Abstract
Several professional guidelines have advocated that low-density lipoprotein (LDL) has to be considered the primary target for atherosclerotic cardiovascular disease (ASCVD) prevention. This long-held recommendation is supported by multiple clinical and epidemiological trials. But there is residual risk present even after desired LDL reduction due to the presence of other atherogenic components. 1 The triglycerides, non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein-a (Lp-a), and apoprotein-B (Apo-B) are considered potential secondary targets beyond LDL to reduce residual risk. A relook at these not-well-proven targets is becoming more relevant with the development of newer and more efficient drugs to reduce triglycerides and Lp-a in the recent past.
Non-high-density Lipoprotein Cholesterol
Non-high-density lipoprotein cholesterol includes LDL, triglyceride-rich lipoproteins (TRL), TRL remnants, and Lp-a. Since they better represent total triglyceride-rich particles, non-HDL can be a more desirable target. It gained attention as an alternate target with the publication of the National Cholesterol Education Program/Adult Treatment Panel III (ATP III) in 2001. Ease of estimation in non-fasting status is an advantage for non-HDL as an independent risk parameter for residual risk. It has a proven role as a risk predictor in those already on statin therapy and those with metabolic problems, such as obesity and type 2 diabetes. 2
Triglycerides
It is well known that moderate elevation of triglycerides is associated with cardiovascular (CV) risk beyond the risk attributable to elevated LDL. As a paradox, severe triglyceridemia (>885 mg/dL), which contains large TG-rich particles (chylomicrons) predominantly, is less atherogenic than when TG is present in the 150-885 mg/dL range. 3 Presence of elevated triglycerides, often with low HDL levels and near-normal LDL, is a characteristic lipid profile in diabetic patients, and more so in South Asian populations. Even in patients on statins or PCSK9 inhibitors with adequate reduction in LDL, poor control of triglycerides remains a challenge. 4 The TG levels also vary with fasting or non-fasting states. However, it is recommended that non-fasting, rather than fasting, TG concentration independently predicts atherosclerosis and CV events. 5
Triglyceride-rich Lipoproteins
Triglyceride-rich lipoproteins refer to very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and chylomicron remnants together. These complexes have been shown to be associated with enhanced risk of major ASCVD, independent of LDL concentration. 6
Apoprotein-B
This molecule is present in two isoforms—Apo-B48 and Apo-B100; the first one is associated with chylomicrons, and the latter with the atherogenic lipoproteins—VLDL, IDL, LDL, and Lp-a—in a single molecule per each particle. A direct measure of Apo-B100 is reflective of the atherogenic burden and is claimed to be a better comprehensive parameter than any other lipid component. There is strong evidence for this observation in studies like INTERHEART and the Apolipoprotein-related Mortality Risk (AMORIS) studies. The latter study showed that Apo-B and the Apo-B/Apo-A1 ratio are better predictors for ASCVD than LDL-C. 7
In an 8-year follow-up analysis of 13,015 statin-treated patients from the Copenhagen general population, elevated Apo-B and non-HDL cholesterol—but not LDL cholesterol—were associated with residual risk of myocardial infarction (MI) and all-cause mortality. Apo-B was a better indicator than LDL for predicting future MI in these patients. 8
Lipoprotein-a
The review article on Lp-a and an invited editorial published in this issue threw light on the controversies and current evidence to recommend estimation of Lp-a as a risk predictor. This biomarker was in the news in the early 90s when Professor Enas Enas went around the globe talking about Lp-a being present in higher levels in South Asians, and it could be an important contributor to a premature and malignant presentation of ASCVD in them compared to the White races. There was no effective treatment for the same except niacin, which was not tolerated by the majority. Moreover, there were no takers for his views on the need for targeting Lp-a for ASCVD prevention. However, there was a resurgence of interest in this parameter in the recent past. The Lp-a level in an individual is genetically determined and is not modifiable by lifestyle changes. What constitutes the limit to label as high-risk is controversial. The experts recommended testing it at least once in the lifetime of an individual. 9 For many years, there was no specific, effective drug available to treat raised Lp-a levels. It is heartening to see that new medications are getting introduced to address elevated levels of Lp-a. The dyslipidemia management, as a part of addressing the residual risk for ASCVD prevention, is still emerging.
