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

Abstract

AbstractObjectiveOlder 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 MethodsHospital-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.ResultsRisk 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]).ConclusionsCausal 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 HighlightsWhy 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.