Efficacy and Safety of Tirzepatide versus Insulin Glargine in Patients with Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4)

Background Efficacy and safety of novel dual GIP/GLP-1 receptor agonist tirzepatide versus insulin glargine was assessed in adults with type 2 diabetes inadequately controlled on metformin, sulfonylurea, and/or SGLT-2i and increased cardiovascular risk. Methods This open-label, Phase-3 study (N=1995, age 63.6y, HbA1c 8.52%, BMI 32.6kg/m2, cardiovascular disease 87%) randomised participants (1:1:1:3) to once-weekly tirzepatide (5, 10, 15mg) or titrated glargine (100U/mL). Study duration was up to 104 weeks. Primary endpoint was mean HbA1c change from baseline at 52 weeks. Safety was assessed over the full study period. Results At 52 weeks, tirzepatide was superior to glargine in HbA1c change from baseline; LSMean treatment differences were –0.80% (95% CI –0.92,–0.68) for 5mg, –0.99% (–1.11,–0.87) for 10mg, and –1.14% (–1.26,–1.02) for 15mg, all p<0.001. Tirzepatide 5, 10, and 15mg decreased body weight (LSMean -7.1, -9.5, and -11.7kg, respectively), while glargine increased weight (+1.9kg). Similar changes were observed to 104 weeks. Nausea (12–23%), diarrhoea (13–22%), decreased appetite (9–11%), and vomiting (5–9%) occurred more frequently with tirzepatide than glargine (2%, 4%, < 1%, and 2%, respectively); most were mild-to-moderate. Hypoglycaemia incidence (<54mg/dL or severe) was lower with tirzepatide (6–9%) than glargine (19%), particularly when not on sulfonylureas (1–3% vs. 16%). 109 participants had adjudicated MACE-4 (cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina) events; HR 0.74 (95% CI 0.51,1.08) for tirzepatide versus glargine. Conclusion HbA1c and body weight reductions with tirzepatide were clinically meaningful and superior to glargine, with no increased cardiovascular risk. Publication History Article published online: 26 May 2022 © 2022. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany