*3.3.1 Treatment of low HDL-C*

Niacin is a medication that raises HDL-C levels and has been examined extensively in clinical studies. Its efficacy in controlling dyslipidemia and lowering the risk of cardiovascular disease is not well established. In a 1975 study comparing the CV merits of niacin, clofibrate, and placebo, treatment with a high dose of 3000 mg/day of moderate-release niacin resulted in a 14% reduction in coronary mortality, and 26% of stroke death [43]. When the research was expanded to include additional possible medicines in the treatment of dyslipidemia, such as estrogens, clofibrate, dextrothyroxine sodium, and niacin, and compared to lactose as a placebo, niacin was found to be encouraging reducing mortality [66]. However, in the AIM-HIGH and HPS2-THRIVE studies, the effects of niacin were only significant on lipid parameters without effect on CV outcomes [61, 62].

CEPT inhibitors came later than niacin and fibrates in terms of development and application. ILLUMINATE, dal-OUTCOMES, ACCELERATE, and REVIEW are among the most notable CEPT inhibitor trials to date. Nonetheless, the results of this medication were similarly unsuccessful due to inconsistencies in genetic research of CEPT. With the exception of the 2017 anacetrapid REVIEW study, which described a reduction in coronary events [63], the majority of the remaining studies suggested that CEPT inhibitors did not improve CVD risk but increased rates of CV mortality or adverse events such as increased CRP levels or increased systolic blood pressure [64–66]. Thus, clinical application studies of drugs that increase HDL-C have not yet provided evidence that HDL-C is beneficial in CVD.

In addition to the genetic aspect mentioned above, another hypothesis about HDL-C levels has been expanded to explicate the incompatible results of studies on HDL-C. When examining at HDL-C levels and mortality in the study population, several studies found a U-shaped relationship between HDL-C levels and overall mortality rates. This is understandable since extremely low or high HDL-C levels increase population mortality [67–69]. In fact, prior HDL-C studies neglected this aspect, requiring more study to more correctly assess HDL- C involvement in ASCVD.

Based on the available evidence, it can be stated that HDL-C modification in clinical practice is currently restricted. Not all HDL-C-increasing medications yield the same outcomes. To better understand the significance of HDL-C, these items must be considered to a greater extent: the threshold concentration of plasma HDL-C and the genetic aspect. It is indeed questionable if increasing HDL-C can assist reducing CV risk.
