Vascular and Metabolic Effects of Combined Therapy With Ramipril and Simvastatin in Patients With Type 2 Diabetes

Abstract

Mechanisms underlying biological effects of statin and angiotensin-converting enzyme inhibitor therapies differ. Therefore, we compared vascular and metabolic responses to these therapies either alone or in combination in patients with type 2 diabetes. This was a randomized, double-blind, placebo-controlled crossover trial with 3 treatment arms (each 2 months) and 2 washout periods (each 2 months). Fifty patients with type 2 diabetes were given simvastatin 20 mg and placebo, simvastatin 20 mg and ramipril 10 mg, or ramipril 10 mg and placebo daily during each 2-month treatment period. Ramipril alone or combined therapy significantly reduced blood pressure when compared with simvastatin alone. When compared with ramipril alone, simvastatin alone or combined therapy significantly improved the lipoprotein profile. All 3 treatment arms significantly improved flow-mediated dilator response to hyperemia and reduced plasma levels of malondialdehyde relative to baseline measurements. However, these parameters were changed to a greater extent with combined therapy when compared with simvastatin or ramipril alone (P<0.001 by ANOVA). When compared with simvastatin or ramipril alone, combined therapy significantly reduced high-sensitivity C-reactive protein levels (P=0.004 by ANOVA). Interestingly, combined therapy or ramipril alone significantly increased plasma adiponectin levels and insulin sensitivity relative to baseline measurements. These changes were significantly greater than in the group treated with simvastatin alone (P<0.015 by ANOVA). Ramipril combined with simvastatin had beneficial vascular and metabolic effects when compared with monotherapy in patients with type 2 diabetes.

Simvastatin Improves Flow-Mediated Dilation but Reduces Adiponectin Levels and Insulin Sensitivity in Hypercholesterolemic Patients

“…Further, there were no significant correlations between endothelial dysfunction and metabolic parameters. By contrast, in previous studies with fenofibrate, ramipril, angiotensin II receptor blockers, or efonidipine, improvement in endothelial dysfunction was accompanied by simultaneous improvement in insulin sensitivity and increased adiponectin levels (15)(16)(17)(18)(19). Taken together, these results suggest that not all mechanisms for improving endothelial dysfunction are tightly coupled to metabolic homeostasis.…”

“…Assays for lipids, glucose, and plasma adiponectin were performed in duplicate by ELISA (R&D Systems, Minneapolis, MN) for high-sensitivity C-reactive protein (CRP) levels by latex agglutination [CRP-Latex(II); Denka-Seiken, Tokyo, Japan], and assays for plasma insulin levels were performed by immunoradiometric assay (INSULIN-RIABEADII; SRL, Tokyo, Japan) as described previously (15)(16)(17)(18)(19). The interassay and intra-assay coefficients of variation were Ͻ6%.…”

“…The Quantitative I n s u l i n -S e n s i t i v i t y C h e c k I n d e x (QUICKI), a surrogate index of insulin sensitivity based on fasting glucose and insulin levels, was calculated as follows (insulin is expressed in microunits per milliliter and glucose in milligrams per deciliter): QUICKI ϭ 1/[log(insulin) ϩ log(glucose)] (20). Imaging studies of the right brachial artery were performed using an ATL HDI 3000 ultrasound machine (ATL-Philips, Bothell, WA) equipped with a 10 MHz linear-array transducer, based on a previously published technique (15)(16)(17)(18)(19).…”

Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Inflammation

“…In hypertensives, 12 weeks of therapy of both enalapril and nifedipine tended to similarly reduce ICAM-1 and E-selectin, while only nifedipine reduced von Willebrand factor Ramipril (vs placebo) Koh et al (2005) [239] In hypercholesterolemic patients with type 2 diabetes ramipril (in combination with simvastatin) reduced significantly CRP and increased adiponectin. [240] In normotensive subjects with successfully repaired coarctation of the aorta (SCR) ramipril 5 mg/day for 4 weeks improved endothelial function (p < 0.001) and decreased the expression of the cytokine IL-6 (p < 0.05), sCD40L (p < 0.01) and sVCAM-1 (p < 0.01), but failed to affect serum levels of C-reactive protein.…”

“…The link between ACEi and statin concurrent therapy was tested by Koh in 2005 [239], assuming that because the impact of simvastatin and ramipril therapies on NO bioactivity, oxidant stress, inflammation, endothelial function, and insulin resistance may differ, the combined therapy may have additive beneficial effects that are greater than those observed with either simvastatin or ramipril therapy alone in hypercholesterolemic patients with type 2 diabetes. This was a randomized, double-blind, placebo-controlled crossover trial with 3 treatment arms (each 2 months) and 2 washout periods (each 2 months).…”