22 Treatment of Hypertension

Transcription

1 Chapter 22 / Elderly Hypertensive Diabetics Treatment of Hypertension in the Elderly Patient With Diabetes James R. Sowers, MD, FACE, FACP, FAHA and L. Michael Prisant, MD, FACC, FACP CONTENTS OVERVIEW DIABETES AND CARDIOVASCULAR DISEASE HYPERTENSION IN THE AGING PATIENT WITH TYPE 2 DIABETES HYPERTENSION AND CARDIOVASCULAR DISEASE IN AGING PATIENTS WITH TYPE 2 DIABETES STROKE IN THE AGING PATIENT WITH TYPE 2 DIABETES AND HYPERTENSION TREATMENT OF HYPERTENSION IN CASES OF DIABETIC NEPHROPATHY SUMMARY REFERENCES OVERVIEW More than 16 million people in the United States have diabetes mellitus (DM), and another 40 million have hypertension. These chronic diseases often coexist in our aging population. Both diseases are important predisposing factors for the development of cardiovascular and renal disease, and the coexistence of these risk factors is a very powerful pro- From: Clinical Hypertension and Vascular Diseases: Hypertension in the Elderly Edited by: L. M. Prisant Humana Press Inc., Totowa, NJ 451

2 452 Hypertension in the Elderly moter of both cardiovascular and renal disease. There is accumulating evidence that the rigorous treatment of hypertension and other risk factors such as dyslipidemia and hyperglycemia lessen the burden of cardiovascular disease (CVD), stroke, and renal disease in patients with DM. Optimal therapy in these patients includes treatment with an aspirin, statins, aggressive control of hyperglycemia, and lowering of blood pressure (BP) to less than 130/80 mmhg (1). There is also considerable data to suggest that the treatment strategies that interrupt the renin angiotensin system have special benefits in diabetic patients and may prevent the development of clinical diabetes in hypertensive patients with impaired glucose tolerance. Reports indicated that angiotensin receptor blockers (ARBs) decrease the rate of development of proteinuria and diabetic renal disease. These observations will likely have a significant impact on new guidelines for treatment of hypertension in patients with type 2 DM. DIABETES AND CARDIOVASCULAR DISEASE Because the populations of many societies are getting older, more obese, and sedentary, the prevalence of diabetes, especially type 2 diabetes, is rapidly increasing throughout the world (2 4). The disease will soon involve more than 20 million people in the United States and 300 million persons worldwide. Diabetes is now the leading cause in the United States of new blindness, end-stage renal disease (ESRD), and nontraumatic amputations (2,3,5). Because diabetes is currently the leading cause of end-stage renal disease in the United States (6), this increase in ESRD, necessitating dialysis and transplantation, is a tremendous burden on our health care resources as well as on families and individuals affected by this medical problem. CVD is the major cause of mortality in aging patients with type 2 diabetes (7 11) (Fig. 1), and hypertension is a major contributor to development of both CVD and renal disease in this population (12). Accordingly, the pathophysiology of and therapeutic approaches to hypertension in the aging diabetic patient are discussed in this chapter. HYPERTENSION IN THE AGING PATIENT WITH TYPE 2 DIABETES The prevalence of hypertension in patients with type 2 diabetes is up to three times greater than in age- and gender-matched non-diabetic patients (6,12,13). Increasing age, obesity, and the onset of renal disease are all factors that increase the prevalence of hypertension in the diabetic

3 Chapter 22 / Elderly Hypertensive Diabetics 453 Fig. 1. Seven-year incidence of cardiovascular risk in type 2 diabetes mellitus. CVA, cerebrovascular accident; MI, myocardial infarction. (From ref. 7.) patient (6,12,13). Obesity, especially central/visceral obesity, is increasingly an important factor predisposing to the development of both diabetes and hypertension (6,12,14). An increased prevalence of obesity in minority populations contributes to the greater incidence of both diabetes and hypertension in these populations (6,14,15). As our population ages, an increasingly sedentary lifestyle also contributes to a high prevalence of diabetes and hypertension. Persons with hypertension have a high prevalence of insulin resistance (15) and have a substantially increased risk of developing type 2 DM (16,17). Further, as patients age they are more likely to have changes in skeletal muscle tissue that predispose to diabetes (8). These changes include altered composition of skeletal muscle tissue (less slow-twitch insulin-sensitive muscle fibers and increased fat interspersed between skeletal muscle fibers) (Table 1). A sedentary lifestyle accentuates these changes with aging. HYPERTENSION AND CARDIOVASCULAR DISEASE IN AGING PATIENTS WITH TYPE 2 DIABETES Hypertension increases the risk for CVD (12) and stroke (18 21) in patients with type 2 diabetes. Within the Multiple Risk Factor Intervention Trial (10), more than 5000 diabetic patients were followed for 12 years and compared to more than 350,000 persons without diabetes. The Multiple Risk Factor Intervention Trial confirmed that hypertension, elevated cholesterol, and cigarette use were independent CVD risk fac-

4 454 Hypertension in the Elderly Table 1 Mechanism of Insulin Resistance in Hypertension Decreased nonoxidative glucose metabolism by skeletal muscle Postreceptor defect Decreased insulin-mediated glucose transport Decreased glycogen synthase activity Altered skeletal muscle fiber type Decreased insulin-sensitive slow-twitch fibers Decreased delivery of insulin and glucose to skeletal muscle Vascular rarefaction Vascular hypertrophy Increased vasoconstriction tors in men with diabetes, and their presence had a greater impact on CVD risk in men with diabetes compared to those without diabetes (10). In the United Kingdom Prospective Diabetes Study (UKPDS), a major risk factor for CVD in type 2 diabetes included systolic blood pressure (SBP) (22). BP was also observed to be a strong CVD risk factor in type 2 diabetic patients in the Prospective Cardiovascular Münster study (23). There is considerable evidence from controlled clinical trials indicating that rigorous control of BP to levels below the conventional control levels of 140/90 mmhg markedly reduces CVD and stroke morbidity/ mortality as well as development of ESRD in persons with type 2 DM (23 27). For example, in the UKPDS in patients assigned to tight BP control (144/82 mmhg), there was a 24% reduction in diabetes-related end points, 32% reduction in death-related end points caused by diabetes, 44% reduction in strokes, and 37% reduction in microvascular end points, especially diabetic retinopathy (Fig. 2) (27). The relative benefit on CVD risk reduction was more powerful for intensive BP reduction than tight glucose control. The Hypertension Optimal Treatment study reported that, in a diabetic subgroup (n = 1501), major CVD events were reduced by 51% in those randomly assigned to a diastolic blood pressure (DBP) goal below 80 mmhg compared to a goal of below 90 mmhg (Fig. 3) (26). In a placebo-controlled trial of treatment of isolated SBP, the Systolic Hypertension in Europe (Syst-Eur) trial, the 492 older patients with diabetes were reported in a post hoc analysis to have significant reductions in CVD mortality, all CVD events, and stroke, with a reduction in mean SBPs from 175 to 153 mmhg (28). These data from the Syst-Eur trial are similar to those of the Systolic Hypertension in the Elderly Program

5 Chapter 22 / Elderly Hypertensive Diabetics 455 Fig. 2. United Kingdom Prospective Diabetes Study 38: tight vs less-tight blood pressure control. (Data from ref. 27.) Fig. 3. Events in patients with diabetes mellitus at baseline in relation lower blood pressure levels (Hypertension Optimal Treatment trial). (Data from ref. 26.)

6 456 Hypertension in the Elderly study, for which elderly persons with type 2 diabetes derived more CVD reduction than those without diabetes (29). In general, diabetic patients in these clinical trials required more antihypertensive agents (two or more drugs) to achieve these more aggressive goals (6,30). The difficulty in achieving the goal BPs primarily relates to achieving an SBP of 130 mmhg (31). Both aging and diabetes result in disproportionate elevations in SBPs (12). The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial enrolled 15,297 diabetic hypertensive participants 55 years or older (32). Thus, 36% of the entire cohort reported a history of diabetes (33). To compare treatment with chlorthalidone, doxazosin, lisinopril, and amlodipine, the rates of fatal coronary heart disease and nonfatal myocardial infarction (MI) were measured as the primary end point (33). Figure 4 shows what can be achieved by titrating therapy and combining additional drugs (β-blocker or reserpine and hydralazine). Many diabetic hypertensive patients will require three or more drugs to achieve a lower target BP (34). For the primary end point or all-cause mortality among hypertensive diabetics, there were no differences among chlorthalidone, lisinopril, amlodipine, and doxazosin (35,36). Only doxazosin was inferior to chlorthalidone for strokes (p = 0.04) (35). All drugs were inferior to chlorthalidone for heart failure (35 37). STROKE IN THE AGING PATIENT WITH TYPE 2 DIABETES AND HYPERTENSION Stroke is the third leading cause of death in the United States (18 21). Age is one of the stronger predictors for an increase. There are more than 700,000 strokes annually, and currently there are over 4.5 million stroke survivors (38,39). Diabetes and aging are well-documented independent modifiable stroke risk factors of increasing importance as the prevalence of diabetes and the numbers of elderly citizens increase (2,18 21). Indeed, the incidence of stroke among diabetic patients is up to three times that in the general population (18 21) with an especially high-risk rates in the southeastern United States (20,21). There is an increase in both shortand long-term mortality in diabetic patients following stroke (18 21). High admission glucoses are one predictor of poor outcomes in these patients (18 21), especially in the older patient with diabetes. As the incidence of strokes is higher and the clinical outcome poorer in diabetic patients, prevention of stroke is very important (18). Hypertension, heart failure, and cigarette and alcohol use are modifiable risk factors for stroke in patients with and without diabetes (5,18,21). In the 8 years of observation in the UKPDS group, an increased risk of stroke

7 Chapter 22 / Elderly Hypertensive Diabetics 457 Fig. 4. Blood pressure control (<140/90 mmhg) and number of antihypertensive drugs in North American Diabetic ALLHAT Participants. (Data from ref. 34.) was strongly associated with systolic hypertension as well as atrial fibrillation (38). Both of these risk factors are more common in the elderly patient with diabetes (39). Intervention trials have provided support for rigorous BP control in prevention of stroke in patients with diabetes. In the UKPDS trial for combined fatal and nonfatal stroke, tight BP control (mean BP achieved 144/82 mmhg) resulted in a striking 44% relative risk reduction compared with less-aggressive control (mean BP of 154/87 mmhg) (38). This 44% risk reduction in stroke was even greater than the 22% reduction with antihypertensive treatment found in the diabetic cohort in the Systolic Hypertension Elderly Program (29). Data from Syst-Eur for those treated with nitrendipine-based antihypertensive therapy showed that the excess risk of stroke associated with diabetes was abolished by antihypertensive treatment of older patients with type 2 diabetes and isolated systolic hypertension (28). In the Microalbuminuria, Cardiovascular, and Renal Outcomes-HOPE subset analysis of the Heart Outcomes Prevention Evaluation (HOPE) study, 3577 diabetic patients treated with ramipril showed a reduction of primary combined end points of MI, stroke, and CVD death by 25% and stroke reduction by 33% (30). Studies have shown the beneficial effects of an ARB (25,40) and an angiotensin-converting enzyme (ACE)/diuretic combination (41) in reduction of primary and secondary strokes in high-risk patients, including diabetics. These data support the guidelines of a BP of less than 130/80 mmhg that is recommended in patients with diabetes and hypertension (Fig. 5)

8 458 Hypertension in the Elderly Fig. 5. Management of hypertension in diabetic patients. *In patients with more than 1 g proteinuria and renal insufficiency, the treatment goal is blood pressure less than 125/75 mmhg. **ARBs, angiotensin receptor blockers. (6,42). Although this goal is more difficult to accomplish in the elderly, it can be achieved using combinations of antihypertensive medications that include a low-dose diuretic as part of the regimen (39). TREATMENT OF HYPERTENSION IN CASES OF DIABETIC NEPHROPATHY Diabetic nephropathy has become the leading etiological cause of ESRD in the United States (6,43,44). Approximately 35% of persons with diabetes will develop diabetic nephropathy characterized by pro-

9 Chapter 22 / Elderly Hypertensive Diabetics 459 teinuria, decreased glomerular filtration rate, and increased BP (6,43,44). In type 2 diabetic patients, the incidence of diabetic nephropathy is approximately 20% (6,43 45). Because 95% of diabetic patients are type 2, more than half of ESRD in diabetes occurs in type 2 patients (6,44). Both the prevalence and incidence of ESRD are approximately twice what they were 10 years ago (43). If the trends of the past two decades persist, approximately 175,000 new cases of ESRD will be diagnosed in 2010 (44). This is partly because type 2 diabetes is expected to double within the next 10 to 15 years, and diabetic patients are living longer and thus are more likely to develop chronic problems, including ESRD. The cost associated with the management of ESRD is expected to exceed $28 billion by 2010 (43). Elderly patients with ESRD will constitute an increasingly large proportion of this population. A routine urinalysis should be performed in all newly diagnosed type 2 diabetes. If the urinalysis is negative for protein, the albumin to creatinine ratio (ACR) in a spot urine collection should be performed (44). Microalbuminuria is present if urine albumin excretion is 30 mg/24 hours or greater (equivalent to 20 μg/minute on a timed specimen or 20 mg/g creatinine on a random collection) (44). A number of factors can artificially increase urinary albumin excretion, including urinary tract infections, exercise, fever, poor glycemic control, and congestive heart failure (44). The current recommendation by the American Diabetes Association (44), as well as the National Kidney Foundation (6), is to have at least two elevated ACRs to affirm microalbuminuria. An adequate collection of urine, either spot or 24 hour, may be especially problematic in elderly patients, who are more prone to have urinary tract infections and heart failure (39). Microalbuminuria has been observed to predict the development of CVD and stroke as well as progression of diabetic nephropathy (6,12,15,44 52). Microalbuminuria has also been associated with insulin resistance or hyperinsulinemia (49), atherogenic dyslipidemia (12,52), and the absence of a nocturnal drop in both SBP and DBP (12) and is a part of the cardiometabolic syndrome (Table 2) (12,15). Because microalbuminuria is part of the cardiometabolic syndrome and is related to endothelial dysfunction and increased oxidative stress (6,12,53), it is not suprising that diabetic glomerulosclerosis parallels the process of diabetic atherosclerosis (12) and is a powerful risk factor for CVD and stroke (12,54). Thus, even after adjustment for renal function, microalbuminuria remained a strong risk factor for CVD in the subset analysis of HOPE (54). In the HOPE trial, the presence of albuminuria doubled the risk for the composite end point of MI, stroke, or CVD death and all-cause mortality.

10 460 Hypertension in the Elderly Table 2 Cardiovascular Disease Risk Factors Associated With Cardiometabolic Syndrome 1. Systolic hypertension 2. Central obesity 3. Hyperinsulinemia/insulin resistance 4. Endothelial dysfunction 5. Microalbuminuria 6. Low high-density lipoprotein cholesterol levels 7. High triglyceride levels 8. Small, dense low-density lipoprotein cholesterol particles 9. Increased apolipoprotein B levels 10. Increased fibrinogen levels 11. Increased plasminogen activator inhibitor-1 and decreased plasminogen activator levels 12. Increased C-reactive protein and other inflammatory markers 13. Absent nocturnal dipping of blood pressure and heart rate 14. Salt sensitivity 15. Left ventricular hypertrophy 16. Premature/excess coronary artery disease, stroke, and peripheral vascular disease The risk of heart failure was 3.7 times greater in type 2 diabetic patients with microalbuminuria compared to those without albuminuria (50). The risks of the composite end points, all-cause mortality, and heart failure hospitalizations in diabetic patients with microalbuminuria were significantly reduced with treatment with the ACE inhibitor ramipril (50). These data suggest that interruption of the renin angiotensin aldosterone system (RAAS) is important in preventing CVD, even in elderly patients with diabetes and hypertension (12). Several studies have provided evidence for unique benefits of antihypertensive agents that interrupt the RAAS in diabetic patients with hypertension (30,40,55,56). In addition to their impact on CVD (12,30, 40,55), ACE inhibitors in six small trials involving 352 type 2 diabetic patients with diabetic nephropathy were more effective in reducing proteinuria than other antihypertensive agents (ARBs were not included) (57,58). Studies have addressed renal protection from ARBs in type 2 DM. The Irbesartan Diabetic Nephropathy Trial (IDNT) evaluated the effects of irbesartan in 1715 patients with hypertension, type 2 diabetes, and proteinuria equal to or greater than 900 mg per day (59). These patients were randomly assigned to the ARB irbesartan, a placebo-control group,

11 Chapter 22 / Elderly Hypertensive Diabetics 461 or amlodipine and had an average follow-up of 2.6 years. The time to the event for the composite end point of doubled serum creatinine, ESRD, or death was 28% in the control group vs 19.8% in the irbesartan group. Amlodipine treatment was associated with a 25.2% reduction in composite end points, which was not different from the control group but less than the irbesartan group. In that study, the amlodipine treatment group had a higher rate of heart failure than in the placebo or irbesartan groups. This is of potential importance, particularly in elderly patients with type 2 DM. In another trial, the Reduction of Endpoints in NIDDM With Angiotensin II Antagonist Losartan (RENAAL) study, the ARB losartan at 50 to 100 mg plus conventional hypertensive therapy was compared to placebo plus conventional hypertensive therapy in 1513 patients (60). Creatinine was required to be between 1.3 and 3 mg/dl, and urine ACR had to be greater than 300 mg/g or 25 mg/mmol. The goal BP was less than 140/90 mmhg, and the patients were followed for 3.4 years. Losartan therapy was associated with a 28% reduction in the risk of ESRD and a 25% reduction in doubling of serum creatinine. Furthermore, there was a 32% reduction in the first hospitalization for congestive heart failure. There was a nonsignificant trend for a reduction in MI in the losartan group. Again, these observations are of relevance to an older population of type 2 diabetic patients. The Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria (IRMA2) study examined the possibility that the ARB irbesartan could delay or prevent the development of clinical proteinuria in patients with type 2 diabetes, microalbuminuria, and a normal serum creatinine level (1.3 mg/dl for men and 1.1 mg/dl for women) (61). Type 2 diabetic patients whose overnight albumin excretion rates (UAER) were 20 to 200 μg/minute on two of three consecutive samples were randomly assigned to receive placebo or mg irbesartan once daily. Goal BP was less than 135/85 mmhg 3 months after randomization; additional antihypertensive agents, except ACE inhibitors and dihydropyridine calcium channel blockers, were added to achieve that goal. The primary end point of the trial was defined as the occurrence of UAER of greater than 200 μg/minute and/or a UAER at least 30% higher than baseline on at least two consecutive measurements. In the IRMA2 study, average BP values were slightly lower in the two groups treated with irbesartan than in the placebo group during the first 6 months of the study, but this small difference disappeared during the last 12 months of the study. Patients were followed for an average of 2 years. In the 150 mg irbesartan vs placebo group, there was a 39% reduction in the development rate of clinical proteinuria; however, in the

12 462 Hypertension in the Elderly 300 mg irbesartan treatment group, there was a 70% reduction in the primary end point. Return to a normal UAER, defined as a UAER of less than 20 μg/minute, was 34% more frequent among patients treated with 300 mg irbesartan than among patients in the placebo group. The results of this study demonstrate that the ARB irbesartan at a dose of 300 mg daily can delay progression of microalbuminuria to clinical proteinuria in patients with type 2 diabetes. In all three of these trials using ARBs, there was a little problem with hyperkalemia, which is a key issue in elderly type 2 diabetic patients (39). There have also been trials examining the impact of combination of an ACE inhibitor and an ARB on diabetic nephropathy (62 64). For instance the Candesartan and Lisinopril Microalbuminuria trial was a randomized study of the effect of combining the ARB candesartan and the ACE inhibitor lisinopril on microalbuminuria in 199 type 2 diabetic patients (63). This was a 12-week combination therapy trial, with 12 weeks of prior monotherapy with either candesartan or lisinopril. In this study, the reduction in the urinary ACR in those receiving candesartan (16 mg/day) and lisinopril (20 mg/day) was significantly greater (50% reduction) than that observed with either agent alone (24% for candesartan and 39% for lisinopril). As is often the case with combination therapy, BP values were lower than with the individual agent, which makes interpretation of the findings difficult. After 24 weeks of therapy, DBP was reduced to a greater degree with combination therapy ( 16.3 mmhg) than with either candesartan ( 10.4 mmhg) or lisinopril ( 10.7 mmhg) alone. Thus, in conclusion, diabetic nephropathy is an increasingly common problem in our aging diabetic population (39). To date, there is no established means to predictably reduce the primary rate of development of diabetic nephropathy. Instead, current practice typically addresses diabetic nephropathy when it is already present, either in the form of microalbuminuria or as the more advanced disease state characterized by macroproteinuria and declining renal function. Important elements of the treatment plan for diabetic nephropathy include meticulous BP control and reduction in urine protein excretion to below 1 g/day. In this regard, ACE inhibitors and/or ARBs are of considerable importance. In type 2 diabetic nephropathy, the available evidence supports the preferential use of ARBs or ACE inhibitors. SUMMARY There are limited data evaluating various interventions in the elderly diabetic with hypertension (65). Most guidelines (6,42,66), but not all

13 Chapter 22 / Elderly Hypertensive Diabetics 463 Table 3 Dietary and Lifestyle Modifications Recommended for Management of Hypertension 1. Weight loss 2. Exercise (aerobic physical activity) minutes at least three times a week 3. Reduced sodium intake to 100 mmol (2.4 g) per day 4. Smoking cessation 5. Adequate intake of dietary potassium, calcium, and magnesium 6. Reduced alcohol intake to less than 1oz of ethanol (24 oz of beer ) per day 7. Diet rich in fruits and vegetables but low in fat guidelines (65,67), favor a target BP of 130/80 mmhg. Thus, elderly patients with diabetes often require three or more medications to control their BP (6,12,31). BP should be reduced gradually to avoid complications (65). As noted in the treatment algorithm (Fig. 5), pharmacological therapy should be initialized in conjunction with hygienic measures (Table 3) (6,12,31). Based on the results of the Dietary Approaches to Stop Hypertension intervention, the reduction of sodium intake to levels below 100 mmol per day along with a diet that is enriched in potassium and other minerals (i.e., magnesium, calcium) is beneficial (68,69). Because many elderly persons are on a limited fixed income, this is often difficult to achieve (39). In the absence of anginal symptoms and lower extremity problems (i.e., foot abnormalities, claudication), the elderly diabetic patient should be encouraged to participate in aerobic exercise, even if that means only walking on a safe surface (i.e., in shopping malls) (39). As stated, the consensus BP goal in diabetic patients is less than 130/ 80 mmhg (6,42,66). Initial therapy is an ACE inhibitor or an ARB. Renal function and potassium levels should be checked within 1 or 2 weeks of initiation, with each titration, and yearly (65). Current recommendations include the use of β-blockers, calcium antagonists, or lowdose diuretics in conjunction with an ACE inhibitor or an ARB (6,12,31). Because of the results of the UKPDS (27) and other studies (70), β- blockers are now considered important antihypertensive agents in elderly patients with diabetes, especially those who have angina. Low-dose diuretics and dihydropyridine calcium antagonists are often required to accomplish adequate BP control, especially systolic control in elderly patients with type 2 diabetes (6,12). In addition to BP control, these patients should receive aspirin in a dose of 81 mg to an adult aspirin dose (12). A large study has demon-

14 464 Hypertension in the Elderly Fig. 6. Effectiveness of intense multifactorial intervention in type 2 diabetes: the Steno-2 Study. CI, confidence interval. (Data modified from ref. 72.) Fig. 7. Risk factor control of diabetes in the United Sates. Third National Health and Nutrition Examination Survey (NHANES III): vs (Data from ref. 75.) strated the benefits of statin therapy in elderly patients as well as those with diabetes (71). Therefore, it is recommended that all elderly diabetic patients have their low-density lipoprotein cholesterol lowered to less than 100 mg/dl with statin therapy. The elderly diabetic patient also should have blood glucoses well controlled (12), with glycated hemoglobins less than 7%. An intense, multiple risk-factor intervention in type 2 diabetes reduces the risk of CVD, nephropathy, retinopathy, and autonomic neuropathy (Fig. 6) compared to conventional treatment (72). However, data indicated that hormone replacement therapy is generally not indicated in the elderly diabetic female (73,74). Despite these data, little progress is being made in risk-factor control in diabetes (Fig. 7) (75). ACKNOWLEDGMENT We wish to thank Paddy McGowan for her usual excellent work in preparing this chapter.

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19 Chapter 22 / Elderly Hypertensive Diabetics Gæde P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348: Humphrey LL, Chan BK, Sox HC. Postmenopausal hormone replacement therapy and the primary prevention of cardiovascular disease. Ann Intern Med 2002;137: Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women s Health Initiative randomized controlled trial. JAMA 2002;288: Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA 2004;291: