Additional Benefit From Lowering Already Low LDL

Megan Brooks

August 03, 2018

Further lowering of low-density lipoprotein (LDL) cholesterol (LDL-C) levels in patients with already low LDL-C produced benefit in terms of reduced risk for major vascular events with no serious adverse effects, a large meta-analysis suggests.

Marc S. Sabatine, MD, Brigham and Women's Hospital, Boston, Massachusetts, and colleagues analyzed data for a subgroup of patients with mean baseline LDL-C levels of 1.7 mmol/L (65.7 mg/dL) from the Cholesterol Treatment Trialists Collaboration (CTTC) meta-analysis.

With statin therapy, the relative risk for major vascular events (coronary heart disease death, myocardial infarction, ischemic stroke, or coronary revascularization) was 22% lower for every 1-mmol/L (38.7 mg/dL) decrease in LDL-C (relative risk [RR], 0.78; 95% confidence interval [CI], 0.65 - 0.94).

A similar benefit emerged when the researchers analyzed data on more than 50,000 patients from three randomized trials of nonstatin LDL-C–lowering therapies added to statins: FOURIER, which used the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor evolocumab; IMPROVE-IT, which used ezetimibe; and REVEAL, which used the cholesteryl ester transfer protein inhibitor anacetrapib.

In these three trials, baseline LDL-C ranged from 1.6 mmol/L to 1.8 mmol/L (63 mg/dL to 70 mg/dL). Nonstatin therapy added to a statin lowered LDL-C by 0.3 to 1.2 mmol/L (11 mg/dL to 45 mg/dL), with a 21% relative risk reduction for major vascular events per 1-mmol/L (38.7 mg/dL) reduction in LDL-C (risk ratio, 0.79; 95% CI, 0.70 - 0.88).

The clinical benefit for every 1-mmol/L reduction in LDL-C was the same with statins or any of the nonstatin medications (combined relative risk reduction, 0.79; 95% CI, 0.71 - 0.87; P < .001), the researchers note.

The study was published online August 1 in JAMA Cardiology.

"There is a consistent relative risk reduction in major vascular events per change in LDL-C in patient populations starting as low as a median of 1.6 mmol/L (63 mg/dL) and achieving levels as low as a median of 0.5 mmol/L (21 mg/dL)," write Sabatine and colleagues.

Importantly, they say, further lowering of LDL-C was not associated with an increased risk for serious adverse events, myalgias and/or myositis, elevation in aminotransferases, new-onset diabetes, hemorrhagic stroke, or cancer.

Convincing Data, but Questions Remain

These are "very important data" and the parallel trends from the three trials plus the statin data are "quite convincing," Robert Bonow, MD, editor in chief, JAMA Cardiology, and professor of cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, said in a podcast he hosted discussing the findings.

With the PCSK9 inhibitors, "we are now at the point where you can essentially dial in your LDL level and get it as low as you like," Antonio Gotto Jr, MD, Weill Cornell Medicine in New York City, and author of a linked editorial, said in the podcast.

But the question remains, "How low should we go? How much is it worth to get this additional reduction and, over a long term period, can we be sure that very low levels are safe?" said Gotto. "We are born with a level of LDL in cord blood somewhere around 35 to 40 mg/dL, so I think the LDL is not like the appendix. I think it's there for some purpose and reason. These are questions we just don't know," he added.

In patients with established cardiovascular disease, Gotto said it's "certainly desirable to get LDL below 70 and I'd say down to 40 or so, but whether we want to go below that, I think that's still an unanswered question until we know the long-term effects of these drugs over a period of time. The relationship between statins, for example, and increased risk of developing type 2 diabetes took 20 years to demonstrate," said Gotto.

Sabatine, who also participated in the podcast, agreed. "I think for the highest-risk patients, it makes sense to really target getting their LDL cholesterol as low as possible to prevent recurrent MI [myocardial infarction], stroke, et cetera. At the population level, I'm not sure you need to drive everyone down that low, and in fact, more moderate changes done over a lifetime I think would actually yield very large population health benefits," said Sabatine.

Bonow said it will be "interesting to see" what impact these new data have on revision of American College of Cardiology/American Heart Association practice guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults, a process that is underway.

Sabatine reports receiving honoraria for consulting from Alnylam, Amgen, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, Dyrnamix, Esperion, Intarcia, Ionis, Janssen Research and Development, Medicines Company, MedImmune, Merck, MyoKardia, and Novartis. Gotto reports holding a position on the board of directors for Esperion Therapeutics, on the data safety monitoring board for Ionis Pharmaceuticals, and as a consultant for Kowa Pharmaceuticals.

JAMA Cardiol. Published online August 1, 2018. Abstract, Editorial

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