Clinical Rules for Management of Patients With
Type 2 Diabetes

Dyslipidemia and Diabetes Mellitus: Pathophysiology and Treatment

Henry N. Ginsberg, MD
Irving Professor of Medicine
Chief, Division of Preventive Medicine and Nutrition
Columbia University College of Physicians and Surgeons
New York, New York

Diabetes mellitus, both type 1 and type 2, is associated with marked increases in the incidence and prevalence of ASCVD the major cause of death in patients with diabetes. ASCVD is affected by several risk factors, including dyslipidemia, hypertension, and hyperglycemia. It appears that in diabetes, the atherosclerotic process is qualitatively similar to that seen in individuals without diabetes, but the atherosclerosis of patients with diabetes is accelerated and more diffuse.

Diabetic dyslipidemia appears to be a very important component of the accelerated atherogenesis that occurs in patients with diabetes. In type 1 diabetes, the majority of patients do not have underlying abnormalities related to plasma lipids and lipoproteins, and the levels of TG, LDL-C, and HDL-C usually reflect control of the disease. With poor glycemic control in these patients, plasma levels of TG and LDL-C may be elevated and HDL-C low, whereas with tight control, plasma lipid levels are usually normal.

By contrast, in type 2 diabetes,
dyslipidemia appears to be a central characteristic component of the insulin resistance syndrome. In fact, patients in whom type 2 diabetes develops often have dyslipidemia in the prediabetic state. This lipid and lipoprotein phenotype is characterized by increased levels of VLDL, which is assembled and secreted by the liver and carries TG and cholesterol; decreased levels of HDL-C; and variable levels of smaller, denser, cholesterol-depleted LDL. Although the degree to which lipid and lipoprotein metabolism is abnormal in patients with type 2 diabetes is partly related to blood glucose control, it is usually not possible to normalize the dyslipidemia simply by treating hyperglycemia.

The pathophysiology underlying diabetic dyslipidemia is closely linked to insulin resistance, which in turn leads to increased release of fatty acids from adipose tissue. The presence of obesity worsens this abnormal release, exacerbating insulin resistance. The role of fatty acids, which are an energy source, in insulin resistance is under intense investigation. However, it is very clear that increased plasma levels of fatty acids increase production of VLDL, TG, and cholesterol by the liver. Increased plasma TG levels are then the "driving force" for low HDL-C and abnormal, small dense LDL. Although individuals with type 2 diabetes present with a wide range of plasma levels of TG and both HDL-C and LDL-C as a result of genetic predisposition and environmental components (eg, diet, alcohol intake, exercise), the underlying dyslipidemic pattern itself derives from the insulin-resistant state.

Treatment of diabetic dyslipidemia is a critical part of any program to reduce the risk of ASCVD. The plan must include optimal glucose control, but this is usually not sufficient, and the healthcare team cannot afford to wait too long in the hope that significant weight loss will be the answer. Glucose control, diet modification, and exercise should be instituted first; and depending on the severity of the dyslipidemia, the physician should then initiate pharmacologic therapy directed at the lipid abnormalities. More severe elevations of TG and LDL-C, or very low levels of HDL-C, require earlier and more aggressive therapy.

A reasonable approach is to use the NCEP guidelines or the newly published ADA Standards of Care guidelines for the treatment of dyslipidemia. Based on the patient’s overall risk for developing ASCVD (always very high in patients with diabetes), the optimal level of LDL-C can be chosen. This will be <130 mg/dL in all patients with diabetes mellitus and <100 mg/dL in many. LDL-C lowering can be readily achieved with an HMG-CoA reductase inhibitor (or "statin"). In both the Simvastatin Scandinavian Survival Study and the CARE study, morbidity and mortality were markedly lowered in the participants who had diabetes and received statin therapy. After the LDL-C goal is achieved, the healthcare team can review the status of TG and HDL-C. TG levels often fall during statin treatment, but HDL-C does not increase much. If TG level is >200 mg/dL and/or HDL-C is <35 mg/dL in males or <40 mg/dL in females, the addition of a fibric acid derivative, such as gemfibrozil or fenofibrate, may be considered. The combination of statin and fibrate results in improvement in all aspects of diabetic dyslipidemia, but is associated with about a 2% to 5% risk of severe myositis. The combined treatment regimen should be used after careful consideration of risks and benefits.