Research in context
Evidence before this study
We searched PubMed on Aug 5, 2021, with no restrictions other than English language, using the terms “albiglutide”, “dulaglutide”, “exenatide”, “liraglutide”, “lixisenatide”, “semaglutide”, “tirzepatide”, “glucagon-like peptide-1 (GLP-1) receptor agonist”, “glucose-dependent insulinotropic polypeptide (GIP)”, “basal insulin”, “insulin degludec”, “insulin glargine”, and “type 2 diabetes”. Basal insulin or GLP-1 receptor agonists are currently recommended as the first injectable therapies for the treatment of type 2 diabetes. Tirzepatide is a novel once-per-week dual GIP and GLP-1 receptor agonist representing a first-in-class medication for the treatment of type 2 diabetes. It has shown clinically meaningful improvements in glycated haemoglobin (HbA1c) and bodyweight in various background therapies when compared with placebo, dulaglutide, semaglutide, and insulin degludec in studies of 26–52 weeks duration. Its non-cardiovascular safety profile is similar to that of GLP-1 receptor agonists. These previous results were obtained in individuals with type 2 diabetes and overall low cardiovascular risk.
Added value of this study
To our knowledge, this was the first study to compare the efficacy and safety of a dual GIP and GLP-1 receptor agonist with a basal insulin in patients with type 2 diabetes and high risk for cardiovascular events. The study duration was longer than other studies in the SURPASS programme, providing the first evidence of the sustained effects of tirzepatide. In addition, conducting the study in this high risk population provided an initial assessment of cardiovascular safety of tirzepatide. As a first injectable treatment, after 52 weeks of treatment, tirzepatide 5 mg, 10 mg, and 15 mg demonstrated clinically meaningful HbA1c reductions and bodyweight loss compared with titrated glargine in people with long duration type 2 diabetes and high cardiovascular risk. Greater proportions of tirzepatide-treated participants achieved HbA1c treatment goals, with a lower incidence of hypoglycaemia (glucose <54 mg/dL or severe). HbA1c and bodyweight reductions were sustained for up to 104 weeks. Tirzepatide also decreased systolic and diastolic blood pressure, triglycerides, and non-HDL cholesterol. The hazard ratio for major adverse cardiovascular events (109 participants with first event of cardiovascular death, myocardial infarction, stroke, or hospitalisation for unstable angina) for pooled tirzepatide groups versus glargine was 0·74 (95% CI 0·51–1·08), indicating no increased cardiovascular risk with tirzepatide treatment compared with glargine.
Implications of all the available evidence
Once-per-week tirzepatide provides long-term meaningful improvement of glycaemic control with low risk of clinically relevant hypoglycaemia in participants with various durations of type 2 diabetes, with or without cardiovascular disease, treated with diverse glucose-lowering medications, including sulfonylureas. Additional benefits of tirzepatide included bodyweight and blood pressure reductions and improvements in the lipid profile. Importantly, no increased cardiovascular risk was observed versus glargine in people with type 2 diabetes and elevated risk for cardiovascular disease. Further clinical research is ongoing to evaluate potential cardiovascular benefits of tirzepatide.