
In 2013, in a manuscript published in Biochemical Pharmacology (http://www.sciencedirect.com/…/article/pii/S0006295213001615) we stated:
"...Current drug design considers plasma HDL-C levels as the primary pharmacological target for HDL-based therapies for CHD. All four CETP inhibitors (torcetrapib, dalcetrapib, anacetrapib and evacetrapib) were designed on this principle. However, this approach does not take into consideration the fact that HDL is a rather heterogeneous mixture of lipoprotein particles with distinct apolipoprotein and lipid composition that dictate their atheroprotective or proatherogenic functions. This may explain why simply raising HDL-C levels by torcetrapib and dalcetrapib failed to yield the expected results in the corresponding clinical trials. We still need to wait for the final outcome from the REVEAL and ACCELERATE clinical trials before we reach solid conclusions, but the failure of torcetrapib and dalcetrapib may be an omen for anacetrapib and evacetrapib..."
In another paper published in 2014 in Expert Review of Cardiocascular Therapy (https://www.ncbi.nlm.nih.gov/pubmed/24650316 ) we insisted:
"...The inverse correlation between HDL-C levels and coronary risk, initially reported by John Gofman [14] and Richard Havel [15], and later confirmed in the Framingham Heart Study [6], led to the principle that high HDL-C levels in plasma protect from atherosclerosis. In a simplistic attempt to create HDL-based therapies, recent efforts focused exclusively on raising HDL-C levels. Such approaches include inhibition of cholesterol-ester transfer protein (CETP) [16] or endothelial lipase (EL) [17] activity in plasma, stimulation of apoA-I gene expression using small molecules [18], administration of purified recombinant apoA-IMilano [19], apoA-I mimetic peptides [20,21], or niacin. Though two large clinical trials that involve increasing HDL-C levels by pharmacological means (REVEAL and ACCELERATE) are still under way [22], the failure of high-dose niacin to reduce the risk for cardiovascular events [23], the increased CHD-related mortality seen in patients treated with Torcetrapib [24,25] and the more recent failure to demonstrate efficacy of Dalcetrapib [26], led to the conclusion that simply increasing HDL-C levels alone in plasma may not be an effective strategy for the prevention and treatment of CHD [22]. These observations reinforced the principle of “HDL quality” in atherosclerosis that refers to the functionality of HDL particle, as defined by its protein and lipid content [27], rather than HDL-C levels in plasma. Based on this modern principle, it is very important to first understand how genes, proteins, and lipids affect HDL atheroprotective functions. In this manuscript we review the atheroprotective properties of HDL particles in relation to the proteins of HDL metabolic pathway and discuss our view on what HDL-associated genes and proteins can tell us about HDL functionality in the assessment of coronary risk..."
It was no surprise to us that on Monday October 12, 2015 drug maker Eli Lilly announced that it would abandon a Phase 3 trial of the CETP inhibitor evacetrapib intended for the treatment of coronary heart disease, due to lack of efficacy (http://fortune.com/2015/10/12/eli-lilly-shares-drop/ ).
It was no surprise either that just a few days ago, on Thursday May 18 2017, the ACCELERATE investigators announced in a publication in NEJM (http://www.nejm.org/doi/full/10.1056/NEJMoa1609581) that:
"...Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998.)..."
My view that simply raising HDL-C is not the proper strategy to create HDL-based drugs, is not a mere prophecy but the result of hard work and meticulous review of the literature. I just feel very sorry that so many millions if not billions of dollars have been wasted to prove it.