Optimal SBP targets for the prevention of progression of type 2 diabetic nephropathy

Cardiovascular disease induced by the coexistence of hypertension and type 2 diabetes mellitus devastates both developed and emerging countries because of the current high worldwide prevalence of the two conditions, which are linked by common epidemiological, pathophysiological, and clinical nexus. Between 70 and 80% of the patients with diabetes mellitus have hypertension, whereas diabetes mellitus is found in up to 40% of hypertensive patients, especially in older patients. The most worrying fact is that the prevalence of the two diseases is increasing for different reasons and this, added to the progressive aging of the population, increased longevity and greater survival because of therapeutic advances, makes the association between hypertension and type 2 diabetes one of the greatest future public health challenges in the overwhelming majority of countries [1–6]. Type 2 diabetes may be considered a cardiovascular disease inducing macrovascular and microvascular complications. Among the latter, diabetic nephropathy is a very severe complication and is the single leading cause of end-stage renal disease (ESRD) in developed countries. Microalbuminuria may be the earliest silent manifestation of ESRD, followed by progression to overt proteinuria and a reduced glomerular filtration rate (GFR). In addition to glycemic control and treatment of the associated dyslipidemia, antihypertensive therapeutic strategies in patients with diabetic nephropathy require strict blood pressure (BP) control to delay the progression of microalbuminuria and overt proteinuria, and the progressive reduction in the GFR [7–9]. Given that the relationship between BP levels and cardiovascular risk is continuous, it was assumed for many years that the aim of antihypertensive treatment should be to reduce BP to the lowest values tolerated by the patient, particularly in patients at high risk [1,10–13]. In patients with diabetic nephropathy and microalbuminuria or overt proteinuria, the rate of progression of renal disease is closely related to BP down to a level of at least 130 mmHg systolic and 70 mmHg diastolic [14]. Therefore, it was thought that more aggressive treatment of hypertension and even lower BP targets would better protect patients with diabetic nephropathy from disease progression to ESRD. For this reason, the 2003 and 2007 European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines [1,10], the Joint National Committee (JNC)-7 report [11], the 2004 British guidelines [12], and the 2004 Canadian guidelines [13] all recommended that office BP should be reduced to less than 130/80 mmHg whenever possible as the primary goal of antihypertensive treatment in diabetic patients, and to less than 125/75 mmHg in patients with renal failure and proteinuria. The paradigm ‘the lower the better’ was accepted and recommended by guidelines and followed by millions of physicians worldwide. However, these recommendations were not based on the best evidence from randomized clinical trials designed to analyze this issue, but rather from observational, retrospective, post-hoc analyses or open studies. For this reason, after a careful review of the evidence, the 2013 ESH/ESC Hypertension Guidelines [3] were less stringent, advising an office BP reduction to less than 140/85 mmHg in diabetic patients. As suggested by the guidelines, there is no Class I/Level A evidence that justifies the fundamentally empirical old recommendation. However, for patients with diabetic nephropathy and overt proteinuria, the ESH/ESC guidelines suggest that office BP values less than 130 mmHg may be pursued, provided that changes in the estimated GFR are monitored. The 2014 JNC-8 report recommended an even more conservative target of less than 140/90 mmHg for diabetic patients [15]. At the same time, and considering similar available evidence, both the 2013 American Diabetes Association (ADA) guidelines [6] and the 2014 American Society of Hypertension/International Society of Hypertension (ASH/ISH) guidelines [4] still recommended a target of less than 130/80 for patients with diabetic nephropathy. In summary, there is no general consensus on the optimal office BP target for preventing or delaying the progression of diabetic nephropathy. In this issue of the Journal of Hypertension, a study of a Japanese population with hypertension and diabetic nephropathy by Ushigome et al.[16] presents very interesting data on this topic. The aim of the study was to evaluate the association between home SBP and the progression of diabetic nephropathy and determine the optimal home SBP levels to prevent the onset or progression of diabetic nephropathy. The study was retrospective and based on data obtained from a cohort of 677 patients with diabetes mellitus included in the KAMOGAWA-Home Blood Pressure study, in which home (self) BP monitoring was used. Diabetic nephropathy was graded in three stages depending on urinary albumin excretion (UAE): normoalbuminuria (UAE <30 mg/g Cr); persistent albuminuria of 30–300 mg/g Cr; and persistent albuminuria of ≥300 mg/g Cr. The change from any stage of baseline UAE to a higher stage during the 2-year follow-up was defined as progression. Using logistic regression models, associations between the progression of diabetic nephropathy and home SBP levels or other factors potentially related to nephropathy were evaluated. The study used the methodology recommended by the Japanese guidelines [17] for home BP monitoring: patients performed triple morning and evening BP measurements in the seated position for 14 consecutive days, and the mean of three morning and evening measurements for 14 consecutive days was taken as the home BP. Morning measurements were made within 1 h of awakening, before eating breakfast or taking any drugs, and after at least 5 min of rest. Evening measurements were obtained in a similar manner just before going to bed. Of the 677 patients, only 86 (13%) had progression of diabetic nephropathy. Adjusted odds ratios (95% confidence interval) for progression of diabetic nephropathy in patients with morning SBP of 120–129 mmHg [2.725 (1.074–6.917), P = 0.035], 130–139 mmHg [3.703 (1.519–9.031), P = 0.004], and at least 140 mmHg [2.994 (1.182–7.581), P = 0.021] were significantly higher than in patients with morning SBP less than 120 mmHg in the multiple logistic analyses, revealing for the first time that the risk for progression of diabetic nephropathy in patients with morning home SBP of at least 120 mmHg was significantly higher than in patients with morning home SBP less than 120 mmHg, independently of other known risk factors for nephropathy such as age, sex, duration of diabetes mellitus, BMI, hemoglobin A1C, total cholesterol, creatinine, smoking status, and alcohol consumption. In addition, no J or U-shaped curve of the relationship between home BP levels and the progression of diabetic nephropathy was observed. Interestingly, the incidence of other cardiovascular events, such as coronary artery disease or heart failure, did not increase in patients with home SBP less than 120 mmHg compared with patients with home SBP more than 120 mmHg. The usefulness of home BP monitoring is well established and has been shown to have greater predictive power for target organ damage compared with office SBP [18]. However, there is no robust evidence for optimal home SBP control in the prevention of the onset or progression of diabetic nephropathy. Despite its limitations, this study adds new information on the subject, and is the first to show an association between home SBP and the onset or progression of diabetic nephropathy in patients with normoalbuminuria or persistent albuminuria of 30–300 mg/g Cr. Although the accepted corresponding values between home and office SBP to define hypertension are 135 and 140 mmHg, respectively, the corresponding office BP values for a home SBP target less than 120 mmHg remain unknown, thus limiting the interpretation of the results. The new evidence reported by this study is not robust enough to change the guidelines on SBP targets for diabetic nephropathy, but should encourage interested researchers to design and perform randomized clinical trials aimed at shedding light on the optimal SBP target in this group of patients and using home BP monitoring, which is much more reliable than office BP values. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.

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