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Familial hypercholesterolemia
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
All medications which lower lipids are contraindicated during pregnancy [107]. A prudent diet for these patients is one low in cholesterol and saturated fat. Oxidative stress contributes to lipid peroxidation and decreases nitric oxide (NO) bioavailability in atherosclerosis. Long-chain (n-3) polyunsaturated fatty acids (PUFA) are easily oxidized and improve endothelial function. In experimental animals, a fish oil-rich diet increased NO production and endothelial NO synthase expression. A fish oil-rich or supplemented diet appears prudent [108]. Double heterozygotes for mutations in LDLR and APOB tend to respond to treatment with statins [3]. Monoclonal antibodies to the PCSK9 convertase have emerged as treatment for even homozygous FH [109]. Two injectable human antibodies, Alirocumab and Evolucumab, have been approved by the FDA. They are capable of reducing LDL cholesterol by 50–70 percent.A cholesterylester transfer protein inhibitor Anacetrapib 100 mg daily added to statin therapy reduced LDL cholesterol by 30 percent [110]. Patients with APOB are responsive to statins [83].
Lipoprotein(a): cardiovascular risk and emerging therapies
Published in Expert Review of Cardiovascular Therapy, 2023
Masashi Fujino, Stephen J Nicholls
Although many therapies have been studied to lower Lp(a), current lipid-lowering therapies either do not lower Lp(a) or, when they do lower it, it is negligible, or even mildly elevated. Dietary and Exercise interventions to lower Lp(a) were negative [64–68]. Traditional approaches to lowering Lp(a) have involved the administration of either estrogen or nicotinic acid, although neither has been demonstrated to reduce CV risk in contemporary clinical trials [69,70]. Statins and ezetimibe, which are established to lower LDL-C, do not lower LP(a); rather, statins have been reported to mildly increase Lp(a), but the detailed mechanism for this is unclear [71,72]. Anacetrapib, a cholesteryl ester transfer protein inhibitor (CETP) that increases HDL cholesterol and decreases Lp(a) (by 20–40%) reduced CV risk, but did not proceed to the clinic due to prolonged adipose tissue accumulation [73]. Lp(a) apheresis is an available therapeutic option for high-risk patients with elevated Lp(a). LP(a) apheresis reduced the mean baseline LP(a) 98.9–104.9 mg/dL by −60–68% after the sessions [74,75]. In patients at high risk for ASCVD with elevated Lp(a) levels and maximally tolerated lipid lowering drugs, Lp(a) apheresis has been reported to reduce CV events over 2 years in a prospective observational multicenter study [75]. However, it is not widely used due to invasiveness, cost, and limited access.
A review of therapeutic failures in late-stage clinical trials
Published in Expert Opinion on Pharmacotherapy, 2023
Ritu Jain, Janakiraman Subramanian, Anurag S. Rathore
In 2008, a phase II study (DEFINE) was conducted with anacetrapib to evaluate the tolerability and long-term safety in patients with coronary heart disease risk. This 6- and 12- month study provided information related to safety that showed no significant effect on blood pressure, serum electrolytes, and aldosterone levels. It also included a prespecified cardiovascular composite endpoint in 16 patients as compared to 21 receiving placebo. After 6 months, the HDL-C levels significantly increased by 138.1% and LDL-C decreased by 39.8%. On account of this study, DSMB recommended to continue further trials using anacetrapib. Clinical trial, REVEAL, started in 2011 involved more than 30,000 patients to explore if the cholesterol changes observed in DEFINE translate to clinical benefits. A 9% relative reduction in acute coronary events and deaths were observed as compared to the placebo group [68]. However, development of this drug was abandoned in 2017, stating that clinical profile for anacetrapib does not support regulatory filings of efficacy and safety [69]. Although the drug was effective, its elimination from the body was a major issue. The drug started to accumulate in the fat tissues making it toxic and the future of the drug became uncertain. This information could have been attained in the early clinical trials if all the guidelines were properly followed. Therefore, it is always recommended to follow the guidelines provided by regulatory authorities and to have an early discussion with authorities, wherever possible.
The mystery of evacetrapib - why are CETP inhibitors failing?
Published in Expert Review of Cardiovascular Therapy, 2020
Stephen J. Nicholls, Kristen Bubb
Anacetrapib is an additional potent CETP inhibitor, raising HDL cholesterol by more than 130% and lowering LDL cholesterol by more than 30% [27]. These findings were observed in patients with both high cardiovascular risk and also in those with familial hypercholesterolemia [28]. An early safety study performed in more than 1600 high vascular risk patients not only demonstrated a lack of torcetrapib like toxicity, but also reported a reduction in cardiovascular events, primarily due to a lower need for coronary revascularization [27]. The largest CETP inhibitor clinical outcomes trial performed to date demonstrated a statistically significant 9% reduction in cardiovascular events in patients treated with anacetrapib for a median of 4.1 years [29]. Analysis of this trial demonstrated a direct association between non-HDL cholesterol levels and cardiovascular events. A subsequent report of longer-term follow-up, after the trial, demonstrated a greater reduction in cardiovascular events in the anacetrapib treated patients [29]. While this finding provided ultimate evidence that the administration of a CETP inhibitor could reduce cardiovascular risk, there were lingering concerns regarding adipose tissue accumulation of the drug [30] and ultimately clinical development did not proceed to the regulatory approval stage.