Journal name: Diabetologia

Publishing date: May 17, 2022

Author: Thomas Karagiannis et.al

A systematic analysis showed superior efficacy for the twincretin, Tirzepatide in glycaemic control and body weight reduction when compared to placebo, GLP-1 RAs and basal insulin.

Why does this study matter?

Tirzepatide is a dual GIP and GLP-1 RA (Hence called a “Twincretin”). It has a greater affinity to GIP receptors, rather than GLP-1 receptors. It has a t½ of approximately 5 days allowing us a once-weekly subcutaneous administration. Early proof-of-concept and phase 2 studies suggested that tirzepatide can improve both markers of beta-cell function and insulin sensitivity compared with selective GLP-1 RA therapy.

On the basis of these findings, the overall efficacy and safety of tirzepatide have been investigated in the SURPASS clinical trial programme in comparison with placebo and other glucose-lowering medications including GLP-1 RAs and basal insulin.

Study Design

The researchers searched PubMed, Embase, Cochrane and ClinicalTrials.gov up until 27 October 2021 for randomised controlled trials with a duration of at least 12 weeks that compared once-weekly btirzepatide 5, 10 or 15 mg with placebo or other glucose-lowering drugs in adults with type 2 diabetes irrespective of their background glucose-lowering treatment. The primary outcome was a change in HbA1c from baseline.

Secondary efficacy outcomes included change in body weight, the proportion of individuals reaching the HbA1c target of 7.0%, 6.5% or 5.7%, and the proportion of individuals with body weight loss of at least   5%, 10% or 15%. Safety outcomes included hypoglycaemia, gastrointestinal adverse events, treatment discontinuation due to adverse events, serious adverse events, and mortality. Seven trials (6609 participants) were included.

Results and Conclusion

A dose-dependent superiority in lowering HbA1c was evident with all three tirzepatide doses vs all comparators, with mean differences ranging from 1.62% to −2.06% vs placebo, −0.29% to −0.92% vs GLP-1 RAs, and −0.70% to −1.09% vs basal insulin regimens. Tirzepatide was more efficacious in reducing body weight; reductions vs GLP-1 RAs ranged from 1.68 kg with tirzepatide 5 mg to 7.16 kg with tirzepatide 15 mg. Incidence of hypoglycaemia with tirzepatide was similar vs placebo and lower vs basal insulin.

Nausea was more frequent with tirzepatide vs placebo, especially with tirzepatide 15mg (OR 5.60 [95% CI 3.12, 10.06]), associated with a higher incidence of vomiting (OR 5.50 [95% CI 2.40, 12.59]) and diarrhoea (OR 3.31 [95% CI 1.40, 7.85]). The odds of gastrointestinal events were similar between tirzepatide and GLP-1 RAs, except for diarrhoea with tirzepatide 10 mg (OR 1.51[95% CI 1.07, 2.15]).

A dose-dependent superiority in glycaemic efficacy and body weight reduction was evident with tirzepatide vs placebo, GLP-1 RAs, and basal insulin. Tirzepatide did not increase the odds of hypoglycaemia but was associated with an increased incidence of gastrointestinal adverse events.

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