Role of combination therapy in diabetes and dyslipidemia

Despite the known pharmacologic effects of fibrates and nicotinic acid in ameliorating the underlying defects of diabetic dyslipidemia (increased triglyceride-rich lipoproteins; low HDL cholesterol; small, dense LDL particles), the role of combining these agents with statins remains uncertain and further clinical trials are needed. Trials like the VA-HIT and DAIS are supportive of the potential of adding fibrates to statins because combined lipid disorders are common in patients who have insulin resistance and type 2 diabetes. In short-term studies, statins and fibrates were more effective in normalizing all lipid abnormalities than either agent alone without significant risk for adverse events, including myositis [51,52]. Caution should be exercised in patients who have potential drug interactions (eg, cyclo-sporin, antifungal agents, protease inhibitors, erythromycin) or renal disease. Long-term trials of combination therapy with statins and fenofi-brate are in progress (Table 5).

In a study of 160 patients who had CHD and low HDL cholesterol (HDL-Atherosclerosis

Treatment Study), combining niacin with somvas-tatin over a 3-year period in one trial resulted in an impressive reduction in angiographic progression of lesions and clinical end points. A subgroup (16%) of these patients had diabetes [53]. Niacin significantly reduced the risk of nonfatal MI and stroke in the Coronary Drug Project, in which 40% of the patients had evidence of abnormal glucose tolerance [54]. Lovastatin, in combination with extended release niacin, is the first fixed-dose combination product that, in dosages of up to 40 mg of niacin plus 2000 mg of niaspan, reportedly lowered LDL cholesterol and triglyceride by 47% and 41%, respectively, and increased HDL cholesterol by 30% [55].

In patients who have diabetic lipemia or severe hypertriglyceridemia, fibrates are the drug of choice; in addition, dietary and lifestyle measures should include a very low fat diet, alcohol restriction, physical activity, glycemic control, and weight management. Many patients are unable to lower triglyceride levels to a safe range (<500 mg/ dL) and require the addition of niacin or fish oils. Usually, the latter is required in large dosages (to provide 3 to 6 g or more of omega-3 fatty acids) [56].

Table 5

Major on-going lipid trials with cardiovascular end points

Study

Active drugs

Comments

TNT ~ 10,000 Atorvastatin, 10 or 80 mg

SEARCH ~12,000 Simvastatin, 20 or 80 mg ± Bj2 and folate

IDEAL 8888 Simvastatin 20-40 or Atorvastatin 80 mg

FIELD ~6000 Fenofibrate or placebo

ACCORD ~5800 Simvastatin 20 mg ± fenofibrate

LDL goal: 100 versus 75 mg/dL LDL ± homocysteine reduction Moderate versus high dose statin Fibrate therapy in diabetes Monotherapy versus combination therapy in diabetes

Abbreviations: ACCORD, Action to Control Cardiovascular Risk in Diabetes; FIELD, Fenofibrate in Lipids and Diabetes; IDEAL, The Incremental Decrease in Endpoints Through Aggressive Lipid Lowering Trial; SEARCH, Study of Effectiveness of Additional Reductions in Cholesterol and Homocysteine; TNT, Treat to New Targets.

The addition of a thiazolidinedione (TZD) is a valid approach to increasing HDL cholesterol in patients who have diabetes that requires glycemic control. Both of the available TZDs, rosiglitazone and pioglitazone, increase HDL cholesterol by 10% to 15%, based on baseline HDL levels [57]. Pioglitazone was shown to lower triglycerides but both agents are effective in correcting the LDL compositional abnormalities that are associated with insulin resistance. The results of on-going long-term trials to assess CHD outcome measures are awaited.

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