Lowering LDL With Statins and Other Selected Agents Should Be Focus of CVD Risk Reduction, Analysis Implies

Statins and other drugs that work by promoting the hepatic clearance of circulating LDL cholesterol achieve similar reductions in the risk of major vascular events with equivalent decreases in LDL cholesterol levels, a new analysis shows.

Each 1-mmol/L reduction in LDL cholesterol with statins, the equivalent of 38.7 mg/dL, was associated with a significant 23% reduction in the risk of major vascular events. Comparatively, each 1-mmol/L reduction in LDL cholesterol achieved with diet, bile acid sequestrants, ileal bypass surgery, and ezetimibe (Zetia, Merck/Schering-Plough), all of which act via the upregulation of LDL receptor expression, was associated with a 25% reduction in the risk of major vascular events.

The “virtually identical” reduction in vascular risk between statin and these nonstatin therapies “suggests there may not be anything magical about statins,” said senior investigator Marc Sabatine, MD (Brigham and Women’s Hospital, Boston, MA). “It may simply be LDL cholesterol reduction.”

Published today in the Journal of the American Medical Association, the study includes 312,175 subjects participating in 49 clinical trials, including 25 statin studies, 9 trials with fibrates, 4 dietary studies, 3 studies with niacin, 3 studies of CETP inhibition, 2 studies testing bile acid sequestrants, and 1 study of ileal bypass. IMPROVE-IT was the sole trial testing ezetimibe.      

To TCTMD, Sabatine said one of the issues in testing various nonstatin therapies is that these drugs, often given on top of statin therapy, had a relatively small impact on LDL cholesterol levels in clinical trials. In studies, the baseline LDL cholesterol levels of participants was quite low, which would result in a relatively smaller reduction in LDL cholesterol with the added therapy and a correspondingly smaller reduction in cardiovascular risk, he said.  

“The question is whether the risk reduction observed with different interventions is simply proportional to the amount of LDL cholesterol reduction,” said Sabatine. “Does it depend on the drug or does it depend on the amount of LDL cholesterol lowering? The answer turns out to be both, in that the nonstatin interventions that work by helping the liver clear LDL cholesterol out of circulation all appear to be equally effective in reducing the risk of cardiovascular events when you normalize the amount of LDL cholesterol reduction the intervention achieves.”

Speaking with TCTMD, Donald Lloyd-Jones, MD (Northwestern University, Chicago, IL), who co-chaired the American College of Cardiology/American Heart Association guidelines on the assessment of cardiovascular risk, said the new analysis is an excellent demonstration of an important principle, one that was emphasized in the 2013 cholesterol guidelines. “Lowering LDL cholesterol, and getting LDL to lower levels, is important for reducing events, but it matters how you do it,” said Lloyd-Jones. “This paper reinforces that message. Not all LDL lowering is equal.”

Nearly 50 Trials Studied

In their analysis, the investigators combined data from the 25 statin studies and 8 studies of diet, bile acid sequestrants, ileal bypass, and ezetimibe—the drug classes that work via the upregulation of LDL receptor expression—and showed that each 1-mmol reduction in LDL cholesterol reduced the risk of vascular events by 23% (RR 0.77; 95% CI 0.75-0.79).

In contrast, the relative reduction in vascular risk achieved with niacin and fibrates was much smaller. In the analysis, similar reductions in LDL cholesterol with niacin translated into a 6% reduction in vascular events. With fibrates, the reduction in LDL cholesterol was associated with a 12% reduction in vascular events. Based on the meta-regression analysis, where the relative risk of vascular events was plotted against the achieved LDL cholesterol reduction, the estimated reduction in risk with niacin was smaller than expected. With fibrates, the reduction in risk was larger than expected.       

LDL cholesterol reductions with cholesteryl ester transfer protein (CETP) inhibitors had no significant impact on vascular events (RR 1.01; 95% CI 0.95-1.09). Based solely on the LDL reduction achieved in the 3 studies of CETP inhibition, a decrease in vascular risk would have been expected. The CETP inhibitors have largely failed in clinical testing, with two studies showing insufficient efficacy and one, torcetrapib, causing an excess of patient deaths.

For Lloyd-Jones, agents that reduce LDL cholesterol levels by mechanisms other than the LDL receptor pathway are clearly weaker and known to be less safe. In the Heart Protection Study-2, for example, there was no clinical benefit of adding niacin and laropiprant, an antiflushing agent, to statin therapy. In fact, niacin/laropiprant was associated with an increased risk of adverse events, such as diabetic complications, new-onset diabetes, infections, and bleeding. AIM-HIGH, a similar study with niacin, was stopped early for lack of benefit, and there was a signal of an increased risk of ischemic stroke.

Niacin, said Lloyd-Jones, has no part in routine clinical care—certainly not for LDL cholesterol reduction—and should not be started. Bile acid sequestrants and ileal bypass are included in the 2013 clinical guidelines for the management of cholesterol, although they are not as effective in lowering LDL cholesterol, he added. That said, the options are safe and well tolerated.     

Reducing the Risk Factor, Which is Cholesterol

The researchers also analyzed the PCSK9 inhibitors alirocumab (Praluent, Sanofi/Regeneron) and evolocumab (Repatha, Amgen), estimating that each 1-mmol reduction in LDL cholesterol translates into a 51% reduction in the risk of vascular events. Based on the regression analysis, their estimated reduction is slightly larger than expected based on preliminary studies. The large-scale cardiovascular outcomes trials testing alirocumab and evolocumab are currently underway, with the FOURIER trial, led by Sabatine and others, expected to be presented in early 2017.

PCSK9 inhibitors also work via the hepatic clearance of LDL cholesterol, but given the lack of randomized outcomes trials with these drugs, the class was analyzed separately, said Sabatine. The reduction in vascular events with the PCSK9 inhibitors is consistent with their overall findings, with the risk protection conferred to drug classes that work via the upregulation of LDL receptor expression, he said.

“There’s clear evidence that statins are very effective for reducing LDL cholesterol and they’re very effective for reducing cardiovascular events,” said Sabatine. “In the 2013 cholesterol guidelines, which were a departure from prior guidelines in that they really focus almost exclusively on statins, really abandoned any discussion of LDL cholesterol targets. The concern was that this might prompt some physicians to focus simply on giving a drug rather than managing the underlying risk factor, which is LDL cholesterol.”

To TCTMD, Sabatine said the take-home message from their analysis is that physicians shouldn’t be focused only on prescribing medication, whether it is moderate- or high-intensity statin therapy. Instead, treatment should return to “looking at the patient and wanting to reduce their risk factor, which is LDL cholesterol, and then asking, what tools do I have at my disposal that are effective?” said Sabatine. “And really, all the agents that work by the upregulation of LDL clearance by the liver are all equally effective if you normalize it for LDL reduction.”

Statins, after diet, are the logical cornerstone of clinical care, said Sabatine, given their effectiveness in lowering LDL cholesterol, safety profile, and cost-effectiveness. After statins, it’s a question of how much additional LDL-cholesterol reduction the patient needs, he added. “Again, I think lower is better and I think we should be targeting well below 70 mg/dL, so based on where that patient’s LDL cholesterol is, it’s a matter choosing a drug to get them to that level,” said Sabatine.   

Lloyd-Jones also emphasized the importance of statins as first-line agents. In April 2016, the American College of Cardiology updated their recommendations for the management of elevated LDL cholesterol levels in high-risk patients. The new “decision pathway,” which was chaired by Lloyd-Jones, states the addition of ezetimibe 10 mg is a reasonable option for patients who require additional LDL lowering beyond that achieved with a statin. Once ezetimibe has been tried, only then should physicians consider adding or replacing ezetimibe with one of the PCSK9 inhibitors.





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  • Silverman MG, Ference BA, Im K, et al. Association between lowering LDL-C and Cardiovascular risk reduction among different therapeutic interventions. JAMA 2016;12:1289-1297.

  • Sabatine reported receiving grant support through Brigham and Women’s Hospital from Abbott Laboratories, Accumetrics, Amgen, AstraZeneca, Bristol-Myers Squibb, Critical Diagnostics, Daiichi Sankyo, Eisai, Genzyme, Gilead, GlaxoSmithKline, Intarcia, Janssen Research and Development, MedImmune, Merck, Novartis, Poxel Roche Diagnostics, Sanofi-Aventis, and Takeda; and serving as a consulting for Alnylam, Amgen, AstraZeneca, Bristol-Myers Squibb, Cubist, CVS Caremark, Intarcia, Ionis, The Medicines Company, Merck, MyoKardia, Pfizer, Quest Diagnostics, Sanofi-Aventis, and Zeus Scientific.
  • Lloyd-Jones reports no conflicts of interest.

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