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The phase III ACHIEVE-4 trial found that orforglipron met the standard for cardiovascular safety compared with insulin glargine in adults with type 2 diabetes and elevated cardiovascular risk. The study did not establish that the pill prevents heart attacks or strokes; a separate outcomes trial is expected to address that question.
Orforglipron, a once-daily oral GLP-1 drug, met a cardiovascular safety benchmark compared with insulin glargine in adults with type 2 diabetes and elevated cardiovascular risk, according to results from the phase III ACHIEVE-4 trial. The findings support that the pill was not associated with a higher rate of major cardiovascular events in the study, but do not show that it prevents those events.
Over a median of two years, major adverse cardiovascular events occurred in 4.2% of participants assigned orforglipron and 5.0% assigned insulin glargine. The hazard ratio was 0.84, with a 95% confidence interval of 0.59 to 1.20. Orforglipron met the trial’s prespecified criterion for noninferiority; ACHIEVE-4 was not designed to establish superiority for cardiovascular outcomes.
The trial enrolled 2,749 adults across 16 countries. Participants had type 2 diabetes, a body mass index of at least 25, and elevated cardiovascular risk; 85.9% had established cardiovascular disease and 37.6% had chronic kidney disease. They were already taking one to three glucose-lowering medicines. Researchers randomized participants to once-daily orforglipron or once-daily injectable insulin glargine.
Orforglipron was associated with sustained improvements in blood sugar control and body weight over 104 weeks. At week 52, the median urinary albumin-to-creatinine ratio fell 24.2% with orforglipron and showed no change with insulin glargine. The estimated decline in kidney function, measured using cystatin C, was also slower in the orforglipron group. These were additional trial findings and do not establish long-term kidney protection.
Gastrointestinal side effects were more common with orforglipron: 62.1% of participants reported them, compared with 14.2% in the insulin group. They were also the most common reason participants stopped orforglipron. Clinically significant or severe low blood sugar was reported in 6.8% of the orforglipron group and 19.2% of the insulin group. The trial was open-label, meaning participants and investigators knew which treatment was assigned.
Safety Findings and Daily Use
The results address a key question for people with diabetes and higher cardiovascular risk: whether orforglipron’s use was associated with more major heart events than an active diabetes treatment. Meeting the noninferiority threshold provides evidence about comparative safety in the population studied. It does not show that taking orforglipron lowers a person’s risk of heart attack, stroke, or cardiovascular death.
The drug is an oral, non-peptide GLP-1 receptor agonist. The report describes it as shelf-stable and says it can be taken without fasting or water restrictions, which may offer a simpler routine than some other oral GLP-1 medicines. The practical effect on access or adherence has not been established by these trial results. Participants also had more gastrointestinal adverse events, a relevant consideration when weighing a daily treatment.
Orforglipron is FDA approved for obesity, according to the report, and is still being developed as a treatment for diabetes. Cardiovascular benefit has been demonstrated for some other GLP-1 medicines, but those findings cannot be assumed to apply to this drug. For now, ACHIEVE-4 adds safety evidence while leaving the question of cardiovascular protection open.
How ACHIEVE-4 Was Designed
ACHIEVE-4 was a phase III trial conducted from 2023 to 2024. Participants had type 2 diabetes with an HbA1c of 7.0% to 10.5% and were taking at least one glucose-lowering medication before enrollment. Their average age was 63.1 years, and average baseline HbA1c was 8.2%. Metformin, SGLT-2 inhibitors, and sulfonylureas were among the medicines participants were already using.
The researchers compared orforglipron at each participant’s maximum tolerated dose with titrated insulin glargine. The major cardiovascular event measure included cardiovascular death, nonfatal heart attack, nonfatal stroke, and hospitalization for unstable angina. A noninferiority result means the study met its statistical threshold for ruling out an unacceptable increase in risk against the comparator; it is not proof of equal effects or a cardiovascular benefit.
Investigators also reported a higher mean pulse rate with orforglipron at week 104: an increase of 4.0 beats per minute, compared with a 0.2-beat decrease with insulin glargine. Events involving supraventricular tachyarrhythmias, including atrial fibrillation or flutter, were reported in 3.2% and 2.7%, respectively. The report notes that the trial had small subgroups and did not adjust those analyses for multiple comparisons.
““These findings support orforglipron as a potential once-daily, oral treatment option with established cardiovascular safety in people with type 2 diabetes and increased cardiovascular risk.””
— ACHIEVE-4 study authors, as quoted in the report
Heart Protection Remains Unproven
ACHIEVE-4 was not statistically powered to determine whether orforglipron is better than insulin glargine at preventing cardiovascular events. The event rates were numerically lower with orforglipron, but the reported confidence interval does not establish a protective effect. Whether the drug can reduce heart attacks, strokes, or cardiovascular deaths remains unanswered.
The study’s open-label design and small subgroup analyses are additional limits noted by investigators. The results also do not resolve how the drug’s longer-term benefits and risks compare across broader patient groups. The reported gastrointestinal effects and sustained pulse increase are part of the safety picture, but the trial does not establish their implications for individual patients.
Dedicated Outcomes Trial Ahead
The ongoing ATTAIN-Outcomes trial is designed to test whether orforglipron can provide cardiovascular benefit compared with placebo. It includes people with established atherosclerotic cardiovascular disease or chronic kidney disease, with or without type 2 diabetes, and is scheduled for completion in 2031. Its results should help determine whether the safety evidence from ACHIEVE-4 is accompanied by proof of protection.
Until those data are available, the ACHIEVE-4 findings support a conclusion about cardiovascular safety in the studied population and period. They do not establish cardiovascular protection or replace an individual assessment of treatment options with a clinician.
Key Questions
Did orforglipron prevent heart attacks or strokes in ACHIEVE-4?
The trial did not establish prevention. It showed that orforglipron met a prespecified cardiovascular noninferiority criterion against insulin glargine over a median of two years.
How many participants had major cardiovascular events?
Major events occurred in 4.2% of participants assigned orforglipron and 5.0% assigned insulin glargine. The study was not designed to prove that the lower observed rate with orforglipron reflected a protective effect.
What side effects were more common with orforglipron?
Gastrointestinal adverse events were reported in 62.1% of the orforglipron group, compared with 14.2% of the insulin glargine group. They were the most common reason for stopping orforglipron.
When could researchers know whether orforglipron protects the heart?
The ongoing ATTAIN-Outcomes trial is designed to assess cardiovascular benefit and is scheduled for completion in 2031, according to the report.
Source: rss
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