Lower LDL Still Best: Very Low Levels of LDL Linked With Reduced CV Events

July 28, 2014

AMSTERDAM, THE NETHERLANDS — The question of how low LDL-cholesterol levels should be in the present statin era, recently addressed with the new US clinical guidelines, is once again questioned with the new publication of a patient-level meta-analysis of eight clinical trials investigating statin therapy[1].

The new meta-analysis, published July 28, 2014 in the Journal of the American College of Cardiology, suggests that lowering LDL-cholesterol levels to very low levels results in a significant reduction in cardiovascular events. Individuals with LDL-cholesterol levels <50 mg/dL had a significantly lower risk of major cardiovascular events compared with individuals who had higher LDL-cholesterol levels, including those with LDL levels 50 to <75 mg/dL and 75 to <100 mg/dL.

"No clinical-outcomes trial with statins has ever achieved a mean LDL-cholesterol level much less than 70 [mg/dL]," senior investigator Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands) told heartwire . "That's why we thought it might be a good idea to get all the individual patient data and see whether we could extend the line a little further down. Of course, this is a nonrandomized, post hoc analysis, with all the caveats you should attach to it, but I think the data are very convincing."

That "line" Kastelein refers to is the cardiovascular risk-reduction curve observed in clinical trials that shows lowering LDL-cholesterol levels reduces major cardiovascular events. In 2010, the Cholesterol Treatment Trialists' (CTT) collaboration showed there was a benefit of lowering LDL cholesterol to around 50 mg/dL. The present meta-analysis extends those findings by suggesting that even lower levels appear to reduce the risk of cardiovascular events further.

In November 2013, the US guidelines for the management of cholesterol elected to do away with treatment goals, stating there was no evidence of cardiovascular benefit in treating to a specific target. The recommendations were surprising, controversial, and in contrast to the previous guidelines that suggested physicians treat high-risk patients to an LDL target of less than 100 mg/dL, with an option to treat patients to less than 70 mg/dL.

In an editorial[2], Dr Ori Ben-Yehuda (Cardiovascular Research Foundation, New York) and Dr Anthony DeMaria (University of California, San Diego) are cautious in interpreting the data from the meta-analysis, noting the new US guidelines recommend only measuring LDL-cholesterol levels to assess adherence. Given the observational, post hoc nature of the data, the editorialists do not believe the present study disproves the US guidelines writing committee's contention that there was insufficient evidence to recommend treating to LDL targets. This is problematic, they say.

"It is indeed regrettable that more than 25 years after the first [Adult Treatment Panel] ATP guidelines, we still do not have clear-cut evidence on what the appropriate LDL-cholesterol targets of therapy should be," write Ben-Yehuda and DeMaria. "The findings from the present meta-analysis will hopefully further spur the design and implementation of lipid trials assessing specific LDL-cholesterol targets rather than specific drug doses."

The Results From the Meta-analysis

The investigators, including first author Dr Matthijs Boekholdt (Academic Medical Center), analyzed eight trials and 38 153 patients treated with statin therapy. The studies included some of the landmark statin trials, including AFCAPS-TexCAPS , 4S , LIPID , SPARCL , TNT , IDEAL , and JUPITER .

The investigators observed a large degree of interindividual variability in the reductions of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B (apoB) levels with statin therapy. Among those treated with high-dose statin therapy, more than 40% of patients failed to achieve an LDL-cholesterol target of less than 70 mg/dL.

Compared with individuals with LDL-cholesterol levels >175 mg/dL, which served as the reference group, individuals who achieved lower levels of LDL cholesterol had a significantly lower risk of major cardiovascular events. For those with LDL-cholesterol levels <50 mg/dL, 50 to <75 mg/dL, and 75 to <100 mg/dL, the relative reduction in risk was 56%, 49%, and 44%, respectively. Regarding the end point of major coronary events and cerebrovascular events, a similar trend was observed with lower LDL cholesterol levels.

Risk of Major Cardiovascular Events by LDL-Cholesterol Level (mg/dL)

Outcome LDL <50 50 to <75 75 to <100 100 to <125 125 to <150 150 to <175 > 175
Major cardiovascular events 0.44 (0.35–0.55) 0.51 (0.42–0.62) 0.56 (0.46–0.67) 0.58 (0.48–0.69) 0.64 (0.53–0.79) 0.71 (0.56–0.89) 1.00 (ref)

Similarly, the reduction in major cardiovascular, major coronary, and cerebrovascular events was significantly reduced among individuals who achieved lower and lower non-HDL cholesterol and apoB levels. Kastelein said a recent paper also suggested that non-HDL cholesterol was a more powerful risk predictor, closely followed by apoB and LDL cholesterol.

"The role of non-HDL cholesterol is very often discussed in reviews," said Kastelein. "Many people are slowly starting to believe it might be a better parameter to follow in patients treated with statins and later on [proprotein convertase subtilisin-kexin type 9] PCSK9-inhibitor therapy, especially if patients have higher triglycerides or have diabetes or the metabolic syndrome. In these individuals, non-HDL cholesterol more accurately predicts residual risk."

Going Low, Low, Low

This latest meta-analysis also showed that physicians can treat to very low levels of LDL cholesterol without any risk, according to the researchers. In their analysis, Kastelein and colleagues did not observe an increased risk of side effects among those who had LDL levels <50 mg/dL. This is positive news in the era of novel cholesterol-lowering drugs, said Kastelein.

The editorialists, however, point out that the risk of diabetes with statin therapy has been documented in clinical studies. In addition, there are some patients who are simply unable to tolerate high-dose statins. As result, Ben-Yehuda and DeMaria wonder what the future will hold for patients treated with these other agents.

"Is it acceptable if a patient reaches a desired LDL-cholesterol level at a less than moderate- or high-intensity statin dose, or is there an additional benefit to receiving a higher dose of a statin?" they ask. "Also uncertain is whether a statin-sparing combination therapy would be as efficacious as high-intensity agents."

Boekholdt reports consulting for Pfizer. Kastelein has received honoraria for serving on the speakers' bureaus of AstraZeneca, Genzyme, Isis Pharma, Kowa, Merck Sharp & Dohme, Novartis Pharmaceuticals, Pfizer, and Roche. Disclosures for the authors are listed in the article. Ben-Yehuda and DeMaria report no conflicts of interest.

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