Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high density lipoprotein level that contributes to the development of atherosclerosis. Causes may be primary (genetic) or secondary. Diagnosis is by measuring plasma levels of total cholesterol, TGs, and individual lipoproteins. Treatment is dietary changes, exercise, and lipid-lowering drugs.
There is no natural cutoff between normal and abnormal lipid levels because lipid measurements are continuous. A linear relation probably exists between lipid levels and cardiovascular risk, so many people with “normal” cholesterol levels benefit from achieving still lower levels. Consequently, there are no numeric definitions of dyslipidemia; the term is applied to lipid levels for which treatment has proven beneficial. Proof of benefit is strongest for lowering elevated low density lipoprotein (LDL) levels. In the overall population, evidence is less strong for a benefit from lowering elevated TG and increasing low high density lipoprotein (HDL) levels, in part because elevated TG and low HDL levels are more predictive of cardiovascular risk in women than in men.
HDL levels do not always predict cardiovascular risk. For example, high HDL levels caused by some genetic disorders may not protect against cardiovascular disorders, and low HDL levels caused by some genetic disorders may not increase the risk of cardiovascular disorders. Although HDL levels predict cardiovascular risk in the overall population, the increased risk may be caused by other factors, such as accompanying lipid and metabolic abnormalities, rather than the HDL level itself.
The pathophysiology of type 2 diabetes is characterized by a defect in insulin secretion, peripheral insulin resistance (decreased glucose uptake by the muscle cells and adipocytes), and increased hepatic glucose output. Insulin resistance is fundamentally important for the development and progression of type 2 diabetes, resulting in an increased demand for insulin secretion that is theorized to lead to β-cell exhaustion. The hepatic and peripheral insulin resistance in patients with type 2 diabetes contributes to hyperglycemia and is often associated with hyperinsulinemia, hypertension, and dyslipidemia. The United Kingdom Prospective Diabetes Study confirmed the need to improve glycemic control in patients with type 2 diabetes. Improvement of insulin sensitivity by regular exercise and weight loss may reduce the progression of type 2 diabetes. However, the major lifestyle changes required are difficult to achieve and sustain in everyday practice unless the patients are extremely motivated.
Therefore, drugs that ameliorate insulin resistance and improve β-cell function are relevant for the treatment of type 2 diabetes. Low HDL-cholesterol is a component of the atherogenic lipid phenotype that is characterized by obesity, insulin resistance, type 2 diabetes mellitus, dyslipidemia, and hypertension. Roughly 80- 90% of all patients with type 2 diabetes belong to this phenotype. Currently this group is estimated to include approximately 50 million patients in the US, EU and Japan. The atherogenic dyslipidemia consists of low HDL-cholesterol, elevations in triglyceride-enriched remnant particles, and normal to borderline LDL-cholesterol levels with a predominance of small, dense LDL particles. Several studies have found that raising HDL-cholesterol in patients with a low baseline serum concentration may be effective for secondary prevention of coronary heart disease (CHD): The VAHIT (Veteran's Affairs HDL Intervention Trial) using gemfibrozil; a trial of simvastatin and niacin; ARBITER 2 trial (arterial biology for the investigation of the treatment effects of reducing cholesterol) examining the effect of extended-release niacin; and the infusion of ApoA-I Milano trial. Triglyceride-lowering has also received increased attention in the recent past.
Fibrates and nicotinic acid are fairly efficacious, but the potential interaction of fibrates with statins and the safety profile of nicotinic acid are factors that limit the use of these classes considerably. Similar to HDL, triglycerides have generally been perceived less significant in the risk profile of a patient and are often only treated if very elevated, but this may change with the availability of new efficacious and safe treatment offerings.