HATS, FATS and AFREGS Metsyn analysis highlights need to target HDL

Combined analysis of the FATS (Familial Atherosclerosis Treatment Study), HATS (HDL-Atherosclerosis Treatment Study) and AFREGS (Armed Forces Regression Study) showed that targeting both high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol decreased progression of coronary stenosis by 83% and reduced cardiovascular events by 54% in high-risk patients with metabolic syndrome. These data emphasize the value of combination lipid-modifying therapy in this group.  The study was reviewed by HDL Forum Editor Professor Philip Barter.

 Zhao X-Q, Krasuski RA, Baer J et al. Effects of combination lipid therapy on coronary stenosis progression and clinical cardiovascular events in coronary disease patients with metabolic syndrome: a combined analysis of the Familial Atherosclerosis Treatment Study (FATS), the HDL-Atherosclerosis Treatment Study (HATS) and the Armed Forces Regression Study (AFREGS). Am J Cardiol 2009;104:1457-64.

 Metabolic syndrome is characterised by a constellation of atherogenic risk factors, including mixed dyslipidemia (specifically low HDL cholesterol, elevated triglycerides and an increase in small LDL particles). Individuals with metabolic syndrome are nearly twice as likely to die from cardiovascular disease, and their risk of MI and stroke is about 3-fold higher than normal (1). Despite this, metabolic syndrome is currently not recognised as a coronary risk equivalent (2). Recent estimates suggest that up to 50% of middle-aged individuals have the metabolic syndrome (3), although these figures are likely to underestimate the real magnitude of this problem.

 FATS, HATS and AFREGS were randomized, double-blind placebo-controlled angiographic trials with similar design which compared a combination lipid-modifying regimen (aimed at raising both HDL and LDL cholesterol) with placebo. Key endpoints were 1) the change in coronary artery progression (based on a mean of 9 proximal segments) and 2) the occurrence of major cardiovascular events (CHD death, nonfatal MI, stroke and revascularization) over 3 years (Table 1).

 In this analysis, the authors included data from 445 patients enrolled in these 3 studies. Metabolic syndrome was defined in accordance with the National Cholesterol Education Program Adult Treatment Panel III criteria (2), i.e. at least 3 of 5 criteria including abdominal obesity, low HDL cholesterol (<40 mg/dL in men or <50 mg/dL in women), elevated triglycerides (>150 mg/dL), and with or receiving treatment for elevated blood pressure (>130/85 mmHg) or high fasting blood glucose (>100 mg/dL).

 The metabolic syndrome group (n=233) was older (55 vs. 53 years), had more women (12% vs. 2%) and a higher BMI (29 vs. 26 kg/m2) than the group without. Both HDL and LDL cholesterol were lower in patients with than without metabolic syndrome (Table 2).

Patients with the metabolic syndrome had 50% more rapid progression of coronary artery stenosis than those without (% change 2.9 vs. 2.0 for placebo patients, and 0.5 vs. -0.3 for those on therapy, p=0.04 for metabolic syndrome). In addition, the presence of metabolic syndrome was associated with 64% increased cardiovascular event frequency (28% vs. 17% for those on placebo and 13% vs. 3% for those on treatment, p=0.01).

 Linear regression analysis showed that each 10% increase in HDL cholesterol (or 10% decrease in LDL cholesterol) was associated with -0.3% change in coronary stenosis. The decrease in cardiovascular event risk was two-fold greater with each 10% increase in HDL cholesterol (22%, p<0.001) than 10% decrease in LDL cholesterol (11%, p=0.02) (Table 3). Intervening against both lipids led to a 20% decrease in risk (hazard ratio 0.80, 95% CI 0.69-0.92, p=0.002).  

 

The authors concluded that the results of this analysis provides evidence for the importance of therapeutic strategies aimed at raising HDL cholesterol, as well as lowering LDL cholesterol, in patients with metabolic syndrome given their higher risk of atherosclerosis progression and cardiovascular events. These findings also add to data from recent imaging studies (4,5) supportive of the HDL cholesterol raising hypothesis. Together these data reinforce the value of raising HDL cholesterol in high-risk statin-treated patients to reduce the residual risk of atherosclerosis and cardiovascular disease.

 References

1. Ford ES. Risks for all-cause mortality, cardiovascular disease and diabetes associated with the metabolic syndrome: a summary of the evidence. Diabetes Care 2005;28:1769-1778

2. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final report. Circulation 2002; 106: 3143-421.

3. Alexander CM, Landsman PB, Teutsch SM, Haffner SM, Third National Health and Nutrition Examination Survey (NHANES III), National Cholesterol Education Program (NCEP). NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants aged 50 years or older. Diabetes 2003;52:1210-1214.

4. Lee JMS, Robson MD, Yu L-M et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function. J Am Coll Cardiol 2009;54:1787-94.

5. Taylor AJ, Villines TC, Stanek EJ et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. New Engl J Med. Published on-line November 15, 2009. DOI 10.1056/NEJMoa0907569.

 


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