Kevin Fernando, MBChBs
First reports from the ACHIEVE-1 randomized controlled trial were presented during the American Diabetes Association 85th Scientific Sessions in Chicago and simultaneously published in The New England Journal of Medicine. ACHIEVE-1 explored the efficacy and safety of orforglipron in early T2D.
As a general practitioner with a role in treating diabetes, I have been delighted to witness the evolution of the GLP-1 receptor agonists (RAs) such as orforglipron.
This journey began with the discovery of exendin-4 in the mid-1990s in the venom of the Gila monster. Exendin-4 is structurally like human GLP-1 and stimulates insulin production in the body. This finding led to the development of twice-daily injectable exenatide and its approval in 2005. It also enabled the development of injectable human GLP-1 analogs such as liraglutide, dulaglutide, and semaglutide.
I was an early advocate of GLP-1 RAs, given their potent glucose-lowering efficacy, secondary benefits of significant weight reduction, and low associated risk for hypoglycemia (if not used alongside sulfonylureas or insulin).
During 2016, the LEADER study, the first cardiovascular outcomes trial (CVOT) of a GLP-1 RA, was published. It demonstrated a significant reduction in major adverse cardiovascular events (MACE) with liraglutide. Significant reductions in MACE were also subsequently demonstrated with semaglutide during 2016 (SUSTAIN-6 CVOT) and with dulaglutide during 2019 (REWIND CVOT). These studies drove a change in guidelines globally and positioned these GLP-1 RAs as preferred therapeutic options for patients with type 2 diabetes (T2D) and comorbid atherosclerotic cardiovascular disease (ASCVD).
During 2019, oral semaglutide was approved by the FDA as the first (and still only) commercially available oral GLP-1 RA to improve glycemic control in adults with T2D. Notably, the manufacture of oral semaglutide is an expensive, complex, and technically demanding process, since it must prevent the degradation of semaglutide within the acidic gastric environment. During March 2025, the SOUL CVOT (also presented at ADA 2025) demonstrated a significant reduction in MACE with oral semaglutide in patients with T2D, ASCVD, or chronic kidney disease.
Again, I was an early adopter of oral semaglutide, and it has been great for my patients with T2D to have the option of taking a noninjectable GLP-1 RA. But it is not without its drawbacks: Oral semaglutide must be taken on an empty stomach at least 30 min before any other food, drink, or medication and with no more than 120 mL of water to maximize absorption and bioavailability. These requirements made it challenging for many of my patients to fit it into their work-life schedules.
A role for GLP-1 RAs in weight loss has emerged alongside their role in T2D. During 2014, liraglutide 3 mg was approved for weight management based on the SCALE studies. During 2021, semaglutide 2.4 mg was similarly approved for weight management, based on the STEP trial program. In 2023, the SELECT trial became the first GLP-1 RA CVOT (using semaglutide 2.4 mg) to demonstrate a significant reduction in MACE in patients with preexisting CVD and overweight or obesity but without T2D. This trial led to a new CV indication to be added to the semaglutide label during 2024.
Finally, since 2022, once-weekly injectable tirzepatide (a dual GLP1-glucose-dependent insulinotropic polypeptide RA) has been available as a therapeutic option for patients with overweight and obesity with and without T2D, based on the SURPASS and SURMOUNT trials. Over the past 18 months, we have seen a slew of comorbidity trials published for injectable semaglutide 2.4 mg and tirzepatide, demonstrating improvements in comorbidities including heart failure with preserved ejection fraction, obstructive sleep apnea, and metabolic dysfunction associated steatotic liver disease.
Orforglipron is a small-molecule, nonpeptide oral GLP-1 RA and the next stage in the evolution of the GLP-1 RA class. Nonpeptide GLP-1 RAs have the potential to provide higher oral bioavailability with no food or water restrictions and therefore simpler administration. Nonpeptide GLP-1 RAs also have a simple manufacturing process. Notably, during April 2025, Pfizer discontinued development of danuglipron (another oral, small-molecule GLP1 RA) because of concerns regarding liver toxicity.
ACHIEVE recruited 559 patients with T2D who were treated only with diet and exercise or had been off other oral or injectable glucose-lowering medications for at least 3 months. Participants were randomly assigned to one of three doses of orforglipron (3 mg, 12 mg, or 36 mg) or placebo for 40 weeks. Mean duration of T2D was 4.4 years, mean HbA1c at baseline was 8%, and mean body weight at baseline was 90.2 kg. About 48% of the participants were women, and 38.3% had previously received a glucose-lowering agent (most commonly metformin). The primary endpoint was change in HbA1c at week 40. A key secondary endpoint was percent change in body weight at week 40.
Orforglipron was associated with significant, dose-dependent, and clinically meaningful reductions in HbA1c (-1.24%, -1.47%, and -1.48% for the 3, 12, and 36 mg doses, respectively) compared with placebo (-0.41%). Mean HbA1c at week 40 was 6.5%-6.7% with orforglipron. 68%-73% of individuals on orforglipron achieved an HbA1c < 7%; 57%-62% of individuals achieved an HbA1c < 6.5%; and 17%-24% of individuals achieved an HbA1c < 5.7% (ie, below US criteria for prediabetes). Glycemic improvement was seen at as early as 4 weeks.
Mean change in weight with orforglipron was -4.5% with the 3 mg dose, -5.8% with the 12 mg dose, and -7.6% with the 36 mg dose. Mean change in weight in the placebo group was -1.7%. 43%-61% of participants on orforglipron achieved a clinically meaningful weight loss of ≥ 5%; 15%-30% of participants lost ≥ 10% of their body weight; and 4%-10% of participants lost ≥ 15% of their body weight.
The researchers also observed improvements in other cardiometabolic markers, including lipids, waist circumference, and systolic blood pressure.
The safety profile was consistent with that of the GLP-1 RA class as a whole; the most common adverse effects were gastrointestinal side effects that were mild to moderate and mostly occurred during dose escalation. The prevalence of gastrointestinal side effects generally decreased over time. No episodes of severe hypoglycemia or cases of pancreatitis occurred. There was no adverse liver signal seen in ACHIEVE-1. In fact, mean alanine transaminase and aspartate aminotransferase levels decreased during the trial. Discontinuation rates with orforglipron were also similar to those of the class.
Whilst direct comparisons are unfair, since there are no published head-to-head trials, ACHIEVE-1 delivers results comparable to those of the similarly designed semaglutide 1 mg monotherapy study SUSTAIN-1.
In conclusion, ACHIEVE-1 positions orforglipron as an efficacious oral GLP-1 RA with a favorable safety profile that could scale globally for the treatment of early T2D and weight management. This option could help reduce health inequalities, especially in low-income countries where factors like affordability, availability, and accessibility hinder the delivery of disease-modifying therapies for T2D. Orforglipron may also drive a change in treatment paradigms and be considered as a first-line therapy for patients with early T2D and overweight or obesity. Further orforglipron studies awaiting completion include comparisons to dapagliflozin (ACHIEVE-2) and oral semaglutide (ACHIEVE-3), as well as ATTAIN, which will assess orforglipron for weight management in patients without T2D.
Fernando is a general practitioner near Edinburgh, Scotland, with a specialist interest in diabetes; cardiovascular, renal, and metabolic diseases; and medical education.
