Orforglipron versus dapagliflozin in type 2 diabetes

Type 2 diabetes is a complex metabolic disorder that often requires combination therapy to achieve individualised treatment targets. Sodium–glucose cotransporter 2 (SGLT2) inhibitors offer proven glucose-lowering efficacy and cardiorenal benefits; however, many users may still not reach glycaemic targets. This highlights the need for new agents that help support individualised therapeutic goals.

Orforglipron is a novel once-daily, oral, non-peptide GLP-1 receptor agonist (RA) that can be taken without restrictions related to food or water intake. Approved for the treatment of overweight and obesity in the USA, it is also being investigated for type 2 diabetes and other cardiometabolic diseases.

The ACHIEVE-2 study compared the efficacy and safety of orforglipron with dapagliflozin, a widely used oral SGLT2 inhibitor, in adults with type 2 diabetes inadequately controlled with metformin. The 40-week phase 3 trial was conducted at 73 sites across six countries.

Eligible adults were receiving ≥1500 mg metformin/day, with an HbA_1c of 53–91 mmol/mol, stable body weight and a BMI of ≥23.0 kg/m². In total, 962 participants were randomly assigned in a 1:1:1:1 ratio to once-daily oral orforglipron 3 mg (n=240), 12 mg (n=241) or 36 mg (n=241), or dapagliflozin 10 mg (n=241). At baseline, 474 participants (49%) were female, mean age was 56.1 years, HbA_1c 8.14% (65 mmol/mol), diabetes duration 8.0 years and BMI 32.6 kg/m².

The primary analysis assessed change in HbA_1c at week 40 using the treatment-regimen estimand (data obtained regardless of study intervention discontinuation or initiation of additional agents). Across all tested doses, orforglipron met criteria for both non-inferiority (margin of 0.3%) and superiority versus dapagliflozin. Mean HbA_1c reductions were −1.23%, −1.50% and −1.56% with orforglipron 3 mg, 12 mg and 36 mg, respectively, compared with −0.81% with dapagliflozin 10 mg. Mean estimated treatment differences versus dapagliflozin were −0.42%, −0.70% and −0.75% with orforglipron 3 mg, 12 mg and 36 mg, respectively (all P<0.0001).

Higher orforglipron doses provided additional metabolic benefits. The 12 mg and 36 mg doses produced greater weight loss than dapagliflozin, with dose-dependent reductions in body weight and a higher likelihood of achieving meaningful weight-loss thresholds. The 36 mg dose also improved several cardiometabolic risk markers versus dapagliflozin, including triglycerides, non-HDL cholesterol and systolic blood pressure, suggesting potential utility beyond glucose lowering.

Orforglipron demonstrated a safety and tolerability profile consistent with that of the GLP-1 RA class. Gastrointestinal adverse events, including nausea, vomiting and diarrhoea, were most frequently reported. These were generally mild to moderate, occurred mainly during dose escalation and attenuated over time. However, adverse event-related discontinuations were more common with orforglipron than with dapagliflozin. No episodes of severe hypoglycaemia were reported, and serious adverse events were broadly similar across groups.

Findings from ACHIEVE-2, alongside those from ACHIEVE-1 and ACHIEVE-3, support orforglipron as a potential therapeutic option for type 2 diabetes in combination with metformin. Given its superior impact on diabetic control, weight and other cardiometabolic risk factors, we may need to consider whether GLP-1 RAs should be preferred over SGLT2 inhibitors. However, dedicated cardiovascular and renal outcome studies are needed to inform potential guideline changes. Such studies could help answer important questions about which drug classes to prioritise for people with early diabetic kidney disease, with the aim of preventing disease progression while improving glycaemic control and broader cardiovascular, renal and metabolic outcomes.

The full article can be read here.