‘Lower Is Better’ Mantra for LDL Cholesterol Questioned by New Analysis, but Experts Urge Caution

Achieving an LDL cholesterol level of 70 to 100 mg/dL is protective against major adverse cardiac events in statin-treated patients with stable ischemic heart disease, but going lower doesn’t seem to carry any additional benefit, an observational study suggests. Experts caution, however, against drawing any definitive conclusions based on the results.

Take Home. ‘Lower is Better’ Mantra for LDL Cholesterol Questioned by New Analysis, but Experts Urge Caution

“Our data do not support recommendations that treating to LDL-C levels below 70mg/dL [is] relevant for all patients with ischemic heart disease, particularly those who are adherent to statin treatment,” lead author Morton Leibowitz, MD (Clalit Research Institute, Tel Aviv, Israel), and colleagues write in a study published online June 20, 2016, ahead of print in JAMA Internal Medicine.

The European Society of Cardiology and European Atherosclerosis Society guidelines call for a reduction to below 70 mg/dL—and/or at least a 50% reduction—in patients at very high cardiovascular risk, while aiming for less than 100 mg/dL in patients at high risk. Similar goals are recommended by the National Lipid Association (NLA), which also gives advice on other treatment targets including non-HDL cholesterol.

Guidelines from the American College of Cardiology and American Heart Association (ACC/AHA) differ in that they do not have established goals. Instead, there are recommendations to use statins at the appropriate intensity to reduce a patient’s cardiovascular risk.

Commenting to TCTMD, James Underberg, MD (NYU Langone Medical Center, New York, NY), who was not involved in the current study, said there is more agreement than conflict across the various guidelines, because they are all based on assessments of cardiovascular risk and all recommend using higher-intensity therapy for patients at higher risk.

In general, the findings of the Israeli study are consistent with the body of evidence correlating LDL cholesterol levels to cardiovascular risk, said Underberg, who is president-elect of the NLA. “I think this is more confirmatory of the LDL hypothesis—I hate calling it a hypothesis because I think it’s clearly been proven—that lower is better when it comes to treatment, certainly with statins,” he said.

The lack of an observed risk reduction at LDL cholesterol levels below 70 mg/dL in the current study could be explained by many factors—such as diabetes, renal disease, hypertension, and metabolic syndrome, which tend to be associated with lower LDL levels—that cannot adequately be accounted for in observational datasets, Underberg said. The study also did not include information on use of cholesterol-lowering medications other than statins, on absolute changes in LDL levels, or on non-HDL cholesterol levels; the latter, he added, have been shown to be more predictive of cardiovascular risk than LDL cholesterol levels.

Ultimately, observational data can only be hypothesis-generating and cannot be used to change practice, especially when they are not consistent with established literature, he said.

“I think you have to be careful in how you interpret observational cohorts, as history has taught us over and over again,” Underberg said, adding that the study “certainly doesn’t dissuade me from current recommendations and guidelines.”

The Study

Leibowitz and colleagues looked at data from a healthcare organization in Israel covering more than 4.3 million members. They included 31,619 patients ages 30 to 84 years who had stable ischemic heart disease and were adherent to statin therapy ( ≥80% of prescriptions filled) for at least a year before an index LDL cholesterol measurement. Those with active cancer or metabolic abnormalities, including LDL cholesterol levels over 130 mg/dL, were excluded.

The patients were divided into three groups according to their index LDL cholesterol measurement:


  • Low (70.0 mg/dL or lower): 29%
  • Moderate (70.1 to 100.0 mg/dL): 53%
  • Higher (100.1 to 130.0 mg/dL): 18%


Through a mean 1.6 years of follow-up, rates of MACE (acute MI, unstable angina, stroke, PCI, CABG, or all-cause mortality) across the three groups—from low to high—were 29.5%, 27.4%, and 30.6%.

On multivariate adjustment, there was no difference in risk between the low and moderate groups (HR 1.02; 95% CI 0.97-1.07), with lower risk seen in the moderate versus high group (HR 0.89; 95% CI 0.84-0.94). Results of a propensity-matched analysis and of an analysis excluding all-cause mortality from the composite endpoint were consistent with those findings.

An analysis of LDL cholesterol as a continuous variable showed that the protective effect of lower levels was no longer significant below about 90 mg/dL.

Certain Patients May Benefit From Lower Levels

Commenting on the research, Neil Stone, MD (Northwestern Memorial Hospital, Chicago, IL), who chaired the writing group for the ACC/AHA cholesterol guidelines, told TCTMD that even though the study includes large patient numbers it cannot be considered conclusive because of the observational design. His concerns centered on the potential for unmeasured confounding and the impact of diabetes, which is associated with a higher coronary risk at any LDL cholesterol level.

“Perhaps what this observational study suggests is that there’s a group of people who don’t need aggressive therapy with high-intensity statins, but it doesn’t mean that there aren’t those with CAD who do need it,” Stone said. “We know from studies of intravascular ultrasound and we know from clinical studies of people with an acute coronary syndrome that there are subgroups who benefit greatly from high-intensity statin therapy.”

In a prepared statement Leibowitz sent to TCTMD, the study authors concede that variability of LDL cholesterol and other potential confounders could have influenced the findings despite propensity matching.

They also acknowledge that “this study’s results do not exclude the possibility that certain subpopulations will benefit from more intensive statin treatment to achieve lower LDL-C levels; this warrants further investigation to identify whether such subgroups exist.”





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Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

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  • Leibowitz M, Karpati T, Cohen-Stavi CJ, et al. Association between achieved low-density lipoprotein levels and major adverse cardiac events in patients with stable ischemic heart disease taking statin treatment. JAMA Intern Med. 2016;Epub ahead of print.

  • The study was funded by the Clalit Research Institute as part of its role in providing policy decision-making support as an internal branch of the Clalit Health Services healthcare organization.
  • Leibowitz and Stone report no relevant conflicts of interest.
  • Underberg reports serving as a consultant to Aegerion, Amarin, Amgen, AstraZeneca, Eli Lilly, Sanofi, Alexion, Synageva, and Recombine; performing contracted research for Aegerion, Genzyme, and Pfizer; serving on the advisory board for Amgen, Aegerion, Sanofi, Regeneron, Genzyme, and Akcea; and serving on the speakers bureau for Amgen, Regeneron, AstraZeneca, Merck, and Alexion/Synageva.