New Lipid Hypothesis Suggests CETP Inhibitors Better Without Statins  

September 06, 2017

BARCELONA,SPAIN — Some of the top names in lipid research have come up with a new lipid hypothesis suggesting that cardiovascular risk reduction with lipid treatment is more closely related to levels of apolipoprotein B (apoB) rather than LDL cholesterol[1].

They also suggest that the cholesteryl ester transfer protein (CETP) inhibitors do have some benefit, and this is related to LDL reduction (or actually apoB reduction) rather than HDL increase but that the benefit is blunted when the drugs are used in combination with statins, which could explain the negative results of previous CETP-inhibitor trials. So there may be a role for CETP inhibitors as monotherapy in patients who can't take statins.

These conclusions come from a new Mendelian randomization study analyzing variants in genes that encode targets of various lipid-lowering drug therapies and correlating these to cardiovascular events.

The study was conducted by a group including many impressive names such as Drs John Kastelein (University of Amsterdam, the Netherlands), John Chapman (National Institute for Health and Medical Research [INSERM], Pitié-Salpêtrière University Hospital, Paris, France), Henry Ginsberg (Columbia University College of Physicians and Surgeons, New York), Stephen Nicholls (University of Adelaide, Australia), and Marc Sabatine (Harvard Medical School, Boston, MA). The research was published online in the Journal of the American Medical Association on August 28, 2017 to correspond with its presentation at the European Society of Cardiology (ESC) 2017 Congress.

Presenting the data at the ESC meeting, lead author Dr Brian Ference (Wayne State University School of Medicine, Detroit, MI) concluded: "Our genetic research shows that the clinical benefit of lowering LDL is actually determined by lowering LDL particles rather than the cholesterol content carried by those particles. Every LDL particle has one apoB particle, so apoB is a very good measure of LDL particles. We should be measuring apoB, not LDL."

He added: "The genetic data also suggest that statins appear to blunt the beneficial effect of CETP inhibitors on cardiovascular risk. We believe CETP inhibitors may have a role as monotherapy in patients who can't or don't want to take statins."

Research Well-Received

The research appears to have been well-received by other experts in the field.

Discussant of the presentation at the ESC hotline session, Dr Borge Nordestgaard, University of Copenhagen, Denmark, described the findings as "solid."

He told | Medscape Cardiology: "Thus, it is the reduced number of all apoB-containing lipoproteins (LDL, remnants, and Lp[a]) that predict reduced risk rather than reduced LDL cholesterol per se. These findings are fully in line with those of the REVEAL anacetrapib trial just presented."

Nordestgaard added: "CETP inhibitors as monotherapy in patients who can't take statins may indeed have a role, if LDL cholesterol, remnant cholesterol, and lipoprotein(a) are reduced."

Dr Steven Nissen (Cleveland Clinic, OH) said: "This is an interesting and provocative hypothesis. Dr Ference has a strong track record of correctly predicting the results of clinical-outcome trials using Mendelian randomization studies."

But Nissen pointed out that "confirming the suggestion about CETP monotherapy will require performing a randomized trial in patients not taking a statin, a very difficult study to perform in an era when statins are indicated in all patients with coronary heart disease."

In an accompanying editorial[2], Dr Allan D Sniderman (McGill University, Montreal, QC) and Dr Eric Peterson (Duke University Medical Center, Durham, NC) say: "These data provide additional support to an already large body of evidence indicating that apoB is a superior marker of cardiovascular disease risk [vs] LDL," adding that "it may well be time to introduce measuring and monitoring apoB levels into routine clinical care."

In the paper, Ference et al note that randomized studies have consistently demonstrated that lower levels of LDL cholesterol may be causally associated with a lower risk of cardiovascular disease, but that a notable exception to this observation is the CETP-inhibitor class of drugs. Although originally designed to increase levels of HDL cholesterol, the more potent CETP inhibitors also robustly lower levels of LDL, but in the ACCELERATE trial, treatment with the CETP inhibitor evacetrapib reduced LDL levels by 29 mg/dL (0.75 mmol/L) but did not reduce the risk of cardiovascular events.

"This result has created uncertainty about the causal effect of LDL on the risk of cardiovascular disease and raises the possibility that the clinical benefit of lowering LDL may depend on how LDL is lowered," they say.

To investigate this issue, they conducted a Mendelian randomization analysis using data from 14 large population cohorts to evaluate the association between lower levels of LDL and other lipoproteins and the risk of cardiovascular events due to variants in the gene that encodes the target of CETP inhibitors. They then compared this result with the association between lower LDL levels and the risk of cardiovascular events due to variants in the genes that encode the targets of statins, ezetimibe, and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors.

The authors included 102,837 individuals who experienced 13,821 major cardiovascular events in the primary analysis and 189,539 individuals, including 62,240 cases of coronary heart disease (CHD), in the validation analyses.

They found that the reduction in cardiovascular disease risk per unit decrease in levels of LDL-C or apoB associated with the CETP genetic score was similar to the risk reduction associated with the statin, PCSK9, or ezetimibe genetic scores.

When the HMGCR (the gene that encodes the target of the statins) score was below the median (simulating no statin treatment), CEPT inhibition was associated with increased HDL levels, reduced LDL levels, reduced apoB levels, and reduced cardiovascular events.

However, when the HMGCR score was greater than the median (simulating statin treatment), higher CEPT scores (equivalent to dual statin–CETP inhibitor therapy) were associated with a reduction in LDL levels and an increase in HDL levels but also with limited nonadditive change in apoB levels and no significant reduction in cardiovascular events.

"These data suggest that the change in apoB levels is a better predictor of clinical response to CETP-inhibitor/statin therapy than either LDL-C or HDL-C levels," Dr Ference stated.

The researchers then went on to analyze 21 genetic variants associated with discordant changes in LDL and apoB levels and another 36 genetic variants associated with concordant changes in LDL and apoB levels. Among individuals with discordant variants, the reduction in CVD events was more closely related to the reduction in apoB levels than to the reduction in LDL levels, whereas the benefit per unit decrease in apoB levels was similar in both the concordant and discordant groups. "This demonstrates again that apoB is the better predictor of cardiovascular risk," Ference said.

He also pointed out that these results are in line with several prior epidemiologic analyses, which demonstrated that when the LDL level is high but the apoB level is low, cardiovascular risk is low, and when the LDL level is low but the apoB level is high, cardiovascular risk is high.

The authors explain that under most circumstances, LDL and apoB levels are highly correlated and therefore provide similar information about cardiovascular risk. It is only when they become discordant (as is seen when CETP inhibitors are given with statins) that the differential effects of LDL-C and apoB are evident.

They say the results of these Mendelian randomization analyses "provide naturally randomized genetic evidence to support the previous findings that the likelihood of an apoB-containing lipoprotein particle entering into and being trapped within the subintimal space of the arterial wall is more closely related to the concentration of circulating apoB-containing lipoproteins than to the variable mass of cholesterol within them."

Explains ACCELERATE and REVEAL Results?

The authors say the studies suggest that adding a CETP inhibitor to a statin leads to an attenuated reduction in apoB-containing lipoproteins compared with treatment with a CETP inhibitor alone. They add that this could explain the results of the ACCELERATE trial in which treatment with evacetrapib plus a statin reduced LDL level by 37% compared with treatment with a statin alone but only reduced plasma apoB level by 15%, less than half the expected apoB reduction with evacetrapib monotherapy.

Ference said these observations were also in line with the latest CETP inhibitor trial—the REVEAL trial with anacetrapib.

"In REVEAL, LDL was reduced by 26 mg/dL with the anacetrapib/atorvastatin combination, which should have translated into a 17% relative risk reduction in event rate, but there was only an 8.9% relative risk reduction, which is totally what one would have expected from the 12-mg/dL reduction in apoB." he told | Medscape Cardiology.

The authors note that the data also suggest that treatment with a potent CETP inhibitor without a statin could lead to large concordant absolute reductions in both LDL and apoB, which could in turn lead to large relative reductions in cardiovascular events. "Future cardiovascular-outcomes trials evaluating CETP inhibitor therapy in statin-intolerant patients could test this hypothesis directly," they say.

Ference reported receiving personal fees from Merck, Amgen, Ionis Pharmaceuticals, and KrKA Pharmaceuticals and grants from Merck, Amgen, and Esperion Therapeutics. Disclosures for the coauthors are listed in the paper. Peterson reported receiving grants from Amgen and grants and personal fees from AstraZeneca, Merck, and Sanofi. Dr Sniderman reported no relevant financial relationships.

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