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.

 

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Conflict of Interest

Disclosure: This study was initially presented at the virtual EASD 2021 – 57th Annual meeting; 27 September – 1 October 2021.

Authors COI: SDP declares grants from AstraZeneca and Boehringer Ingelheim; consulting fees from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Merck Sharpe and Dohme, Novartis Pharmaceuticals, Novo Nordisk, Sanofi; and honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Merck Sharpe and Dohme, Novartis Pharmaceuticals, Novo Nordisk, and Sanofi. SEK declares consulting fees from Casma Therapeutics, Eli Lilly and Company, Intarcia, Merck, Novo Nordisk, Pfizer and Third Rock Ventures; and honoraria for lectures from Boehringer Ingelheim. IP, GJW, ZY, RJH, JSR and RJW are employees and shareholders of Eli Lilly and Company. JD declares grants from Eli Lilly and Company; honoraria as a speaker from Sanofi Aventis, Eli Lilly and Company, AstraZeneca, Novo Nordisk; support for attending meetings from Eli Lilly and Company, Novo Nordisk and Sanofi Aventis; and has served on advisory boards and other boards for Eli Lilly and Company, Novo Nordisk, Hellenic Diabetes Association, National Health Service and Hellenic Ministry of Health. DA and AGW report no competing interests.

Publication History

Article published online:
26 May 2022