The Impact of Frailty on the Effectiveness and Safety of Intensive Glucose Control and Blood Pressure-Lowering Therapy for People With Type 2 Diabetes: Results From the ADVANCE Trial

<b>Objective. </b>To develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), amongst participants with type-2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. <p><b>Research Design and Methods. </b>Cox proportional-hazard models were used to estimate the effectiveness and safety of intensive glucose control and BP intervention according to frailty (defined as FI>0.21) status. The primary outcomes were macrovascular events and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycaemia, and discontinuation of BP treatment due to hypotension/dizziness.</p> <p><b>Results.</b> There were 11140 participants (mean age 65.8, 42.5% female, 25.7% frail). Frailty was an independent predictor of all primary outcomes and secondary outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail: HRs for combined major macro- and micro-vascular events 1.03, 95%CI 0.90-1.19 in the frail vs 0.84, 95%CI 0.74-0.94 non-frail (p=0.02). A similar trend was observed with BP intervention. <a>Severe hypoglycaemia rates (per 1000 person-years) were higher in the frail: 8.39 (6.15–10.63) vs. 4.80 (3.84–5.76) in non-frail</a> (p<0.001). There was no significant difference in discontinuation of BP treatment between frailty groups.</p> <p><b>Conclusions. </b>It was possible to retrospectively estimate frailty in a trial population, and this FI identified those at higher risk of poor outcomes. Participants with frailty had some attenuation of benefit from intensive glucose lowering and BP lowering treatments. </p>