The J-Curve Limbo: How Low Can You Go?

Abstract

Patients with diabetes have a significantly higher incidence of cardiovascular events including more than double the risk of stroke compared with subjects without diabetes (1). Ample data from randomized clinical trials have shown that blood pressure (BP) lowering in hypertensive diabetes patients reduces the risk of cardiovascular morbidity and mortality. The question is to what level BP should be lowered to optimize treatment. International guidelines have recommended a BP target less than 130/80 mm Hg in patients with diabetes (2, 3). However, the evidence for this recommendation was scant and results from recent studies have refueled the debate as to how low the BP can be safely lowered. The J-curve phenomenon has been debated since Stewart in 1979 (4) reported that in patients with severe hypertension, the risk of myocardial infarction (MI) was more than 5-fold higher in individuals who had achieved a diastolic BP below 90 mm Hg compared with 100–109 mm Hg. The J-curve conceptualizes the notion that a nadir exists, below which further BP reduction incurs increased risk. A J-curve must exist (as BP approaches zero survivors will be exceedingly few), but the question is, whether the nadir occurs within clinically relevant BP ranges. The answer is neither easy nor obvious. Indeed, a number of previous large-scale intervention trials including the Hypertension Optimal Treatment (HOT) (5), Systolic Hypertension in the Elderly Program (SHEP) (6), United Kingdom Prospective Diabetes Study (UKPDS) (7), the Systolic Hypertension in Europe (SystEur) (8), and the Heart Outcomes Prevention Evaluation (HOPE) (9) studies demonstrated significant cardiovascular risk reductions (25%–40%) in diabetes patients with even modest BP lowering. However, these reductions were seen with achieved systolic blood pressures in the range of 153–139 mm Hg. Only in the normotensive part of the small Appropriate Blood Pressure Control in Diabetes trial (ABCD-NT) were systolic BP values below 130 mm Hg (128 mm Hg) achieved, and they were associated with only a reduction of stroke (10). The recent large Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial showed a significant 9% reduction in a combined macroand microvascular endpoint and significant reductions in cardiovascular and all-cause mortality, with in-treatment BP of 134 vs 140 mm Hg (11). The Action to Control Cardiovascular Risk in Diabetes—Blood Pressure-lowering arm (ACCORD-BP) trial studied the effect of even further BP reductions and found no significant reduction in a combined macrovascular endpoint with a systolic BP less than 120 mm Hg (mean 119 mm Hg) vs less than 140 mm Hg (mean 133 mm Hg) (12). Diastolic blood pressures were 64.4 vs 70.5 mm Hg, respectively. The prespecified endpoint total stroke was reduced significantly, with a yearly rate of 0.32% vs 0.53% (P .01), but the occurrence of serious adverse events was significantly increased in the intensive therapy group, 3.3% vs 1.3% (P .001). The available trial evidence thus suggests that the benefit of BP lowering flattens at lower BP levels in diabetes patients, at least for other outcomes than stroke. Yet the question remains at what BP levels the cardiovascular risk