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

Tu N Nguyen, Katie Harris, Mark Woodward, John Chalmers, Mark Cooper, Pavel Hamet, Stephen Harrap, Simon Heller, Stephen MacMahon, Giuseppe Mancia, Michel Marre, Neil Poulter, Anthony Rogers, Bryan Williams, Sophia Zoungas, Clara K Chow, Richard I Lindley, Tu N Nguyen, Katie Harris, Mark Woodward, John Chalmers, Mark Cooper, Pavel Hamet, Stephen Harrap, Simon Heller, Stephen MacMahon, Giuseppe Mancia, Michel Marre, Neil Poulter, Anthony Rogers, Bryan Williams, Sophia Zoungas, Clara K Chow, Richard I Lindley

Abstract

Objective: 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), among participants with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.

Research design and methods: 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 macro- and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycemia, and discontinuation of BP treatment due to hypotension/dizziness.

Results: There were 11,140 participants (mean age, 65.8 years; 42.5% women, 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: hazard ratios for combined major macro- and microvascular events 1.03 (95% CI 0.90-1.19) in the frail versus 0.84 (95% CI 0.74-0.94) in the nonfrail (P = 0.02). A similar trend was observed with BP intervention. Severe hypoglycemia rates (per 1,000 person-years) were higher in the frail: 8.39 (6.15-10.63) vs. 4.80 (3.84-5.76) in nonfrail (P < 0.001). There was no significant difference in discontinuation of BP treatment between frailty groups.

Conclusions: 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.

Trial registration: ClinicalTrials.gov NCT00145925.

© 2021 by the American Diabetes Association.

Figures

Figure 1
Figure 1
Adjusted HRs of frailty (frail vs. nonfrail) on the study outcomes (all treatment groups combined). Adjusted for intensive glucose treatment, age, and sex.
Figure 2
Figure 2
Unadjusted HRs of intensive glucose treatment vs. standard control and blood pressure intervention vs. placebo on the study outcomes in frail and nonfrail participants.

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