Cutaneous microangiopathy is suspected to play a role in the pathogenesis of diabetic foot ulcers (1). Because microcirculatory flow is regulated in part by the endothelium and prior studies of the coronary microcirculation showed significant improvement in endothelium-dependent vasodilatory responses with lipid-lowering therapy (2), we examined the effect of lipid lowering on endothelial function in cutaneous microcirculation in patients with type 2 diabetes.
Patients aged 21–80 years with diabetes and LDL cholesterol >3.4 mmol/l were randomized in a double-blind fashion to treatment with either simvastatin 40 mg daily or placebo and followed for 3 months after randomization. All patients received dietary counseling with regard to lowering LDL, but no attempt was made to alter glycemic control. The study was approved by the Institutional Review Board of the Mount Sinai School of Medicine, and informed consent was obtained before enrollment.
Cutaneous microcirculatory flow from the same site of the dorsum of the foot was measured with the Periflux System PF3 (Perimed, Järfälla, Sweden) at every visit in all patients. The flow response to heating was recorded at a skin temperature of 32°C and then at 44°C (the skin temperature at which maximal flow is achieved) (3). Endothelium-dependent and -independent microcirculatory responses were recorded using acetylcholine (ACh) and sodium nitroprusside (SNP) iontophoresis, respectively (PeriIont Micropharmacology System PF380; Perimed). All flow measurements were performed with subjects in a fasting state. Normalized values of flow (the ratio of flow in response to ACh or SNP to the flow reaction to heating to 44°C) were used for comparisons between the groups. When appropriate, Mann-Whitney U and Wilcoxon tests were used for group comparisons. P < 0.05 was considered significant.
A total of 18 diabetic patients were enrolled in the study. Five patients dropped out for logistical reasons, none because of adverse reactions. Of the 13 patients who completed the study, 7 were randomized to the simvastatin group (all women; 5 African-Americans and 2 Latinos) and 6 to the placebo group (5 women; 5 African-Americans and 1 Latino). The subjects were elderly (61 ± 6 vs. 60 ± 5 years of age, simvastatin versus placebo, respectively), obese (BMI: 33 ± 5 vs. 32 ± 5 kg/m2), and had a relatively long duration of diabetes (11 ± 8.5 vs. 6.7 ± 3.8 years). Diabetes was poorly controlled (HbA1c 9.3 ± 1.7 vs. 9.1 ± 2.5%) and LDL cholesterol levels were elevated (4.6 ± 0.5 vs. 4.2 ± 0.6 mmol/dl) in both groups. The two groups were not significantly different in any of the above parameters. Endothelium-dependent and -independent responses (ACh: 0.7 ± 0.6 vs. 0.8 ± 0.3; SNP: 1.6 ± 1.0 vs. 1.5 ± 1.0) were also similar at baseline. LDL cholesterol was significantly reduced at 3 months in the simvastatin group (from 4.6 ± 0.5 to 2.8 ± 0.6 mmol/dl, P < 0.01) but not in the placebo group (from 4.2 ± 0.6 to 3.8 ± 0.6 mmol/dl, P = NS). There was no significant change in HbA1c over the course of the study. Endothelium-dependent vasodilatation remained unchanged in both the simvastatin and the placebo groups (ΔACh: −0.1 ± 1 vs. 0.3 ± 1.1, P = NS; ΔSNP: −0.6 ± 1.4 vs. 0.2 ± 1.4, P = NS).
The main result of this study is the lack of beneficial effect of lipid lowering on skin microcirculation vasomotion in this population of poorly controlled diabetic patients. Neither endothelium-dependent nor -independent responses were significantly improved in the treated group, although total and LDL cholesterol were significantly lowered by simvastatin. A similar lack of improvement in endothelial function in a large conduit artery (brachial artery) was recently reported in type 2 diabetic patients treated with simvastatin (4). Our results extend this finding to the microcirculation. This negative result may be explained by several factors. First, a longer follow-up may be necessary to demonstrate significant improvement in cutaneous microcirculation in the population of patients with a long duration of diabetes. Second, glycemic control may be needed to achieve beneficial effects of LDL lowering on endothelial function. This hypothesis is further supported by the recent finding that glycated LDL from diabetic patients reduces endothelial cell nitric oxide synthesis and bioactivity (5). Therefore, in our study, we speculate that glycated LDL may have interfered with endothelium-dependent vasorelaxation in both groups. Finally, it could not be excluded that the long duration of diabetes may have induced diabetic neuropathy, which may affect flow response to ACh (6). However, this possibility is less likely because we systematically excluded patients with neuropathy on physical examination.
In summary, LDL lowering does not appear to improve endothelial function in the microcirculation without adequate glycemic control. Further studies are needed to assess the benefit of optimal control of diabetes in conjunction with lipid lowering on endothelium-dependent microcirculation vasomotion.
Article Information
This work was supported in part by a grant (5MO1-RR-00071) for the Mount Sinai General Clinical Research Center from the National Center for Research Resources, National Institutes of Health, and by a Medical School Grant from Merck.
References
Address correspondence to Robert A. Phillips, MD, PhD, FACC, Director, Department of Medicine, Lenox Hill Hospital, 100 East 77th St., New York, NY 10021. E-mail: [email protected].
L.G.N. holds stock in Merck. R.A.P. currently does limited consulting for and has a research grant with Merck.
