Diabetic dyslipidemia

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Lipid disorders assume a position of utmost importance in patients with diabetes because of the high risk of macrovascular disease in this condition. Patients with well controlled type 1 diabetes mellitus (DM) have lipoprotein concentrations similar to the background non-diabetic population. With poor control, increased concentrations of triglyceride-rich lipopro-teins are seen giving rise to hypertriglyceridemia. The most common lipoprotein abnormality in type 2 diabetes is an elevation in triglycerides and very-low-density lipoprotein (VLDL) caused by an overproduction of VLDL triglyceride. Lipoprotein lipase activity is probably decreased in type 2 diabetes, possibly as a manifestation of insulin resistance, and this may be a direct cause of elevated VLDL levels. No consistent changes in low-density lipoprotein (LDL) cholesterol are seen in type 2 diabetes, but a number of potentially atherogenic changes in LDL composition have been observed particularly a predominance of small dense LDL particles. The finding of decreased high-density lipoprotein (HDL) concentrations is very prevalent in type 2 diabetes adding to the atherogenic lipid profile of this disorder. No consistent change in lipoprotein a (Lp(a)) concentrations has been found in type 2 diabetes.

Evidence is accumulating that patients with type 2 DM benefit at least as much as non-diabetic subjects from statin therapy. Simvastatin treated patients with diabetes in the Scandinavian Simvastatin Survival Study (4S Trial) exhibited reductions in major coronary events and revascularization procedures of 42% and 48%, respectively. In the Cholesterol and Recurrent Events Trial (CARE), pravastatin therapy reduced the incidence of recurrent coronary heart disease (CHD) events (CHD death, non-fatal myocardial infarction, coronary artery bypass graft and revascular-ization) by 25%. There were 586 patients with diabetes in this study. In the Veterans Affairs HDL Intervention Trial (VA-HIT), gemfibrozil was used as secondary prevention. Patients had documented CHD with low HDL cholesterol levels and the aim was to study the effect of gemfibrozil on the risk of recurrent CHD events. About half of the patients had either type 2 DM or abdominal obesity and hyperinsuline-mia (insulin resistance/metabolic syndrome). Gemfi-brozil reduced the risk of myocardial infarction and CHD-related mortality by 22% without any lowering of LDL cholesterol.

The Collaborative Atorvastatin Diabetes Study (CARDS) included 2838 patients with type 2 diabetes and no documented previous history of cardiovascular disease (CVD) with at least one of the following features: retinopathy, albuminuria, current smoking or hypertension. Patients had an LDL cholesterol concentration of 4.14mmol/l (160mg/dl) or lower. As compared to a placebo, addition of atorvastatin 10 mg daily led to a 37% reduction in major cardiovascular events and reduced the risk of stroke by 48% with overall a highly statistically significant reduction in the composite primary end point of acute coronary events, coronary revascularization and stroke. A 27% fall in all-cause mortality was also observed, however, this just failed to reach statistical significance.

Patients with type 2 DM are thought to be at the same risk of a CVD event as non-diabetic patients with existing CVD. Lipid-lowering therapy is likely to be as clinically effective and cost-effective in patients with type 2 diabetes who have not yet sustained a cardiovascular event as in non-diabetic subjects with documented CVD.

All adult patients with diabetes should have a fasting lipid profile to assess their lipid status and to search for any lipid disorder that necessitates lipid-lowering treatment. How often this should be done is debatable. The American Diabetes Association (ADA) suggests screening for hyperlipidemia on an annual basis. Lifestyle modification focusing on the reduction of saturated fat and cholesterol intake, weight loss (where indicated) and increased physical activity is recommended for diabetic patients with hyperlipi-demia and has been shown to improve the lipid profile. The ADA position statement on lipid disorders is as follows.

Individuals with diabetes who are over the age of 40 years with a total cholesterol > 135mg/dl (3.5mmol/l) without overt CVD should be treated with a statin to achieve an LDL cholesterol reduction of 30-40% regardless of baseline LDL level, and with a primary goal of reducing LDL cholesterol to < 100mg/dl (2.6mmol/l). Those individuals less than 40 years of age without overt CVD but with cardiovascular risk factors or long duration of diabetes should have lipid-lowering therapy to reduce LDL cholesterol to <100 mg/dl (2.6 mmol/l) if this target is not reached by lifestyle modification alone. Patients with diabetes and overt CVD should all be treated with a statin with an option of a lowered LDL cholesterol target of <70mg/dl (1.8mmol/l). Triglycerides should be lowered to <150 mg/dl (1.7 mmol/l) and HDL cholesterol should be raised to >40 mg/dl (1.15 mmol/l). In women, an HDL target of > 50 mg/dl should be considered.

High LDL levels should be treated with a statin (hydroxymethylglutaryl-coenzyme A reductase inhibitor) examples of which include simvastatin, atorvastatin, pravastatin and rosuvastatin. The typical dyslipidemia of type 2 DM of raised triglycerides and low HDL cholesterol may respond better to a fibrate, such as fenofibrate, bezafibrate or gemfibrozil. Fibrates bind to the peroxisome proliferator-activated receptor (PPARa) ultimately leading to an interaction with several genes critical to the control of lipid metabolism. Ezetimibe is an extremely potent and specific inhibitor of dietary and biliary cholesterol absorption. In one study, compared to placebo, ezetimibe produced a 15% reduction in total cholesterol, a 20% reduction in LDL cholesterol, an 8% reduction in triglycerides and a 3% rise in HDL cholesterol.

Combination therapy such as statin/fibrate and statin/ezetimibe may be necessary to achieve lipid targets, although more careful monitoring is required as such combinations are likely to be associated with known side-effects of some lipid-lowering agents such as myositis.

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