Intensive Risk Factor Management and Cardiovascular Autonomic Neuropathy in Type 2 Diabetes: The ACCORD Trial

Abstract

Objective: The effects of preventive interventions on cardiovascular autonomic neuropathy (CAN) remain unclear. We examined the effect of intensively treating traditional risk factors for CAN, including hyperglycemia, hypertension, and dyslipidemia, in individuals with type 2 diabetes (T2D) and high cardiovascular risk participating in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

Research design and methods: CAN was defined as heart rate variability indices below the fifth percentile of the normal distribution. Of 10,251 ACCORD participants, 71% (n = 7,275) had a CAN evaluation at study entry and at least once after randomization. The effects of intensive interventions on CAN were analyzed among these subjects through generalized linear mixed models.

Results: As compared with standard intervention, intensive glucose treatment reduced CAN risk by 16% (odds ratio [OR] 0.84, 95% CI 0.75-0.94, P = 0.003)-an effect driven by individuals without cardiovascular disease (CVD) at baseline (OR 0.73, 95% CI 0.63-0.85, P < 0.0001) rather than those with CVD (OR 1.10, 95% CI 0.91-1.34, P = 0.34) (P interaction = 0.001). Intensive blood pressure (BP) intervention decreased CAN risk by 25% (OR 0.75, 95% CI 0.63-0.89, P = 0.001), especially in patients ≥65 years old (OR 0.66, 95% CI 0.49-0.88, P = 0.005) (P interaction = 0.05). Fenofibrate did not have a significant effect on CAN (OR 0.91, 95% CI 0.78-1.07, P = 0.26).

Conclusions: These data confirm a beneficial effect of intensive glycemic therapy and demonstrate, for the first time, a similar benefit of intensive BP control on CAN in T2D. A negative CVD history identifies T2D patients who especially benefit from intensive glycemic control for CAN prevention.

Trial registration: ClinicalTrials.gov NCT00000620.

© 2020 by the American Diabetes Association.

Figures

Figure 1

Flow diagram of the study population included in the analysis. Intensive and standard glycemic and BP refer to intensive and standard glycemic and BP interventions.

Figure 2

Effects of interventions in ACCORD on CAN. The primary model was adjusted by fixed effects including trial assignments, seven clinical center networks, time after randomization, prior CVD events, and baseline CAN status. The full model was adjusted by additional baseline characteristics as fixed effects, namely, age, sex, diabetes duration, HbA1c, BMI, height, alcohol, cigarettes, SBP and DBP, LDL cholesterol, triglycerides, HDL cholesterol, UACR, and use of thiazolidinediones, insulin, β-blockers, ACEIs/ARB, and statins. Both models included participants as random effects.

Figure 3

Effects of ACCORD interventions on CAN risk in the subgroups prespecified for the analysis of the ACCORD primary outcome.

Figure 3

Effects of ACCORD interventions on CAN risk in the subgroups prespecified for the analysis of the ACCORD primary outcome.

Figure 4

Effects of the combination of intensive glycemic control with intensive BP control (ACCORD BP) (A) and fenofibrate (ACCORD Lipid) (B) on CAN risk.