1Section of Vascular Biochemistry, Division of Cardiovascular and Medical Sciences, 4th Floor QEB, Glasgow Royal Infirmary, University of Glasgow, Glasgow G31 2ER, UK
2MRC Epidemiology Unit, Cambridge CB1 8RN, UK
* Corresponding author. Tel: +44 141 211 4312; fax: +44 141 553 2558. E-mail address: nsattar{at}clinmed.gla.ac.uk
This editorial refers to Impact of statins in microalbuminuric subjects with the metabolic syndrome: a substudy of the PREVEND Intervention Trial
by C.A. Geluk et al., on page 1314
Geluk et al.1 describe a subgroup analysis of the PREVEND trial in which they tested whether pravastatin reduced risk for major adverse cardiac events in micro-albuminuric patients with and without the metabolic syndrome defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP III) criteria.2 Although pravastatin did not reduce incidence of adverse cardiac events in the total cohort,3 an impressive 60% relative risk reduction was noted in the subgroup with both micro-albuminuria and metabolic syndrome [hazard ratio (HR) 0.39, 95% confidence interval (CI) 0.170.89], whereas micro-albuminuric individuals without metabolic syndrome did not appear to benefit. The higher event rate in the former group concurs with other evidence indicating a more malignant outcome when micro-albuminuria accompanies other risk factors (e.g. endothelial dysfunction4) than when it occurs in isolation. The investigators suggested that their study supports the use of statins in micro-albuminuric subjects with metabolic syndrome to reduce incidence of major coronary events.
So what does this mean for clinicians in practice? Should we advocate that metabolic syndrome status be recorded in all micro-albuminuric patients, and that differential treatment with statins of micro-albuminuric patients with and without metabolic syndrome become routine practice? To address these issues, several aspects of the currently reported findings would benefit from further comment. First, the total number of cardiac events in this study numbered <50, relatively modest compared with major statin trials. Therefore, one explanation for lack of apparent statin benefit in subjects with micro-albuminuria but without metabolic syndrome is simply lack of power. Several major statin trials, incorporating several hundred cardiovascular (CVD) events and thus far greater power, have examined whether statin treatment has differential effect in those with vs. those without metabolic syndrome. The majority of such subgroup analyses (e.g. WOSCOPS5) indicate a similar statin-induced relative risk reduction in those with (HR 0.73, 95% CI 0.531.01) vs. those without (HR 0.69, 95% CI 0.540.89) metabolic syndrome, but because of the significantly higher event risk in those with metabolic syndrome, the absolute risk reduction was generally greater in this group. Similar findings were reported in a recent subgroup analysis of the Scandinavian Simvastatin Survival (4S) trial.6 Such findings, in turn, agree with the totality of statin trial evidence indicating similar statin-mediated relative risk reductions across the range of primary and secondary prevention populations and in subjects with and without diabetes. Whether fibrates impart a differential risk reduction in subjects with features of the metabolic syndrome is less well studied. In the Veterans' Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) study,7 which examined effects of gemfibrozil in men with CHD, the subgroup of men with greater insulin resistance (as determined by homeostasis model assessment, HOMA-IR) were at far higher absolute event risk and appeared to gain greater absolute risk reduction when compared with those without insulin resistance, although once again relative risk reductions were not dissimilar. Statins and fibrates are primarily lipid-lowering agentsconsequently, whether insulin sensitizing agents convey superior CVD relative risk reduction in insulin resistant subjects or those with metabolic syndrome will be a more illuminating future question.
Secondly, regardless of potential differential effects of cardioprotective therapies in subjects with and without metabolic syndrome, a more fundamental issue is whether the user-friendly ATP III metabolic syndrome criteria offer any clinical benefit. The ATP III criteria were generated by a panel of predominantly cardiologists to enable them to more readily scrutinize the relevance of metabolic syndrome to CVD risk. The literature is now rich in papers examining, often re-examining, cross-sectional and prospective data on the basis of the ATP III metabolic syndrome criteria. Indeed, a simple search on Medline revealed over 200 papers using such criteria (or slight modifications thereof) since the first publication of these criteria in 2001.2 Yet, while numerous studies confirm an unsurprising higher prevalent or incident CVD or indeed diabetes risk in those with vs. without the metabolic syndrome, they currently fail to convince of the need to incorporate such criteria into widespread clinical practice. Many studies have either omitted, or where they have done so, have insufficiently tested whether the ATP III criteria meaningfully improve upon risk prediction beyond established CVD prediction models. For example, in our examination of the WOSCOPS study results,5 while a modified version of the ATP III criteria did appear to predict CVD events independent of conventional risk factors in multivariate analyses, a more rigorous test such as receiver operator characteristic curves (ROC) was not included. Geluk et al.1 also did not extend their findings in this manner. Interestingly, ROC analyses were employed in the San Antonio Heart Study by Stern et al.8 These investigators demonstrated that not only were the ATP III criteria inferior to Framingham-based models for predicting CVD events on a direct comparison, but more importantly, addition of metabolic syndrome yielded no improvement in prediction of events beyond Framingham score. Of note, Stern et al.8 included examination of the World Health Organisation (WHO) metabolic syndrome criteria and these also afforded no additional predictive benefit beyond Framingham score. Such results are perhaps unsurprising given that Framingham-based charts incorporate age, LDL-cholesterol, and smoking, three critical CVD risk factors not included in either the ATP III or WHO metabolic syndrome criteria. In addition, the dichotomized treatment of continuous variables in the ATP III and WHO criteria also limits their predictive ability; most conventional CVD predictive charts, e.g. Joint British Societies Coronary Risk Prediction Chart used in the UK, use continuous variables for blood pressure and lipids (cholesterol to HDL-cholesterol ratio), together with several age cut-offs. Beyond such limitations, other valid concerns about the ATP III metabolic syndrome criteria have recently been raised by Reaven9 and Meigs10 and include the relative modest association of metabolic syndrome with directly measured insulin resistance and the lack of applicability of waist circumference cut-offs to different ethnic groups. In line with the limitations of current evidence, it is our experience that while the vast majority of cardiologists and diabetologists, and albeit a small proportion of primary care physicians, are aware of the recent ATP III metabolic syndrome criteria, very few use it in their clinical practice.
Finally, have there been any beneficial developments resulting from the surge of publications on ATP III metabolic syndrome criteria? One potential development is that cardiologists and vascular physicians, perhaps, now place more emphasis on at least documenting obesity and glycaemic dysregulation in their patients. They may also consider emphasizing lifestyle changes, in particular physical activity, more often in the management of their patients. With respect to glycaemic abnormalities, evidence from other sources indicate that a significant proportion of apparently non-diabetic patients admitted to hospital with myocardial infarction (MI) have either frank diabetes or glucose intolerance as determined by an oral glucose tolerance test at discharge and repeated at 3 months.11,12 In parallel, a number of disparate observations suggest that abnormalities linked to insulin resistance such as hyperinsulinaemia,7 obesity, endothelial dysfunction, or indeed elevated C-reactive protein13 predict worse outcome in post MI patients who do not necessarily have diabetes. The next critical question in such patients regardless of diabetic status is whether agents specifically targeting insulin sensitization, e.g. metformin or PPAR activators, will lessen CHD event risk in the face of adequate statin and other cardioprotective therapy. Ongoing and future trials will undoubtedly address such questions. Certainly, the accumulating and consistent data on the CVD risk reduction induced by metformin in persons with diabetes are encouraging14 but such work in non-diabetic persons and in formal randomized controlled trials is currently lacking.
In summary, therefore, while the concept of metabolic syndrome has proved useful in demonstrating pathophysiological parallels between conditions such as diabetes and CVD, it is far too premature to incorporate specific metabolic syndrome criteria, such as the ATP III criteria, shortly due to be revised, into clinical practice for CVD risk prediction. The clinical utility of metabolic syndrome criteria for this purpose can thus presently be regarded as work in progress.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
References
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