Physical Activity and Risk for Cardiovascular Events in Diabetic Women

Cardiovascular disease is the leading cause of death in persons with diabetes mellitus. This disorder affects approximately 16 million Americans, at least 15 million of whom have type 2 diabetes mellitus (1). Among diabetic persons, coronary heart disease causes more than 50% of all deaths and stroke causes an additional 15% (2). Diabetic women are at particularly high risk for cardiovascular disease, and diabetes eliminates the usual female advantage for death from coronary disease. While an inverse association between increased physical activity and lower risk for cardiovascular disease is well established in the general population (3), sparse data are available among diabetic persons (4, 5). Intervention studies have shown that exercise increases insulin sensitivity and glucose tolerance and induces favorable changes in blood lipid levels among persons with type 2 diabetes mellitus (6). Exercise as an adjunct to diet regimens yields greater and more sustained weight loss in obese patients with type 2 diabetes mellitus (7). Even moderately intense exercise, such as walking, improves insulin sensitivity and reduces body weight (8). Because walking is safe and easy, it may provide a promising way to reduce risk for cardiovascular events among diabetic persons. In this study, we examined in detail the relationship between levels of physical activity and incidence of coronary heart disease and stroke among women with type 2 diabetes mellitus in the Nurses' Health Study. In particular, we evaluated walking (the most common form of physical activity among diabetic persons) in relation to cardiovascular events. Methods Study Sample The Nurses' Health Study cohort was established in 1976. The original cohort consisted of 121 700 female registered nurses who were 30 to 55 years of age and resided in 11 large U.S. states. The nurses completed a mailed questionnaire about their medical history and lifestyle, and follow-up questionnaires administered every 2 years update information on potential risk factors and identify newly diagnosed cases of coronary heart disease and other illness. Our study includes 5125 women who, on any questionnaire from 1976 to 1992, reported having physician-diagnosed diabetes mellitus and being 30 years of age or older at disease onset (a working definition for type 2 diabetes mellitus). Women who reported a history of coronary heart disease (including myocardial infarction, angina, or coronary revascularization), stroke, or cancer on or before the 1980 questionnaire (when physical activity was first assessed) were excluded at baseline. The follow-up rate for nonfatal events was 97% of the total potential person-years. Confirmation of Diabetes Mellitus A supplementary questionnaire regarding symptoms, diagnostic tests, and hypoglycemic therapy was mailed to women who indicated on any biennial questionnaire that they had received a diagnosis of diabetes. A case of diabetes was considered confirmed if at least one of the following was reported on the supplementary questionnaire: 1) classic symptoms plus a fasting plasma glucose level of at least 140 mg/dL (7.8 mmol/L) or a random plasma glucose level of at least 200 mg/dL [11.1 mmol/L], 2) at least two elevated plasma glucose concentrations on different occasions (a fasting level 140 mg/dL [7.8 mmol/L] or a random level 200 mg/dL [11.1 mmol/L], a concentration 200 mg/dL after 2 hours or more on oral glucose tolerance testing, or both] in the absence of symptoms, or 3) treatment with hypoglycemic medication (insulin or an oral hypoglycemic agent). The validity of this questionnaire has been verified in a subsample of the study cohort (9). Of a random sample of 84 women classified by the questionnaire as having type 2 diabetes mellitus, 71 gave permission for their medical records to be reviewed; records were available for 62 of 71. An endocrinologist blinded to the information on the supplementary questionnaires reviewed the records according to National Diabetes Data Group (NDDG) criteria (10). The diagnosis of type 2 diabetes mellitus was confirmed in 61 of 62 women (98%) (9). A secondary set of analyses included only women with definite type 2 diabetes mellitus according to the NDDG criteria. We used the NDDG diagnostic criteria because the analytic cohort preceded the American Diabetes Association guideline, which was published in 1997 (11). Assessment of Physical Activity Women were first asked about physical activity on the 1980 questionnaire. They were asked to report the average number of hours they had spent each week during the past year on such moderate and vigorous recreational activities as vigorous sports, jogging, brisk walking or striding, bicycling, heavy gardening, and heavy housework. On the 1982 questionnaire, women were asked a slightly different question: For how many hours per week, on average, do you engage in activity strenuous enough to build up a sweat? In 1986, 1988, and 1992, women were asked to report the average time spent per week on the following activities: walking, jogging, running, bicycling, lap swimming, playing tennis or squash, and participating in calisthenics. They were also asked to report the average number of flights of stairs that they climbed each week. Women also reported their usual walking pace: easy (<2 miles per hour [mph]), average (2 to 2.9 mph), brisk (3 to 3.9 mph), or very brisk ( 4 mph). Because fewer than 2% of women reported a very brisk pace, we combined the brisk and very brisk categories in analyses of walking pace and diabetes risk. For 1980, 1982, 1986, 1988, and 1992, we created a measure of average hours per week spent in moderate or vigorous recreational activities (all activities described above except for hours spent walking at an easy or average pace). For 1986, 1988, and 1992, using a list of physical activities (12), we calculated a weekly metabolic equivalent of task (MET) score for total physical activities, vigorous activities (requiring 6 MET/h), nonvigorous activities (requiring<6 MET/h), and walking. The validity of the questionnaire in assessing physical activity has been described elsewhere (13). Correlation between activities reported in four 1-week diaries and those reported on the questionnaire was 0.62. Ascertainment of End Points The primary end points for this study were incident coronary heart disease (defined as nonfatal myocardial infarction or fatal coronary heart disease) and stroke that occurred after the 1980 questionnaire was returned but before 1 June 1994. We requested permission to review the medical records of women who reported having a nonfatal myocardial infarction or stroke on a follow-up questionnaire. Study physicians with no knowledge of the women's self-reported risk factors reviewed the records. Nonfatal myocardial infarction was confirmed if it met the criteria of the World Health Organization of symptoms and the patient's records showed diagnostic electrocardiographic changes or elevated cardiac enzyme levels (14). Infarctions that required hospital admission and were confirmed by interview or letter but for which no medical records were available were designated as probable (19%). We included all confirmed and probable cases in the analyses because the results were the same after probable cases were excluded. Stroke was confirmed by medical records according to the criteria of the National Survey of Stroke (15), which define it as a constellation of neurologic deficits, sudden or rapid in onset, lasting at least 24 hours. Events were further subclassified as hemorrhagic stroke (subarachnoid or intraparenchymal), ischemic stroke (thrombotic or embolic), or stroke of unknown cause. Deaths were reported by next of kin and the U.S. Postal Service or were ascertained through the National Death Index. After combining all sources, we estimated that follow-up for deaths was more than 98% complete (16). Fatal coronary heart disease was defined as fatal myocardial infarction if confirmed by hospital records or autopsy or if coronary heart disease was listed as the cause of death on the death certificate, was the underlying and most plausible cause, and was supported by evidence of previous coronary heart disease. The cause of death on the death certificate was never in itself considered to provide sufficient confirmation of death from coronary heart disease. We also included sudden death within 1 hour of onset of symptoms in women with no plausible cause other than coronary disease (8% of fatal cases). Fatal strokes were coded by using the same criteria as nonfatal cases, but autopsy evidence as well as the death certificate listing was accepted. Statistical Analysis The study base was defined as the pool of person-time that gives rise to incident cases of cardiovascular disease among patients with both prevalent and incident diabetes. We conducted two sets of analyses, one using 1980 as the baseline to evaluate long-term overall effects of moderate or vigorous activities and the other using 1986 as the baseline to examine specific effects of regular walking. Person-time for each participant was calculated from the date of return of the 1980 or 1986 questionnaires to the date of confirmed cardiovascular disease, death from any cause, or 1 June 1994, whichever came first. In the first set of analyses, relative risks were computed as the incidence rate in a specific category of average hours spent on moderate or vigorous activities per week divided by the incidence rate in the lowest category, with adjustment for 5-year categories of age. Tests of linear trend across increasing categories of average hours spent on moderate or vigorous activities were conducted by treating the categories as a single continuous variable and assigning the median score for the category as its value. To best represent long-term levels of physical activity for individual women and to reduce measurement error, we created measures of the cumulative average of physical ac