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Improvement in Endothelial Dysfunction With LDL Cholesterol Level <80 mg/dl in Type 2 Diabetic Patients

¹ Division of Endocrinology and Metabolism and the
² Division of Cardiology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan

Type 2 diabetes is associated with a marked increase in the risk of coronary heart disease (CHD). Furthermore, a 7-year follow-up study showed that diabetic patients without previous myocardial infarction have as high a risk of myocardial infarction as nondiabetic patients with previous myocardial infarction (1). All of these observations indicate the importance of aggressive cholesterol lowering in diabetic patients. We have previously shown that type 2 diabetic Chinese subjects are characterized by impaired endothelial-dependent and -independent brachial arterial vasoactivity when compared with nondiabetic individuals (2). However, we failed to demonstrate that treatment with simvastatin (10 mg daily) had beneficial effects on brachial arterial vasoreactivity in type 2 diabetic subjects, despite a 26–35% reduction in LDL cholesterol levels. Because coronary angiographic trials suggested that more intensive LDL cholesterol lowering (<100 mg/dl) is associated with regression or arrest of progression of coronary lesions compared with moderate LDL cholesterol reduction (3), we tested the hypothesis that aggressive lowering of LDL cholesterol would be associated with more beneficial endothelial vasoreactivity in type 2 diabetic subjects.

We recruited 12 type 2 diabetic subjects with hypercholesterolemia (8 men and 4 women, mean age 64 ± 2 years [mean ± SEM], mean HbA_1c 8.1 ± 0.1%). After 6 weeks on a lipid-lowering dietary advisory period, 20 mg simvastatin every night was prescribed. If a participant’s LDL cholesterol concentration still exceeded 100 mg/dl, the dose of simvastatin was doubled 4 weeks later. The total treatment period was 12 weeks. Brachial artery vasoactivity was evaluated as described previously (2). After determination of baseline arterial diameter and blood flow velocity, a blood pressure cuff was inflated to a pressure of 200 mmHg and maintained for 5 min. The brachial artery was scanned before and immediately after cuff deflation and for 20 min thereafter. Twenty minutes later, nitroglycerin (0.6 mg) was administered sublingually and measurement was continued for an additional 20 min.

In response to simvastatin treatment (20 mg in eight subjects and 40 mg in four subjects), total cholesterol decreased from 229 ± 9 to 158 ± 4 mg/dl (P < 0.001), LDL cholesterol values decreased from 144 ± 9 to 75 ± 4 mg/dl (P < 0.001), fasting plasma triglyceride did not change (226 ± 22 vs. 202 ± 18 mg/dl, P = 0.530), and HDL cholesterol levels increased marginally (40 ± 2 vs. 43 ± 2 mg/dl, P = 0.078). In particular, a significant improvement of peak flow–mediated (endothelium-dependent) brachial arterial dilation was observed (5.6 ± 1.7 vs. 13.6 ± 2.6%, P < 0.028) only in subjects with LDL cholesterol <80 mg/dl (n = 6, range 57–76 mg/dl) but not in patients (4.4 ± 1.8 vs. 8.2 ± 1.6%, P = 0.173) with a higher LDL cholesterol level (n = 6, range 81–92 mg/dl) at the end of the study. Endothelium-independent dilation of the brachial artery did not change in either group.

Recent evidence indicated that, in addition to their lipid-lowering effects, statins carry a wide variety of vascular protection effects including vasodilation, antithrombosis, antioxidation, antiproliferation, anti-inflammation, and plaque stabilization (4). Also, previous studies have demonstrated that lipid-lowering therapy beneficially alters endothelial dysfunction in nondiabetic subjects with hypercholesterolemia and coronary atheroslcerosis (5). However, we failed to show similar beneficial effects in response to simvastatin treatment in type 2 diabetic subjects (2). Recently, the level of cholesterol, which should be set as a goal of LDL cholesterol lowering, has become a topic of debate. The Post Coronary Artery Bypass Graft Trial demonstrated that subjects with aggressive LDL cholesterol lowering (decreased to 95 ± 2 mg/dl) had significantly less angiographic progression and fewer future combined events than those with less aggressive control (decreased to 134 ± 2 mg/dl) (3). Tamai et al. (6) also showed that a large magnitude reduction of LDL cholesterol by apheresis led to a significant benefit in vasomotor activity. Shechter et al. (7) reported that better dilation of flow-mediated vasoreactivity occurred in coronary heart disease subjects whose LDL cholesterol was <100 mg/dl when compared with those whose LDL cholesterol was >100 mg/dl. Our study demonstrates that aggressive LDL cholesterol lowering to <80 mg/dl by simvastatin led to improvement of endothelial-dependent vasoreactivity in type 2 diabetic subjects with hypercholesterolemia. The magnitude of percent flow–mediated brachial vasoreactivity (14%), as determined by Shechter et al. (7), is very similar to that observed in the present study (13.6%). Our results provide a preliminary report stating that more aggressive LDL cholesterol lowering is necessary to improve endothelial function in type 2 diabetic subjects. However, it remains to be demonstrated whether lowering LDL cholesterol to <80 mg/dl will result in better cardiovascular outcome in type 2 diabetic individuals.

ACKNOWLEDGMENTS

Supported in part by a grant from the National Science Council, Taiwan ROC (NSC 89-2314-B075A-026) and from Merck Sharp and Dohme, Taiwan Branch.

FOOTNOTES

Address correspondence and reprint requests to Wayne Huey-Herng Sheu, MD, PhD, Taichung Veterans General Hospital, No. 160, Section 3, Chung-Kang Rd., Taichung 407, Taiwan. E-mail: whhsheu{at}vghtc.vghtc.gov.tw.

References

1. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M: Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 339:229–234, 1998[Abstract/Free Full Text]
   
2. Sheu WHH, Juang B-L, Chen Y-T, Lee W-J: Endothelial dysfunction is not reversed by simvastatin treatment in type 2 diabetic subjects with hypercholesterolemia (Letter). Diabetes Care 22:1224–1225, 1999[Free Full Text]
   
3. The Post Coronary Artery Bypass Graft Trial Investigators: the effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 336:153–162, 1997[Abstract/Free Full Text]
   
4. Davignon J, Laaksonen R: Low-density lipoprotein-independent effects of statins. Curr Opio Lipidology 10:543–559, 1999
   
5. Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP, Ganz P: The effect of cholesterol-lowering and anti-oxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med 332:488–493, 1995[Abstract/Free Full Text]
   
6. Tamai O, Matsuoka H, Itabe H, Wada Y, Kohno K, Imaizumi T: Single LDL apheresis improves endothelium-dependent vasodilation in hypercholesterolemic humans. Circulation 95:76–82, 1997[Abstract/Free Full Text]
   
7. Shechter M, Sharir M, Labador MJP, Forrester J, Merz CNB: Improvement in endothelium-dependent brachial artery flow-mediated vasodilation with low-density lipoprotein cholesterol levels <100 mg/dl. Am J Cardiol 86:1256–1259, 2000 [Medline]
   

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