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Non-inferiority and clinical superiority of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors: Systematic analysis of cardiorenal outcome trials in type 2 diabetes

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journal contribution
posted on 29.07.2022, 16:51 authored by F Zaccardi, DE Kloecker, K Khunti, MJ Davies

Aims: Most trials leading to the approval of glucagon-like peptide receptor agonists (GLP-1RAs) and sodium-glucose co-transporter-2 inhibitors (SGLT2is) were primarily designed to confirm their non-inferiority to placebo (commonly using an upper 95% confidence limit threshold of 1.3) and, if confirmed, superiority (threshold 1): this asymmetry of margins (1 vs. 1.3) favours the active intervention. We aimed to quantify the probability of clinical superiority of the active treatment by applying the same threshold used to claim non-inferiority.

Materials and Methods: We searched PubMed and Cochrane CENTRAL for cardiorenal outcome trials in subjects with type 2 diabetes published before 5 December 2021, to reconstruct from Kaplan-Meier plots individual-level data for the primary outcome or all-cause mortality. We calculated Bayesian posterior densities to obtain the probability for a treatment effect (hazard ratio) <0.769, which is symmetric to the 1.3 threshold (i.e. its reciprocal 1/1.3), emulating a scenario where the active treatment is placebo and placebo is the active treatment. 

Results: We extracted data from 27 Kaplan-Meier plots (18 for the primary outcome, nine for mortality). Probabilities of clinical superiority to placebo varied significantly: for GLP-1RAs, from a minimum of 0% to a maximum of 69% for the primary outcome and from 0% to 8% for mortality; corresponding estimates for SGLT2is were 0% to 96% and 0% to 93%. Probabilities were on average greater for SGLT2is, particularly in trials investigating kidney or heart failure outcomes. Conclusions: The probability of clinical superiority to placebo varies widely across trials previously reported as showing superiority of GLP-1RAs or SGLT2is compared with placebo. These results showed within- and between-class differences, highlight the drawbacks of a binary interpretation of the results, particularly in the context of the current designs of non-inferiority trials, and have implications for decision makers and future clinical recommendations.

Funding

National Institute for Health and Care Research (NIHR); NIHR Leicester Biomedical Research Centre

History

Citation

Zaccardi F, Kloecker DE, Khunti K,Davies MJ. Non-inferiority and clinical superiority of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors: Systematic analysis of cardiorenaloutcome trials in type 2 diabetes.Diabetes Obes Metab. 2022;24(8):1598‐1606. doi:10.1111/dom.14

Author affiliation

NIHR Leicester Biomedical Research Centre; Leicester Real World Evidence Centre

Version

VoR (Version of Record)

Published in

Diabetes, Obesity and Metabolism

Volume

24

Issue

8

Pagination

1598‐1606

Publisher

Wiley

issn

1462-8902

eissn

1463-1326

Acceptance date

28/04/2022

Copyright date

2022

Available date

29/07/2022

Spatial coverage

England

Language

eng