ABSTRACT CARDIOVASCULAR RISK MANAGEMENT

Management of Hypertension in Patients with Type 2 Diabetes Saman Nazarian, MD, and Roger S. Blumenthal, MD, FACC, FCCP ABSTRACT Type 2 diabetes is a common condition that accounts for significant morbidity and mortality because it is a major cardiovascular risk factor. It is now recognized as part of the metabolic syndrome. Given the frequency of vascular complications in patients with type 2 diabetes, antihypertensive management is of paramount importance. Many studies of different antihypertensive agents have been performed, and there are now abundant data regarding the role of calcium channel blocking agents, beta blocking agents, angiotensin-converting enzyme inhibitors, and angiotensin receptor blocking agents. This article reviews current guidelines for selecting appropriate antihypertensive agents for the treatment of hypertension in patients with diabetes. (Adv Stud Med. 2003;3(6):326-334) Type 2 diabetes is prevalent in the United States and variable across races. The prevalence for people 20 years of age and older is 5.0% (4.4 5.6) for Caucasians, 1 6.9% (6.2 7.7) for African Americans, 5.6% (5.1 6.2) for Mexican Americans, and at least 40% in some native Americans aged 45 74 years. 2 Diabetes is 1 of 4 abnormalities that, in conjunction with obesity, dyslipidemia, and high blood pressure, have become the cluster of criteria for diagnosing the metabolic syndrome in individuals. Insulin resistance may also be included in this syndrome. Also known as syndrome X or the insulin resistance syndrome, metabolic syndrome qualifies as a syndrome because each abnormality is recognizable independently of the others, and any patient may have some or all of the abnormalities. 3 The clinical signs of the metabolic syndrome are shown in Table 1. (The D-R-O- P acronym is used to remember these signs.) All of the abnormalities associated with the metabolic syndrome lead to higher mortality. The current recommendations are to diagnose these abnormalities early and to treat patients aggressively to reduce insulin resistance, low-density lipoprotein cholesterol levels, triglyceride levels, and blood pressure. VASCULAR COMPLICATIONS OF HYPERTENSION Hypertension leads to cardiac events by inducing or accelerating atherosclerosis and by causing left ventricular hypertrophy (LVH). Heart disease and stroke are the first and third most common causes of death in Dr Nazarian is Fellow, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Dr Blumenthal is Director, Preventive Cardiology, Associate Professor of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Dr Nazarian reports having no financial or advisory relationships with corporate organizations related to this activity. Dr Blumenthal reports he receives grants/research support and honoraria from Bristol-Myers Squibb Company, Merck & Co, Inc, Pfizer Inc, and Wyeth Pharmaceuticals. Off-Label Product Discussion: The authors of this article do not include information on off-label use of products. Correspondence to: Roger S. Blumenthal, MD, FACC, FCCP, Division of Cardiology, Carnegie 538, The Johns Hopkins Ciccarone Preventive Cardiology Center, 600 N. Wolfe Street, Baltimore, MD 21287. E-mail: rblument@jhmi.edu. 326 Vol. 3, No. 6 June 2003

HYPERTENSION IN DIABETES the United States. 4 The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VII) has recently redefined the classifications for normal and abnormal blood pressure and added a new category, prehypertension (Table 2). 4 The committee recommends that for patients with diabetes, the goal blood pressure should be below 130/80 mm Hg, which is the same goal recommended by the American Diabetes Association (ADA) and the National Kidney Foundation (NKF). According to the JNC-VII, patients who have diabetes and a blood pressure of 130/80 mm Hg are included in the prehypertension group, and the committee s report recommends that such patients begin antihypertensive drug therapy immediately. 4-6 For patients with proteinuria (more than 1 g/d), the goal of both the ADA and NKF is 125/75 mm Hg. 5,6 A small increase in blood pressure can affect mortality. Stamler et al, in the Multiple Risk Factor Intervention Trial (MRFIT) involving middle-aged men with systolic hypertension, showed that compared with systolic measures of 130 mm Hg (highnormal hypertension), Stage 1 hypertension (140 mm Hg) confers a higher risk of fatal coronary heart disease (Figure 1). 7 Even high-normal blood pressure is not benign. Patients up to 65 years of age with high-normal blood pressure have a 2.5-fold increased 10-year risk of cardiovascular disease. This effect is even greater in patients older than 65 years of age. 8 Numerous studies have shown that lowering blood pressure reduces cardiovascular disease risk. In the Systolic Hypertension in the Elderly (SHEP) trial, 4736 patients 60 years of age or older received antihypertensive medications and were followed up for an average of 4.5 years. 9 Average blood pressure was lowered from 170/77 mm Hg at baseline to 143/68 mm Hg in the treatment arm vs 155/72 mm Hg in the placebo arm. The results showed that antihypertensive medications given in a stepped-care fashion (ie, adding additional antihypertensive medication at timed intervals during the study) reduced the incidence of total stroke from 8.2% to 5.2% (P =.0003). Nonfatal myocardial infarction (MI) and all-cause mortality were also reduced by 27% and 13%, respectively. The Hypertension Optimal Treatment (HOT) study evaluated the benefits of aggressively lowering diastolic blood pressure to below 80 mm Hg by using a 5-step regimen (ie, felodipine plus other agents at 5 timed intervals) in 18 790 patients. 10 In the 1501 patients within the subgroup with diabetes, there was a 51% reduction in major cardiovascular events for those with diastolic blood pressure of 80 mm Hg or below (Figure 2). Cardiovascular events included fatal and nonfatal MI, fatal and nonfatal strokes, and all other deaths due to cardiovascular disease. Results for the study group as a whole revealed that the lowest incidence of cardiovascular events Table 1.The D-R-O-P Acronym D R O P Dyslipidemia Fasting triglycerides >140 mg/dl OR HDL cholesterol <40 mg/dl OR LDL particle size <260 Å Insulin Resistance Fasting plasma glucose 110 mg/dl OR Type 2 diabetes mellitus Obesity Body mass index >25 kg/m 2 OR Waist/hip >0.85 OR Waist >100 cm High Blood Pressure Systolic blood pressure 140 mm Hg OR Diastolic blood pressure 90 mm Hg HDL = high-density lipoprotein; LDL = low-density lipoprotein. Reprinted with permission from Fagan et al. Am J Med. 1998;105(1A):77S-82S. 3 Table 2. JNC-VII Classification of Blood Pressure for Adults Category Systolic (mm Hg) Diastolic (mm Hg) Normal* <120 and <80 Prehypertension 120 139 or 80 89 Hypertension Stage 1 140 159 or 90 99 Stage 2 160 or 100 These criteria are for individuals who are not taking antihypertensive medication and who have no acute illness. This classification is based on the average of 2 or more blood pressure readings taken in accordance with JNC-VII recommendations at each of 2 or more visits after an initial screening visit. When systolic and diastolic pressures fall into different categories, the higher category should be selected to classify the individual s blood pressure. *Optimal blood pressure with respect to cardiovascular risk is below 120/80 mm Hg. However, unusually low readings should be evaluated for clinical significance. Adapted from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. 4 Advanced Studies in Medicine 327

Figure 1. Risk of Fatal CHD by Systolic Blood Pressure Level N = 356 222 men aged 35 to 37 years at baseline, followed up for 6 years. CHD = coronary heart disease. Adapted with permission from Stamler J, Neaton JD, Wentworth DN. Blood pressure (systolic and diastolic) and risk of fatal coronary heart disease. Hypertension. 1989;13(5 suppl)-i2-i12. 7 Figure 2. Incidence of Cardiac Events Increases as Diastolic Blood Pressure Level Increases in Diabetic Patients: Results of the HOT Trial occurred in patients with a mean diastolic pressure of 82.6 mm Hg. These data are the basis for the current recommendations for treating hypertension as outlined in JNC-VII and shown in Table 3. Risk stratification in JNC-VII is based on whether the patient has 1 or more of the compelling conditions the report lists. Patients with diabetes are considered in the highest risk category requiring immediate pharmacotherapy and lifestyle intervention. 4 Risk factors include smoking, dyslipidemia, diabetes mellitus, age older than 60 years, sex (men and postmenopausal women), and family history of cardiovascular disease in women younger than 65 years or men younger than 55 years. Clinical cardiovascular disease is defined as heart disease (LVH, angina/prior MI, prior coronary revascularization, heart failure), stroke or transient ischemic attack, nephropathy, peripheral arterial disease, or retinopathy. The Third Adult Treatment Panel for the National Cholesterol Education Program has now identified diabetes as a risk factor equivalent to heart disease. 11 A summary of lifestyle modifications for the management of hypertension is outlined in Table 4. Results of the landmark study by Haffner et al showed that the 7-year incidence of MI among 1373 nondiabetic subjects was 18.8% and 3.5%, respectively (P <.0001), for those with and without previous MI. The incidence of MI among the 1059 diabetic subjects was 45% and 20.2%, respectively (P <.0001). This study underscored the importance of modifying risk factors by showing that diabetic patients without previous coronary disease have at least as high a risk of MI as nondiabetic patients with known coronary disease. 12 This study and others discussed below provide the rationale for aggressive treatment of hypertension in diabetic patients. *P =.005. HOT = Hypertension Optimal Treatment. Data from Hansson et al. 10 CHOOSING AN APPROPRIATE ANTIHYPERTENSIVE REGIMEN FOR PATIENTS WITH DIABETES Current antihypertensive drug therapy consists of diuretics, beta blocking agents, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, and angiotensin receptor blockers (ARBs). Typically, pharmacotherapy is started at low doses, but JNC-VII identifies diabetes as one of several high-risk compelling indications for more aggressive therapy. For patients with diabetes (and any of the other compelling indications), the report recommends initiating therapy with 2 agents, 1 of which usually should be a thiazide-type diuretic. The second agent should be an ACE inhibitor, ARB, beta blocker, or a calcium channel blocker. 328 Vol. 3, No. 6 June 2003

HYPERTENSION IN DIABETES The choice of a thiazide diuretic as one of the first-line agents is supported by the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Randomizing 33 357 patients with hypertension and at least 1 other cardiac risk factor to antihypertensive therapy with either a thiazide diuretic (chlorthalidone), calcium channel blocker (amlodipine), or ACE inhibitor (lisinopril) revealed no significant difference in fatal coronary heart disease or nonfatal MI. Moreover, treatment with the ACE inhibitor compared with the diuretic was associated with higher 6-year rates of combined cardiovascular disease (33.3% vs 30.9%; P<.001), stroke (6.3% vs 5.6%; P=.02), and heart failure (8.7% vs 7.7%, P<.001). 13 For patients without diabetes, a second or third agent may need to be added after a short treatment trial if control is not achieved. It may be necessary to start treatment with more than 1 drug in some patients. After hypertension has been controlled for 1 year, step-down therapy can be initiated. The usual starting doses for patients without diabetes are shown in Table 5. As noted with all other patient populations, the lower the dosing frequency, the higher the compliance rate. 4 Two important studies have shown the cardiovascular benefits of ACE inhibitors in diabetic patients with hypertension. The Appropriate Blood Pressure Control in Diabetes (ABCD) study compared the hemodynamic benefits and risks of cardiovascular complications with a calcium channel blocker (nisoldipine) and with an ACE inhibitor (enalapril) in patients with type 2 diabetes and hypertension. In 470 patients included in the trial, calcium channel blocker therapy was associated with a greater occurrence of fatal or nonfatal MI (25 events) compared with enalapril (5 events; adjusted risk ratio [ARR], 7.0; 95% CI, 2.3-21.4; P <.001). However, it should be noted that in this study, cardiovascular events were secondary endpoints, and there was no significant difference in the rate of stroke, CHF, or death from cardiovascular or any other cause. 14 Similarly, the Fosinopril vs Amlodipine Cardiovascular Events Randomized Trial (FACET) compared an ACE inhibitor (fosinopril) and a calcium channel blocker (amlodipine) in patients with type 2 diabetes and hypertension. Again, cardiovascular events were secondary outcomes, but the results revealed a significantly lower risk of acute MI, stroke, or hospitalization for angina (combined outcomes) with fosinopril (Figure 3). 15 Many studies have supported the benefits of controlling blood pressure and the associated Table 3. JNC-VII Risk Stratification and Treatment Approach for Hypertension and Diabetes Initial Drug Therapy Initial Drug Therapy Blood Pressure Lifestyle without Compelling with Compelling Classification Modification Indication(s) Indication(s) Prehypertension Yes None Appropriate antihypertensive therapy tailored to compelling indication(s) Hypertension Stage 1 Yes Thiazide diuretic Appropriate antihypertensive therapy tailored to compelling indication(s) Stage 2 Yes Thiazide diuretic Appropriate antihypertensive and ACE inhibitor, therapy tailored to ARB, beta blocker, or compelling indication(s) calcium channel blocker JNC-VII = Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure; ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker. Adapted from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. 4 Table 4. Lifestyle Modifications for Hypertension Management* Expected Systolic Blood Pressure Modification Recommendation Reduction Weight reduction Goal BMI, 18.5 24.9 kg/m 2 5 20 mm Hg per 10-kg weight loss DASH diet Fruits, vegetables, low-fat dairy 8 14 mm Hg products, and reduced content of saturated and total fat Sodium restriction <100 meq/l (2.4 g sodium) per day 2 8 mm Hg Physical activity 30 min aerobic activity most days 4 9 mm Hg of the week Reduced alcohol <24 oz beer, 10 oz wine, or 3 oz 2 4 mm Hg intake 80-proof whiskey in men and half of that amount in women per day *For overall cardiac risk reduction, stop smoking. The effects of implementing these modifications are dose and time dependent, and may be greater for some individuals. BMI = body mass index; DASH = Dietary Approaches to Stop Hypertension. Adapted from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. 4 Advanced Studies in Medicine 329

Drug vascular factors in patients with diabetes. These benefits include reduced risk of diabetic complications, cardiovascular events, and development of LVH. The United Kingdom Prospective Diabetes Study (UKPDS) of 3867 patients with newly diagnosed diabetes showed that blood glucose control and blood pressure control reduced the risk of microvascular complications. In the group with tight BP control, treatment with an ACE inhibitor reduced by 34% the risk of mortality due to the combined endpoint of MI, sudden death, stroke and peripheral vascular disease Table 5. Commonly Used Oral Antihypertensive Drugs Usual Dose Range, Total mg/day Thiazide diuretics Chlorthalidone 12.5 25 Hydrochlorothiazide 12.5 50 ACE inhibitors Benazepril 10 40 Captopril (G) 25 100 Enalapril 2.5 40 Fosinopril 10 40 Lisinopril 10 40 Moexipril 7.5 30 Quinapril 10 40 Ramipril 2.5 20 Trandolapril 1 4 ARBs Irbesartan 150-300 Losartan 150-300 Valsartan 80-320 ACE inhibitors + diuretics Benzapril + 5, 10, or 20 hydrochlorothiazide 6.25, 12.5, or 25 Captopril + 25 or 50 hydrochlorothiazide 15 or 25 Enalapril + 5 or 10 hydrochlorothiazide 12.5 or 25 Lisinopril + 10 or 20 hydrochlorothiazide 12.5 or 25 ARB + diuretic Losartan + 50 or 100 hydrochlorothiazide 12.5 or 25 Doses listed are for patients without diabetes. For those with diabetes, the clinician should consider initiating therapy with 2 agents, 1 of which should usually be a thiazide diuretic. In addition, the clinician should consider prescribing the next higher dose of both antihypertensive agents in order to achieve the goal blood pressure of 130/80 mm Hg as soon as possible. ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker. Adapted from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. 4 (P =.019). 16 The Heart Outcomes Prevention Evaluation (HOPE) study showed that blood pressure control with the ACE inhibitor ramipril reduced the risk of cardiovascular events (MI, stroke, or death from cardiovascular cause) in the subpopulation with diabetes and reduced the rate of new-onset diabetes by 32% in the overall study population. 17,18 MICRO- HOPE was a substudy of HOPE comprising 3577 patients with diabetes aged 55 years or older with a previous cardiovascular event or at least 1 other cardiovascular risk factor. 19 MICRO-HOPE showed that ACE inhibitors lowered the risk of the combined primary outcome (MI, stroke, or cardiovascular death) by 25% (95% CI, 12% 36%; P =.0004), MI by 22% (6% 36%; P =.01) stroke by 33% (10% 50%; P =.007) cardiovascular death by 37% (21% 51%; P =.0001), total mortality by 24% (8% 37%; P =.004), revascularization by 17% (2% 30%; P =.03), and overt nephropathy by 24% (3% 40%; P =.027). The authors noted that the cardiovascular benefit was greater than that attributable to the decrease in blood pressure. 19 Mathew et al, in a study in which 38% of the participants had diabetes, showed that ACE inhibitors decreased the development or progression of electrocardiographic markers of LVH independently of lowering blood pressure. Those without LVH had a reduced risk of cardiovascular death, MI, stroke, and congestive heart failure (Table 6). 20 Treatment with an ACE inhibitor offers other vascular benefits for patients with diabetes, including decreased atherosclerosis and renoprotection. Protection against diabetic nephropathy is particularly important, as diabetes is the leading cause of end-stage renal disease in the United States: 40% of patients with type 1 diabetes will develop diabetic nephropathy. 20 Prevention is also important given the natural history of diabetic nephropathy, which rarely develops before 10 years of uncontrolled hyperglycemia. 21 Functional kidney changes (ie, increased glomerular filtration rate, reversible albuminuria, and increased kidney size) begin just a few years after the onset of diabetes. Structural changes continue in the following several years, and the predictors of nephropathy (ie, hyperfiltration, microalbuminuria, rising blood pressure, poor glycemic control) begin to appear during an approximately 15-year silent period. By 17 years after the onset of diabetes, frank proteinuria is observed in those destined to develop nephropathy. Of those with proteinuria, 50% will develop end-stage renal disease within 7 years. 21 By blocking the renin-angiotensin-aldosterone system, the kidneys are protected from failure because blocking angiotensin II decreases efferent arteriolar resistance, 330 Vol. 3, No. 6 June 2003

HYPERTENSION IN DIABETES which lowers intraglomerular pressure. The lower pressure decreases the albumin excretion rate and progression of chronic renal failure. 22,23 The Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E (SECURE), a substudy of HOPE, compared an ACE inhibitor (ramipril) with an antioxidant in 732 patients with vascular disease or diabetes and at least 1 other risk factor but without heart failure or left ventricular dysfunction. 24 Patients were followed up for 4.5 years, and the progression slope of the mean maximal carotid artery intimal-medial thickness (IMT), measured by ultrasonography, was monitored. The IMT increased an average of 0.0217 mm/year in the placebo group, 0.0180 mm/year in the ramipril group that received 2.5 mg/d, and 0.0137 mm/year in the ramipril group that received 10 mg/d (P =.033). These results, which parallel clinical outcomes, show that atherosclerosis was significantly less progressive in patients taking ramipril, and that the response was dose dependent. The African American Study of Kidney Disease and Hypertension (AASK) compared a beta blocker, calcium channel blocker, and ACE inhibitor in African American patients with hypertensive renal disease at 2 different goal diastolic blood pressure ranges (102 to 107 mm Hg vs 92 mm Hg or lower). 25 The clinical composite outcome of reduction in glomerular filtration rate by 50% or more from baseline, end-stage renal disease, or death was lower in the ACE inhibitor group (6.9%) compared with those taking beta blockers (8.7%) (relative risk [RR], 22% [1% 38%]; P =.04) or calcium channel blockers (8.2%; RR, 38% [14% 56%]; P =.004). These trials strongly support the use of ACE inhibitors in patients with diabetes, not only to reduce hypertension, but also to reduce microvascular and macrovascular complications of diabetes, including functional and structural kidney changes and cardiovascular events. Because angiotensin II is produced by multiple pathways, ACE inhibitors may not offer full protection against its hypertensive and vascular effects. ARBs inhibit the effects of angiotensin II via the type 1 receptor, irrespective of how much angiotensin II is produced or by which pathway. The clinical effect of possible overstimulation of type 2 receptors is not yet known. ARBs have been shown, however, to offer hemodynamic and renoprotective effects similar to those of ACE inhibitors. The Evaluation of Losartan in the Elderly (ELITE) study is perhaps the best example of a direct comparison between these classes of drugs. 26 Another advantage of ARBs is that classrelated adverse events seen with using ACE inhibitors, such as cough (occurring in up to 39% of patients) and angioedema (rare but serious), are absent. 27 Studies have shown the frequency of cough with ARBs is similar to that of placebo (1.5% to 3%); angioedema appears to be less frequent with ARBs compared with ACE inhibitors, although data on this adverse effect are still being collected. 28 ARBs therefore appear to have a possible role as alternative or adjunctive therapy to ACE Figure 3. Probability of Remaining Free of Stroke, Acute MI, or Angina Requiring Hospitalization in Diabetic Patients with Hypertension: Results of the FACET Trial The number of patients at each time point according to treatment is indicated above the x-axis of the graph. MI = myocardial infarction; FACET = Fosinopril vs Amlodipine Cardiovascular Events Randomized Trial. Adapted with permission from Tatti et al. Diabetes Care. 1998;21(4):597-603. 15 Table 6. Impact of Left Ventricular Hypertrophy Reversal or Prevention on Primary Outcome and Heart Failure in Patients with and without DM Combined Primary Outcome* CHF Regression/prevention 12.3% 9.3% Development/persistence 15.8% 15.4% P value.006 <.0001 *Cardiovascular death, myocardial infarction, or stroke. DM = diabetes mellitus CHF = congestive heart failure. Data from Mathew et al. 18 Advanced Studies in Medicine 331

inhibitors for reducing hypertension and protecting against diabetic nephropathy, but their exact role is yet to be defined. Three large-scale studies to show the effect of ARBs on patients with diabetes who have nephropathy are ongoing or completed. The Irbesartan Type 2 Diabetic Nephropathy Trial (IDNT) is a multinational, multicenter, randomized, controlled trial comparing amlodipine with irbesartan and placebo in 1650 subjects over 3 years of follow-up (mean 2.6 years). The primary composite endpoint was a doubling of the baseline serum creatinine concentration, the development of end-stage renal disease, or death from any cause. Treatment with an ARB (irbesartan) was associated with a 20% (3%-34%) lower risk of the primary outcome compared with placebo (P =.02), and a 23% (7%-37%) lower risk compared with a calcium channel blocker (P =.006). In particular, irbesartan was associated with a lower risk of doubling serum creatinine (33% [13%-48%] and 37% [19%-52%] lower than placebo and the calcium channel blocker, respectively), and a 23% (-3% to 43%) lower risk of end-stage renal disease compared with a calcium channel blocker. Of note, these differences in risk were not explained by the reductions in blood pressure. 29 The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial compared the effects of an ARB (losartan) vs a beta blocker (atenolol) in 1195 patients with diabetes, hypertension, and ECG-LVH. 30 The primary endpoint was a composite of morbidity and mortality from cardiovascular death, stroke, or MI. The results show a reduction in risk of cardiovascular death (RR, 62% [1%-41%]; P =.017), and stroke (RR, 78% [19%-54%]; P =.019), in addition to a nonsignificant reduction in MI (RR, 81% [31%- 54%]; P =.318). Regarding the composite endpoint of cardiovascular death, stroke, and MI, there was a significant reduction (RR, 73% [1%- 57%]; P = 0.017). Regarding the composite endpoint of cardiovascular death, stroke, and MI, there was a significant reduction (RR, 0.73; P = 0.017) with the ARB compared with the beta blocker. A larger, similarly designed study in 9193 patients with essential hypertension and ECG- LVH showed new-onset diabetes was less frequent in patients treated with losartan compared with atenolol (6% vs 8%). 31 The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study is an ongoing placebo-controlled trial in 1513 patients with type 2 diabetes and nephropathy who were taking concurrent antihypertensive medications (87% of the losartan group and 90% of the placebo group). 32 The distribution of concurrent medications is similar in both groups: diuretics (84% each), alpha blockers (40% and 46%, respectively), and beta blockers (34% and 37%, respectively). 32 As with the LIFE study, the data to date suggest that ARBs are renoprotective in patients with type 2 diabetes, independent of the effect on blood pressure. ARBs offer hemodynamic benefits and delay the progression of nephropathy in type 2 diabetes, although their precise role in patients with type 2 diabetes is being evaluated. Given the multiple pathways for producing angiotensin II, it is possible that combination therapy with ACE inhibitors and ARBs may offer additive benefit by further shutting down the effects of angiotensin II. The Valsartan Heart Failure Trial (Val-HeFT) compared the effect of valsartan with placebo in more than 5000 patients with heart failure. 33 Patients were allowed to continue with other medications during the study; 93% of enrollees were taking ACE inhibitors at baseline. The study was not designed to directly assess the additive effects of valsartan with an ACE inhibitor. However, data analysis showed attenuation of cardiovascular benefits with valsartan in the subgroup taking both ACE inhibitors and beta blockers. FUTURE RESEARCH It is likely that future research will focus on various combinations of available medications for the treatment of hypertension in patients with diabetes. More aggressive control of blood pressure and treatment of all components of the metabolic syndrome will be investigated. In order to manage cardiovascular risk aggressively in this high-risk population, the role of novel markers of cardiovascular disease, such as high-sensitivity C-reactive protein, lipoprotein profiling, and calcium scoring by electron-beam computed tomography, will also need to be defined. STRATEGIES FOR THE PRIMARY CARE PHYSICIAN The challenge for primary care physicians today lies in early identification of patients at high risk. As evidenced by the above studies, medical therapy of hypertension in patients with diabetes can significantly alter disease progression. Therefore, early identification of patients at risk by careful gathering of family history, examination, and laboratory analysis is of utmost importance. Once these patients are identified, the above guidelines should be used to start medical therapy. Close follow-up to ensure compliance and effective treatment is warranted. Lack of response to medical therapy or signs of end-organ damage, such as LVH, nephropathy, or coronary disease, should invite consultation. 332 Vol. 3, No. 6 June 2003

HYPERTENSION IN DIABETES CONCLUSION Diabetes is a part of a constellation of risk factors for heart disease that constitute the metabolic syndrome. Although aggressive attention to all risk factors is important, hypertension in diabetic patients deserves special care because of the increased risk for macrovascular and microvascular complications leading to increased risk of coronary events. Thiazide diuretics play an important role in first-line therapy of hypertensive patients at risk for coronary disease, but ACE inhibitors are the cornerstone of antihypertensive pharmacotherapy for the patient with diabetes. In patients who do not tolerate ACE inhibitors, substitution with an ARB is acceptable. Regardless of the stage at which hypertension is discovered, lifestyle modifications are warranted in patients with diabetes because of the myriad benefits they provide for the other clinical disorders associated with the metabolic syndrome. The primary care physician is in an advantageous position to address all of the concerns associated with hypertension and its treatment in patients with diabetes, before the onset of nephropathy and other microvascular complications. REFERENCES 1. Harris M. Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in US adults. Diabetes Care. 1998;21:518-524. 2. Lee ET,.Howard BV, Savage PJ, et al. Diabetes and impaired glucose tolerance in three American Indian populations aged 45-74 years. Diabetes Care. 1995;18:599-610. 3. Fagan TC, Deedwania PC. The cardiovascular dysmetabolic syndrome. Am J Med. 1998;105(1A): 77S-82S. 4. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Washington, DC: National Institutes of Health; 2003. NIH publication 03-5233. Available at: http://www.nhlbi.nih.gov/ guidelines/hypertension/express.pdf. Accessed May 19, 2003. 5. American Diabetes Association. Clinical practice recommendations 2002. Diabetes Care. 2002;25(suppl 1):S1-S147. 6. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36:646-661. 7. Stamler J, Neaton JD, Wentworth DN. Blood pressure (systolic and diastolic) and risk of fatal coronary heart disease. Hypertension. 1989;13 (5 suppl):i2-i12. 8. Vasan RS, Larson MG, Leip EP, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med. 2001;345(18): 1291-1297. 9. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265(24):3255-3264. 10. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351(9118):1755-1762. 11. Executive summary of the third report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497. 12. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339(4):229-234. 13.ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic; the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288: 2981-2997. 14. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin dependent diabetes and hypertension. N Engl J Med. 1998;338(10):645-652. 15. Tatti P, Pahor M, Byington RP, et al. Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care. 1998;21(4):597-603. 16. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications of type 2 diabetes: UKPDS 38. BMJ. 1998;317:703-713. 17. The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000; 342(3):145-153. 18. Yusuf S, Gerstein H, Hoogwerf B, et al. Ramipril and the development of diabetes. JAMA. 2001; 286(15):1882-1885. 19. The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with dia- Advanced Studies in Medicine 333

betes mellitus: results of the HOPE and MICRO-HOPE substudy. Lancet. 2000;355(9200):253-259. 20. Mathew J, Sleight P, Lonn E, et al. Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril. Circulation. 2001;104(14):1615-1621. 21. Breyer JA. Diabetic nephropathy in insulin-dependent patients. Am J Kidney Dis. 1992;20(6):533-547. 22. Dunn MJ. Prostaglandins, angiotensin II, and proteinuria. Nephron. 1990;55(suppl 1):30-37. 23. Melchoir WR, Bindlish V, Jaber LA. Angiotensin-converting enzyme inhibitors in diabetic nephropathy. Ann Pharmacother. 1993;27:344-350. 24. Lonn EM, Yusuf S, Dzavik V, et al. Effects of ramipril and vitamin E on atherosclerosis: the Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Rampril and Vitamin E (SECURE). Circulation. 2001;103:919-925. 25. Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK study. JAMA. 2002; 288(19):2421-2431. 26. Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997;349(9054):747-752. 27. Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med. 1992; 117(3):234-242. 28. Rodgers JE, Patterson JH. Angiotensin II-receptor blockers: clinical relevance and therapeutic role. Am J Health Syst Pharm. 2001;58(8):671-683. 29. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001; 345(12):851-860. 30. Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention for Endpoint Reduction in Hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002; 359:1004-1010. 31. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint Reduction in Hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995-1003. 32. Brenner BM, Cooper ME, Zeeuw DD, et al. The losartan renal protection study: rationale, study design, and baseline characteristics of RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan). J Renin Angiotensin Aldosterone Syst. 2000;1(4):328-335. 33. Konstam MA. Val-HeFT and angiotensin-receptor blockers in perspective: a tale of the blind man and the elephant. J Card Fail. 2002;8(2):56-58. 334 Vol. 3, No. 6 June 2003