Is non-high-density lipoprotein cholesterol a marker and therapeutic target for dyslipidemia in metabolic syndrome?

Several lines of evidence show that low-density lipoprotein cholesterol (LDL-C) is a major risk factor for atherosclerotic cardiovascular disease (ACVD). Beyond LDL-C, levels of very-low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) also contribute to ACVD risk. This is not surprising because LDL is the product of VLDL and IDL catabolism. In fact, LDL and its precursors are equally atherogenic. Results from clinical trials employing statins also show that lowering LDL-C reduces risk of morbidity and mortality from ACVD. Thus, evidence from metabolic studies and epidemiological surveys and results from clinical trials provide a compelling rationale for targeting the three lipoproteins for therapy to optimize ACVD risk reduction. This view is also in accord with treatment recommendations of at-risk individuals, particularly those with metabolic syndrome and/or type 2 diabetes mellitus (T2DM). These metabolic disorders are associated primarily with elevated VLDL and IDL levels, marginal elevation of LDL-C, and reduced levels of HDL-C. Measurement of LDL and its precursors is necessary for assessment of dyslipidemia in these metabolic disorders, and one way to accomplish this goal is to combine the three lipoproteins into a single lipid measure designated as ‘‘non-HDL-C. ’’ The term ‘‘non HDL-C’’ represents the sum of LDL-C and its metabolic precursors VLDL-C and IDL-C. Measurement of non-HDL-C is very simple because it is calculated as the difference between total cholesterol and HDL-C levels. Both of these measurements are readily available standard-of-care tests. Non-HDL-C is recommended as a therapeutic target in subjects with hypertriglyceridemia [plasma triglycerides (TGs) <500 mg/dL] by the National Cholesterol Education Program Adult Treatment Panel III guidelines (NCEP ATP III). Accordingly, the suggested goal of therapy depends on the risk level of the individual patient. Thus, the goals of therapy for subjects with moderate hypertriglyceridemia at a high ACVD risk ( ‡ 20%), intermediate ACVD risk ( < 20%), or low risk of ACVD (0–1 risk factor) are non-HDL-C levels of 130 mg/dL, 160 mg/dL, or 190 mg/dL, respectively. A therapeutic option for all of these risk categories is lifestyle modification alone or in combination with lipid-lowering pharmacotherapy. Lifestyle modification alone has proven to be very effective in reducing the incidence of T2DM by as much as 58%, as shown in the Diabetes Prevention Program, and may also be expected to provide a similar benefit for patients with metabolic syndrome. However, intensive lifestyle modification alone does not reduce morbidity and mortality from ACVD, as shown in subjects with T2DM in the Look Ahead trial. The study by Kim et al. published in this issue employed a diet low in carbohydrates, proteins, and fat for a 12-week period, after which, both men with and without metabolic syndrome had a significant weight reduction. However, this study also revealed that weight reduction significantly lowered blood levels of non-HDL-C in middle-aged, obese men with metabolic syndrome but not in those without metabolic syndrome. Weight reduction has a number of beneficial metabolic effects, including the improvement of insulin sensitivity that impacts the metabolic alterations of VLDL and IDL. By choosing non-HDL-C as the target of treatment, Kim et al. focused on a lipid parameter that is predictive of ACVD risk. In contrast, dyslipidemia of the metabolic syndrome is usually linked to insulin resistance, and the focus of attention for treatment is high TGs, low HDL-C, and marginally elevated LDL-C, i.e., small, dense LDL. Of interest, McLaughlin et al. have proposed that 3 metabolic markers are useful to identify overweight individuals who may be insulin resistant and therefore at risk for metabolic syndrome. The three markers are insulin ( ‡ 109 pmol/L), TGs ( ‡ 130 mg/dL), and the ratio of TGs-to-HDLC ( ‡ 3.0). These markers correlate with measures of insulin sensitivity. Insulin is not a standardized test; therefore, it has been suggested that either TGs or the ratio of TGs-to-HDL C may be a simple measure that meets the NCEP ATP III criteria for diagnoses and treatment of the metabolic syndrome. Neither LDL-C nor non-HDL-C is a marker of insulin resistance. A divergent view has evolved based on the lipoprotein phenotype that presents in cases of metabolic syndrome. It has been difficult to sort out ‘‘markers’’ of the metabolic disorder from ‘‘targets’’ of therapy for reduction of risk from morbidity and mortality from ACVD. One view holds TG as target of treatment because TGs are also a biomarker of