Neuropathy: The Crystal Ball for Cardiovascular Disease?

Cardiovascular Disease? C ardiovascular disease (CVD) is a major cause of death in patients with type 2 diabetes. Unclear, however, is the effect of intensive therapy in reducing the development of cardiovascular complications. The UK Prospective Diabetes Study (UKPDS), involving patients with newly diagnosed disease, showed a nonsignificant trend in the reduction of rates for myocardial infarction (MI) (1). However, data 10 years after cessation of the trial showed a 15% reduction in the risk of MI for those in the original intensive therapy group (2). This benefit from early intensive therapy persisted despite the fact that the within-trial differences for A1C between the intensive and conventional therapy groups were lost within 1 year of completion of the trial. The sustained benefit from early aggressive treatment is referred to as the legacy effect or metabolic memory. The question of more intensive therapy and reduction in cardiovascular complications was addressed for people with type 2 diabetes of long duration in three other studies (i.e., the Action to Control Cardiovascular Risk in Diabetes [ACCORD] [3], the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation [ADVANCE] [4], the Veterans Affairs Diabetes Trial [VADT] [5]). Although the three studies utilized different patient cohorts, with varying durations of diabetes (ACCORD, 10 years; VADT, 11.5 years; and ADVANCE, 8 years) and had different treatment regimens, the results of these trials indicated that intensive glucose control did not reduce CVD events. In fact, the ACCORD trial was terminated early because an increased rate of mortality was found to be associated with intensive control of hyperglycemia (6). A higher rate of mortality for those on intensive treatment was not, however, found in ADVANCE and VADT. Recent articles from the ACCORD trial, by Pop-Busui et al. (7) and Calles Escandon et al. (8), examined whether the effects of cardiovascular autonomic neuropathy (CAN) or self-reported history of neuropathy at baseline could have been a contributor to the higher mortality risk in the intensive glycemic arm. Physiological activities of the cardiovascular system are under the control of the autonomic nervous system. Damage to the autonomic nerves that innervate the heart and blood vessels results in dysfunction in heart rate control and vascular dynamics (i.e., CAN) (9). Autonomic imbalance between the sympathetic and parasympathetic nervous systems’ regulation of cardiovascular function contributes to metabolic abnormalities (10) and significant morbidity and mortality for individuals with diabetes (11–13). Clinical manifestations of cardiovascular autonomic dysfunction (e.g., exercise intolerance, intraoperative cardiovascular liability, orthostatic tachycardia and bradycardia syndromes, silent myocardial ischemia) can result in life-threatening outcomes (11,12). In fact, the ultimate outcome of increased risk of mortality is clearly associated with the presence of autonomic dysfunction (12). Results from the ACCORD trial again confirmed the association of CAN and mortality. These investigators showed that the individuals in this trial with baseline CAN were 1.55– 2.14 times as likely to die as individuals without CAN (7). Furthermore, CAN in the presence of peripheral neuropathy was the highest predictor of CVD mortality (i.e., hazard ratio [HR] 2.95, P 0.008). Indeed, combining indexes of autonomic dysfunction have been shown to be associated with the risk of mortality (12–14). In the ACCORD trial, assessment of CAN included heart rate (reflecting overall autonomic function and cardiorespiratory fitness), a measure of heart rate variability (i.e., time domain marker of overall autonomic function–SD of normally conducted R-R intervals [SDNN]), and QT index (reflecting sympathetic function) computed from 10-s resting electrocardiograms (7). The investigators did not find that the presence of CAN appeared to contribute to the increased mortality observed in the intensive versus standard glycemic therapy group. Unfortunately, there is no consensus on the best measures for assessing CAN, thus it is possible that there was an underestimation of the impact of autonomic dysfunction based on methodological issues. It should be noted that a nonstatistically significant (P 0.07) trend toward an increased incidence of CAN (based on the development of autonomic symptoms) in patients on intensive versus standard therapy was shown in the VADT (5). Results from the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study showed that the presence of cardiac autonomic dysfunction (defined via change in heart rate from lying to standing, a measure reflecting parasympathetic dysfunction) was among the highest HR (4.33) associated with the primary events (i.e., cardiac death or nonfatal MI) (15). Just as the number and type of assessment modalities used to identify the presence of CAN affects prevalence rates and the association with mortality (12), the methods in the ACCORD trial used to assess CAN may have affected the ability to determine an association with intensive glucose therapy and mortality. It is well known that prior hypoglycemic episodes attenuate the response of the autonomic nervous system to subsequent hypoglycemia (16). Recently, it has been suggested that prior hypoglycemia could attenuate the autonomic response to specific cardiovascular stresses (17). These findings have significant clinical implications given that antecedent hypoglycemia attenuates cardiovascular autonomic control and thus could impact the use of rigorous glycemic control in individuals with diabetes. Nonetheless, antecedent hypoglycemia associated with CAN did not appear to explain the increase in mortality associated with rigorous control reported in the ACCORD study (7). It should be noted, however, that in post hoc comparisons between the intensive and standard glycemic arms in the ACCORD trial, a differential effect on mortality was found for those that self reported history of neuropathy (8). The disparity between different forms of neuropathy as a predictor of outcomes has been shown by others. In the ACCORD study (8), the Michigan Neuropathy Screening Instrument (MNSI) detected peripheral neuropathy in 4,357 patients, whereas only 2,737 reported a history of neuropathy. Of those who reported a history of neuropathy, 61% had a MNSI score that indicated neuropathy. In the DIAD study, a relationship with CVD was found with numbness and absent sensaE d i t o r i a l s