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Randomized Controlled Trial
. 2016 Nov;82(5):1351-1357.
doi: 10.1111/bcp.13062. Epub 2016 Aug 18.

Blood Pressure-Lowering Effects of Sulodexide Depend on Albuminuria Severity: Post Hoc Analysis of the Sulodexide Microalbuminuria and Macroalbuminuria Studies

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Free PMC article
Randomized Controlled Trial

Blood Pressure-Lowering Effects of Sulodexide Depend on Albuminuria Severity: Post Hoc Analysis of the Sulodexide Microalbuminuria and Macroalbuminuria Studies

Rik H G Olde Engberink et al. Br J Clin Pharmacol. .
Free PMC article

Abstract

Aims: It has been suggested that sulodexide is able to lower blood pressure (BP). This may be attributed to its ability to restore the endothelial surface layer (ESL). As ESL perturbation is known to be related to the degree of kidney damage, we investigated whether albuminuria, reflecting ESL status, modified the BP-lowering potential of sulodexide.

Methods: A post hoc analysis of the double-blind, randomized, placebo-controlled sulodexide microalbuminuria (Sun-MICRO) and macroalbuminuria (Sun-MACRO) studies, including 1056 microalbuminuric and 843 macroalbuminuric subjects with type 2 diabetes receiving maximal tolerated renin-angiotensin-aldosterone system inhibitor therapy, was carried out. We compared the effect of placebo and sulodexide on systolic BP (SBP) among albuminuria groups.

Results: Analysis of covariance, including data from both trials, showed that baseline urine albumin-to-creatinine ratio (UACR) was the only modifier of the SBP response (interaction with treatment P = 0.001). In subjects with an UACR >1000 mg g-1 , sulodexide lowered SBP by 4.6 mmHg [95% confidence interval (CI) 3.6, 5.6; P < 0.001] compared with placebo, whereas a 2.3 mmHg (95% CI 0.9,3.7; P = 0.001) reduction was seen in subjects with a UACR of 300-1000 mg g-1 . Sulodexide did not lower SBP in subjects with a UACR <300 mg g-1 (-0.2 mmHg, 95% CI -0.8, 0.5; P = 0.60). SBP-lowering effects were not accompanied by changes in body weight.

Conclusion: The BP-reducing potency of sulodexide is modified by the degree of albuminuria in subjects with type 2 diabetes. As ESL status deteriorates with increasing albuminuria and nephropathy severity, this suggests that ESL restoration may represent a new target for BP treatment in subjects with diabetic nephropathy.

Keywords: albuminuria; blood pressure; cardiovascular; glycosaminoglycan; hypertension; sulodexide.

Figures

Figure 1
Figure 1
Sulodexide reduced systolic blood pressure (SBP) in patients with macroalbuminuria. Estimated marginal means (standard error of the mean) of SBP at baseline and after treatment with sulodexide and placebo in the sulodexide microalbuminuria (Sun‐MICRO) (A) and sulodexide macroalbuminuria (Sun‐MACRO) (B) trials. In patients with microalbuminuria, SBP was identical in both groups (P = 0.88). In macroalbuminuric patients, SBP was, on average, 2.4 mmHg lower [95% confidence interval (CI) 0.4, 4.4; P = 0.020) in the sulodexide group (n = 204) when compared with placebo (n = 198). We used a general linear model repeated measures test, with correction for baseline SBP for calculations
Figure 2
Figure 2
The blood pressure (BP)‐lowering potential of sulodexide depends on albuminuria severity. (A) Regression lines and 95% confidence intervals (CIs) of the analysis of covariance (ANCOVA) demonstrating the significant interaction (P = 0.001) between the baseline urine albumin‐to‐creatinine ratio (UACR) and treatment arms (placebo vs. sulodexide). The regression line slopes of placebo (P < 0.001) and sulodexide (P < 0.001) were both significantly different from zero. (B) Quantitative analysis of the results of the ANCOVA, showing that subjects with an UACR >1000 mg g–1 benefit most from sulodexide treatment in terms of BP (mean and 95% CI). Sulodexide resulted in a 2.0 mmHg (95% CI −2.6, −1.3) systolic BP (SBP) reduction, while placebo increased SBP by 2.5 mmHg (95% CI 1.9, 3.3). In the group with an UACR between 300–1000 mg g–1, sulodexide decreased BP by 0.8 mmHg (95% CI −1.8, 0.2) and placebo increased BP by 1.6 mmHg (95% CI 0.6, 2.5), while subjects with an UACR <300 mg g–1 had an identical BP response (0.2 mmHg, 95% CI −0.5, 0.8; P = 0.60)

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