non-HDL & LDL

Please find below key recommendations and rationales for non-HDL and LDL as specific therapeutic targets for CVD prevention. Text has been slightly modified for easier and succinct reading. Part 1 of guidelines were published by National Lipids Association in April 2015

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EXCERPTS FROM THE GUIDELINES

When intervention beyond public health recommendations for long-term ASCVD risk reduction is used, levels of atherogenic cholesterol (non–HDL-C and LDL-C) should be the primary targets for therapies. LDL is the major atherogenic lipoprotein carrying cholesterol in a majority of patients, and LDL-C comprises ~75% of the cholesterol in circulation carried by lipoprotein particles other than HDL, although this percentage may be lower in those with hypertriglyceridemia. Although LDL-C has traditionally been the primary target of therapy in previous lipid guidelines and in the practice of clinical lipidology, the NLA Expert Panel’s consensus view is that non–HDL-C is a better primary target for modification than LDL-C. Non– HDL-C comprises the cholesterol carried by all potentially atherogenic particles, including LDL, IDL, VLDL and VLDL remnants, chylomicron particles and chylomicron remnants, and Lp (a). Epidemiologic studies have shown that non–HDL-C is a stronger predictor of ASCVD morbidity and mortality than LDL-C. Pooled analyses of data from intervention studies have shown that non–HDL-C changes and levels during treatment are at least as strongly associated with risk for CHD as changes in LDL-C or on-treatment levels of LDL-C. Moreover, when on-treatment values are discordant (ie, only 1 of the 2 is elevated), risk is more closely aligned with non–HDL-C than LDL-C.

Possible explanations for the superiority of non–HDL-C over LDL-C for predicting ASCVD event risk in those who are untreated and those receiving lipid-altering therapy include (1) as with LDL, some triglyceride-rich lipoprotein particles (remnants) enter the arterial wall and thus contribute to the initiation and progression of atherosclerosis; (2) non–HDL-C correlates more closely with apo B than LDL-C, thus may be a better indicator of the total burden of atherogenic particles; (3) elevated levels of triglycerides and triglyceride-rich lipoprotein cholesterol indicate hepatic production of particles with greater atherogenic potential, such as those having poor interactivity with hepatic receptors, resulting in longer residence time in the circulation; and (4) elevated levels of triglyceride-rich lipoproteins, particularly in the postprandial state, may trigger an inflammatory response by monocytes, increasing their propensity to become macrophages.

Although both non–HDL-C and LDL-C are termed atherogenic cholesterol, non–HDL-C is listed first to emphasize its primary importance. Both non–HDL-C and LDL-C are considered targets for lipid-altering therapy, and goals for therapy have been defined for both. Using non–HDL-C as a target for intervention also simplifies the management of patients with high triglycerides (200–499 mg/dL). An elevated triglyceride concentration confounds the relationship between LDL-C and ASCVD risk, even in cases when the triglyceride elevation is borderline, but this appears to be less of an issue with non–HDL-C. Non–HDL-C incorporates the triglyceride level indirectly because the triglyceride concentration is highly correlated with the concentration of triglyceride-rich lipoprotein cholesterol. Non–HDL-C testing is also preferable because it is calculated as the difference between 2 stable and easily measured parameters, Total-C and HDL-C, and thus is less subject to artifact than LDL-C measurement or calculation. Furthermore, non–HDL-C is more accurately measured in the nonfasting state compared with LDL-C.

Goal levels of non–HDL-C may be attained by targeting either or both of the main components of non–HDL-C: LDL-C and VLDL-C. However, it should be emphasized that goal thresholds apply to both non–HDL-C and LDL-C, because discordance may occur, and effective management of atherogenic cholesterol would ideally result in achieving goal levels for both. Desirable levels of atherogenic cholesterol for primary prevention (ie, those without clinical evidence of ASCVD or other very high-risk conditions) are <130 mg/dL for non–HDL-C and <100 mg/dL for LDL-C; for very high risk patients, the desirable levels are <100 mg/dL for non–HDL-C and <70 mg/dL for LDL-C.

Support for these thresholds derives primarily from observational evidence showing low ASCVD incidence rates in groups with levels in these ranges. In several studies, the risk for CHD was shown to decrease progressively to a Total-C concentration of ~150 mg/dL, and populations with total-C below this level have low ASCVD morbidity and mortality. This corresponds to an LDL-C concentration of ~100 mg/dL. Examination of genetic variants that result in below-average levels of atherogenic cholesterol throughout life also support an LDL-C concentration of <100 mg/dL and a non–HDL-C level of <130 mg/dL for prevention of ASCVD.

Data from RCTs show that risk for ASCVD events is reduced with a variety of atherogenic cholesterol–lowering interventions, including cholesterol-lowering drugs and dietary modification, in a pattern that is generally consistent with expectations based on observational evidence. An examination of the pravastatin-to-simvastatin conversion lipid optimization program cohort indicated that lipid-lowering therapy which reduced LDL-C to <100 mg/dL was associated with a significantly lower percentage of total and CHD-related deaths (40% vs 61%) compared with patients with LDL-C of >100 mg/dL. The relationship between lower levels of atherogenic cholesterol with lower risk for ASCVD events has been shown to be present to LDL-C values as low as of <55 mg/dL.

The designation of non–HDL-C treatment targets as 30 mg/dL more than the LDL-C concentration is based on the assumption that ‘‘normal’’ VLDL-C concentration when triglycerides are <150 mg/dL is typically <30 mg/dL, and when triglycerides are elevated, VLDL-C is typically >30 mg/dL. In observational studies, each 1 mg/dL increment in triglyceride-rich lipoprotein cholesterol is associated with an increment in ASCVD event risk at least as large as that for each 1 mg/dL increase in LDL-C. As further research is conducted to investigate the atherogenic properties of triglyceride-rich lipoproteins, including VLDL particles, the accepted values for typical VLDL-C and associated non–HDL-C targets may be modified.

 

NLA Guidelines, Part 1

Journal of Clinical Lipidology

April 2015