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Obesity, Regional Body Fat Distribution, and the Metabolic Syndrome in Older Men and Women
6.
from n-3 PUFA results in both antiplatelet effects and a decrease in sudden death. The other findings are consistent with general knowledge of the literature with the exception of niacin, which has been shown to decrease mortality. The Coronary Drug Project was conducted between 1966 and 1975 to assess the long-term efficacy and safety of five lipid-influencing drugs (2 doses of estrogens, thyroid, niacin, clofibrate) in 8/341 men aged 30 to 64 years with ECG-documented previous myocardial infarction (MI). The only drug with a treatment effect was niacin, which resulted in a decrease in nonfatal recurrent MI but did not decrease total mortality. With a mean follow-up of 15 years, nearly 9 years after termination of the trial, mortality from all causes in each of the drug groups, except for niacin, was similar to that in the placebo group. Mortality in the niacin group was 11% lower than in the placebo group (52% vs. 58.2%; p⫽0.0004). This late benefit of niacin, occurring after discontinuation of the drug, is best explained by decrease in CV mortality as a result of decreasing new lesion formation. MR
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Obesity, Regional Body Fat Distribution, and the Metabolic Syndrome in Older Men and Women
Pharmacologic and Surgical Management of Obesity in Primary Care: A Clinical Practice Guideline From the American College of Physicians
Goodpasture BH, Krishnaswami S, Harris TB, et al. Arch Intern Med 2005;165:777– 83.
Snow V, Barry P, Fitterman N, Qaseem A, Weiss K, for the Clinical Efficacy and Assessment Subcommittee of the American College of Physicians. Ann Intern Med 2005;142:525–31.
Study Question: Are the patterns of regional fat deposition associated with the metabolic syndrome found in the elderly? Methods: A cross-sectional study was performed that included a random, population-based, volunteer sample within the general communities of Pittsburgh, PA, and Memphis, TN. Subjects consisted of 3035 men and women aged 70 to 79 years, of whom 41.7% were black. Metabolic syndrome was defined as per the adenosine triphosphate (ATP)-III panel criteria of at least three of the five components. Visceral, subcutaneous abdominal, intermuscular, and subcutaneous thigh adipose tissue was measured by computed tomography. Results: Overall prevalence of the metabolic syndrome was 39%, and it was higher in men and women who were obese (63% and 61%, respectively), overweight (37% and 46%), and of normal weight (12% and 22%, respectively). Visceral adipose tissue was associated with the metabolic syndrome in men who were of normal weight (odds ratio [OR], 2.1; 95%CI 1.6 –2.9), overweight (1.8; 1.5–2.1), and obese (1.2; 1.0 –1.5), and in women who were of normal weight (3.3; 2.4 – 4.6), overweight (2.4; 2.0 –3.0), and obese (1.7; 1.4 –2.1), each adjusting for race. Subcutaneous abdominal adipose tissue was associated with the metabolic syndrome only in normal-weight men (1.3; 1.1–1.7). Intermuscular adipose tissue was associated with the metabolic syndrome in normal weight (2.3; 1.6 –3.5) and overweight (1.2; 1.1– 1.4) men. In contrast, subcutaneous thigh adipose tissue was inversely associated with the metabolic syndrome in obese men (0.9; 0.8 –1.0) and women (0.9; 0.9 –1.0).
10 Points to Remember: 1.
2.
3.
4.
5.
Additional weight loss over 12 months from drug therapy tested in clinical trials ranges from 2.89 kg with orlistat to 4.45 kg with sibutramine, but there is no evidence of an advantage of a particular drug. Bariatric surgery should be considered as a treatment option for patients with morbid or extreme obesity who failed an adequate trial of exercise and diet with or without adjunctive drug therapy. Surgery is a particularly good option for patients with related co-morbid conditions, such as hypertension, impaired glucose tolerance or diabetes, hyperlipidemia, and obstructive sleep apnea. The reported surgical mortality ranges from 0.3% to 1.9% with evidence for operator learning curves for each of the surgical options including several gastric bypass procedures and gastroplasty. Patients should be recommended to high-volume bariatric surgery programs whose outcomes are generally better. MR
Obesity, defined as a body mass index (BMI) of 30 kg/m2 or greater, is present in 64% of the US adult population, and extreme or morbid obesity, a BMI of 40 kg/m2 or greater, is present in 4.7%. Counsel all obese persons with lifestyle and behavioral interventions of diet and exercise with “personal achievable goal setting,” which includes lowering of blood pressure and blood sugar as appropriate. Though no evidence exists of a direct benefit of behavioral intervention on mortality or morbidity from obesity, the indirect evidence of benefit includes enhanced insulin sensitivity and lower blood sugars, improved lipid metabolism, and reduced blood pressure. Pharmacologic therapy can be offered to obese patients who fail to achieve their goals though diet and exercise alone, but with the emphasis on careful physician monitoring of side effects and realization that the drug approach is temporary and that long-term safety data are lacking. For obese patients who choose adjunctive drug therapy, options include sibutramine, orlistat, phentermine, diethylpropion, fluoxetine, and bupropion. The choice depends on the patient’s willingness to tolerate side effects.
ACC CURRENT JOURNAL REVIEW July 2005
11
Conclusions: In addition to general obesity, the distribution of body fat is independently associated with the metabolic syndrome in older men and women, particularly among those of normal body weight. Perspective: The prevalence of the metabolic syndrome in the elderly (about 40%) is nearly double that reported in middle-aged adults. The routine measurement of abdominal girth should be performed regardless of weight in both the middle aged and elderly. Generalized obesity manifest by increasing subcutaneous fat is not associated with the metabolic syndrome and is probably related to higher levels of adiponectin (a peptide produced in fat cells), which increases insulin sensitivity. MR
nonsignificant finding with respect to the primary end point. Perspective: The actual CV event rate was only 253 per 100,000 person-years and annual rate of MI ⬍1/1000. Clearly, low-risk women do not benefit from aspirin. Do women respond differently from men? That is not clear but possible. Aspirin did benefit the relatively low-risk men participating in the Physicians’ Health Study that used 325 mg of aspirin every other day. This elegant study does not answer the question whether aspirin reduces CV events in women who are at intermediate and high risk. As aspirin is effective in women with coronary disease and does decrease the stroke rate in older women, my bias is to use aspirin in women with a coronary risk equivalent (2% or greater annual risk), and in those with a Global Risk Score of ⬎1% and hs-CRP ⬎3 mg/dL or WBC ⬎7500. MR
A Randomized Trial of Low-Dose Aspirin in the Primary Prevention of Cardiovascular Disease in Women
Risk of Cardiovascular Disease by Hysterectomy Status, With and Without Oophorectomy
Ridker PM, Cook NR, Lee IM, et al. N Engl J Med 2005;352:1293–304.
Howard BV, Kuller L, Langer R, Manson JE, et al. Circulation 2005;111:1462–70.
Study Question: Is there a value in low-dose aspirin for the primary prevention of cardiovascular (CV) disease in women? Methods: In the Women’s Health Study (WHS), a two-bytwo factorial trial evaluating the benefit of aspirin and vitamin E, 39,876 initially healthy women 45 years of age or older were randomly assigned to receive 100 mg of aspirin on alternate days or placebo and vitamin E 600 IU or placebo and then monitored for 10 years for a first major CV event (i.e., nonfatal myocardial infarction [MI], nonfatal stroke, or death from CV causes) and for cancer. Results: Mean age was 54.7 years, 29% had hyperlipidemia, 13% were smokers, 27% were premenopausal, and 10-year risk of coronary heart disease (CHD) was ⬍5% in 84%, 5.0% to 9.9% in 11%, and ⱖ10 in 4% of women. The average duration of follow-up was 10.1 years. During follow-up, 477 major CV events were confirmed in the aspirin group as compared with 522 in the placebo group, a nonsignificant reduction in risk with aspirin (RR, 0.91; 95% CI, 0.80 –1.03). There was a 17% reduction in the risk of stroke with aspirin as compared to placebo (RR, 0.83; 95%CI, 0.69 – 0.99; p⫽0.04), reflecting a 24% reduction in the risk of ischemic stroke (RR, 0.76; 95%CI, 0.63– 0.93; p⫽0.009). Aspirin had no significant effect on the risk of fatal or nonfatal MI (RR, 1.02; 95%CI, 0.84 –1.25; p⫽0.83) or death from CV causes. Gastrointestinal bleeding requiring transfusion was infrequent (0.6% 10 years) and was more frequent with aspirin than in the placebo group (RR, 1.40; 95%CI, 1.07–1.83; p⫽0.02). Subgroup analyses showed that aspirin significantly reduced the risk of major CV events, ischemic stroke, and MI among women 65 years of age or older. Conclusions: In this large primary-prevention trial among women, aspirin lowered the risk of stroke without affecting the risk of MI or death from CV causes, leading to a
Study Question: Does a hysterectomy with or without oophorectomy affect cardiovascular disease (CVD) risk? Methods: A total of 89,914 women in the Women’s Health Initiative (WHI) Observational Study were assessed for demographic characteristics, medical history, dietary habits, physical activity, medications, and previous hysterectomy (with or without oophorectomy). Baseline weight, height, waist circumference, and blood pressure were measured. The CVD events were ascertained during 5.1 years of mean follow-up and adjudicated with standard criteria. Results: About 85% of women were white, 9% black, 4% Hispanic, 3% Asian/Pacific Islander, and ⬍1% American Indian. Black, Hispanic, and American Indian women had higher rates of hysterectomy than did white women (52.9%, 44.6% and 49.2% vs. 40.0%, respectively), and Asian/Pacific Islander women had lower rates (33.8%). Women with a hysterectomy (regardless of oophorectomy status) had an adverse risk profile at baseline compared with women with no hysterectomy, including a higher proportion of hypertension, diabetes, high cholesterol, obesity, and lower education, income, and physical activity (all p⬍0.01). There was no difference in regular use of aspirin, or in BP, WBC, or BMI. Total mortality and fatal and nonfatal CVD were higher among women with a hysterectomy. Hysterectomy (regardless of oophorectomy status) was a significant predictor of CVD (HR: 1.26; p⬍0.001). After adjustment for demographic variables and CVD risk factors, the effect was reduced and nonsignificant. Conclusions: Women with a hysterectomy had a worse risk profile and higher prevalence and incidence of CVD in this cohort. Multivariate models suggest that hysterectomy is not the major determinant of this outcome; rather, CVD risk may be due to the more adverse initial risk profile of women who had undergone hysterectomy.
ACC CURRENT JOURNAL REVIEW July 2005
12
from n-3 PUFA results in both antiplatelet effects and a decrease in sudden death. The other findings are consistent with general knowledge of the literature with the exception of niacin, which has been shown to decrease mortality. The Coronary Drug Project was conducted between 1966 and 1975 to assess the long-term efficacy and safety of five lipid-influencing drugs (2 doses of estrogens, thyroid, niacin, clofibrate) in 8/341 men aged 30 to 64 years with ECG-documented previous myocardial infarction (MI). The only drug with a treatment effect was niacin, which resulted in a decrease in nonfatal recurrent MI but did not decrease total mortality. With a mean follow-up of 15 years, nearly 9 years after termination of the trial, mortality from all causes in each of the drug groups, except for niacin, was similar to that in the placebo group. Mortality in the niacin group was 11% lower than in the placebo group (52% vs. 58.2%; p⫽0.0004). This late benefit of niacin, occurring after discontinuation of the drug, is best explained by decrease in CV mortality as a result of decreasing new lesion formation. MR
7.
8.
9.
10.
Obesity, Regional Body Fat Distribution, and the Metabolic Syndrome in Older Men and Women
Pharmacologic and Surgical Management of Obesity in Primary Care: A Clinical Practice Guideline From the American College of Physicians
Goodpasture BH, Krishnaswami S, Harris TB, et al. Arch Intern Med 2005;165:777– 83.
Snow V, Barry P, Fitterman N, Qaseem A, Weiss K, for the Clinical Efficacy and Assessment Subcommittee of the American College of Physicians. Ann Intern Med 2005;142:525–31.
Study Question: Are the patterns of regional fat deposition associated with the metabolic syndrome found in the elderly? Methods: A cross-sectional study was performed that included a random, population-based, volunteer sample within the general communities of Pittsburgh, PA, and Memphis, TN. Subjects consisted of 3035 men and women aged 70 to 79 years, of whom 41.7% were black. Metabolic syndrome was defined as per the adenosine triphosphate (ATP)-III panel criteria of at least three of the five components. Visceral, subcutaneous abdominal, intermuscular, and subcutaneous thigh adipose tissue was measured by computed tomography. Results: Overall prevalence of the metabolic syndrome was 39%, and it was higher in men and women who were obese (63% and 61%, respectively), overweight (37% and 46%), and of normal weight (12% and 22%, respectively). Visceral adipose tissue was associated with the metabolic syndrome in men who were of normal weight (odds ratio [OR], 2.1; 95%CI 1.6 –2.9), overweight (1.8; 1.5–2.1), and obese (1.2; 1.0 –1.5), and in women who were of normal weight (3.3; 2.4 – 4.6), overweight (2.4; 2.0 –3.0), and obese (1.7; 1.4 –2.1), each adjusting for race. Subcutaneous abdominal adipose tissue was associated with the metabolic syndrome only in normal-weight men (1.3; 1.1–1.7). Intermuscular adipose tissue was associated with the metabolic syndrome in normal weight (2.3; 1.6 –3.5) and overweight (1.2; 1.1– 1.4) men. In contrast, subcutaneous thigh adipose tissue was inversely associated with the metabolic syndrome in obese men (0.9; 0.8 –1.0) and women (0.9; 0.9 –1.0).
10 Points to Remember: 1.
2.
3.
4.
5.
Additional weight loss over 12 months from drug therapy tested in clinical trials ranges from 2.89 kg with orlistat to 4.45 kg with sibutramine, but there is no evidence of an advantage of a particular drug. Bariatric surgery should be considered as a treatment option for patients with morbid or extreme obesity who failed an adequate trial of exercise and diet with or without adjunctive drug therapy. Surgery is a particularly good option for patients with related co-morbid conditions, such as hypertension, impaired glucose tolerance or diabetes, hyperlipidemia, and obstructive sleep apnea. The reported surgical mortality ranges from 0.3% to 1.9% with evidence for operator learning curves for each of the surgical options including several gastric bypass procedures and gastroplasty. Patients should be recommended to high-volume bariatric surgery programs whose outcomes are generally better. MR
Obesity, defined as a body mass index (BMI) of 30 kg/m2 or greater, is present in 64% of the US adult population, and extreme or morbid obesity, a BMI of 40 kg/m2 or greater, is present in 4.7%. Counsel all obese persons with lifestyle and behavioral interventions of diet and exercise with “personal achievable goal setting,” which includes lowering of blood pressure and blood sugar as appropriate. Though no evidence exists of a direct benefit of behavioral intervention on mortality or morbidity from obesity, the indirect evidence of benefit includes enhanced insulin sensitivity and lower blood sugars, improved lipid metabolism, and reduced blood pressure. Pharmacologic therapy can be offered to obese patients who fail to achieve their goals though diet and exercise alone, but with the emphasis on careful physician monitoring of side effects and realization that the drug approach is temporary and that long-term safety data are lacking. For obese patients who choose adjunctive drug therapy, options include sibutramine, orlistat, phentermine, diethylpropion, fluoxetine, and bupropion. The choice depends on the patient’s willingness to tolerate side effects.
ACC CURRENT JOURNAL REVIEW July 2005
11
Conclusions: In addition to general obesity, the distribution of body fat is independently associated with the metabolic syndrome in older men and women, particularly among those of normal body weight. Perspective: The prevalence of the metabolic syndrome in the elderly (about 40%) is nearly double that reported in middle-aged adults. The routine measurement of abdominal girth should be performed regardless of weight in both the middle aged and elderly. Generalized obesity manifest by increasing subcutaneous fat is not associated with the metabolic syndrome and is probably related to higher levels of adiponectin (a peptide produced in fat cells), which increases insulin sensitivity. MR
nonsignificant finding with respect to the primary end point. Perspective: The actual CV event rate was only 253 per 100,000 person-years and annual rate of MI ⬍1/1000. Clearly, low-risk women do not benefit from aspirin. Do women respond differently from men? That is not clear but possible. Aspirin did benefit the relatively low-risk men participating in the Physicians’ Health Study that used 325 mg of aspirin every other day. This elegant study does not answer the question whether aspirin reduces CV events in women who are at intermediate and high risk. As aspirin is effective in women with coronary disease and does decrease the stroke rate in older women, my bias is to use aspirin in women with a coronary risk equivalent (2% or greater annual risk), and in those with a Global Risk Score of ⬎1% and hs-CRP ⬎3 mg/dL or WBC ⬎7500. MR
A Randomized Trial of Low-Dose Aspirin in the Primary Prevention of Cardiovascular Disease in Women
Risk of Cardiovascular Disease by Hysterectomy Status, With and Without Oophorectomy
Ridker PM, Cook NR, Lee IM, et al. N Engl J Med 2005;352:1293–304.
Howard BV, Kuller L, Langer R, Manson JE, et al. Circulation 2005;111:1462–70.
Study Question: Is there a value in low-dose aspirin for the primary prevention of cardiovascular (CV) disease in women? Methods: In the Women’s Health Study (WHS), a two-bytwo factorial trial evaluating the benefit of aspirin and vitamin E, 39,876 initially healthy women 45 years of age or older were randomly assigned to receive 100 mg of aspirin on alternate days or placebo and vitamin E 600 IU or placebo and then monitored for 10 years for a first major CV event (i.e., nonfatal myocardial infarction [MI], nonfatal stroke, or death from CV causes) and for cancer. Results: Mean age was 54.7 years, 29% had hyperlipidemia, 13% were smokers, 27% were premenopausal, and 10-year risk of coronary heart disease (CHD) was ⬍5% in 84%, 5.0% to 9.9% in 11%, and ⱖ10 in 4% of women. The average duration of follow-up was 10.1 years. During follow-up, 477 major CV events were confirmed in the aspirin group as compared with 522 in the placebo group, a nonsignificant reduction in risk with aspirin (RR, 0.91; 95% CI, 0.80 –1.03). There was a 17% reduction in the risk of stroke with aspirin as compared to placebo (RR, 0.83; 95%CI, 0.69 – 0.99; p⫽0.04), reflecting a 24% reduction in the risk of ischemic stroke (RR, 0.76; 95%CI, 0.63– 0.93; p⫽0.009). Aspirin had no significant effect on the risk of fatal or nonfatal MI (RR, 1.02; 95%CI, 0.84 –1.25; p⫽0.83) or death from CV causes. Gastrointestinal bleeding requiring transfusion was infrequent (0.6% 10 years) and was more frequent with aspirin than in the placebo group (RR, 1.40; 95%CI, 1.07–1.83; p⫽0.02). Subgroup analyses showed that aspirin significantly reduced the risk of major CV events, ischemic stroke, and MI among women 65 years of age or older. Conclusions: In this large primary-prevention trial among women, aspirin lowered the risk of stroke without affecting the risk of MI or death from CV causes, leading to a
Study Question: Does a hysterectomy with or without oophorectomy affect cardiovascular disease (CVD) risk? Methods: A total of 89,914 women in the Women’s Health Initiative (WHI) Observational Study were assessed for demographic characteristics, medical history, dietary habits, physical activity, medications, and previous hysterectomy (with or without oophorectomy). Baseline weight, height, waist circumference, and blood pressure were measured. The CVD events were ascertained during 5.1 years of mean follow-up and adjudicated with standard criteria. Results: About 85% of women were white, 9% black, 4% Hispanic, 3% Asian/Pacific Islander, and ⬍1% American Indian. Black, Hispanic, and American Indian women had higher rates of hysterectomy than did white women (52.9%, 44.6% and 49.2% vs. 40.0%, respectively), and Asian/Pacific Islander women had lower rates (33.8%). Women with a hysterectomy (regardless of oophorectomy status) had an adverse risk profile at baseline compared with women with no hysterectomy, including a higher proportion of hypertension, diabetes, high cholesterol, obesity, and lower education, income, and physical activity (all p⬍0.01). There was no difference in regular use of aspirin, or in BP, WBC, or BMI. Total mortality and fatal and nonfatal CVD were higher among women with a hysterectomy. Hysterectomy (regardless of oophorectomy status) was a significant predictor of CVD (HR: 1.26; p⬍0.001). After adjustment for demographic variables and CVD risk factors, the effect was reduced and nonsignificant. Conclusions: Women with a hysterectomy had a worse risk profile and higher prevalence and incidence of CVD in this cohort. Multivariate models suggest that hysterectomy is not the major determinant of this outcome; rather, CVD risk may be due to the more adverse initial risk profile of women who had undergone hysterectomy.
ACC CURRENT JOURNAL REVIEW July 2005
12