San Francisco, CA - Patients with coronary heart disease (CHD) and metabolic syndrome are at significantly higher risk of a major cardiovascular event than those with only CHD, but this risk is significantly reduced with intensive lipid-lowering therapy [1]. These are the findings from a new post hoc analysis of the Treating to New Targets (TNT) study, published online September 5, 2006 in the Lancet.

"What this study does is look specifically at patients with metabolic syndrome—first, to determine whether they were at higher risk, and they indeed were when compared with the TNT population without metabolic syndrome," lead investigator Dr Prakash Deedwania (University of California San Francisco School of Medicine) told heartwire. "We then wanted to know if these metabolic-syndrome patients benefit [from aggressive LDL-cholesterol reduction] as much as or more than . . . reducing their LDL-C levels to only about 100 mg/dL. And again, yes, we showed that not only do these patients have higher risk, they have greater benefit than patients who do not have metabolic syndrome."

First presented during the late-breaking clinical-trials session at the American College of Cardiology (ACC) 2005 Scientific Sessions and then published in the New England Journal of Medicine [2], TNT investigators showed that substantially lowering LDL-cholesterol levels in stable CHD patients below current targets results in better clinical outcomes. In the TNT study, intensive lipid lowering with atorvastatin (Lipitor, Pfizer) 80 mg daily provided greater protection from major cardiovascular events than low-dose atorvastatin in stable CHD patients. High-dose atorvastatin reduced the primary composite end point of death from CHD, nonfatal MI, resuscitation after cardiac arrest, and fatal or nonfatal stroke 22%.

The TNT trial was a parallel-group study randomizing 10 001 patients from 14 countries to double-blind treatment with either high- or low-dose atorvastatin. Patients included were men and women 35 to 75 years with clinically evident CHD, defined as previous MI, previous or present angina with evidence of atherosclerotic CHD, or having undergone a coronary revascularization procedure. The post hoc analysis included 5584 patients, more than 55% of the TNT cohort, with metabolic syndrome, as defined by the 2005 National Cholesterol Education Panel ATP III criteria.

After a median follow-up of 4.9 years, 262 patients (9.5%) with metabolic syndrome receiving atorvastatin 80 mg and 367 patients (13%) receiving atorvastatin 10 mg had a primary event, a finding that translates into a 29% reduction in the risk of a major cardiovascular event among those treated with intensive statin therapy. Secondary end points also favored high-dose atorvastatin and, consistent with the overall population, there was no significant difference between treatments for all-cause mortality. Investigators also report that in a subgroup of metabolic-syndrome patients without diabetes at screening, there was a 30% reduction in the risk of major cardiovascular events among those treated with atorvastatin 80 mg.

Asked about the clinical importance of metabolic syndrome, a topic that has been much debated in cardiology circles, Deedwania stressed that the syndrome is clinically relevant; this study shows that the clustering of risk factors associated with metabolic syndrome adds to total cardiovascular risk, even in a high-risk population with existing disease.

"In patients who don't have coronary heart disease, the risk of an event is significantly greater if they have metabolic syndrome," said Deedwania. "This study is showing that patients who have coronary heart disease with metabolic syndrome have even higher event rates. So doctors should be checking for it. From a more practical standpoint, this allows us to identify a high-risk cohort; if cost is a constriction, then you can further stratify to identify patients who stand to benefit the most from intensive statin therapy. The other group will benefit, those with coronary disease, but this group will benefit a lot more."

In a univariate analysis of the individual characteristics of metabolic syndrome, there was a significantly higher risk of major cardiovascular events in patients with low HDL-cholesterol levels, hypertension, triglycerides >150 mg/dL, fasting glucose levels >100 mg/dL, and a body mass index >28 kg/m². In addition, an analysis of all patients treated with atorvastatin 10 mg revealed that the risk of major cardiovascular events increased with the presence of each additional component of the metabolic syndrome, whereas in those assigned to atorvastatin 80 mg, the incremental increase was attenuated, although the trend was still significant.

"Those with three or more components of metabolic syndrome had significantly greater reductions in risk with more intensive LDL-C lowering [than] patients without metabolic syndrome or those with less than three components," said Deedwania. "It tells us that the components of metabolic syndrome are additive, that clustering is additive, and while we can say that more risk factors result in higher mortality, the question is whether they collectively identify patients where we can make more cost-effective decisions with aggressive LDL-C lowering: the answer is yes."

In an editorial accompanying the TNT analysis, also published online September 5, 2006 in the Lancet [3], Dr Andre Scheen (University of Liege, Belgium) writes that the data in this most recent study help establish how to stratify risk to determine how aggressive initial statin therapy should be.

He points out that the number needed to treat to avoid one major cardiovascular event over a five-year period with 80 mg vs 10 mg atorvastatin was 45 in the whole TNT population. After removing metabolic-syndrome patients from the analysis, the number needed to treat increased to 167. However, in CHD patients with diabetes or metabolic syndrome, the number needed to treat is 24 and 28, respectively.

"Thus, focusing aggressive therapy on patients with metabolic syndrome or diabetes in a population with stable coronary heart disease allows the number needed to treat to be reduced substantially, which [leads to] a significant improvement in the cost-effectiveness of high-dose statin," writes Scheen. He adds that the results from TNT support the implementation of lipid goals that are lower than those currently recommended by the guidelines. The current data published by Deedwania and colleagues, he notes, also support aggressive treatment, especially in those with higher risk, such as those with diabetes or metabolic syndrome.