Genetic Studies Help Clarify the Complexities of Lipid Biology and Treatment

Abstract

A randomized controlled trial of laparoscopic Nissen fundoplication versus proton pump inhibitors for the treatment of patients with chronic gastroesophageal reflux disease (GERD).

LDL cholesterol: How low to go?

“…This observation contrasts with findings from Mendelian randomisation studies which showed that having a lower LDLc associated with PCSK9 variants was linked to increased risk of diabetes in a manner similar to that seen for variation in the gene for 3-hydroxy-3methyl-glutaryl co-enzyme A (mimicking statin therapy) (40). This discordancy between genotypicand clinical trial -findings reflects the strengths and weaknesses of each approach to determining the benefits and disadvantages on an intervention (see (41) for a review). As noted, the duration of FOURIER at just over 2 years limits the ability to detect late-appearing treatment-emergent side effects, and the genetic observations leave the diabetes link an open question.…”

Lower LDL is better – can this be achieved with CETP inhibition therapy?

“…Up to a 130% increase in HDL-C and a 40% decrease in LDL-C (calculated using the Friedewald formula) were observed in phase 3 trials with four different CETP inhibitors, the trial populations of which consisted predominantly of individuals with documented atherosclerotic cardiovascular disease (ASCVD). Note, however, that the reductions in LDL-C, calculated in most CETP trials by the Friedewald equation, more than likely overestimated the extent of LDL-C lowering [8,9]. Overestimation of LDL-C reductions holds particularly true at lower LDL-C levels, as in those patients recruited in the phase 3 CETP inhibitor trials, who were on statin therapy during the trials [9].…”

“…Note, however, that the reductions in LDL-C, calculated in most CETP trials by the Friedewald equation, more than likely overestimated the extent of LDL-C lowering [8,9]. Overestimation of LDL-C reductions holds particularly true at lower LDL-C levels, as in those patients recruited in the phase 3 CETP inhibitor trials, who were on statin therapy during the trials [9]. LDL-C reductions of up to 20%, determined in later trials by beta quantification, more accurately reflect LDL-C lowering achieved with the addition of CETP inhibitors to statin therapy, and are in effect a proxy for the extent of apoB lowering produced, which is a more accurate predictor of CVD outcomes [8,10].…”

“…This is made even more apparent in the fact that the results of the REVEAL trial fit well on the slope of the regression line of non-HDL-C levels (a proxy for apoB) reported in trials of statins, ezetimibe, and PCSK9 inhibitors and the corresponding risk of coronary heart disease (CHD) [18]. This effect is attributed to the fact that apoB plasma concentrations are indicative of the absolute number of LDL particles (one apoB molecule is present per LDL particle) that enter the arterial wall and, thereby, induce and promote ASCVD in proportion to their numbers [9,19].…”