LDL, Statins and Cancer Risk

Jacob Schor, ND, FABNO

November 25, 2008

There appears to be a link between low levels of low density lipoprotein  (LDL) and risk of cancer.  Everyone is well aware of the link between high levels of LDL and heart disease.  That’s the cholesterol issue people worry about.  Still for a number of years researchers have been concerned about low LDL because of a possible link to cancer and feared that lipid lowering drugs might be somehow causing these cancers.

As of September 30, 2008 we can breath a sigh of relief as the current opinion is that statins do not cause cancer.  At least for now.  This business is complicated.  For an example read this sentence from Elsevier Global Medical News about this business and see if it makes sense:

“There is no evidence that statin use causes cancer, although patients who reduce their LDL cholesterol level with statins appear to have a significantly increased risk of the disease…..”

As with many complicated things, the best way to understand this is to start at the beginning.

In the July 2007 edition of the Journal of the American College of Cardiology, Dr. Alawi A. Alsheikh-Ali of Tufts University, and colleagues reported a significant relationship between low LDL cholesterol levels and cancer among patients who take statins. No disrespect meant but I am going to abbreviate the esteemed Dr Alsheikh-Ali’s name as A-4. He and his colleagues were analyzing older studies to see if there was a relationship between how much a statin drug lowered LDL cholesterol and the risk of liver or muscle damage from the drugs.  They evaluated 23 prior drug trials yielding 309,506 person-years of follow-up data.  They found no significant relationship between how much the LDL cholesterol decreased while taking the drugs to liver damage as measured by elevated liver enzymes or muscle damage called rhabdomylysis.  As expected these unwanted side effects were correlated to drug doses.  What they did see that got our attention is that, “… the risk of cancer is significantly associated with lower achieved LDL-C levels. …. the cardiovascular benefits of low achieved levels of LDL-C may in part be offset by an increased risk of cancer.” 

In simpler words lower LDL levels in these studies were associated with increased risk of cancer.  The obvious concern was that statins cause cancer.

This came as a surprise to many as over the past decade there had been a feeling that statins might offer some protection against cancer.    This hope was dampened by 2006 paper wasn’t able to show any protection.

The concern that statins could cause cancer is certainly not new. Newman pointed this out in a JAMA article in 1996.

Dr. A-4 and colleagues went back to their data and published the definitive follow up paper this September 30.

 

In their first paper they only looked at data from patients taking statins.  This new paper included data from both people taking the drugs and those in the control groups not taking the drugs. It included data gathered in 15 randomized, controlled trials that included more than 97,000 patients yielding 437,000 person-years of follow-up.

During these trials, 5,752 patients developed a new cancer. The incidence was 4%-27% per 1,000 person-years of those taking statins, and 6%-24% per 1,000 person-years in the people not taking the drugs. There wasn’t an appreciable difference between those taking statins and those not.  Yet in every analysis of the data, the low LDL cholesterol and increased risk for cancer association remained strong.

This was true even for the patients getting placebo and not taking statins.

So if it isn’t the statins that are to blame, what is going on?   Accompanying the article by A-4 et al was an editorial by Daniel Steinberg  suggesting the LDL association is an "unsuspected sickness phenomenon": instead of low LDL causing cancer, undiagnosed early cancers were lowering the LDL.

"We know that cancers can significantly lower cholesterol levels as much as 10 years before they surface clinically," Dr. Steinberg wrote. In other words people were recruited into these studies with undiagnosed cancer.  In hindsight we might have suspected they had cancer because of their low cholesterol levels.

Cancer cells use LDL cholesterol at a faster than normal cells.  Thus it is reasonable to expect that any large randomly recruited population followed for 5 years, even with no statin treatment, will yield data showing this relationship between low LDL and cancer.

This seems to be a reasonable explanation even if three of the four study authors get paid by drug companies that sell statin drugs.

The question that we are left unanswered is how much should we be worry about patients that have low LDL cholesterol and who are not taking statin drugs?  Is there a level at which we should consider low LDL an early warning and actively look for the cancer?   Though this would seem to be useful information to have, these current studies do not address these questions.  Their focus was proving statins safe.

But what about cholesterol, particularly LDL as a predictor for other illnesses besides cardiovascular disease.

A 2005 paper in the Journal of American Geriatric Society tell us that low cholesterol is a ‘robust predictor of early mortality.’  Old people with low cholesterol die sooner than those with high cholesterol. 

Elderly people with levels of total cholesterol, non-HDL cholesterol, and LDL cholesterol in the lowest quartile were about twice as likely to die as those in the highest quartile.   That wasn’t what you were expecting to read.

About the same results are reported in a 2008 paper in Age and Aging; older people with low cholesterol are twice as likely to die as those with high cholesterol.  This affects Hispanics less affected than your typical white guys.   Unfortunately though those people in the upper quartile of LDL levels live longer they are almost three times as likely to get heart disease or stroke.

Yet we are still stuck with the same quandary; are high LDL levels helpful or are low LDL levels just an early warning of cancer and that’s why people with low LDL more likely to die?

So what’s our bottom line here?  It seems that low LDLs are a possible early warning sign of cancer and possibly of other causes of death. 

Links to past cholesterol articles:

We’ve sent out several earlier newsletters about concerns about lipid lowering medications. A 2004 newsletter touched on our concerns about C Q-10 depletion, suicide rates and early concerns about cancer.

http://denvernaturopathic.com/news/lipitor.html

Another newsletter touched on the statin concerns raised in the book, Overdosed America;  the data don’t support current cholesterol guidelines for women.

http://denvernaturopathic.com/OverdosedAmerica.htm

References:

Sullivan, MG. Statins Don't Cause Cancer in Patients With Low LDL Cholesterol.

Elsevier Global Medical News. 20080720

Alsheikh-Ali AA, Maddukuri PV, Han H, Karas RH. Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials.  J Am Coll Cardiol. 2007 Jul 31;50(5):409-18.

Bonovas S, Filioussi K, Tsavaris N, Sitaras NM.  Statins and cancer risk: a literature-based meta-analysis and meta-regression analysis of 35 randomized controlled trials. J Clin Oncol. 2006 Oct 20;24(30):4808-17.      Department of Pharmacology, School of Medicine, University of Athens, Greece. sbonovas@med.uoa.gr

    PURPOSE: A growing body of literature suggests that statins may have chemopreventive potential against cancer. Our aim was to examine the strength of this association through a detailed meta-analysis and meta-regression analysis of randomized controlled trials (RCTs). METHODS: A comprehensive search for trials published up to 2005 was performed, reviews of each study were conducted, and data were abstracted. Before meta-analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk (RR) estimates and 95% CIs were calculated using the random- and fixed-effects models. Subgroup, sensitivity, and meta-regression analyses were also conducted. RESULTS: Thirty-five RCTs of statins for cardiovascular outcomes contributed to the analysis (n = 109,143). The degree of variability between trials was consistent with what would be expected to occur by chance alone. Statin use was not associated with a substantially increased or decreased overall risk of cancer (RR = 0.99; 95% CI, 0.94 to 1.04). Similarly, statin use did not significantly affect respiratory cancer risk (RR = 0.95; 95% CI, 0.83 to 1.09). However, the meta-regression analysis indicated that age of study participants modified the association between statin use and cancer risk (P = .003). CONCLUSION: Our findings do not support a protective effect of statins against cancer. However, this conclusion is limited by the relatively short follow-up periods (4.5 years on average) of the studies analyzed. Thus, it is important to continue monitoring the long-term safety profiles of statins. Until then, physicians need to be vigilant in ensuring that statin use remains restricted to the approved indications.

JAMA. 2006 Jan 4;295(1):74-80.  

    Statins and cancer risk: a meta-analysis.    Dale KM, Coleman CI, Henyan NN, Kluger J, White CM.

    University of Connecticut School of Pharmacy, Storrs, Conn, USA.

    CONTEXT: Statins are cholesterol-lowering drugs that have been proven in randomized controlled trials to prevent cardiac events. Recent retrospective analyses have suggested that statins also prevent cancer. OBJECTIVES: To investigate the effect of statin therapy on cancer incidence and cancer death and to analyze the effect of statins on specific cancers and the effect of statin lipophilicity or derivation. DATA SOURCES: A systematic literature search of MEDLINE, EMBASE, CINAHL, Web of Science, CANCERLIT, and the Cochrane Systematic Review Database through July 2005 was conducted using specific search terms. A review of cardiology and cancer abstracts and manual review of references was also performed. STUDY SELECTION: Twenty-seven of the 8943 articles (n = 86,936 participants) initially identified met the inclusion criteria, reporting 26 randomized controlled trials of statins, with a mean duration of follow-up of at least 1 year, enrolling a minimum of 100 patients, and reporting data on either cancer incidence (n = 20 studies) or cancer death (n = 22 studies). DATA EXTRACTION: All data were independently extracted by 3 investigators using a standardized data abstraction tool. Weighted averages were reported as odds ratios (ORs) with 95% confidence intervals (CIs) using a random-effects model (DerSimonian and Laird methods). Statistical heterogeneity scores were assessed with the Q statistic. DATA SYNTHESIS: In meta-analyses including 6662 incident cancers and 2407 cancer deaths, statins did not reduce the incidence of cancer (OR, 1.02; 95% CI, 0.97-1.07) or cancer deaths (OR, 1.01; 95% CI, 0.93-1.09). No reductions were noted for any individual cancer type. This null effect on cancer incidence persisted when only hydrophilic, lipophilic, naturally derived, or synthetically derived statins were evaluated. CONCLUSIONS: Statins have a neutral effect on cancer and cancer death risk in randomized controlled trials. We found that no type of cancer was affected by statin use and no subtype of statin affected the risk of cancer.

Free text: http://jama.ama-assn.org/cgi/content/full/295/1/74

Newman TB, Hulley SB.Carcinogenicity of lipid-lowering drugs. JAMA 1996 Jan 3;275(1):55-60

J Am Coll Cardiol. 2008 Sep 30;52(14):1141-7.  

    Statins, low-density lipoprotein cholesterol, and risk of cancer.    Alsheikh-Ali AA, Trikalinos TA, Kent DM, Karas RH.

    Institute for Clinical Research and Health Policy Studies, Department of Medicine, Tufts Medical Center and Tufts University School of Medicine, Boston, Massachusetts 02111, USA.

    OBJECTIVES: We sought to assess whether statin-mediated reductions in low-density lipoprotein cholesterol (LDL-C) are associated with an increased risk of cancer. BACKGROUND: We recently reported an inverse association between on-treatment LDL-C levels and incident cancer in statin-treated patients enrolled in large randomized controlled trials, raising concern that LDL-C lowering by statins may increase cancer risk. However, meta-analyses suggest a neutral overall effect of statins on incident cancer. METHODS: A systematic literature search identified 15 eligible randomized controlled trials of statins with >or=1,000 person-years of follow-up that provided on-treatment LDL-C levels and rates of incident cancers (19 statin and 14 control arms, 437,017 person-years cumulative follow-up, and 5,752 incident cancers). RESULTS: In the statin arms, meta-regression analysis demonstrated an inverse association between on-treatment LDL-C and incident cancer, with an excess of 2.2 (95% confidence interval: 0.7 to 3.6) cancers per 1,000 person-years for every 10 mg/dl decrement in on-treatment LDL-C (p=0.006). The corresponding difference among control arms was 1.2 (95% confidence interval: -0.2 to 2.7, p=0.09). Compared with the control arms, the statin regression line was significantly shifted leftward, such that similar rates of incident cancer were associated with lower on-treatment LDL-C (p<0.05). Meta-regression demonstrated that statins lack an effect on cancer risk across all levels of on-treatment LDL-C. CONCLUSIONS: There is an inverse association between on-treatment LDL-C and incident cancer. However, statins, despite producing marked reductions in LDL-C, are not associated with an increased risk of cancer.

J Am Coll Cardiol. 2008 Sep 30;52(14):1148-9.

    Statin treatment does not cause cancer.    Steinberg D.

J Am Geriatr Soc. 2005 Feb;53(2):219-26.Click here to read Links    Relationship between plasma lipids and all-cause mortality in nondemented elderly.    Schupf N, Costa R, Luchsinger J, Tang MX, Lee JH, Mayeux R.

    G. H. Sergievsky Center, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.

    OBJECTIVES: To investigate the relationship between plasma lipids and risk of death from all causes in nondemented elderly. DESIGN: Prospective cohort study. SETTING: Community-based sample of Medicare recipients, aged 65 years and older, residing in northern Manhattan. PARTICIPANTS: Two thousand two hundred seventy-seven nondemented elderly, aged 65 to 98; 672 (29.5%) white/non-Hispanic, 699 (30.7%) black/non-Hispanic, 876 (38.5%) Hispanic, and 30 (1.3%) other. MEASUREMENTS: Anthropometric measures: fasting plasma total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and non-HDL-C, body mass index, and apolipoprotein E (APOE) genotype. clinical measures: neuropsychological, neurological, medical, and functional assessments; medical history of diabetes mellitus, heart disease, hypertension, stroke, and treatment with lipid-lowering drugs. Vital status measure: National Death Index date of death. Survival methods were used to examine the relationship between plasma lipids and subsequent mortality in younger and older nondemented elderly, adjusting for potential confounders. RESULTS: Nondemented elderly with levels of total cholesterol, non-HDL-C, and LDL-C in the lowest quartile were approximately twice as likely to die as those in the highest quartile (rate ratio (RR)=1.8, 95% confidence interval (CI)=1.3-2.4). These results did not vary when analyses were adjusted for body mass index, APOE genotype, diabetes mellitus, heart disease, hypertension, stroke, diagnosis of cancer, current smoking status, or demographic variables. The association between lipid levels and risk of death was attenuated when subjects with less than 1 year of follow-up were excluded (RR=1.4, 95% CI=1.0-2.1). The relationship between total cholesterol, non-HDL-C, HDL-C, and triglycerides and risk of death did not differ for older (>or=75) and younger participants (>75), whereas the relationship between LDL-C and risk of death was stronger in younger than older participants (RR=2.4, 95% CI=1.2-4.9 vs RR=1.6, 95% CI=1.02-2.6, respectively). Overall, women had higher mean lipid levels than men and lower mortality risk, but the risk of death was comparable for men and women with comparable low lipid levels. CONCLUSION: Low cholesterol level is a robust predictor of mortality in the nondemented elderly and may be a surrogate of frailty or subclinical disease. More research is needed to understand these associations.

    PMID: 15673344 [PubMed - indexed for ME

Age Ageing. 2008 Mar;37(2):207-13.    Relation of plasma lipids to all-cause mortality in Caucasian, African-American and Hispanic elders.    Akerblom JL, Costa R, Luchsinger JA, Manly JJ, Tang MX, Lee JH, Mayeux R, Schupf N.

    Department of Epidemiology, Columbia University, New York, USA.

    OBJECTIVES: to investigate the relation of plasma lipids to all-cause mortality in a multi-ethnic cohort of non-demented elderly. SETTING: community-based sample of Medicare recipients, 65 years and older, residing in Northern Manhattan. PARTICIPANTS: about two thousand five hundred and fifty-six non-demented elderly, 65-103 years. Among participants, 66.1% were women, 27.6% were White/non-Hispanic, 31.2% were African-American and 41.2% were Hispanic. METHODS: a standardised assessment, including functional ability, medical history, physical and neurological examination and a neuropsychological battery was conducted. Vital status was ascertained through the National Death Index (NDI). We used survival analyses stratified by race and ethnicity to examine the relation of plasma lipids to subsequent all-cause mortality. RESULTS: hispanics had the best overall survival, followed by African-Americans and Whites. Whites and African-Americans in the lowest quartiles of total cholesterol, non-HDL cholesterol and low-density lipoprotein cholesterol (LDL cholesterol) were approximately twice as likely to die as those in the highest quartile (White HR: 2.2, for lowest total cholesterol quartile; HR: 2.3, for lowest non-HDL cholesterol quartile; and HR: 1.8, for lowest LDL cholesterol quartile. African-American HR: 1.9, for lowest total cholesterol, HR: 2.0, for lowest non-HDL cholesterol and HR: 1.9, for lowest LDL cholesterol). In contrast, plasma lipid levels were not related to mortality risk among Hispanics. CONCLUSIONS: hispanic ethnicity modifies the associations between lipid levels and all-cause mortality in the elderly.

JAMA. 1999 Jul 21;282(3):254-60.   Low-density lipoprotein cholesterol and the risk of dementia with stroke.    Moroney JT, Tang MX, Berglund L, Small S, Merchant C, Bell K, Stern Y, Mayeux R.

    Gertrude H. Sergievsky Center, Department of Neurology, Columbia University, College of Physicians and Surgeons and Columbia-Presbyterian Medical Center, New York, NY 10032, USA.

    CONTEXT: Next to Alzheimer disease, vascular dementia is the second most common form of dementia in the elderly, yet few specific risk factors have been identified. OBJECTIVE: To investigate the relationship of plasma lipids and lipoproteins to dementia with stroke. DESIGN AND SETTING: Prospective longitudinal community-based study over a 7-year period (1991-1998). PARTICIPANTS: A total of 1111 nondemented participants (mean [SD] age, 75.0 [5.9] years) were followed up for an average of 2.1 years (range, 1-7.8 years). MAIN OUTCOME MEASURE: Incident dementia with stroke according to standardized criteria, by baseline levels of total plasma cholesterol and triglycerides, low-density lipoprotein (LDL) cholesterol, LDL levels corrected for lipoprotein(a), high-density lipoprotein cholesterol, lipoprotein(a), and apolipoprotein E genotype. RESULTS: Two hundred eighty-six (25.7%) of the 1111 subjects developed dementia during follow-up; 61 (21.3%) were classified as having dementia with stroke and 225 (78.7%) as having probable Alzheimer disease. Levels of LDL cholesterol were significantly associated with an increased risk of dementia with stroke. Compared with the lowest quartile, the highest quartile of LDL cholesterol was associated with an approximately 3-fold increase in risk of dementia with stroke, adjusting for vascular risk factors and demographic variables (relative risk [RR], 3.1; 95% confidence interval [CI], 1.5-6.1). Levels of LDL corrected for lipoprotein(a) were an even stronger predictor of dementia with stroke in the adjusted multivariate analysis. Compared with the lowest quartile, the RR of dementia with stroke for the highest quartile of lipoprotein(a)-corrected LDL cholesterol was 4.1 (95% CI, 1.8-9.6) after adjusting for vascular factors and demographic variables. Lipid or lipoprotein levels were not associated with the development of Alzheimer disease in our cohort. CONCLUSIONS: Elevated levels of LDL cholesterol were associated with the risk of dementia with stroke in elderly patients. Further study is needed to determine whether treatment of elevated LDL cholesterol levels will reduce the risk of dementia with stroke.