dose (up to 36 mg capsule [17·2 mg tablet]) or daily injectable titrated insulin glargine, each administered once daily. All participants had established cardiovascular or chronic kidney disease.

The primary objective was to demonstrate that orforglipron is non-inferior to insulin glargine in time to occurrence of 4-component major adverse cardiovascular events (collectively called MACE-4), including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for unstable angina. The primary endpoint and other safety endpoints were assessed in all participants who took at least one dose of assigned treatment using all data points from baseline until withdrawal or study completion, regardless of treatment adherence.

The study randomised 2749 participants (1371 to orforglipron and 1378 to insulin glargine), 2362 (85.9%) participants with established cardiovascular disease, and 1031 participants (37.5%) with chronic kidney disease. Mean baseline age, HbA1c, and BMI were 63 years, 8·2%, and 33 kg/m2, respectively.

Over a median follow-up of 2 years, the primary outcome occurred in 57 (4·2%) of 1358 orforglipron participants and 67 (5·0%) of 1343 insulin glargine participants, showing non-inferiority to insulin glargine for MACE-4, with a hazard ratio 16% lower but not statistically significant for orforglipron, and non-inferiority statistically proven.

For the other key secondary endpoints, orforglipron demonstrated non-inferiority (non-inferiority margin of 0·3%) and superiority over insulin glargine for HbA1c (estimated treatment difference [ETD] –0·50%; / –5·5 mmol/mol) and superiority for bodyweight reduction (ETD –8·9%; figure 3, appendix p 42). The mean decreases in HbA1c and bodyweight with orforglipron versus titrated insulin glargine were sustained through 104 weeks of treatment (appendix p 41).

A significantly greater proportion of participants assigned to orforglipron than to insulin glargine reached prespecified HbA1c and bodyweight reduction thresholds at week 52: for HbA1c, 65·7% on orforglipron versus 46·0% on insulin glargine attained HbA1c less than 7·0%; 53·8% versus 26·8% HbA1c less than or equal to 6·5%, 12·9% versus 2·1% attained HbA1c less than 5·7%.

For bodyweight reduction, 63·1% on orforglipron versus 13·4% on insulin glargine reached 5% or greater bodyweight reduction; 35·6% versus 4·4% reached 10% or greater bodyweight reduction, and 15·1% versus 1·3% reached 15% or greater bodyweight reduction (appendix p 53).

GI adverse events were reported in 851 (62·1%) of 1371 orforglipron participants and 193 (14·2%) of 1355 insulin glargine participants; clinically significant or severe hypoglycaemia (glucose <3 mmol/L [54 mg/dL]) occurred in 93 (6·8%) of 1371 orforglipron participants and 260 (19·2%) of 1355 insulin glargine participants. Sixty-two deaths were reported during the study: 19 (1.4%) of 1371 participants receiving orforglipron and 43 (3.2%) of 1355 participants receiving insulin glargine; all but one death (in the insulin glargine group) was deemed unrelated to treatment.

The authors say: “In people with type 2 diabetes at increased cardiovascular risk, the cardiovascular safety of orforglipron was confirmed by demonstrating non-inferiority to insulin glargine relating to serious adverse cardiovascular events. Gastrointestinal adverse events were the most frequent adverse event and most common reason for treatment discontinuation with orforglipron, while clinically significant hypoglycaemia occurred less frequently with orforglipron than with insulin glargine. These findings support orforglipron as a potential once-daily, oral treatment option for people with type 2 diabetes.”

The authors note that previously observed effects of orforglipron on additional cardiometabolic risk factors were confirmed in individuals at increased cardiovascular risk, and new findings in this study suggest orforglipron may be associated with improvements in markers of kidney function and damage.

They conclude: “In the ACHIEVE trials, once-daily oral orforglipron provided improvements in blood sugar control and bodyweight across the continuum of type 2 diabetes, including in participants with varying disease duration, diverse comorbidities, and a broad range of background glucose lowering medications with a safety profile generally consistent with that of other GLP‑1 RAs. The results of this ACHIEVE-4 study confirm the cardiovascular safety of once-daily oral orforglipron, ruling out excess cardiovascular risk with orforglipron compared with insulin glargine in people with type 2 diabetes and increased cardiovascular risk. Therefore, orally administered small molecules have the potential to retain the pharmacological benefits of peptide-based GLP-1RAs while providing a convenient route of administration to meet the needs and preferences of people living with type 2 diabetes.”

Dr Klein adds: “The ACHIEVE-4 study reaffirmed the safety of orforglipron while demonstrating clinically meaningful improvements in blood sugar control and weight. Combined with the convenience of a shelf-stable, once-daily oral medication that can be taken without fasting or water restrictions, these results highlight the potential of orforglipron to expand access to effective diabetes treatment globally.”

Reference:

New daily orforglipron pill demonstrated cardiovascular safety in its largest and longest study of type 2 diabetes (ACHIEVE-4 study), European Association for the Study of Diabetes, Meeting: Annual Meeting of the European Association for the Study of Diabetes (EASD).