Masoor Kamalesh, M.D., FACC and Roopa Rao, M.D., Krannert Institute of Cardiology and Clinical Cardiology Research-VA Medical Center, Indiana University, Indianapolis

The rising rates of obesity and diabetes are fueling an increasing prevalence of metabolic syndrome [1]. The close association of metabolic syndrome (MS) with coronary disease has led major health organizations such as the AHA and ADA to focus resources on management of this epidemic of the 21st century [1]. There is a real concern that the benefits accrued over the last several decades in reducing cardiovascular mortality and morbidity through scientific research may be undone if efforts are not directed towards controlling rising rates of obesity, diabetes, and MS. Although control of risk factors non-pharmacologically through exercise, weight loss, and dietary modification would alleviate many of the problems, in many instances these are either not practical or feasible. Thus pharmacologic therapy is often needed to assist lifestyle modification for these patients.

Lipid lowering therapy has been firmly established as a means for reducing cardiovascular mortality and morbidity. However, despite lowering LDL to the recommended levels as per NCEP guidelines, high risk subjects have substantial residual cardiac events. Although statins lower LDL very effectively and the bulk of the benefit seen with statins is attributed to this, statins have other effects which may have an important role in modifying the course of coronary plaques and subsequent events [2]. These are referred to as the pleiotropic effects of statins and include, among other things, the ability of these medications to reduce inflammation. This effect of statins may be especially important in patients with MS since inflammation is one of the key features of MS and in turn is linked to severity of endothelial dysfunction. High dose simvastatin causes greater reduction in inflammation and improvement in endothelial function than lower doses [3]. Another feature of MS is low HDL levels. Higher doses of simvastatin again have a greater effect of raising HDL levels than lower doses [4]. In light of these two effects of simvastatin, it is useful to study the effect of high dose of simvastatin in patients with MS where inflammation and low HDL cholesterol are two of the major components of the syndrome complex.

To test the hypothesis that high dose statins may be of particular benefit in MS patients, we analyzed data for cardiovascular risk factors and outcomes in 213 veteran subjects, and stratified results according to the presence or absence of MS. Of the total, 44.6% of the cohort met criteria for MS. After an average 1.4 years of simvastatin treatment, both groups showed significant reductions in both low-density lipoprotein (LDL) cholesterol and non-HDL cholesterol. Reduction in non-HDL cholesterol, which is an indirect measure of apo-lipoprotein B, was similar in the two groups. Although post-treatment LDL cholesterol levels were significantly lower in the metabolic syndrome patients (88 versus 98 mg/dl), the absolute reductions were no different between the groups.

Adverse cardiovascular outcomes - including both "hard" (myocardial infarction, stroke, death) and "soft" (angina, percutaneous coronary intervention) events - was similar in the two groups. These results suggest that simvastatin 80 mg/day may reduce excess events in very high-risk cohorts of patients with the MS. The similar levels of non-HDL cholesterol in the two groups also suggest that the HDL raising effect and possibly non-lipid modifying effects of simvastatin are involved in the reduction of events in this small retrospective study. (See Figure 1 [5].)

Where do we go from here? This pilot study is hypothesis generating and needs to be confirmed in an adequately sized prospective randomized trial to confirm the findings. Ongoing trials such the JUPITER trial and others will undoubtedly clarify some of these burgeoning issues. However, given the fact that simvastatin has a track record of safety and efficacy and is now generic, it would make economic sense to test this statin in patients with MS. If a prospective trial confirms our pilot data, it would have a tremendous clinical and economic impact. Such a trial is urgently needed.

References

1. American Heart Association; National Heart, Lung, and Blood Institute; Grundy SM, Cleeman JI, Daniels SR, Donato KA, et al. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Executive summary. Cardiol Rev 2005;13:322-27
2. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004;109:III39-43.
3. Hognestad A, Aukrust P, Wergeland R, et al. Effects of conventional and aggressive statin treatment on markers of endothelial function and inflammation. Clin Cardiol 2004;4:199-203.
4. Ballantyne CM, Blazing MA, Hunninghake DB, et al. Effect on high-density lipoprotein cholesterol of maximum dose simvastatin and atorvastatin in patients with hypercholesterolemia: results of the Comparative HDL Efficacy and Safety Study (CHESS). Am Heart J 2003:146:862-69.
5. Kamalesh M, Rao R, Sawada S, Friend A, Schellhase E, Evans T. Effect of 80 mg/day simvastatin therapy on cardiovascular outcomes in adults with versus without metabolic syndrome. Am J Cardiol 2006;97:1487-89.