Safety and effectiveness of SGLT2-inhibitors in people with type 2 diabetes over 70: UK population-based study using an Instrumental Variable approach

Objective Older adults are underrepresented in trials, meaning the benefits and risks of glucose lowering agents in this age group are unclear. We applied causal analysis to assess the safety and effectiveness of SGLT2-inhibitors in people with type 2 diabetes (T2D) over 70. Research Design and Methods Hospital-linked UK primary care data (Clinical Practice Research Datalink, 2013-2020) were used to compare adverse events and effectiveness in individuals initiating SGLT2-inhibitors compared to DPP4-inhibitors. Analysis was age-stratified: <70 years (SGLT2-inhibitors n=66810, DPP4-inhibitors n=76172), ≥70 years (SGLT2-inhibitors n=10419, DPP4-inhibitors n=33434). Outcomes were assessed using the Instrumental Variable causal inference method and prescriber preference as instrument.

Risk of DKA was increased with SGLT2-inhibitors in those aged ≥70 (Incidence risk ratio compared to DPP4i: 3.82 [95%CI 1.12,13.03]), but not in those <70 (1.12 [95%CI 0.41,3.04]). However incidence rates with SGLT2-inhibitors in those ≥70 was low (29.6 [95%CI 29.5,29.7]) per 10000 person-years. SGLT2-inhibitors were associated with similarly increased risk of genital infection in both age groups (IRR <70 2.27 [2.03,2.53]; ≥70 2.16 [1.77,2.63]). There was no evidence of an increased risk of volume depletion, poor micturition control, urinary frequency, falls or amputation with SGLT2-inhibitors in either age group. In those ≥70, HbA1c reduction was similar with SGLT2-inhibitors and DPP4-inhibitors (−0.3 mmol/mol [−1.6,1.1], −0.02% [0.1,0.1]), but in those <70 SGLT2-inhibitors were more effective (−4 mmol/mol [4.8,−3.1], −0.4% [−0.4,−0.3]).

Causal analysis suggests SGLT2-inhibitors are effective in adults ≥70, but increase risk for genital infections and DKA. Our study extends RCT evidence to older adults with T2D. Article Highlights Why did we undertake this study? – Current guidelines for type 2 diabetes recommend an individualised approach to treatment, but evidence for older adults is limited. What is the specific question(s) we wanted to answer? – To assess the safety and effectiveness of SGLT2-inhibitors in older adults by applying a causal inference framework to address potential confounding bias in observational data. What did we find? – SGLT2-inhibitors are effective in reducing HbA1c and weight and generally safe for older adults. Adverse events in this older group include genital infections and a small increase in DKA. What are the implications of our findings? – SGLT2-inhibitors are effective and safe for older adults, but clinicians should be aware of the risks for genital infections and DKA. Competing Interest Statement The authors have declared no competing interest. Funding Statement This research was funded by the Medical Research Council (UK) (MR/N00633X/1), and supported by EFSD/Novo Nordisk. 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: This article is based on data from Clinical Practice Research Datalink obtained under licence from the UK Medicines and Healthcare products Regulatory Agency. CPRD data is provided by individuals and collected by the NHS as part of their care and support. Approval for the study was granted by the CPRD Independent Scientific Advisory Committee (ISCA 22_002000). This study was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. 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 Data Availability CPRD data are available by application to the CPRD Independent Scientific Advisory Committee. R code to preproduce the analysis in this paper is available at https://github.com/Exeter-Diabetes/CPRD-Laura-SGLT2i-in-older-adults. https://github.com/Exeter-Diabetes/CPRD-Laura-SGLT2i-in-older-adults