Systematic Review of CETP Inhibitors for Increasing High-Density Lipoprotein Cholesterol: Where Do These Agents Stand in the Approval Process?

Bishop BM.
Am J Ther. 2013 Apr 5. [Epub ahead of print]

Background

In the quest for drugs that increase HDL-C one of the therapeutic targets being explored is cholesteryl ester transfer protein (CETP). CETP mediates the exchange of triglycerides from VLDL-C for cholesteryl esters from HDL-C. VLDL-C is ultimately converted to LDL-C, thus CETP contributes to LDL-C levels. Furthermore, CETP has a role in the uptake of HDL-C by adipocytes.
HDL-C is important for reverse cholesterol transport (RCT); the process by which cholesterol is removed from the periphery, metabolised in the liver and ultimately excreted. RCT is thought to be the first of two protective cardiovascular mechanisms of HDL-C. The other mechanism is non-cholesterol-mediated, possibly through anti-oxidative, anti-inflammatory, antithrombotic/profibrinolytic and vasoprotective effects.
Since low levels of HDL-C have been identified as a risk factor for coronary heart disease (CHD), pharmacological strategies are being developed that can enhance HDL-C levels. We here summarise the review article that discusses current strategies to increase HDL-C.

Current therapies that increase HDL-C levels

Non-pharmacological strategies to increase HDL-C levels include exercise, tobacco cessation, weight reduction, moderate alcohol intake, and increasing dietary monounsaturated fatty acids and polyunsaturated fatty acids. Existing pharmacological therapeutic classes are nicotinic acid (increases HDL-C by 20-30%), fibric acid (10-20%) and statins (5-10%).
Niacin, a nicotinic acid, was shown to impressively increase HDL-C levels, although these results were mostly obtained before statins were available. Recent clinical trials show no clinical benefit of niacin in addition to statin treatment, despite producing significant HDL-C increases.
Fibric acid derivates or fibrates are recommended for the treatment of hypertriglyceridemia. Their potential to increase HDL-C gets higher with increasing triglyceride levels, while they have only a modest effect on LDL-C. They are often used with concomitant statin treatment, although most of the data on fibrates also dates from the era before statins were introduced. Clinical trials have yielded varying results on the efficacy of fibrates.
Since clinical outcomes of these drug classes are not satisfying, other mechanisms that raise HDL-C levels are explored to use as therapeutical targets.

Overview of CETP inhibitors and trial data

The author has performed a systematic review of the literature regarding CETP inhibitors. We refer to the original review article for details on the trials described and give a summary of the therapeutic strategies that are discussed.
After genetic mutations in the CETP gene were found to result in increased HDL-C levels, the possibility of drugs that can inhibit CETP started to be explored. Anacetrapib, dalcetrapib, evacetrapib and torcetrapib are four CETP inhibitors that have been tested over the past several years. None of them have been approved, due to conflicting results with regard to their clinical effect and concerns for adverse effects in the case of torcetrapib.

Torcetrapib

The Initial excitement after an early trial that showed a more than 100% increase in HDL-C levels after torcetrapib use, quickly vanished when subsequent, larger trials showed negative results. Overall, no difference was seen in the primary efficacy endpoints as compared to the control groups, despite substantial increases in HDL-C levels. It is possible that any benefit thereof was counteracted by the increased blood pressure that was consistently observed after torcetrapib treatment. Furthermore, the drug increased the risk of serious cardiovascular adverse effects. Efforts of the manufacturer to pursue regulatory approval have been ceased in the United States.

Dalcetrapib

Dalcetrapib was shown to be safe, with no increase in blood pressure or no increased rate of serious adverse effects as compared to placebo. HDL-C increased in comparison to control treatment, but to a lesser extent than did torcetrapib. Dalcetrapib failed to show an effect on the primary efficacy endpoint.  Thus, dalcetrapib lacked the off-target toxicity associated with torcetrapib, but did not give a clinical benefit either.

Anacetrapib

Anacetrapib is a newer, more potent CETP inhibitor that effectively increases HDL-C and also lowers LDL-C levels. No difference in changes in blood pressure was reported in comparison to matched placebo treatment. Current data stem from a safety trial, which show an acceptable adverse effect profile. The promising results obtained thus far on the LDL-C-lowering and HDL-C-increasing effects of anacetrapib next to baseline statin treatment remain to be confirmed in large clinical trials that are currently underway.

Evacetrapib

Evacetrapib is another potent inhibitor of CETP. It is structurally different from torcetrapib, dalcetrapib and anacetrapib, and showed no effect on blood pressure in animal models. Early clinical data show that evacetrapib is effective at increasing HDL-C, as well as lowering LDL-C, without causing significant safety concerns. Evacetrapib requires further clinical validation in large randomised clinical trials, which are ongoing.

Conclusion

Despite the promising results of evacetrapib and anacetrapib, the question remains why there is no general clinical benefit of the class of CETP inhibitors, as two agents showed either harm (torcetrapib) or neutral effect (dalcetrapib). The lack of clinical efficacy might be explained by difference in HDL-C subfractions after treatment, yielding HDL-C that is less efficient in excretion of cholesterol. There is considerable debate around this hypothesis and both evidence for and against it exists.

The place that CETP inhibitors hold in therapy remains to be established. Early clinical data show promising results. Anacetrapib and evacetrapib seem to combine the high potency of torcetrapib with the safety profile of dalcetrapib. Ongoing and future trials will reveal the efficacy of these CETP inhibitors.


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