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Impotent drug regulation
Published in Peter C. Gøtzsche, Richard Smith, Drummond Rennie, Deadly Medicines and Organised Crime, 2019
Peter C. Gøtzsche, Richard Smith, Drummond Rennie
Other lipid-altering drugs are also interesting. It was expected to be beneficial to increase high-density lipoprotein, but a drug that does this had no effect on the progression of coronary atherosclerosis in trials of about 1000 patients.107 The chemical name of the drug is torcetrapib. Can you pronounce and remember this? One reason why the chemical names, which are invented by the drug companies, are so foolish is that doctors are then forced to use the trade name and therefore less likely to prescribe a cheaper generic when the drug comes off patent. Luckily, the company did a large trial in 15 000 patients, and since it showed that the drug kills people, the manufacturer halted the development of the drug.
Lipid disorders and emerging risk factors for cardiovascular disease
Published in Clive Handler, Gerry Coghlan, Marie-Anne Essam, Preventing Cardiovascular Disease in Primary Care, 2018
Clive Handler, Gerry Coghlan, Marie-Anne Essam
There may be risks associated with increasing HDL cholesterol levels. The torcetrapib trial – torcetrapib is a cholesterylester transfer protein inhibitor – was stopped prematurely due to increased mortality in the torcetrapib and atorvastatin arm of the study in comparison with those using atorvastatin alone.
Lipoprotein Metabolism and Implications for Atherosclerosis Risk Determination and Treatment Decisions
Published in P. K. Shah, Risk Factors in Coronary Artery Disease, 2006
H. Robert Superko, Szilard Voros, Spencer King III
Two CETP inhibitor agents have been tried in human subjects: JTT-705, and torce trapib. Initial small human trials with torcetrapib have revealed a 16% to 91% increase in HDL-C when doses of 10 mg to 240 mg/day are utilized (223). In patients with low HDL-C (< 40 mg/dL) 120 mg–240 mg/day resulted in a 46% to 106% increase in HDL-C with an associated increase in mean HDL particle size (224).
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.
Safety and tolerability of injectable lipid-lowering drugs: an update of clinical data
Published in Expert Opinion on Drug Safety, 2019
Larysa Strilchuck, Federica Fogacci, Arrigo Fg Cicero
In this context, new treatment options become a major innovation in lipid-lowering therapy, especially for high-risk and statin-intolerant patients. However, not all news are necessarily good news. For instance, the cholesterol ester transfer protein inhibitor torcetrapib significantly increased high-density lipoproteins cholesterol (HDL-C), but the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE, n = 15,067) was terminated prematurely because of an increased risk of death from any cause and CV events in patients receiving torcetrapib together with atorvastatin comparing to atorvastatin only arm. The investigators at least partly related the CV risk increase associated with torcetrapib intake to an increase in systolic blood pressure (5.4 mm Hg), a decrease in serum potassium, and increases in serum sodium, bicarbonate, and aldosterone [20].
Cardiovascular outcomes trial with anacetrapib in subjects with high cardiovascular risk – are major benefits REVEALed?
Published in Expert Opinion on Pharmacotherapy, 2018
There is no evidence from REVEAL that increasing the levels of HDL-cholesterol by inhibiting CETP is the mechanism underlying the beneficial effects of anacetrapib. Coupled with the fact that the other HDL-cholesterol-increasing CETP inhibitors, which have been subjected to major clinical outcomes, have not shown clinical benefits (see Section 1), it is not surprising that the development of torcetrapib was stopped by Pfizer in 2007, dalcetrapib by Hoffman-La Roche in 2012, evacetrapib by Eli Lilly in 2015, and anacetrapib by Merck in 2017 [8]. There are also no recent reports of ongoing development of other CETP inhibitors in the earlier phases of clinical trials, CDK-519, DRL-17822, or obicetrapib (TA-8995) [21]. Thus, it is likely that we have reached the end of the development of CETP inhibitors for use in the prevention of cardiovascular outcomes. Focus should now be on basic research to identify other targets that may prevent cardiovascular outcomes.