Heterogeneous Treatment Effects of Intensive Glycemic Control on Kidney Microvascular Outcomes and Mortality in ACCORD

Abstract

Significance statement: Identifying and quantifying treatment effect variation across patients is the fundamental challenge of precision medicine. Here we quantify heterogeneous treatment effects of intensive glycemic control in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, considering three outcomes of interest-a composite kidney outcome (driven by macroalbuminuria), all-cause mortality, and first assisted hypoglycemic event. We demonstrate that the effects of intensive glycemic control vary with risk of kidney failure, as predicted by the kidney failure risk equation (KFRE). Participants at highest risk of kidney failure gain the largest absolute kidney benefit of intensive glycemic control but also experience the largest absolute risk of death and hypoglycemic events. Our findings illustrate the value of identifying clinically meaningful treatment heterogeneity, particularly when treatments have different effects on multiple end points.

Objective: Clear criteria to individualize glycemic targets in patients with type II diabetes are lacking. In this post hoc analysis of the ACCORD, we evaluate whether the KFRE can identify patients for whom intensive glycemic control confers more benefit in preventing kidney microvascular outcomes.

Research design and methods: We divided the ACCORD trial population into quartiles on the basis of 5-year kidney failure risk using the KFRE. We estimated conditional treatment effects within each quartile and compared them with the average treatment effect in the trial. The treatment effects of interest were the 7-year restricted mean survival time (RMST) differences between intensive and standard glycemic control arms on ( 1 ) time-to-first development of severely elevated albuminuria or kidney failure and ( 2 ) all-cause mortality.

Results: We found evidence that the effect of intensive glycemic control on kidney microvascular outcomes and all-cause mortality varies with baseline risk of kidney failure. Patients with elevated baseline risk of kidney failure derived the most from intensive glycemic control in reducing kidney microvascular outcomes (7-year RMST difference of 114.8 [95% confidence interval 58.1 to 176.4] versus 48.4 [25.3 to 69.6] days in the entire trial population) However, this same patient group also experienced a shorter time to death (7-year RMST difference of -56.7 [-100.2 to -17.5] v. -23.6 [-42.2 to -6.6] days).

Conclusions: We found evidence of heterogenous treatment effects of intensive glycemic control on kidney microvascular outcomes in ACCORD as a function of predicted baseline risk of kidney failure. Patients with higher kidney failure risk experienced the most pronounced reduction in kidney microvascular outcomes but also experienced the highest risk of all-cause mortality.