Only in recent years have clinical studies been modified to reflect the impact of gender on medical conditions and drug response. With the significant functional differences in normal physiological systems between men and women, the results from a male-dominated test population cannot be automatically extrapolated to females. The differences become striking when examining the pathological progressions of diabetes to cardiovascular (CV) disorders, how the signs of disease are expressed, as well as the responses to the symptomsboth from the therapy and the health care providers.
Differences and Challenges in the Disease Process
As a cause of premature death and disability, CV disease will likely rise from 5th to 1st place and become the leading cause of death worldwide within a generation. Currently, 1 in 3 women die of heart disease in the United States every year, a ratio that outpaces that in men. Women have a more rapid heart rate at rest, a longer corrected QT interval, and a higher frequency of prolapsed mitral valves, all of which increase the likelihood of arrhythmia. Women who use oral contraception are also at a 2 to 3 times greater risk of developing hypertension.
Symptoms of CV crises also differ with gender. One fifth of women having a myocardial infarction will not experience chest pain; rather, they become diaphoretic, experience epigastric pain, and exhibit shortness of breath. As a result, women often report to the emergency department 1 to 2 hours later than men having chest pain, and, once there, they are often misdiagnosed or receive less aggressive treatment. Because of this, referrals to cardiac rehabilitation units are less likely, and women become more likely to die within a year of experiencing an initial heart attack.
CV disease rarely occurs alone in either gender. One of the main coexisting disorders is diabetes. Women with diabetes are at a 4-to 6-fold increased risk for coronary artery disease (compared to the 2-fold increase in men), and diabetes in women also greatly reduces the success of bypass surgery or balloon angioplasty procedures.
Pregnancy can present other complications. Gestational diabetes increases the risk of postpartum insulin resistance associated with the metabolic syndrome, with up to a 25% increase in hypertension.
Responses to Treatments
At the hepatic level, the CYP3A4 component of the P450 system metabolizes more than half of all drugs. This component is 40% more active in women, with its likely clinical significance being investigated. In addition, specific typical treatments in treating CV and comorbid conditions show differences in response in the female population.
Aspirin. The benefits of daily aspirin, with doses ranging from 81 to 325 mg, appear in different patterns among women. One recent study concluded that women under the age of 65 taking aspirin receive little benefit for heart attack prevention. Over the age of 65, however, women receive a greater cardiac benefit than that seen in men, with an added advantage of stroke prevention.
Statin therapy. Half of American women exceed the maximum goal for total cholesterol (200 mg/dL), and nearly a quarter have high-density lipoprotein (HDL) values less than 50 mg/dL (in men, the HDL goal is 40 mg/dL or greater). Statin therapy, according to the recent Heart Protection Study, can reduce vascular disease by ~25%, regardless of initial levels of low-density lipoprotein (LDL) or HDL. The American Diabetes Association also recommends statin therapy for patients with LDL cholesterol more than 100 mg/dL, and among women with diabetes even if the LDL is less than 100 mg/dL.
Gender does not appear to influence the LDL-lowering abilities of statins, and, despite earlier theories to the contrary, the use of statins does not appear to cause a reduction in endogenous hormone production in women. In fact, statin use appears to improve endothelial dysfunction and reduce vascular smooth muscle cell proliferation associated with CV disease. Furthermore, a reduction in general inflammatory processes is reflected by a reversal of C-reactive protein levels often associated with oral hormone replacement therapy in postmenopausal women. Nevertheless, higher HDL levels are noted among women, even with ongoing therapy, suggesting that many clinicians mistakenly view dyslipidemia as a less critical factor in women.
Lecithin. Elevated triglyceride levels are a factor for both CV diseases and diabetes. Lecithin, derived from soy, has been successfully used to reduce triglyceride levels. Studies making use of daily doses of up to 12 g of lecithin have shown reduction of triglycerides by nearly 25%, with an added benefit of increasing HDL while reducing overall cholesterol levels. Soy itself is a valuable supplement for women in general as a source of calcium, phytoestrogens, and plant protein, in addition to lecithin.
Magnesium. Magnesium is frequently overlooked in its many important functions in human physiology. A chronic deficiencymore common than generally expectedcan complicate successful outcomes in managing CV diseases. Low levels of magnesium are also associated with the onset of atherosclerosis, with all of the attending CV consequences, and a 2-fold increase in developing type 2 diabetes. Mitral valve prolapse, most common among women of childbearing age, is also associated with low magnesium levels, which also drop during pregnancy and lactation. Magnesium modulates serum lipids and lipid uptake and is an important cofactor in preventing calcium loss and osteoporosis. Taking twice the recommended daily allowance (RDA) (for women, the RDA represents a range of 310 to 400 mg, depending on age and gestational state) of even marginally bioavailable magnesium supplements can provide enough to replenish diminished levels. Diarrhea is the primary indication that the dose might be too high, with this symptom generally alleviated by lowering the dose.
Hypertension treatments. Lowering systolic blood pressure can reduce the incidence of stroke by 30% to 40%, heart attack by 20% to 25%, and heart failure overall by 50% in both men and women. Angiotensin-converting enzyme inhibitors are commonly employed; however, women are more prone to the side effect of idiosyncratic coughing. With calcium channel-blocking drugs, women are more likely to develop secondary edema. Women are also more responsive to the sympatholytic effects of beta-blockers. The importance of hypertension therapy is further reinforced in a recent study concluding that, for every 10-mm-Hg elevation in blood pressure, the risk of fibroids in premenopausal women rises 8% to 10%.
Added benefits of diabetes therapy. The oral hypoglycemic agent metformin provides more than glycemic control to women who may be experiencing CV problems in conjunction with diabetes. Metformin (850 mg twice daily), with the antiandrogen agent flutamine, reduces the incidence of polycystic ovary syndrome. Metformin use also appears to be effective in preventing type 2 diabetes following a history of gestational diabetes. Other studies support the use of metformin in restoring normal menstrual cycles and even improving pregnancy rates.
Gender remains an important, and often overlooked, variable in treating patients with the comorbidity of CV disease and diabetes. Clinicians need to be aware of these differences to provide proper diagnoses and create a more effective plan of care.
Mr. Middleton is an instructor of pharmacology for Kellogg Community College in Battle Creek, Mich.
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