Cardiovascular autonomic neuropathy (CAN) is a common complication that independently predicts cardiovascular (CV) morbidity and mortality in persons with type 2 diabetes (T2D). The effect of preventive interventions on CAN remains unclear. We examined the effects of intensively targeting hyperglycemia, hypertension, and dyslipidemia on CAN, in persons with T2D and high CV risk from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. CAN was defined as heart rate variability indices below the 5th percentile of the normal distribution (standard deviation of all normal-to-normal R-R intervals [SDNN] <8.2 ms and root mean square of successive differences between normal-to-normal R-R intervals [rMSSD] <8.0 ms). Among 10,251 ACCORD participants, 71% (n=7,275) had valid CAN measures at study entry and at least once during follow-up. As compared to standard treatment, intensive glycemic control had a protective effect on CAN (OR=0.83, 95% CI 0.74 - 0.93, p=0.002), especially in persons with no CVD history (OR= 0.72, 0.62 - 0.83, p<0.0001). Intensive BP therapy also decreased the odds of CAN (OR=0.82, 0.72 - 0.94, p=0.01), especially in persons with positive CVD history (OR=0.71, 0.53 - 0.96, p=0.03). Fenofibrate did not have a significant impact on the dichotomous CAN outcome (OR=0.91, 0.77 - 1.06, p=0.22), but showed a significant benefit on continuous CAN outcomes SDNN (β=1.04, 1.01 - 1.08, p=0.02) and rMSSD (β=1.06, 1.02 - 1.10, p=0.003). No significant interactions were observed between treatments. This study is, to our knowledge, the first to demonstrate a clear benefit of intensive glycemic and BP control, and fenofibrate therapy on CAN in a large T2D cohort and high CV risk. The finding of possible heterogeneity in the benefit of these interventions on CAN across clinical strata suggests personalization of these treatments as a path forward to optimize their use.
Y. Tang: None. H. Shah: None. C. Bueno Junior: None. X. Sun: None. J. Mitri: Consultant; Spouse/Partner; Janssen Pharmaceuticals, Inc., kymera. Consultant; Self; national dairy council/local dairy council. Research Support; Spouse/Partner; AbbVie Inc., beigene, Janssen Pharmaceuticals, Inc. Research Support; Self; Kowa Pharmaceuticals America, Inc., national dairy council. Research Support; Spouse/Partner; pharma cyclic, TG therapeutics. M. Sambataro: None. L. Sambado: None. H.C. Gerstein: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Kowa Pharmaceuticals America, Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Sanofi. V. Fonseca: Consultant; Self; Abbott, Asahi Kasei Corporation, AstraZeneca, Bayer Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Stock/Shareholder; Self; Amgen, Bravo4health. A. Doria: Research Support; Self; Sanofi. R. Pop-Busui: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Consultant; Self; Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca. Other Relationship; Self; American Diabetes Association.
National Institutes of Health (N01HC95178, N01HC95179, N01HC95180, N01HC95181, N01HC95182, N01HC95183, N01HC95184, IAAY1HC-9035, IAAY1HC1010)