Orforglipron pill shown to reduce HbA1c and weight more than oral semaglutide in head-to-head trial

A phase 3 trial has reported that once-a-day pill of orforglipron, a small-molecule glucagon-like peptide 1 receptor agonist, has delivered larger falls in HbA1c and body mass than oral semaglutide in adults with type 2 diabetes after 52 weeks

A once-daily pill – orforglipron – has produced greater reductions in blood glucose and body weight than oral semaglutide in adults with type 2 diabetes (T2DM), according to a phase 3 randomised trial. The ACHIEVE-3 study compared two doses of orforglipron – 12 mg and 36 mg – with two doses of oral semaglutide – 7 mg and 14 mg – across 52 weeks.

Glucagon-like peptide 1 (GLP-1) receptor agonists are widely used in the treatment of T2DM because they lower glucose levels, support weight loss and reduce cardiometabolic risk factors in many patients. Semaglutide is the only GLP-1 receptor agonist available as an oral therapy at present but it requires dosing on an empty stomach with restrictions on food and fluid intake around the time of administration.

Orforglipron is a non-peptide, small-molecule GLP-1 receptor agonist that trial reports indicate patients can take with or without food which could support greater adherence in routine care settings such as home use.

The trial enrolled more than 1,500 participants with T2DM in 131 research centres and hospitals across Argentina, China, Japan, Mexico and the USA. Investigators randomised participants to receive one of the two orforglipron doses or one of the two semaglutide doses for one year.

Across both dose comparisons, participants who received orforglipron achieved larger average improvements in glycaemic control than those who received semaglutide, with the analysis focused on change in HbA1c – the standard laboratory measure that reflects average blood glucose over roughly three months. In clinical practice, shifts in HbA1c of this kind matter because sustained reductions correlate with lower risk of microvascular complications, including diabetic retinopathy and kidney disease.

Weight loss also favoured orforglipron. Participants started at an average weight of about 97 kg and lost, on average, roughly six to eight per cent of body weight with orforglipron compared with around four to five per cent with semaglutide. The difference matters because excess adiposity is a major driver of insulin resistance and can worsen blood pressure and lipid profiles, so even modest additional weight loss can translate into meaningful shifts in long-term cardiometabolic risk.

However, tolerability of orforglipron remained the key trade-off. Discontinuation from the trial due to adverse events occurred in about nine to 10 per cent of participants assigned to orforglipron, compared with about four to five per cent assigned to semaglutide. Gastrointestinal symptoms were the most common reason to stop treatment.

Such side effects are common across the GLP-1 receptor agonist class but higher discontinuation rates can blunt real-world effectiveness if patients cannot persist with therapy. Clinicians typically manage these effects through dose escalation, dietary advice and careful patient selection. Nevertheless persistence can still prove difficult for some patients.

The authors concluded that orforglipron could expand options for people with T2DM who prefer a pill over having to give a self-injection and who also want to avoid restrictions on food and fluid intake around administration, as with oral semaglutide. The wider clinical impact will depend on how well patients tolerate the treatment outside of trial settings and whether longer-term studies can confirm benefits on cardiovascular outcomes and complications associated with T2DM.

For further reading please visit: 10.1016/S0140-6736(26)00202-3