Elsevier

The Lancet

Volume 398, Issue 10313, 13 November 2021, Pages 1811-1824
The Lancet

Articles
Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial

https://doi.org/10.1016/S0140-6736(21)02188-7Get rights and content

Summary

Background

We aimed to assess efficacy and safety, with a special focus on cardiovascular safety, of the novel dual GIP and GLP-1 receptor agonist tirzepatide versus insulin glargine in adults with type 2 diabetes and high cardiovascular risk inadequately controlled on oral glucose-lowering medications.

Methods

This open-label, parallel-group, phase 3 study was done in 187 sites in 14 countries on five continents. Eligible participants, aged 18 years or older, had type 2 diabetes treated with any combination of metformin, sulfonylurea, or sodium-glucose co-transporter-2 inhibitor, a baseline glycated haemoglobin (HbA1c) of 7·5–10·5% (58–91 mmol/mol), body-mass index of 25 kg/m2 or greater, and established cardiovascular disease or a high risk of cardiovascular events. Participants were randomly assigned (1:1:1:3) via an interactive web-response system to subcutaneous injection of either once-per-week tirzepatide (5 mg, 10 mg, or 15 mg) or glargine (100 U/mL), titrated to reach fasting blood glucose of less than 100 mg/dL. The primary endpoint was non-inferiority (0·3% non-inferiority boundary) of tirzepatide 10 mg or 15 mg, or both, versus glargine in HbA1c change from baseline to 52 weeks. All participants were treated for at least 52 weeks, with treatment continued for a maximum of 104 weeks or until study completion to collect and adjudicate major adverse cardiovascular events (MACE). Safety measures were assessed over the full study period. This study was registered with ClinicalTrials.gov, NCT03730662.

Findings

Patients were recruited between Nov 20, 2018, and Dec 30, 2019. 3045 participants were screened, with 2002 participants randomly assigned to tirzepatide or glargine. 1995 received at least one dose of tirzepatide 5 mg (n=329, 17%), 10 mg (n=328, 16%), or 15 mg (n=338, 17%), or glargine (n=1000, 50%), and were included in the modified intention-to-treat population. At 52 weeks, mean HbA1c changes with tirzepatide were −2·43% (SD 0·05) with 10 mg and −2·58% (0·05) with 15 mg, versus −1·44% (0·03) with glargine. The estimated treatment difference versus glargine was −0·99% (multiplicity adjusted 97·5% CI −1·13 to −0·86) for tirzepatide 10 mg and −1·14% (−1·28 to −1·00) for 15 mg, and the non-inferiority margin of 0·3% was met for both doses. Nausea (12–23%), diarrhoea (13–22%), decreased appetite (9–11%), and vomiting (5–9%) were more frequent with tirzepatide than glargine (nausea 2%, diarrhoea 4%, decreased appetite <1%, and vomiting 2%, respectively); most cases were mild to moderate and occurred during the dose-escalation phase. The percentage of participants with hypoglycaemia (glucose <54 mg/dL or severe) was lower with tirzepatide (6–9%) versus glargine (19%), particularly in participants not on sulfonylureas (tirzepatide 1–3% vs glargine 16%). Adjudicated MACE-4 events (cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina) occurred in 109 participants and were not increased on tirzepatide compared with glargine (hazard ratio 0·74, 95% CI 0·51–1·08). 60 deaths (n=25 [3%] tirzepatide; n=35 [4%] glargine) occurred during the study.

Interpretation

In people with type 2 diabetes and elevated cardiovascular risk, tirzepatide, compared with glargine, demonstrated greater and clinically meaningful HbA1c reduction with a lower incidence of hypoglycaemia at week 52. Tirzepatide treatment was not associated with excess cardiovascular risk.

Funding

Eli Lilly and Company.

Introduction

Current guidelines recommend GLP-1 receptor agonists as the first injectable therapy in people with type 2 diabetes.1 Treatment with GLP-1 receptor agonists achieves similar or better glycaemic control than basal insulins with weight loss and lower risk of hypoglycaemia,2, 3, 4, 5 but is associated with frequent gastrointestinal side-effects.6

Combined GIP and GLP-1 receptor activation has been established as a promising therapeutic concept for the treatment of type 2 diabetes.7 Tirzepatide (Eli Lilly and Company, Indianapolis, IN, USA), a novel dual GIP and GLP-1 receptor agonist, is under development for the treatment of type 2 diabetes. When compared with a GLP-1 receptor agonist, tirzepatide further improves glycaemic control by actions on pancreatic β cells to enhance insulin secretion, by reducing glucose adjusted glucagon secretion, and by insulin-sensitising effects beyond the level explained by weight loss.8 In addition, tirzepatide treatment is associated with improvements in adipose tissue and lipoprotein metabolism, blood pressure, and other surrogate markers of cardiovascular protection.9, 10 It also has a marked anorexigenic effect, probably by integrating the activation signals of both GLP-1 and GIP receptor pathways in the brain.10, 11 When compared with placebo,12 semaglutide 1 mg per week,13 or insulin degludec,14 tirzepatide was more effective in achieving glycaemic control and weight reduction in people with type 2 diabetes over 40–52-week treatment periods.

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.

Although tirzepatide has been shown to be superior to other glucose-lowering agents for glycaemic and weight effects, and has shown favourable effects on cardiovascular risk factors, its long-term efficacy and safety have not been evaluated. In particular, cardiovascular safety remains to be addressed in individuals with type 2 diabetes and high cardiovascular risk, especially in those with a history of cardiovascular disease or chronic kidney disease. Tirzepatide has been evaluated against the basal insulin degludec,14 but not against glargine, one of the most frequently prescribed basal insulins used for blood glucose management in type 2 diabetes. Therefore, the objective of SURPASS-4 was to compare the efficacy and safety of three doses of tirzepatide (5 mg, 10 mg, and 15 mg) versus glargine titrated to a fasting glucose of less than 100 mg/dL in people with type 2 diabetes and high cardiovascular risk inadequately controlled on oral glucose-lowering medications.

Section snippets

Study design

This randomised, open-label, active-controlled, parallel-group, phase 3 study was conducted at 187 sites in 14 countries (Argentina, Australia, Brazil, Canada, Greece, Israel, Mexico, Poland, Romania, Russia, Slovakia, Spain, Taiwan, and the USA) on five continents. The protocol was approved by institutional review boards for each site and the trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol for this study is available in the

Results

The study was initiated on Nov 20, 2018, with participant recruitment continuing until Dec 30, 2019. The study was completed on April 22, 2021. 3045 participants were screened, with 2002 participants randomly assigned to tirzepatide or glargine. 1995 received at least one dose of tirzepatide 5 mg (n=329, 17%), 10 mg (n=328, 16%), or 15 mg (n=338, 17%), or glargine (n=1000, 50%). 1819 (91%) participants had the primary endpoint measured at 52 weeks while still on study medication and 1909 (95%)

Discussion

In this study of individuals with long-standing type 2 diabetes at high cardiovascular risk and inadequately controlled glycaemia with up to three oral glucose-lowering medications, including sulfonylureas, all three doses of the dual GIP and GLP-1 receptor agonist tirzepatide markedly improved glucose control, reduced bodyweight, and improved the cardiovascular risk profile. A higher proportion of participants reached the glycaemic targets with fewer clinically significant hypoglycaemic events

Data sharing

Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymisation, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the USA and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent

Declaration of interests

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,

References (35)

  • D Russell-Jones et al.

    Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial

    Diabetologia

    (2009)
  • PN Weissman et al.

    HARMONY 4: randomised clinical trial comparing once-weekly albiglutide and insulin glargine in patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea

    Diabetologia

    (2014)
  • M Nauck

    Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors

    Diabetes Obes Metab

    (2016)
  • JJ Holst et al.

    GIP as a therapeutic target in diabetes and obesity: insight from incretin co-agonists

    J Clin Endocrinol Metab

    (2020)
  • MK Thomas et al.

    Dual GIP and GLP-1 receptor agonist tirzepatide improves beta-cell function and insulin sensitivity in type 2 diabetes

    J Clin Endocrinol Metab

    (2021)
  • JM Wilson et al.

    The dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist, tirzepatide, improves lipoprotein biomarkers associated with insulin resistance and cardiovascular risk in patients with type 2 diabetes

    Diabetes Obes Metab

    (2020)
  • JP Frías et al.

    Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes

    N Engl J Med

    (2021)
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    *

    Contributed equally

    Investigators listed in the appendix

    Dr Riesmeyer died in April, 2021

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