Hypertension and Diabetic Nephropathy

It is my great pleasure to introduce this “virtual” special issue on hypertension to you: over the past few months, we have successively published a number of remarkable articles on the subject and we are proud to present here grouped together in one. The main topic of this special issue is the connection between arterial hypertension and diabetes, especially diabetic nephropathy. The link between hypertension and diabetic complications is an old one [1]. However, the target blood pressure for diabetic patients remains a hot topic since decades. The actual JNC 8 guidelines tried to make things easy by recommending a target of 140/90 mmhg for almost everybody [2].

Since the publication of the results of the SPRINT study things seem to change again [3]. One could argue, that SPRINT was exactly what the industry needed, but things are much more complicated. SPRINT was a randomized clinical trial funded by the National Institutes of Health in which 9 361 non-diabetic hypertensive patients at high risk of cardiovascular disease, were randomly assigned to be treated to a goal systolic blood pressure of less than 140 vs. less than 120 mmHg. The trial recruited hypertensive individuals in the United States who were older than 50 years of age and had never had a stroke and were not diabetic, but were either older than 75 years of age, had chronic kidney disease, or had clinical or subclinical cardiovascular disease. One year after randomization patients achieved a systolic blood pressure of 121.4 mmHg in the intensive treatment group and 136.2 mmHg in the standard treatment group, a difference that was maintained throughout the trial. SPRINT was stopped early after a median follow-up of 3.26 years because of a 25% relative risk reduction in the intensive treatment group of the primary endpoint and 27% in all-cause mortality. The beneficial results were found across all groups. However, it is noteworthy that individuals older than 75 years of age appeared to benefit more than younger subjects. The protocol required that individuals assigned to the standard therapy group who entered with lower blood pressure than goal have their antihypertensive medication down-titrated. In contrast, those assigned to the intensive therapy group would be up-titrated. No specific drug algorithm was used but ACE-inhibitors were used in the intensive therapy group more frequently. However, the rise in blood pressure after down-titration may also have contributed to the higher event rates for these conditions. Importantly, serious adverse effects related to treatment including hypotension and syncope, and acute kidney injury, as well as hyponatremia and hypokalemia were twice as frequent in the intensive therapy group than in the standard therapy group. In addition the way the blood pressure was measured is of interest: the measurements were made with the use of an automated measurement system at an office visit while the patient was seated and after 5 min of quiet rest. This has to be taken into account, when defining blood pressure goals with regard to overtreatment in the usual clinical setting, measuring blood pressure in a white coat.

Since no diabetic subjects participated in the trial, it is important therefore to compare these results with those of the ACCORD BP trial [4]. In ACCORD there was no significant benefit for the intensive therapy group targeting a systolic blood pressure of 120 vs. 140 mmHg, except for stroke that was more frequent in the standard therapy group. The differences in study outcomes between these trials are unlikely to be the result of fundamental difference in pathobiology of the cardiovascular system in diabetes compared to non-diabetic subjects. Whether some of the conclusions derived from SPRINT will be extended to diabetic subjects will have to be considered [5] [6]. However, a recent meta-analysis about the treatment of hypertension in diabetic patients raises doubts about transferring the results of SPRINT to diabetic patients in a general manner leaving us still somewhat uncertain regarding the optimal blood pressure target for diabetic patients [7].

This virtual special issue of the journal leaves the question of the optimal blood pressure target unanswered, but considers many aspects of hypertension and diabetes that are of interest and need to be taken into account in the treatment of diabetic patients. At first Stanton gives a broad overview over the incidence, pathophysiology and treatment of hypertension and diabetic nephropathy [8]. Brito Alvarez et al. then highlight the role of oxidative stress with regard to the development of diabetic nephropathy [9]. Another review providing insights from basic research and transferring them into clinical practice demonstrates the emerging role of sirtuins in the field of diabetes, hypertension and diabetic nephropathy [10]. The focus then moves to treatment of hypertension in diabetes and reveals a discussion of renin angiotensin aldosterone blockade in general [11] and the role of dual RAS blockade in detail [12]. Besides medical treatment as recently underlined by the PATHWAY-2-study [13], there might be alternative options such as yoga [14] or more invasive procedures such as renal denervation [15], which are also discussed extensively in this issue. However one should not underestimate the coincidence of other diseases leading to hypertension, such as primary aldosteronism [16] and renal artery stenosis [17], also reviewed in detail.

In summary the reader will gain insight into the pathology of diabetes, hypertension and diabetic nephropathy, possible treatment options and other diseases that have to be considered, when treating hypertension, leaving the question for an optimal blood pressure target open – for this time. Taken together the current evidence means: Neither a systolic blood pressure >140 nor <120 mmHg seems to be favorable for diabetic patients. The multiple available drugs and other interventions have to be adjusted to their side-effects, and in comparison to other treatment targets in diabetic patients, such as blood sugar lowering, life-style modifications, diet, sports etc. blood pressure lowering is by far the most effective and most important part regarding outcome and mortality. Therefore the current virtual issue “Diabetes and Hypertension” is of special interest.

• References

• 1 Lewis EJ, Hunsicker LG, Bain RP et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. NEJM 1993; 329: 1456-1462
• 2 James PA, Oparil S, Carter BL et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). Jama 2014; 311: 507-520
• 3 Group SR. Wright Jr JT, Williamson JD, Whelton KM et al. A randomized trial of intensive vs. standard blood-pressure control. NEJM 2015; 373: 2103-2116
• 4 Group AS. Cushman WC, Evans GW, Byington RP et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. NEJM 2010; 362: 1575-1585
• 5 Xie X, Atkins E, Lv J et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet 2016; 387: 435-443
• 6 Ettehad D, Emdin CA, Kiran A et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet 2016; 387: 957-967
• 7 Brunstrom M, Carlberg B. Effect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus: systematic review and meta-analyses. BMJ 2016; 352: i717
• 8 Stanton RC. Diabetic kidney disease and hypertension. Exp Clin Endocrinol Diab 2016; 124: 93-98
• 9 Brito R, Castillo G, Gonzalez J et al. Oxidative stress in hypertension: mechanisms and therapeutic opportunities. Exp Clin Endocrinol Diab 2015; 123: 325-335
• 10 Guclu A, Erdur FM, Turkmen K. The emerging role of sirtuin 1 in cellular metabolism, diabetes mellitus, diabetic kidney disease and hypertension. Exp Clin Endocrinol Diab 2016; 124: 131-139
• 11 Bolignano D, Pisano A, Coppolino G. The dark side of blocking ras in diabetic patients with incipient or manifested nephropathy. Exp Clin Endocrinol Diab 2016; 350-360
• 12 Grolla E, Bonanni L, Cutolo A et al. Disputes in the treatment of diabetic nephropathy: the dual blockade of renin-angiotensin system. Exp Clin Endocrinol Diab 2016; 361-366
• 13 Williams B, MacDonald TM, Morant S et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 2015; 386: 2059-2068
• 14 Cramer H. The efficacy and safety of yoga in managing hypertension. Exp Clin Endocrinol Diab 2016; 124: 65-70
• 15 Kuhl C, Frey N, Frank D. Recent developments and controversies in the treatment of resistant hypertension. Exp Clin Endocrinol Diab 2016; 124: 178-186
• 16 Asbach E, Williams TA, Reincke M. Recent developments in primary aldosteronism. Exp Clin Endocrinol Diab 2016; 124: 335-341
• 17 Kihm MC, Vogel B, Zeier M et al. Renal artery stenosis – are there patients who benefit from intervention?. Exp Clin Endocrinol Diab 2016; 342-349