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January 3, 1996, Vol 275, No. 1 >
ARTICLE | January 3, 1996

Carcinogenicity of Lipid-Lowering Drugs FREE

Thomas B. Newman, MD, MPH; Stephen B. Hulley, MD, MPH
[+] Author Affiliations

Reprint requests to University of California, San Francisco, Box 0626, Department of Laboratory Medicine, San Francisco, CA 94143-0626 (Dr Newman).


JAMA. 1996;275(1):55-60. doi:10.1001/jama.1996.03530250059028
Text Size: A A A
Published online
Article
References

Objective.  —To review the findings and implications of studies of rodent carcinogenicity of lipid-lowering drugs.

Data Sources.  —Summaries of carcinogenicity studies published in the 1992 and 1994 Physicians' Desk Reference (PDR), additional information obtained from the US Food and Drug Administration, and published articles identified by computer searching, bibliographies, and consultation with experts.

Study Sample.  —We tabulated rodent carcinogenicity data from the 1994 PDR for all drugs listed as "hypolipidemics." For comparison, we selected a stratified random sample of antihypertensive drugs. We also reviewed methods and interpretation of carcinogenicity studies in rodents and results of clinical trials in humans.

Data Synthesis.  —All members of the two most popular classes of lipid-lowering drugs (the fibrates and the statins) cause cancer in rodents, in some cases at levels of animal exposure close to those prescribed to humans. In contrast, few of the antihypertensive drugs have been found to be carcinogenic in rodents. Evidence of carcinogenicity of lipid-lowering drugs from clinical trials in humans is inconclusive because of inconsistent results and insufficient duration of follow-up.

Conclusions.  —Extrapolation of this evidence of carcinogenesis from rodents to humans is an uncertain process. Longer-term clinical trials and careful postmarketing surveillance during the next several decades are needed to determine whether cholesterol-lowering drugs cause cancer in humans. In the meantime, the results of experiments in animals and humans suggest that lipid-lowering drug treatment, especially with the fibrates and statins, should be avoided except in patients at high short-term risk of coronary heart disease.(JAMA. 1996;275:55-60)

REFERENCES

1 +
Wysowski DK, Kennedy DL, Gross TP.  Prescribed use of cholesterol-lowering drugs in the United States, 1978 through 1988 . JAMA . 1990;; 263:2185-2188.
2 +
 Use of cholesterol-lowering drugs, United States, 1992. Stat Bull Metrop Insur Co . 1993;;74:10-17.
3 +
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.  Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA . 1993;;269:3015-3023.
4 +
Giles WH, Anda RF, Jones DH, Serdula MK, Merritt RK, DeStefano F.  Recent trends in the identification and treatment of high blood cholesterol by physicians: progress and missed opportunities. JAMA . 1993;;269:1133-1138.
5 +
Muldoon MF, Manuck SB, Matthews KA.  Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. BMJ . 1990;;301:309-314.
6 +
Criqui MH.  Cholesterol, primary and secondary prevention, and all-cause mortality. Ann Intern Med . 1991;;115:973-976.
7 +
Newman TB, Browner WS, Hulley SB.  Childhood cholesterol screening: contraindicated. JAMA . 1992;;267:100-102.
8 +
Smith GD, Pekkanen J.  Should there be a moratorium on the use of cholesterol lowering drugs? BMJ . 1992;;304:431-434.
9 +
Smith GD, Song F, Sheldon T.  Cholesterol lowering and mortality: the importance of considering initial level of risk. BMJ . 1993;;306:1367-1373.
10 +
Arky R, ed, Physicians' Desk Reference . 48th ed. Montvale, NJ: Medical Economics Data; 1994;.
11 +
Zurich D, Duffy M, eds. Physicians' Desk Reference . 46th ed. Montvale, NJ: Medical Economics Data; 1992;.
12 +
Rall DP, Hogan MD, Huff JE, Schwetz BA, Tennant RW.  Alternatives to using human experience in assessing health risks. Annu Rev Public Health . 1987;;8:355-385.
13 +
Freedman D, Zeisel H.  From mouse-to-man: the quantitative assessment of cancer risks. Stat Sci . 1988;;3:3-56.
14 +
Huff JE, McConnell EE, Haseman JK, et al.  Carcinogenesis studies: results of 398 experiments on 104 chemicals from the U.S. National Toxicology Program. Ann N Y Acad Sci . 1988;;534:1-30.
15 +
Gori GB.  Cancer risk assessment: the science that is not. Regul Toxicol Pharmacol . 1992;;16:10-20.
16 +
Gregory AR.  Cancer risk: does anyone really care? Regul Toxicol Pharmacol . 1992;;15:271-277.
17 +
International Agency for Research on Cancer.  IARC monographs on the evaluation of carcinogenic risks to humans.  In: Pharmaceutical Drugs . Lyon, France: International Agency for Research on Cancer; 1990;:17.
18 +
Tomatis L, Aitio A, Wilbourn J, Shuker L.  Human carcinogens so far identified. Jpn J Cancer Res . 1989;;80:795-807.
19 +
Lave LB, Ennever FK, Rosenkranz HS, Omenn GS.  Information value of the rodent bioassay. Nature . 1988;;336:631-633.
20 +
Purchase IF.  Inter-species comparisons of carcinogenicity. Br J Cancer . 1980;;41:454-468.
21 +
Haseman JK, Crawford DD, Huff JE, Boorman GA, McConnell EE.  Results from 86 two-year carcinogenicity studies conducted by the National Toxicology Program. J Toxicol Environ Health . 1984;; 14:621-639.
22 +
Sabadie N, Malaveille C, Camus AM, Bartsch H.  Comparison of the hydroxylation of benzo(a) pyrene with the metabolism of vinyl chloride, N-nitrosomorpholine, and N-nitroso-N′-methylpiperazine to mutagens by human and rat liver microsomal fractions. Cancer Res . 1980;;40:119-126.
23 +
Reddy JK, Azarnoff DL, Hignite CE.  Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens. Nature . 1980;; 283:397-398.
24 +
Reddy JK, Lalwai ND.  Carcinogenesis by hepatic peroxisome proliferators: evaluation of the risk of hypolipidemic drugs and industrial plasticizers to humans. Crit Rev Toxicol . 1983;;12:1-58.
25 +
Hanefeld M, Kemmer C, Kadner E.  Relationship between morphological changes and lipid-lowering action of p-chlorphenoxyisobutyric acid (CPIB) on hepatic mitochondria and peroxisomes in man. Atherosclerosis . 1983;;46:239-246.
26 +
De La Iglesia FA, Lewis JE, Buchanan RA, Marcus EL, McMohan G.  Light and electron microscopy of liver in hyperlipoproteinemic patients under long-term gemfibrozil treatment. Atherosclerosis . 1982;;43:19-37.
27 +
Graham MJ, Wilson SA, Winham MA, et al.  Lack of peroxisome proliferation in marmoset liver following treatment with ciprofibrate for 3 years. Fundam Appl Toxicol . 1994;;22:58-64.
28 +
Bentley P, Calder I, Elcombe C, Grasso P, Stringer D, Wiegand HJ.  Hepatic peroxisome proliferation in rodents and its significance for humans. Food Chem Toxicol . 1993;;31:857-907.
29 +
Cohen A.  Review of the hepatic response to hypolipidemic drugs in rodents and assessment of its toxicological significance to man. Food Cosmetics Toxicol . 1981;;19:585-605.
30 +
Hanefeld M, Kemmer C, Leonhardt W, Kunze KD, Jaross W, Haller H.  Effects of p-chlorophenoxyisobutyric acid (CPIB) on the human liver. Atherosclerosis . 1980;;36:159-172.
31 +
Gold LS, Slone TH, Stern BR, Manley NB, Ames BN.  Rodent carcinogens: setting priorities. Science . 1992;;258:261-265.
32 +
Davies TS, Monro A.  Marketed human pharmaceuticals reported to be tumorigenic in rodents. J Am Coll Toxicol . 1995;;14:90-107.
33 +
Contrera J, Jacobs A, Prasanna H, Mehta M, DeGeorge J, Schmidt W.  A systemic exposure based alternative to the MTD for carcinogenicity studies of human therapeutics. J Am Coll Toxicol . 1995;; 14:1-10.
34 +
Taylor M.  International Conference on Harmonisation: draft guideline on dose selection for carcinogenicity studies of pharmaceuticals availability. Federal Register . 1994;;59:9752-9755.
35 +
 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet . 1994;;344:1383-1389.
36 +
Rossouw JE, Lewis B, Rifkind BM.  The value of lowering cholesterol after myocardial infarction. N Engl J Med . 1990;;323:1112-1119.
37 +
Hulley SB, Walsh JM, Newman TB.  Health policy on blood cholesterol: time to change directions. Circulation . 1992;;86:1026-1029.
38 +
Hulley SB, Newman TB, Grady D, Garber AM, Baron RB, Browner WS.  Should we be measuring blood cholesterol in young adults? JAMA . 1993;; 269:1416-1419.
39 +
Silberberg JS, Henry DA.  The benefits of reducing cholesterol levels: the need to distinguish primary from secondary prevention, 1: a meta-analysis of cholesterol-lowering trials. Med J Aust . 1991;; 155:665-666, 669-670.
40 +
Jacobs D, Blackburn H, Higgins M, et al.  Report of the Conference on Low Blood Cholesterol: mortality associations. Circulation . 1992;;86:1046-1060.
41 +
Law MR, Thompson SG.  Low serum cholesterol and the risk of cancer: an analysis of the published prospective studies. Cancer Causes Control . 1991;;2:253-261.
42 +
Kritchevsky SB.  Dietary lipids and the low blood cholesterol-cancer association. Am J Epidemiol . 1992;;135:509-520.
43 +
Kritchevsky SB, Wilcosky TC, Morris DL, Truong KN, Tyroler HA.  Changes in plasma lipid and lipoprotein cholesterol and weight prior to the diagnosis of cancer. Cancer Res . 1991;;51:3198-3203.
44 +
Iribarren C, Reed DM, Burchfiel CM, Dwyer JH.  Serum total cholesterol and mortality: confounding factors and risk modification in Japanese-American men. JAMA . 1995;;273:1926-1932.
45 +
Law MR, Thompson SG, Wald NJ.  Assessing possible hazards of reducing serum cholesterol. BMJ . 1994;;308:373-379.
46 +
Pearce ML, Dayton S.  Incidence of cancer in men on a diet high in polyunsaturated fat. Lancet . 1971;;1:464-467.
47 +
Heady JA, Morris JN, Oliver MF.  WHO clofibrate/cholesterol trial: clarifications. Lancet . 1992;; 340:1405-1406.
48 +
Huttunen J, Heinonen O, Manninen V, et al.  The Helsinki Heart Study: an 8.5 year safety and mortality follow-up. J Intern Med . 1994;;235:31-39.
49 +
Kritchevsky SB, Kritchevsky D.  Serum cholesterol and cancer risk: an epidemiologic perspective. Annu Rev Nutr . 1992;;12:391-416.
50 +
Frick MH, Heinonen OP, Huttunen JK, Koskinen P, Manttari M, Manninen V.  Efficacy of gemfibrozil in dyslipidaemic subjects with suspected heart disease: an ancillary study in the Helsinki Heart Study frame population. Ann Med . 1993;;25: 41-45.
51 +
Canner PL, Berge KG, Wenger NK, et al.  Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol . 1986;;8:1245-1255.
52 +
Ogawa T, Makino T, Kosahara K, Koga A, Nakayama F.  Promoting effects of both dietary cholesterol and cholestyramine on pancreatic carcinogenesis initiated by N-nitrosobis(2-oxopropyl)amine in Syrian golden hamsters. Carcinogenesis . 1992;; 13:2047-2052.
53 +
The Lipid Research Clinics Investigators.  The Lipid Research Clinics Coronary Primary Prevention Trial: results of 6 years of post-trial follow-up. Arch Intern Med . 1992;;152:1399-1410.
54 +
Shepherd J, Cobbe SM, Ford I, et al.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med . 1995;;333:1301-1307.

Figures

Tables

Interactive Graphics

Video

Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Wysowski DK, Kennedy DL, Gross TP.  Prescribed use of cholesterol-lowering drugs in the United States, 1978 through 1988 . JAMA . 1990;; 263:2185-2188.
2 +
 Use of cholesterol-lowering drugs, United States, 1992. Stat Bull Metrop Insur Co . 1993;;74:10-17.
3 +
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.  Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA . 1993;;269:3015-3023.
4 +
Giles WH, Anda RF, Jones DH, Serdula MK, Merritt RK, DeStefano F.  Recent trends in the identification and treatment of high blood cholesterol by physicians: progress and missed opportunities. JAMA . 1993;;269:1133-1138.
5 +
Muldoon MF, Manuck SB, Matthews KA.  Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. BMJ . 1990;;301:309-314.
6 +
Criqui MH.  Cholesterol, primary and secondary prevention, and all-cause mortality. Ann Intern Med . 1991;;115:973-976.
7 +
Newman TB, Browner WS, Hulley SB.  Childhood cholesterol screening: contraindicated. JAMA . 1992;;267:100-102.
8 +
Smith GD, Pekkanen J.  Should there be a moratorium on the use of cholesterol lowering drugs? BMJ . 1992;;304:431-434.
9 +
Smith GD, Song F, Sheldon T.  Cholesterol lowering and mortality: the importance of considering initial level of risk. BMJ . 1993;;306:1367-1373.
10 +
Arky R, ed, Physicians' Desk Reference . 48th ed. Montvale, NJ: Medical Economics Data; 1994;.
11 +
Zurich D, Duffy M, eds. Physicians' Desk Reference . 46th ed. Montvale, NJ: Medical Economics Data; 1992;.
12 +
Rall DP, Hogan MD, Huff JE, Schwetz BA, Tennant RW.  Alternatives to using human experience in assessing health risks. Annu Rev Public Health . 1987;;8:355-385.
13 +
Freedman D, Zeisel H.  From mouse-to-man: the quantitative assessment of cancer risks. Stat Sci . 1988;;3:3-56.
14 +
Huff JE, McConnell EE, Haseman JK, et al.  Carcinogenesis studies: results of 398 experiments on 104 chemicals from the U.S. National Toxicology Program. Ann N Y Acad Sci . 1988;;534:1-30.
15 +
Gori GB.  Cancer risk assessment: the science that is not. Regul Toxicol Pharmacol . 1992;;16:10-20.
16 +
Gregory AR.  Cancer risk: does anyone really care? Regul Toxicol Pharmacol . 1992;;15:271-277.
17 +
International Agency for Research on Cancer.  IARC monographs on the evaluation of carcinogenic risks to humans.  In: Pharmaceutical Drugs . Lyon, France: International Agency for Research on Cancer; 1990;:17.
18 +
Tomatis L, Aitio A, Wilbourn J, Shuker L.  Human carcinogens so far identified. Jpn J Cancer Res . 1989;;80:795-807.
19 +
Lave LB, Ennever FK, Rosenkranz HS, Omenn GS.  Information value of the rodent bioassay. Nature . 1988;;336:631-633.
20 +
Purchase IF.  Inter-species comparisons of carcinogenicity. Br J Cancer . 1980;;41:454-468.
21 +
Haseman JK, Crawford DD, Huff JE, Boorman GA, McConnell EE.  Results from 86 two-year carcinogenicity studies conducted by the National Toxicology Program. J Toxicol Environ Health . 1984;; 14:621-639.
22 +
Sabadie N, Malaveille C, Camus AM, Bartsch H.  Comparison of the hydroxylation of benzo(a) pyrene with the metabolism of vinyl chloride, N-nitrosomorpholine, and N-nitroso-N′-methylpiperazine to mutagens by human and rat liver microsomal fractions. Cancer Res . 1980;;40:119-126.
23 +
Reddy JK, Azarnoff DL, Hignite CE.  Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens. Nature . 1980;; 283:397-398.
24 +
Reddy JK, Lalwai ND.  Carcinogenesis by hepatic peroxisome proliferators: evaluation of the risk of hypolipidemic drugs and industrial plasticizers to humans. Crit Rev Toxicol . 1983;;12:1-58.
25 +
Hanefeld M, Kemmer C, Kadner E.  Relationship between morphological changes and lipid-lowering action of p-chlorphenoxyisobutyric acid (CPIB) on hepatic mitochondria and peroxisomes in man. Atherosclerosis . 1983;;46:239-246.
26 +
De La Iglesia FA, Lewis JE, Buchanan RA, Marcus EL, McMohan G.  Light and electron microscopy of liver in hyperlipoproteinemic patients under long-term gemfibrozil treatment. Atherosclerosis . 1982;;43:19-37.
27 +
Graham MJ, Wilson SA, Winham MA, et al.  Lack of peroxisome proliferation in marmoset liver following treatment with ciprofibrate for 3 years. Fundam Appl Toxicol . 1994;;22:58-64.
28 +
Bentley P, Calder I, Elcombe C, Grasso P, Stringer D, Wiegand HJ.  Hepatic peroxisome proliferation in rodents and its significance for humans. Food Chem Toxicol . 1993;;31:857-907.
29 +
Cohen A.  Review of the hepatic response to hypolipidemic drugs in rodents and assessment of its toxicological significance to man. Food Cosmetics Toxicol . 1981;;19:585-605.
30 +
Hanefeld M, Kemmer C, Leonhardt W, Kunze KD, Jaross W, Haller H.  Effects of p-chlorophenoxyisobutyric acid (CPIB) on the human liver. Atherosclerosis . 1980;;36:159-172.
31 +
Gold LS, Slone TH, Stern BR, Manley NB, Ames BN.  Rodent carcinogens: setting priorities. Science . 1992;;258:261-265.
32 +
Davies TS, Monro A.  Marketed human pharmaceuticals reported to be tumorigenic in rodents. J Am Coll Toxicol . 1995;;14:90-107.
33 +
Contrera J, Jacobs A, Prasanna H, Mehta M, DeGeorge J, Schmidt W.  A systemic exposure based alternative to the MTD for carcinogenicity studies of human therapeutics. J Am Coll Toxicol . 1995;; 14:1-10.
34 +
Taylor M.  International Conference on Harmonisation: draft guideline on dose selection for carcinogenicity studies of pharmaceuticals availability. Federal Register . 1994;;59:9752-9755.
35 +
 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet . 1994;;344:1383-1389.
36 +
Rossouw JE, Lewis B, Rifkind BM.  The value of lowering cholesterol after myocardial infarction. N Engl J Med . 1990;;323:1112-1119.
37 +
Hulley SB, Walsh JM, Newman TB.  Health policy on blood cholesterol: time to change directions. Circulation . 1992;;86:1026-1029.
38 +
Hulley SB, Newman TB, Grady D, Garber AM, Baron RB, Browner WS.  Should we be measuring blood cholesterol in young adults? JAMA . 1993;; 269:1416-1419.
39 +
Silberberg JS, Henry DA.  The benefits of reducing cholesterol levels: the need to distinguish primary from secondary prevention, 1: a meta-analysis of cholesterol-lowering trials. Med J Aust . 1991;; 155:665-666, 669-670.
40 +
Jacobs D, Blackburn H, Higgins M, et al.  Report of the Conference on Low Blood Cholesterol: mortality associations. Circulation . 1992;;86:1046-1060.
41 +
Law MR, Thompson SG.  Low serum cholesterol and the risk of cancer: an analysis of the published prospective studies. Cancer Causes Control . 1991;;2:253-261.
42 +
Kritchevsky SB.  Dietary lipids and the low blood cholesterol-cancer association. Am J Epidemiol . 1992;;135:509-520.
43 +
Kritchevsky SB, Wilcosky TC, Morris DL, Truong KN, Tyroler HA.  Changes in plasma lipid and lipoprotein cholesterol and weight prior to the diagnosis of cancer. Cancer Res . 1991;;51:3198-3203.
44 +
Iribarren C, Reed DM, Burchfiel CM, Dwyer JH.  Serum total cholesterol and mortality: confounding factors and risk modification in Japanese-American men. JAMA . 1995;;273:1926-1932.
45 +
Law MR, Thompson SG, Wald NJ.  Assessing possible hazards of reducing serum cholesterol. BMJ . 1994;;308:373-379.
46 +
Pearce ML, Dayton S.  Incidence of cancer in men on a diet high in polyunsaturated fat. Lancet . 1971;;1:464-467.
47 +
Heady JA, Morris JN, Oliver MF.  WHO clofibrate/cholesterol trial: clarifications. Lancet . 1992;; 340:1405-1406.
48 +
Huttunen J, Heinonen O, Manninen V, et al.  The Helsinki Heart Study: an 8.5 year safety and mortality follow-up. J Intern Med . 1994;;235:31-39.
49 +
Kritchevsky SB, Kritchevsky D.  Serum cholesterol and cancer risk: an epidemiologic perspective. Annu Rev Nutr . 1992;;12:391-416.
50 +
Frick MH, Heinonen OP, Huttunen JK, Koskinen P, Manttari M, Manninen V.  Efficacy of gemfibrozil in dyslipidaemic subjects with suspected heart disease: an ancillary study in the Helsinki Heart Study frame population. Ann Med . 1993;;25: 41-45.
51 +
Canner PL, Berge KG, Wenger NK, et al.  Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol . 1986;;8:1245-1255.
52 +
Ogawa T, Makino T, Kosahara K, Koga A, Nakayama F.  Promoting effects of both dietary cholesterol and cholestyramine on pancreatic carcinogenesis initiated by N-nitrosobis(2-oxopropyl)amine in Syrian golden hamsters. Carcinogenesis . 1992;; 13:2047-2052.
53 +
The Lipid Research Clinics Investigators.  The Lipid Research Clinics Coronary Primary Prevention Trial: results of 6 years of post-trial follow-up. Arch Intern Med . 1992;;152:1399-1410.
54 +
Shepherd J, Cobbe SM, Ford I, et al.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med . 1995;;333:1301-1307.

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