Impact of renin angiotensin system blockade on night to day blood pressure ratio in diabetic nephropathy

Sir, Elevated systemic blood pressure is a risk factor for progression of diabetic nephropathy. Ambulatory blood pressure measurements offer additional risk stratification compared to office blood pressure in patients with hypertension [1]. In addition, an abnormal diurnal blood pressure pattern characterized by an elevated night to day ratio is found more commonly in diabetic patients and, as reviewed by Miller et al. [2], is associated with poor renal outcome. The renin angiotensin system (RAS) is involved in both initiation and progression of diabetic nephropathy and blocking this system with ACE-inhibitors (ACE-I) and/or angiotensin II receptor blockers (ARBs) improves kidney survival and prognosis. Miller et al. [2] reported that treatment with enalapril (0.1 mg/kg BID) corrects the abnormally high night to day blood pressure ratio found in 10 uncomplicated adolescents, and this could contribute to the beneficial renoprotective effects of RAS blockade. In this letter, we further investigate whether RAS blockade corrects an abnormal 24 h blood pressure pattern by presenting data on the short-term effects of single and dual blockade of the RAS on a 24 h blood pressure profile and a night to day blood pressure ratio in type 1 diabetic patients with diabetic nephropathy. Our data are a post-hoc analysis of three earlier studies [3–5]. As described previously [3], we performed a randomized, double blind, cross-over trial, in which 18 patients received 8 weeks of placebo, benazepril 20 mg once daily, valsartan 80 mg once daily and a combination of benazepril 20 mg and valsartan 80 mg once daily in random order [3]. The main findings were: (1) mono-therapy with ACE-I or ARBs treatment was equally effective with regard to antialbuminuric and antihypertensive effects; (2) dual blockade of the RAS caused a further reduction in albuminuria of 43% and 7/6 mmHg in 24 h blood pressure compared with both mono-therapies; (3) night to day ratio of 24 h blood pressure on each treatment is shown in Table 1. A post-hoc power calculation estimated a power in each study of ∼0.80 to detect a difference of 0.05 in night to day ratio with a significance level of 0.05. Night to day ratio of 24 h blood pressure in type 1 diabetic patients with diabetic nephropathy—relation to RAS blockade aMedian (range). bMean Night/day ratio not statistically different between groups. Night to day ratio of 24 h blood pressure in type 1 diabetic patients with diabetic nephropathy—relation to RAS blockade aMedian (range). bMean Night/day ratio not statistically different between groups. In agreement, when looking at the fraction of patients with night to day blood pressure ratio above the median on placebo treatment (>0.91), we found no changes in the night to day ratio on RAS blockade. Furthermore, in two other studies demonstrating that dual blockade of the RAS lowered albuminuria 25–37%, reduced 24 h blood pressure 8/4–5 mmHg and raised plasma renin compared with ACE-I alone in type 1 diabetic patients with nephropathy, we found no changes in the night to day blood pressure ratio (Table 1) [4,5]. Since, no placebo treatments were included, no data of the effects of single agent blockade of the RAS on blood pressure profile are available in these latter studies. The discrepancy between treatment effects on night to day blood pressure ratio in our complicated diabetic patients and the uncomplicated patients included in the study by Miller et al. [2] may well reflect the fact that the causes of abnormalities in blood pressure variation are different, leading to different degrees of reversibility. In conclusion, our short term data indicates that commonly used ACE-I and ARBs, given once daily in the morning, reduce both night and day blood pressure, but do not influence the night to day ratio, in type 1 diabetic patients with diabetic nephropathy. Specific beneficial effects of RAS blockade are likely to involve local renal effects, and seem unrelated to an impact on 24 h blood pressure profile. However, a change in timing of RAS blockade to night time dosing is worth investigating. Conflict of interest statement. P.K.J has received a lecture fee from Sanofi-Avensis. H.H.P. has been a consultant for Sanofi-Avensis, Merck, Pfizer, Novartis, Amgen and has received a grant from Sanofi-Avensis and Merck and lecture fees from the above mentioned pharmaceutical companies. 1Steno Diabetes Center Gentofte, Denmark2 Faculty of Health Science University of Aarhus Denmark