Treat high LDL-C and reduce secondary risk.

ANNOTATION

Initial Therapy: Evidence clearly supports initiation of pharmacotherapy when LDL is >130 mg/dL in patients with CHD (Scandinavian Simvastatin Survival Study Group, 1994). For CHD and CHD equivalents (i.e., type 2 DM) and patients with HDL >40 mg/dL and LDL <130 mg/dL, there is insufficient evidence on which to base a recommendation for pharmacotherapy. Individual clinicians may choose to initiate drug therapy for LDL >100mg/dL for secondary CHD prevention, based on consensus opinion. However, the CARE study, a prospective secondary prevention trial, found no outcomes benefit when high-dose pravastatin was initiated at a baseline LDL < 125 mg/dL (Sacks, 1996).

Choice of Drug: Statins are the best studied and show most benefit, in terms of absolute LDL reduction and patient outcome. Older trials with niacin and bile acid resins have shown modest reduction in LDL (10 to 20 percent) and CHD event rates, with some evidence of small mortality benefit. Fibrates, which have minimal effect on LDL, have shown reduced CHD event rates but not mortality (Frick et al., 1987; Rubins et al., 1999). Statin-based outcome trials have included lovastatin, pravastatin, and simvastatin. There is no convincing evidence that one statin is better than another. Choice and starting dose should be dictated by the required LDL reduction, as statins differ in their potency. The dose should be adjusted at six to eight week intervals until the LDL reduction goal is achieved.

Aggressiveness of LDL Reduction: There is no direct evidence from RCTs that demonstrates a net benefit (in terms of clinically relevant endpoints) of treating to an LDL goal of less than 130 mg/dL. Indirect evidence from the 4S Trial (1994) demonstrated that in patients with previous CHD, treated with simvastatin to an average LDL of 118 mg/dL, the benefits clearly outweighed the harms. NCEP III recommends lowering LDL to <100 mg/dL in the secondary CHD and CHD equivalents (i.e., type 2 diabetes mellitus) prevention setting. Trials are now underway to determine whether even more aggressive treatment produces additional benefit. An angiographic trial in coronary artery bypass grafting (CABG) patients showed that patients treated to a target LDL <140mg/dL had worse outcomes than those treated more aggressively to a target LDL <85mg/dL (Post CABG Trial, 1997). After four years, angiographic progression for the aggressive and moderate groups was 27 percent and 39 percent, respectively. Revascularization was reduced by 29 percent in the lower LDL group. Some experts argue that it is the percentage drop in LDL, not the absolute LDL achieved, that is important in achieving benefit. Treating to New Targets (TNT) is a five year RCT currently under way looking at lowering LDL to very low target levels in patients with CHD, who are randomizing to atorvastatin 10 mg versus 80 mg/day. The results of the 4S Trial suggest that there may be additional benefits of lowering LDL to less than 130 mg/dL. The VA/DoD Working Group for the management of dyslipidemia recommend a treatment goal of <120 mg/dL, while waiting for a more definitive answer.

HDL Cholesterol <40 mg/dL with LDL <130 mg/dL: Large epidemiologic trials have shown that a low HDL is associated with an increased risk for cardiovascular events (Gordon, 1989). In the VA-HIT trial (1999), patients with established cardiovascular disease, an HDL <40 mg/dL and an LDL <140 mg/dL were randomized to treatment with gemfibrozil versus placebo. The mean entry HDL of the treatment arm was 32 mg/dL and the mean entry LDL level was 111 mg/dL. Following a mean follow-up of five years, the gemfibrozil treatment arm saw a 22 percent relative risk reduction in the combined end point of nonfatal myocardial infarction or death due to cardiovascular disease, and a 25 percent reduction in stroke. (Rubins et al., 1999) Subgroup analysis of VA-HIT strongly suggests that CHD patients with low HDL, triglycerides >200 mg/dL, hypertension, or impaired fasting glucose were particularly likely to benefit from gemfibrozil therapy. The study was not powered to detect an overall mortality benefit.
Based on this single trial, gemfibrozil should be considered in patients with a HDL-cholesterol <40 mg/dl and a normal LDL-cholesterol. However, the effects of a combination of a HMG Co-A reductase inhibitor (a 'statin') and a fibrate (gemfibrozil) are not known.