Abstract
Because the dyslipidemia of the metabolic syndrome is not a disorder predominantly typified by an elevated level of low-density lipoprotein cholesterol (LDL-C), one cannot rule out the pleiotropic antiinflammatory effects of statins as being significant. 1,2 With regard to lowering LDL-C, other viable strategies, in addition to diet and statin therapy, include bile acid sequestrants and the cholesterol absorption inhibitor ezetimibe. However, neither of these therapies has been shown in clinical trials in patients with metabolic syndrome to confer benefit with regard to CVE reduction. With regard to bile acid sequestrants, colesevelam has been shown to have beneficial effects on hyperglycemia and reduces glycosylated hemoglobin (HbA1c) levels, but it should not be used in patents with triglyceride levels >300 mg/dL. 3 However, patients with metabolic syndrome, in spite of the benefit of statin therapy, have substantial residual risk.
Other therapies that would appear efficacious in patients with metabolic syndrome include niacin therapy and therapy with peroxisome proliferator-activated receptor-α (PPAR-α) agonists, such as fenofibrate and bezafibrate. With respect to niacin therapy, the recent AIM HIGH study was published. 4 In this report, 3414 individuals with established cardiovascular disease, who were over the age of 45 years, were studied. All patients received baseline therapy with simvastatin, 40–80 mg per day, plus ezetimibe, 10 mg per day. In addition they received placebo (n=1696) or niacin (n=1718) in a dose range of 1.5–2 g per day. The LDL-C goal was 40–80 mg/dL. A total of 81% of the patients in the AIM HIGH study had metabolic syndrome, and 33.9% were diabetic. Niacin therapy resulted in a significant increase in HDL-C and a reduction in median LDL-C and triglyceride (TG) levels. In patients with CVD and a low level of baseline HDL-C, with LDL-C below 80 mg/dL, extended-release niacin plus simvastatin compared to simvastatin alone was associated with no significant reduction in the primary end point or its subcomponents [composite of the first event of death from coronary heart disease, nonfatal myocardial infarction (MI), ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization] over a mean follow-up of 36 months. Furthermore, there was no benefit on the composite secondary or tertiary end points.
This study is extremely disappointing in that it shows that niacin therapy should not be considered as a combination therapy in addition to statin–ezetimibe therapy in patients with metabolic syndrome and CVD. Also niacin therapy might not be a prudent choice in patients with metabolic syndrome because it raises glucose and uric acid levels, both of which manifest in these patients and thus can be accentuated. 5 However, there is an ongoing clinical trial, the Heart Protection Study 2 (HPS2), which would help us further understand the null result in AIM HIGH with regard to secondary prevention of niacin–statin combination therapy in a group of patients that largely had the metabolic syndrome.
The other class of drugs that should be considered is the PPAR-α agonists (fibrate therapy). 5 The safe PPAR-α agonist fenofibrate was used in two clinical trials. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, 9725 type 2 diabetes mellitus (T2DM) patients not on statin therapy were given fenofibrate versus placebo. 6 However, there was a nonsignificant 11% reduction in the primary end point of CHD death and nonfatal MI (P=0.16), a 24% reduction in nonfatal MI (P=0.01), a nonsignificant increase in coronary heart disease (CHD) mortality of 19% (P=0.22), and total CVEs (comprising CVD death, MI, stroke, and revascularization) were reduced by 11% (P=0.035). However, it is interesting that in a subsequent post hoc analysis of this study, 7 the effect of fenofibrate treatment in patients with metabolic syndrome was explored. In the patients with metabolic syndrome, there was a trend to benefit [hazard ratio (HR) of 0.89; confidence interval (CI) 0.79–1.0; P=0.052]. However, there is a significant benefit in patients with reduced HDL-C, hypertension, TG ≥1.7 mmol/L and a reduced HDL-C, TG ≥2.3 mmol/L, and TG ≥2.3 mmol/L and reduced HDL-C.
This post hoc analysis suggests that there might be a benefit for fenofibrate therapy in metabolic syndrome patients, especially with those with high TG levels and low HDL-C levels. This post hoc analysis of FIELD concurs with the post hoc analysis of the Bezafibrate Infarction Prevention (BIP) Study, a secondary prevention study. Although in the parent study there was no significant benefit of bezafibrate therapy on the primary end point of fatal and nonfatal MI and sudden death over a 6.2-year follow-up, using a modified definition of metabolic syndrome of a body mass index (BMI) of 28 kg/m2 instead of waist circumference as a criterion, there was a significant reduction in new MI, nonfatal MI, and the primary end point in a subgroup of 1470 patients. 8 This post hoc analysis is the only clear evidence of benefit with a fibrate in patients with metabolic syndrome.
In the ACCORD lipid trial, 5518 men and women with T2DM were studied. Fenofibrate and simvastatin were compared to simvastatin therapy, and the patients were followed up for an average of 5 years. There was no significant benefit of the primary end points, which were a composite of nonfatal MI, nonfatal stroke, and CVD death or any other prespecified secondary end points. 5,9 Also, in the prespecified subgroup analyses, there was a benefit for men and possible harm for women. Furthermore, unlike the clear benefit seen in the FIELD study, there was only a trend to benefit in the patients with both high TG (≥204 mg/dL) and low HDL-C (<34 mg/dL) (P=0.057).
Thus, a trend in the ACCORD lipid trial in the dyslipidemic group, i.e., high TG and low HDL-C, appears to concur with that reported in previous fibrate trials post hoc analysis. 7,8 Ginsberg concluded that ACCORD data coupled with the post hoc analysis of the other fibrate trials would suggest in patients with TG >200 mg/dL and HDL-C >35 mg/dL that following statin therapy having achieved significant LDL-C, fibrate therapy could be a consideration at least in men. 10 This is a very realistic conclusion based on these large clinical trials, with the caveat that these were either post hoc or prespecified subgroup analyses and not the primary end point that yielded a null result in all three trials. Whereas the Veterans Affairs High Density Lipoprotein Intervention Trial (VA-HIT) clearly showed a benefit on the primary end point and in diabetics, this study did not report on patients with metabolic syndrome defined at least by Adult Treatment Panel III (ATP III) criteria. 11
To conclude, in patients with metabolic syndrome in primary and secondary prevention, statin therapy has clearly been shown to reduce CVEs. However, niacin therapy in the AIM-HIGH Study, which comprised 81% of patients with metabolic syndrome, had a null effect on the primary end point and subcomponents of the primary end point. The post hoc analysis of BIP and FIELD and a trend to benefit in the ACCORD Study would suggest that fibrate therapy might not be an unreasonable second option if there is no contraindication or elevated creatinine levels, in addition to statin therapy in patients with metabolic syndrome, to optimize the lipid profile and hopefully reduce the residual risk. However, the targets for metabolic syndrome should still be LDL-C and non-HDL-C levels below 100 mg/dL and 130 mg/dL in primary prevention and below 70 mg/dL and 100 mg/dL in secondary prevention, respectively, until new guidelines suggest otherwise. Until the ongoing clinical trials demonstrate benefit and safety of the new cholesterol ester transfer protein (CETP) inhibitors, no firm conclusion can be drawn about the use of CETP inhibitors in metabolic syndrome. 12