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Commentary |
Division of Endocrinology, Metabolism, and Hypertension (J.R.K., S.J.J., J.R.S.), Department of Physiology (D.F.S., J.L.R.), Wayne State University School of Medicine, Detroit, Michigan 48201
Address all correspondence and requests for reprints to: James R Sowers, M.D., Division of Endocrinology, Metabolism, and Hypertension, Wayne State University School of Medicine, 4201 St. Antoine, UHC-4H, Detroit, Michigan 48201. E-mail: sowers{at}intmed.wayne.edu
Abstract
The incidence of cardiovascular disease (CVD) with age is increasing in the United States, and elderly women constitute a disproportional component of the aging population. Elderly women also have a relatively high incidence of diabetes, which contributes to this relatively high CVD risk. Although CVD is less common in premenopausal women than in men, this difference begins to disappear after the onset of menopause, presumably related to decreased levels of female sex hormones (estrogen and/or progesterone). Diabetes mellitus removes the normal premenopausal gender-related differences in the prevalence of CVD by mechanisms that are not clearly defined, including metabolic and hemodynamic factors associated with diabetes. Dyslipidemia in diabetes mellitus consists of low high density lipoprotein cholesterol, elevated triglyceride levels, and a small, dense, more atherogenic low density lipoprotein particle (i.e. oxidized). Dyslipidemia interacts with associated hemodynamic (i.e. hypertension) and metabolic abnormalities (i.e. increased platelet aggregation and plasminogen activator inhibitor-1 levels) to promote CVD risks in diabetic women. Recent controlled trials underscore the critical importance of aggressively treating CVD risk factors, especially dyslipidemia, in women with diabetes.
Although cardiovascular disease (CVD)
is the leading cause of death in women in the United States (1), there
have been very few studies that focus on women with CVD and even fewer
studies that focus on women with both diabetes mellitus and CVD (1, 2, 3, 4, 5).
Both CVD and diabetes mellitus increase with advancing age in the
United States and parallels increases in the incidence of both
hypertension and diabetes (1, 5, 6, 7). Diabetes mellitus greatly
increases the risk for CVD in postmenopausal as well as premenopausal
women. Other risk factors for CVD include hypercholesterolemia,
smoking, and family history of premature CHD (5, 6). The disparity
between CHD in premenopausal women and men of the same age suggests
that endogenous sex hormones, such as estrogen, progesterone, and/or
androgens, have a major effect on atherosclerosis (4) and the
vasculature (8, 9). There is considerable preliminary evidence
suggesting that estrogen replacement therapy (ERT) exerts protective
effects against CHD and stroke in postmenopausal women (10, 11, 12, 13, 14).
Postmenopausal ERT increases high density lipoprotein (HDL) and
decreases low density lipoprotein (LDL) cholesterol, LDL oxidation, and
lipoprotein(a) (5, 6, 15); however, only 25–35% of the
antiatherogenic effects of ERT can be attributed to the beneficial
effects on the lipid profile (4, 16) (Fig. 1
). Indeed, there is considerable
evidence that estrogen exerts direct antiatherogenic effects on the
vasculature (4). Diabetes negates much of the protective effects of
female sex hormones (5, 17), as discussed in this review.
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Diabetes mellitus is a known independent risk factor for coronary heart disease (CHD) and other macrovascular complications, including stroke and peripheral vascular disease (5, 6). CVD (myocardial infarction and stroke) is the leading cause of death among female diabetics (5). In the Framingham study (6), myocardial infarction, angina, and sudden death were 2 times higher in diabetic compared to nondiabetic subjects. Diabetes mellitus removes the normal premenopausal gender-related differences in the prevalence of CHD (5, 19, 20). For individuals 50–59 yr old, diabetes is a greater CHD mortality risk factor in women than in men (6). Women with diabetes are also more likely to die after a myocardial infarction than women who do not have diabetes mellitus or men with or without diabetes (6, 19, 20). The risk of death from CHD in women with diabetes is more than 3 times that of nondiabetic women (6, 19).
Dyslipidemia probably accounts for some of the high risk of CHD in diabetic women. Total plasma cholesterol is a predictor of CHD in women as well as men (6). Although there are no studies that specifically involve diabetic women and the effects of lipid lowering, there are some that have a small subset of diabetic women within the study population. Women, especially diabetic women, should be screened as aggressively as men (19), and some recommend that diabetic subjects have their LDL cholesterol lowered to less than 100 mg/dL.
Many factors contribute to the increase in CVD in diabetic women as
well as men. These include endothelial dysfunction, increased vascular
oxidative stress, and abnormalities of platelet function, coagulation,
fibrinolysis, and lipoproteins (5) (Table 1). For any lipoprotein level, diabetics
have more significant coronary artery disease than do nondiabetics, due
partly to qualitative differences in lipoproteins (5). Oxidation of
lipoproteins is enhanced in the presence of hyperglycemia and
hypertriglyceridemia (21). Triglycerides are elevated in the diabetic,
in part due to a decrease in lipoprotein lipase activity. Oxidized
lipoproteins are cytotoxic to vascular endothelial and smooth muscle
cells and contribute to atherogenesis (21). There is increased
glycation of apolipoprotein B in the hyperglycemic state. This results
in impaired recognition of LDL by hepatocyte receptors and an increase
in LDL half-life (5), thereby increasing exposure of the endothelium to
atherogenic lipoproteins. The glycation of HDL increases the clearance
of HDL and decreases its half-life (21). The resulting lipoprotein
profile includes increases in plasma very low density lipoprotein, LDL,
and lipoprotein(a) and a decrease in plasma HDL (5, 21). Lipoprotein(a)
is a modified form of LDL that can bind to endothelium and components
of the extracellular matrix (21), resulting in localized cholesterol
accumulation and increased atherogenesis. In several large prospective
studies, lipoprotein(a) has been shown to be a powerful predictor of
premature atherosclerotic vascular disease (16, 21). Its structure is
similar to that of plasminogen, and it interferes with fibrinolysis and
accentuates thrombosis by competing with plasminogen for binding sites
(5, 21). Finally, increased oxidation and glycation of the LDL particle
make it much more atherogenic in the diabetic state (21).
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Diabetic subjects are prone to thrombosis through a complex
interplay among hyperlipidemia, platelets, fibrinolysis, thrombosis,
and endothelial injury (5, 22, 23, 24) (Table 2). Diabetics have increased levels of
plasminogen activator inhibitor (PAI-1) (5) compared to nondiabetics,
and PAI-1 blocks fibrinolysis. Elevated levels of PAI-1 have been
associated with hyperinsulinemia and hypertriglyceridemia (5, 21).
Fibrinolytic activity is also decreased. There are decreased levels of
antithrombin III, protein C, and protein S levels (5, 22),
predisposing to thrombosis. The procoagulant state associated with
diabetes can also be attributed to levels of coagulation factors that
are higher than normal. Plasma levels of von Willebrand factor are
elevated, especially in association with endothelial cell injury,
microvascular and macrovascular damage, and poor diabetic control (5).
A high concentration of factor VIII with hyperglycemia accelerates the
rate of thrombin formation, which may contribute to occlusive vascular
disease. Levels of fibrinogen, factor VII, and thrombin-antithrombin
complexes have been noted to be higher in diabetics (5, 21, 22). This
prolongs the survival of provisional clots on injured endothelium.
Increased concentrations of thrombin-antithrombin complexes result in
increased thrombin generation in the diabetic state (5, 22).
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Endothelial cell dysfunction
There are important abnormalities in vascular endothelium
associated with diabetes mellitus (5, 24) (Table 3). Endothelial cell lipoprotein lipase
activity is decreased (5). This impairs conversion of very low density
lipoprotein to LDL, partly accounting for the high triglyceride levels
in diabetics (5, 21). Hyperglycemia alters endothelial matrix
production, which is thought to lead to basement membrane thickening.
It also increases endothelial cell collagen and fibronectin synthesis,
delays endothelial cell replication, and causes cell death by enhancing
both oxidation and glycation (5). Hypercholesterolemia, which
frequently accompanies diabetes, impairs endothelium-dependent
relaxation. There is increased destruction of endothelium-derived NO
and reduced responsiveness to NO, as previously discussed with regard
to platelets (5). In addition, there is impaired degradation of
glycosylated fibrin, increased concentrations of glycated end products,
and elevated expression, synthesis, and plasma concentrations of
endothelin-1, all contributing to reduced vascular compliance and
increased vasoconstriction in the diabetic state (5).
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There is a large void in our knowledge of the benefits of hormone replacement therapy in diabetic women. There is circumstantial evidence from the Postmenopausal Estrogen/Progestin Interventions trial that ERT may improve glycemia and lipids in women who are not diabetic (14). In a recent case control study of 334 diabetic women, it was observed that the use of postmenopausal estrogen does not increase the risk of CHD in diabetic women (25). Diabetic postmenopausal women currently taking ERT had a reduced risk of myocardial infarction compared to diabetic postmenopausal women who had never taken ERT. Among subjects who were current estrogen users, the risk of myocardial infarction declined with each year of estrogen use, suggesting that postmenopausal ERT does not increase the risk of myocardial infarction in diabetic women, and the sustained use of ERT may be beneficial. Postmenopausal women who had used ERT in the past had a similar or slightly higher risk of myocardial infarction as subjects who had never used ERT.
The limited benefit of ERT in diabetic women is of concern for several reasons. First, the risk of endometrial carcinoma is increased in diabetic women (26). Secondly, persons with diabetes manifest the same risks for myocardial infarction and stroke as nondiabetic subjects who have already had such events (27). Thus, one would anticipate that diabetic women would respond to hormone replacement therapy in a fashion similar to women with CHD, i.e. the Heart and Estrogen/progestin Replacement Study (HERS).
The HERS study was a randomized controlled trial of 2763 postmenopausal women with coronary artery disease (28). Treatment with estrogen and progestin did not reduce the rate of CHD events (i.e. nonfatal myocardial infarction or CHD-related deaths). One explanation for the difference between the volume of observational data that supports the use of estrogen as a cardioprotective agent and the results of the HERS study is selection bias. Women who elect to take ERT are in better health and have a more favorable CHD risk profile than those who do not (29, 30). Women randomized to ERT in observational studies were often younger and healthier before treatment, in contrast to the participants in the HERS study (30). In the HERS study the subjects were older, had coronary artery disease before randomization (perhaps similar to diabetic women), and were treated with both estrogen and progestin. Another explanation for the difference between previous observational studies and the HERS data is that HERS did not account for the effect of cholesterol lowering on CHD. More women in the placebo group than in the hormone-treated group also had therapy with lipid-lowering agents. Most diabetic women would presumably also be receiving lipid-lowering therapy. A final explanation is that the early CHD events are secondary to the procoagulant effects of HRT. This may be accentuated in women with diabetes mellitus.
The HERS study is the first large trial on estrogen plus progestin replacement therapy in postmenopausal women and its effect on cardiovascular risk. It did not evaluate the effect of hormone replacement therapy on primary prevention of CHD, and it is therefore difficult to extrapolate the HERS results to women without coronary artery disease. Other ongoing randomized trials are likely to provide answers to questions raised by the HERS trial. Trials of ERT are especially needed in diabetic women, given their very high risks for CHD and stroke.
Received January 5, 1999.
Revised February 26, 1999.
Accepted March 2, 1999.
References
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