Age- and Sex- Differences in Efficacy of Treatments for Type 2 Diabetes: Network Meta-Analysis of Aggregate and Individual Level Data

Importance Sodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor analogues (GLP1ra) and dipeptidyl peptidase-4 inhibitors (DPP4i) improve hyperglycaemia and, in the case of SGLT2i and GLP1ra, reduce the risk of major adverse cardiovascular events (MACE) in type 2 diabetes. It is not clear whether efficacy varies by age or sex. Objective Assess whether age or sex are associated with differences in efficacy of SGL2i, GLP1ra and DPP4i. Data sources Medline, Embase and clinical trial registries. Study selection Two independent reviewers screened for randomised controlled trials of SGLT2i/GLP1ra/DPP4i, compared to placebo/active comparator, in adults with type 2 diabetes. Data extraction and synthesis We sought individual participant data (IPD) all eligible studies. Where IPD were available, we modelled age- and sex-treatment interactions for each trial. Otherwise, we assessed age-sex distributions along with results from aggregate trial data. IPD and aggregate findings were combined in a Bayesian network meta-analysis. Main outcome measures HbA1c and MACE. Results We identified 616 eligible trials (604 reporting HbA1c, 23 reporting MACE) and obtained IPD for 75 trials (6 reporting MACE). Mean age was 59.0 (10.7) years and 64.0 (8.6) in HbA1c and MACE trials, respectively. Proportions of female were 43.1% and 44.0% in HbA1c and MACE trials, respectively. SGLT2i reduced HbA1c by 0.5-1.0% overall compared to placebo. This reduction versus placebo was attenuated in older participants (change in HbA1c 0.25 percentage-points less for 75-year-olds compared to 45-year-olds). SGLT2i showed greater relative efficacy in MACE risk reduction among older than younger people. This finding was sensitive to the exclusion of one of the IPD MACE trials, however, in all sensitivity analyses, SGLT2i were either as efficacious or more efficacious in older participants. There was no consistently significant difference in efficacy by age for GLP1ra or DPP4i for HbA1c or MACE, nor were there consistent significant sex differences for any class. Conclusion Newer glucose-lowering drugs are efficacious across age and sex groups. SGLT2i are more cardioprotective in older than younger people despite smaller HbA1c reductions. Age alone should not be a barrier to treatments with proven cardiovascular benefit providing they are well tolerated align with patient priorities. ### Competing Interest Statement John Petrie reports personal fees (via his employing institution) from Merck KGaA (Lectures), research support from Merck KGaA (Grant), personal fees from Novo Nordisk (Lectures/ Advisory) and personal fees from IQVIA (Boehringer Ingelheim Adjudication Committees) - all outside the submitted work. Dr Petrie has received non-financial support as co-CI of a JDRF-funded trial ([NCT03899402][1]) from Astra Zeneca (donation of investigational medicinal product to US site only) and Novo Nordisk - donation of investigational medicinal product to UK site only; supplementary financial support (to mitigate a budget cut during the COVID-19 pandemic). Robert Lindsey reports Event registration paid for by Novo Nordisk 2021, no personal fees. And is current local PI for SOUL study (Novo Nordisk)- no personal fees. Amanda Adlers trials unit is undertaking a trial funded by NovoNordisk. The indication is not diabetes. Naveed Sattar declares grant funding from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics; consulting fees from Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Menarini-Ricerche, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; payment for lectures or presentations from Abbott Laboratories, AbbVie, AstraZeneca, Boeringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi. All work was unrelated to this manuscript. All other authors declare no conflicts of interest. ### Funding Statement This study was funded by the Medical Research Council (Grant reference MR/T017112/1). The funder had no role in the design, conduct or interpretation of the analysis. The pharmaceutical companies that provided the data did not provide any funding or support to the study and had no role in the design, conduct or interpretation of the analysis. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval for IPD use was obtained from the University of Glasgow MVLS College Ethics Committee (Project: 200160070). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Individual-level participant data was obtained through the Vivli project, subject to a data sharing agreement. Data are available on application to the data holder via Vivlis application process. All aggregate data, as well as summary data from all analyses of individual participant data, are available at https://github.com/Type2DiabetesSystematicReview/nma\_agesex\_public, along with analysis code for all the analyses presented in the manuscript and supplementary appendices. [https://github.com/Type2DiabetesSystematicReview/nma\_agesex\_public][2] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03899402&atom=%2Fmedrxiv%2Fearly%2F2024%2F06%2F24%2F2024.06.23.24309242.atom [2]: https://github.com/Type2DiabetesSystematicReview/nma_agesex_public