Correspondence

The Prevention of Coronary Heart Disease in Women

N Engl J Med 1995; 333:1570-1572December 7, 1995

Article

To the Editor:

Lipid-lowering drugs are generally expensive and frequently have bothersome side effects. Although primary-prevention trials have shown that lipid-lowering therapy can reduce the incidence of coronary heart disease in middle-aged men, meta-analysis of these trials has shown no effect of this type of therapy on overall survival.1 Concern about serious adverse effects of lipid-lowering drugs has prompted some to urge caution in their use in healthy, asymptomatic people.2

Although the Journal's recent review of primary prevention of coronary heart disease in women (June 29 issue)3 does not directly advocate the use of lipid-lowering drugs in women, we are concerned that the statement by Rich-Edwards and colleagues that “interventions to lower LDL [low-density lipoprotein] cholesterol levels and raise HDL [high-density lipoprotein] cholesterol levels would benefit women as well as men” will imply to many that there is evidence for using LDL cholesterol–based treatment guidelines in women. Although the authors point out the paucity of clinical-trial data for women, they stress the consistency of the prospective observational studies showing that total cholesterol is positively associated with coronary heart disease in women as well as men. The authors also emphasize the congruent results of three studies showing that higher levels of HDL cholesterol are strongly protective against coronary heart disease in women. However, they did not mention that only two observational studies have investigated LDL cholesterol as a predictor of the disease in women. The Framingham Study, which examined the incidence of coronary heart disease as well as the mortality associated with it, found LDL to be a significant predictor, although it was less powerful than HDL cholesterol.4 The Lipid Research Clinics Follow-up Study, which used only mortality end points, found no association of the disease with LDL cholesterol.5

We believe that the available data do not suggest that LDL cholesterol–based guidelines for treatment with lipid-lowering drugs can readily be extrapolated to women. Treating women like men, as suggested by Rich-Edwards et al., may result in large numbers of women receiving ineffective or even harmful therapy.

Karen L. Margolis, M.D., M.P.H.
Hennepin County Medical Center, Minneapolis, MN 55415

Kristine Ensrud, M.D., M.P.H.
Minneapolis Veterans Affairs Medical Center, Minneapolis, MN 55417

5 References

1. 1

   Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. BMJ 1990;301:309-314
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2. 2

   Smith GD, Pekkanen J. Should there be a moratorium on the use of cholesterol lowering drugs? BMJ 1992;304:431-434
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3. 3

   Rich-Edwards JW, Manson JE, Hennekens CH, Buring JE. The primary prevention of coronary heart disease in women. N Engl J Med 1995;332:1758-1766
   Full Text | Web of Science | Medline

4. 4

   Kannel WB. Metabolic risk factors for coronary heart disease in women: perspective from the Framingham Study. Am Heart J 1987;114:413-419
   CrossRef | Web of Science | Medline

5. 5

   Jacobs DR Jr, Mebane IL, Bangdiwala SI, Criqui MH, Tyroler HA. High density lipoprotein cholesterol as a predictor of cardiovascular disease mortality in men and women: the follow-up study of the Lipid Research Clinics Prevalence Study. Am J Epidemiol 1990;131:32-47
   Web of Science | Medline

To the Editor:

Rich-Edwards et al. present a succinct review of many coronary risk factors in women and potential management strategies for the prevention of coronary heart disease. Although the authors mention that diabetes mellitus is a stronger risk factor for coronary heart disease in women than men, there was minimal attention to the insulin-resistance syndrome and lipid changes related to diabetes.

Elevated plasma insulin levels and insulin resistance play an important part in the development of coronary heart disease in diabetes, as well as in other cardiovascular diseases.1 Insulin resistance is strongly associated with coronary risk factors such as non-insulin-dependent diabetes mellitus, essential hypertension, hyperlipidemia, and obesity. Recent data suggest that hyperandrogenism in women, as measured by either low levels of sex hormone–binding globulin or higher levels of testosterone, may induce insulin resistance.2 Differences between the sexes in plasma insulin levels and insulin resistance have been found in young African-American women and men, as well as a positive correlation between hyperandrogenism and hyperinsulinemia, independent of obesity.3

Diabetes adversely affects lipid profiles of women to a greater degree than men.4 It is particularly striking that diabetic women sustain greater reductions in HDL cholesterol than diabetic men. As Rich-Edwards et al. discuss in the section on cholesterol, HDL cholesterol is a predictor of cardiovascular disease in women.

Maria Maldonado, B.A.
Pamela Charney, M.D.
Albert Einstein College of Medicine, Bronx, NY 10461

4 References

1. 1

   DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14:173-194
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2. 2

   Andersson B, Makin P, Lissner L, Vermeulen A, Bjorntorp P. Testosterone concentrations in women and men with NIDDM. Diabetes Care 1994;17:405-411
   CrossRef | Web of Science | Medline

3. 3

   Falkner B, Hulman S, Kushner H. Gender differences in insulin-stimulated glucose utilization among African-Americans. Am J Hypertens 1994;7:948-952
   Web of Science | Medline

4. 4

   Walden CE, Knopp RH, Wahl PW, Beach KW, Strandness E Jr. Sex differences in the effect of diabetes mellitus on lipoprotein triglyceride and cholesterol concentrations. N Engl J Med 1984;311:953-959
   Full Text | Web of Science | Medline

To the Editor:

In their review of the prevention of coronary heart disease in women, Rich-Edwards et al. do not mention the role of excess stored iron in causing the disease. It has been 14 years since Sullivan1 suggested that the protection from coronary heart disease observed in menstruating women was due to lower stored iron levels as compared with men. A protective effect of estrogens has not yet been demonstrated.2,3 Sullivan's hypothesis explains many apparently disparate aspects of the prevention of coronary heart disease by the common mechanism of a protective effect of iron depletion.4 Lower Third World rates of the disease are explained by lower iron consumption (less meat), the interference of dietary fiber with absorption, and chronic gastrointestinal and genitourinary blood loss from parasite infestations. The protective effect of long-term aspirin use may be the result of cumulative iron loss due to chronic microbleeding from the stomach, since the protective effect extends well beyond the disappearance of aspirin from the bloodstream when aspirin therapy is stopped.

Evidence shows that free iron greatly accelerates the peroxidation of lipoproteins through free-radical reactions, most importantly in the sequestered microenvironment of the vessel wall, and oxidized cholesterol has atherogenic effects that native cholesterol does not have. Lower levels of stored iron, as measured by the levels of serum ferritin, explain the otherwise inexplicable protection of menstruating women who are heterozygous for hypercholesterolemia.4 Postmenopausal bleeding resulting from estrogen-replacement therapy is considered an inconvenience, but it prolongs the potential benefits of iron loss. Newer formulations to prevent undesired bleeding may simply increase the risk of coronary heart disease by allowing iron to accumulate faster.

Tom Clayton, M.D.
Nacogdoches Medical Center, Nacogdoches, TX 75961

4 References

1. 1

   Sullivan JL. Iron and the sex difference in heart disease risk. Lancet 1981;1:1293-1294
   CrossRef | Web of Science | Medline

2. 2

   Goldman L, Tosteson ANA. Uncertainty about postmenopausal estrogen -- time for action, not debate. N Engl J Med 1991;325:800-802
   Full Text | Web of Science | Medline

3. 3

   Posthuma WF, Westendorp RG, Vandenbroucke JP. Cardioprotective effect of hormone replacement therapy in postmenopausal women: is the evidence biased? BMJ 1994;308:1268-1269
   CrossRef | Web of Science | Medline

4. 4

   Sullivan JL. The iron paradigm of ischemic heart disease. Am Heart J 1989;117:1177-1188
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: In response to Clayton, we believe that at present the totality of evidence does not even begin to support any judgment of a cause–effect relation between iron and coronary heart disease. The well-described and accepted mechanisms of endogenous and exogenous estrogens, as well as aspirin, are far more plausible explanations for their beneficial effects. Premenopausal women who undergo hysterectomy without oophorectomy, as well as premenopausal women who have undergone oophorectomy and who receive estrogen-replacement therapy, do not have higher rates of coronary heart disease than other premenopausal women.1

Nobody would disagree with Maldonado and Charney concerning the crucial importance of the insulin-resistance syndrome and lipid changes related to diabetes. Before this can be translated into any clinical recommendation for primary prevention, however, much more research is required.

Finally, although we concur with Margolis and Ensrud that there are fewer data on women than men concerning lipid lowering, we believe that the totality of evidence supports clinical recommendations for primary prevention. Overall, the data show clear evidence of benefits with regard to cardiovascular mortality and no consistent excess of nonvascular deaths; the data are inadequate to address conclusively the question of mortality from all causes.2 Thus, on the basis of the available evidence, we concur with the guidelines of the National Cholesterol Education Program from the National Heart, Lung, and Blood Institute.3

Janet Rich-Edwards, Sc.D.
JoAnn Manson, M.D., Dr.P.H.
Charles Hennekens, M.D., Dr.P.H.
Julie Buring, Sc.D.
Brigham and Women's Hospital, Boston, MA 02115

3 References

1. 1

   Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speizer FE, Hennekens CH. Menopause and the risk of coronary heart disease in women. N Engl J Med 1987;316:1105-1110
   Full Text | Web of Science | Medline

2. 2

   Gaziano JM, Hebert P, Hennekens C. Cholesterol lowering and total mortality. Ann Intern Med (in press).
   

3. 3

   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
   CrossRef | Web of Science