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Low LDL Cholesterol, but Not Statin Use, Associated With an Increased Risk of Cancer

  • Authors: News Author: Michael O'Riordan
    CME Author: Désirée Lie, MD, MSEd
  • CME/CE Released: 8/22/2008
  • Valid for credit through: 8/22/2009, 11:59 PM EST
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Target Audience and Goal Statement

This article is intended for primary care clinicians, cardiologists, oncologists, and other specialists who care for patients who are taking statin medications.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  1. Describe the association between low-density lipoprotein cholesterol levels and the risk for cancer.
  2. Describe the association between statin use and cancer risk.


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  • Michael O'Riordan

    Michael O'Riordan is a journalist, part of the WebMD Professional Network. Previously, he worked for WebMD Canada. Michael studied at Queen's University in Kingston and the University of Toronto and has a master's degree in journalism from the University of British Columbia, where he specialized in medical reporting. He can be contacted at [email protected].


    Disclosure: Michael O'Riordan has disclosed no relevant financial relationships.


  • Laurie E. Scudder, MS, NP-C

    Nurse Planner, Medscape; Adjunct Assistant Professor, School of Health Sciences, George Washington University, Washington, DC;  Curriculum Coordinator, Nurse Practitioner Alternatives, Inc., Ellicott City; Nurse Practitioner,  Baltimore City School-Based Health Centers, Baltimore, Maryland


    Disclosure: Laurie Scudder, MS, NP-C, has disclosed that she has owns stock, stock options, or bonds in Johnson & Johnson and Procter & Gamble.


  • Brande Nicole Martin

    Brande Nicole Martin is the News CME editor for Medscape Medical News.


    Disclosure: Brande Nicole Martin has disclosed no relevant financial information.

CME Author(s)

  • Désirée Lie, MD, MSEd

    Clinical Professor, Family Medicine, University of California, Orange; Director, Division of Faculty Development, UCI Medical Center, Orange, California


    Disclosure: Désirée Lie, MD, MSEd, has disclosed no relevant financial relationships.

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Low LDL Cholesterol, but Not Statin Use, Associated With an Increased Risk of Cancer

Authors: News Author: Michael O'Riordan CME Author: Désirée Lie, MD, MSEdFaculty and Disclosures

CME/CE Released: 8/22/2008

Valid for credit through: 8/22/2009, 11:59 PM EST


From Heartwire — a professional news service of WebMD

August 22, 2008 — There is an inverse and significant association between on-treatment low-density lipoprotein (LDL)-cholesterol levels and cancer in statin-treated patients, an association that remained even after adjustment for age and other variables, a new analysis has shown [1]. However, there was a similar relationship between LDL-cholesterol levels and incident cancer among control patients not treated with statins, report investigators, and statin therapy, despite significantly reducing LDL-cholesterol levels, was not associated with an increased risk of cancer.

"We found that there is indeed an association, that the lower the LDL cholesterol, the higher the risk of cancer," senior investigator Dr Richard Karas (Tufts University School of Medicine, Boston, MA) told heartwire . "Despite the LDL-lowering capacity of statins, however, the data are quite reassuring that statins don't increase the risk of cancer."

The analysis, published online today as an expedited paper in the Journal of the American College of Cardiology (JACC), was prompted by a 2007 study published in JACC by Dr Alawi Alsheikh-Ali (Tufts University School of Medicine), of which Karas was also senior author. The study, reported by heartwire at that time, was initially designed to determine whether there was a correlation between the extent to which statins lowered LDL-cholesterol levels and liver and muscle toxicity, but it raised some alarm, as it showed lower LDL-cholesterol levels were associated with an increased risk of cancer in various statin studies.

"This raised the obvious question and concern that interventions that lower LDL cholesterol might offset the lowered risk of heart disease by increasing the risk of cancer," said Karas. "There is a bit of a conundrum, because previous studies have looked at whether the use of statins increased the risk of cancer, and the answer to that was no. So we had a bit of quandary: how could it be that low LDL is associated with a higher risk of cancer, but statins, which lower LDL cholesterol, don't seem to cause cancer?"

Background to the new research

With these questions in mind, Alsheikh-Ali and Karas, as lead and senior investigators, respectively, reviewed data from 15 randomized controlled trials of statins that included ≥ 1000 person-years of follow-up to determine whether statin-mediated reductions in LDL cholesterol were associated with a cancer risk. Overall, they reviewed data on 51,797 patients treated with statins and 45,043 patients treated with a placebo, and patients were followed for, on average, 4.5 years. During that time, there were 5752 new cases of cancer reported.

Assessing on-treatment LDL-cholesterol levels and incident cancer in the statin arms, they observed a significant inverse relationship between on-treatment LDL levels and cancer risk, with 2.2 incident cancers per 1000 patient-years for every 10-mg/dL decrease in LDL cholesterol. The relationship was significant after adjustment for various baseline variables, including age, gender, smoking status, diabetes mellitus, hypertension, and body-mass index. Similarly, they also observed an inverse relationship between on-treatment LDL-cholesterol levels and cancer risk among individuals treated with placebo, with 1.2 incident cancer per 1000 patient-years for every 10-mg/dL decrease in LDL cholesterol.

After analyzing whether statin use was associated with cancer risk compared with placebo, Karas said it was not. Among placebo-treated patients, there was an average of 12.6 new cancer cases for 1000 person-years of follow-up. With 2.2 cancers for every 10-mg/dL decrease in LDL cholesterol, and statin interventions lowering LDL cholesterol a mean of 40 mg/dL, there would be approximately eight more cancer cases per 1000 person-years of follow-up in the statin arms. This was not the case, however, as the cancer rate among those treated with a statin was 12.7 per 1000 person-years of follow-up, nearly identical to the placebo arm.

Although Karas said the data are reassuring that statins do not increase the risk of cancer, he said the study is a wake-up call for heart-disease researchers to track and monitor the development of cancer so there is a better understanding of the overall risk and benefit of these interventions. In addition, there is a need for more basic science research to understand the biology behind the association between low LDL-cholesterol levels and cancer risk.

"We don't know why it's true, and we can only speculate about the reason," Karas told heartwire . One possible mechanism might be related to the counterbalancing role of the inflammatory system and atherosclerosis. Individuals who develop atherosclerosis, he said, have overactive immune systems, whereas those without atherosclerosis have a low activation of the immune system. "People with low levels of LDL also have a low risk of atherosclerosis, but it's not known if they have low levels of inflammatory reactions. That's important, because the immune system is part of the surveillance system for ridding the body of cancer. Your own immune system is trying to find cells that are mutating into cancer cells and get rid of them."

Two editorials weigh in on the issue

Two editorials accompany the publication of the analysis by Alsheikh-Ali and colleagues, one by Dr Daniel Steinberg [2] and one by Drs Ori Ben-Yehuda and Anthony DeMaria [3], all of whom are from the University of California, San Diego (UCSD).

Commenting on the findings, Steinberg, an advocate of pushing LDL-cholesterol levels to as low 50 mg/dL to prevent cardiovascular disease, agrees with the investigators about the safety of statin therapy, noting that statins had "nothing to do with" the cancer risk observed with the low levels of LDL cholesterol. Untreated subjects, he points out, had the same "low-LDL/higher-cancer-risk" relationship as those treated with statins, and the epidemiologic correlation should not be interpreted as a causal connection.

To account for the association between low LDL cholesterol and cancer risk, Steinberg believes this is the "unsuspected-sickness phenomenon," with cholesterol levels lowered by subclinical disease. He notes that cancers can significantly lower cholesterol levels almost a decade before they surface clinically. "The randomly recruited cohorts in the large statin trials undoubtedly included some subjects who had low LDL levels at the time they entered the study because they already had cancer," writes Steinberg. "Low LDL is the result, not the cause, of cancer."

Karas is not convinced of such an interpretation, noting that the studies excluding the first five years of follow-up, when cancer is likely to show up in individuals with latent disease, still show an excess of cancer among those with low LDL-cholesterol levels. Moreover, most randomized controlled clinical trials include only healthy patients, with cancer patients not likely to be enrolled.

In a review paper published just a few weeks ago [4], Steinberg, along with Drs Christopher Glass and Joseph Witztum (both also from UCSD), said clinicians are doing "too little, too late" and pushed for more aggressive use of lipid-lowering therapies and earlier intervention in the development of atherosclerosis. In his editorial, he reiterates his case, writing that low LDL-cholesterol levels do not carry any intrinsic danger of cancer or other serious consequences.

Ben-Yehuda and DeMaria, the editors of JACC, write that the 2007 Alsheikh-Ali paper that first uncovered the cancer risk stimulated intense scrutiny and discussion. They are not entirely convinced the issue is resolved, either. The Effects of Simvastatin and Ezetimibe on Clinical Outcomes in Patients with Aortic Stenosis (SEAS) trial, a study presented last month during a press conference and slated for presentation at the European Society of Cardiology 2008 Congress in Munich, Germany in September, also had significantly higher rates of cancer in the active arm compared with the placebo-treated patients.

While an analysis of two other studies — Improved Reduction of Outcomes: VYTORIN Efficacy International Trial (IMPROVE-IT) and Study of Heart and Renal Protection (SHARP) — showed no excess of cancers, Ben-Yehuda and DeMaria write that the link between low LDL-cholesterol levels and cancer has not yet been resolved, even if it appears that statins do not increase the risk of cancer. Like Karas, they note the reporting of cancer rates is incomplete in many studies, and further research is needed. They are reassured by the Tufts University analysis, but new data from SEAS highlight the need for more study.

Dr. Karas has received honoraria from Merck and Abbot and research support from Pfizer. Dr. Alsheikh-Ali is the recipient of a faculty development award from Pfizer/Tufts Medical Center. Dr. Ben-Yehuda has served as an adviser to Schering-Plough Pharmaceuticals and received research grants from Merck.


  1. Alsheikh-Ali AA, Trikalinos TA, Kent DM, Karas RH. Statins, low-density lipoprotein cholesterol, and risk of cancer. J Am Coll Cardiol. 2008; DOI: 10.1016/j.jacc.2008.06.037. Available at:
  2. Steinberg D. Statin treatment does not cause cancer. J Am Coll Cardiol. 2008; DOI: 10.1016/j.jacc.2008.06.036. Available at:
  3. Ben-Yehuda O, DeMaria AN. Low LDL-C levels and cancer: Reassuring but still not definitive. J Am Coll Cardiol. 2008; DOI: 10.1016/j.jacc.2008.08.001. Available at:
  4. Steinberg D, Glass CK, Witztum JL. Evidence mandating earlier and more aggressive treatment of hypercholesterolemia. Circulation. 2008;118:672-67.

The complete contents of Heartwire , a professional news service of WebMD, can be found at, a Web site for cardiovascular healthcare professionals.

Clinical Context

Previous studies have demonstrated an inverse association between on-treatment LDL-cholesterol level with statin use and the risk for cancer, rasing concerns about the association between statin use and cancer risk, but this association could reflect the level of LDL cholesterol only, independent of statin use.

This is a meta-analysis and meta-regression study of trials of statin use for LDL-cholesterol lowering, accounting for on-treatment LDL-cholesterol levels to determine if the association of LDL cholesterol with cancer risk is attributable to statins.

Study Highlights

  • The investigators conducted a MEDLINE search July 2007 for eligible randomized clinical trials of satin therapy that included LDL-cholesterol levels at baseline and during the study, with at least 1000 person-years of follow-up.
  • They also searched the reference lists of meta-analyses.
  • From the articles, data on the type of statin, dose, numbers of patients, LDL-cholesterol levels, follow-up duration, and number of patients with a diagnosis of new cancer were extracted.
  • The association of on-treatment LDL-cholesterol levels and cancer risk was determined by univariate meta-regression for patients receiving statins and patients receiving control medication.
  • The association of on-treatment LDL-cholesterol levels and cancer risk was then compared for the 2 groups.
  • Of 2026 citations screened at the abstract level, 15 statin trials were eligible, of which there were 19 statin groups and 14 control groups with a total of 51,797 patients receiving statins and 45,043 patients receiving control treatment for a mean of 4.4 years.
  • There was an inverse association between on-treatment LDL-cholesterol levels and incident cancer in the statin groups, with 2.2 incident cancers per 1000 person-years for every 10-mg/dL decrement in LDL-cholesterol level.
  • There was also a significant association between incident cancer and age (P = .031) and a history of hypertension (P = .049).
  • In the control groups, there was also an inverse association between LDL-cholesterol levels and cancer incidence, with an excess of 1.2 incident cancers per 1000 person-years for every 10-mg/dL decrement in LDL-cholesterol level (P = .09).
  • However, when on-treatment LDL-cholesterol level and cancer risk for the statin and control groups was compared, there was no association between statin use and cancer risk.
  • The authors concluded that the association between low LDL-cholesterol level and cancer was independent of statin use during the time frame analyzed for the studies.
  • One possible explanation was that LDL-cholesterol lowering with statins had both a proneoplastic and an antineoplastic effect resulting in a neutral effect on cancer risk.
  • Another possibility was that the duration examined was too short to demonstrate a neoplastic effect of statins.
  • Yet another theory is that the risk for cancer was a proxy for the reverse association of the LDL-cholesterol–lowering effect of early, undetected cancer.

Pearls for Practice

  • There is an inverse association between LDL-cholesterol level and the risk for cancer.
  • Statin use alone is not associated with an increased risk for cancer during 4 years of follow-up.


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