PHARMACOLOGIC STRATEGIES

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1 RISK FACTOR REDUCTION: PHARMACOLOGIC AND NONPHARMACOLOGIC STRATEGIES George L. Bakris, MD* ABSTRACT The renin-angiotensin-aldosterone system is one of the systems that serve as a fulcrum upon which blood pressure is maintained. Therefore, it is the target of many of our most effective treatments for hypertension. Three major sets of guidelines provide a consensus on the prevention and management of hypertension in patients with type diabetes to avoid cardiovascular disease and outcomes and renal failure first-line treatments should be angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs). However, polypharmacy will most likely be necessary in most people. It is important for clinicians to understand why ARBs and ACEIs are therapies that must be included in the regimen for this patient population, but it is also important to examine the evidence for other therapies, which in most cases will need to be added to achieve blood pressure targets. Treating or preventing hypertension in patients with type diabetes cannot be done with a cookie cutter approach; treatment must be tailored to each individual patient s comorbidities, risk factors, medical history, and personal situations. Throughout all considerations in a treatment plan must be the recognition and continued reinforcement of lifestyle modifications, which address *Professor of Medicine, Director, Hypertension Unit, Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Division of Biological Sciences, The University of Chicago, Pritzker School of Medicine, Chicago, Illinois. Address correspondence to: George L. Bakris, MD, Professor of Medicine, Director, Hypertension Unit, Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Division of Biological Sciences, The University of Chicago, Pritzker School of Medicine, Chicago, IL gbakris@earthlink.net. every cardiovascular risk factor, not just hypertension. This article will discuss the safety and efficacy of antihypertensive therapies in patients with type diabetes, in addition to strategies for implementing the necessary lifestyle changes. (Adv Stud Med. 007;7():37-38) INTRODUCTION As reviewed in the article by Dr White, the reninangiotensin-aldosterone system (RAAS) is the fulcrum upon which blood pressure is maintained. Therefore, it is the target of many of our most effective treatments for hypertension. Three major sets of guidelines provide a consensus on the prevention and management of hypertension in patients with type diabetes to avoid cardiovascular disease (CVD) and outcomes and renal failure. -3 The recommended first-line treatments for patients with type diabetes are angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs) not thiazide diuretics, which are recommended first-line therapy for most people in the general population. However, polypharmacy is also necessary for most people. Concurrent with any pharmacologic treatment (at all stages of hypertension) are lifestyle modifications that have important clinical benefits beyond those offered by drug therapy. This article will discuss the safety and efficacy of antihypertensive therapies in patients with type diabetes, a patient population particularly at risk for CVD, in addition to strategies for implementing the necessary lifestyle changes. PHARMACOLOGIC STRATEGIES EFFICACY CONSIDERATIONS Antihypertensive therapy drug classes include diuretics, β blockers, calcium channel blockers, direct vasodilators, central α agonists, and several classes of drugs that act on the RAAS (ie, ACEIs, ARBs, nonse- 37 Vol. 7, No. October 007

2 lective and selective aldosterone antagonists, and renin inhibitors). For the general population, thiazide-like diuretics are typically considered first-line for people older than the age of 55 years because of their superior efficacy shown in the Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and their lower cost. 4 However, for patients with type diabetes, a preference for ACEIs and ARBs has been stated by all of the consensus guidelines. A review of 7 randomized trials of antihypertensive drugs (that included patients with diabetes and 5 34 patients without diabetes) by the Blood Pressure Trialists Collaboration showed virtually no difference among the different classes of antihypertensive drugs with regard to short-term cardiovascular events. 5 The authors concluded that the data also suggest that clinicians may reasonably choose from a wide range of blood pressure-lowering agents in their efforts to reduce short- to mediumterm risks of macrovascular complications in patients with diabetes. However, the authors also note that this study did not characterize the effects of antihypertensive agents based on renoprotective effects, such that important benefits from the selective use of certain agents, such as those that antagonize the reninangiotensin system, cannot be excluded. 5 The Heart Outcomes Prevention Evaluation (HOPE) is the landmark study that showed the renoprotective benefits of the ACEI ramipril dosed at night. 6 The HOPE study was a large, randomized double-blind comparison of the ACEI ramipril to placebo in 954 patients at high risk of cardiac events (ie, a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes, plus at least other risk factor). Of note, patients need not have been hypertensive to be part of the study. A % risk reduction in the primary composite outcome of cardiovascular death, stroke, and myocardial infarction was observed in those receiving ramipril. In a subanalysis of 3577 patients with diabetes enrolled in this trial (micro-hope), ramipril treatment again showed cardiovascular benefits, with significantly reduced rates of cardiovascular death, myocardial infarction, stroke, and total mortality compared to placebo. 7 The HOPE/micro-HOPE study also showed that ACE inhibition with ramipril, administered for 4.5 years, reduced rates of overt nephropathy by 4% (3% 40%; P =.07) in patients with type diabetes. 7 Ironically, the effect on blood pressure measures was comparable between the groups. Therefore, the investigators noted that only a small part of the benefit could be attributed to a reduction in blood pressure because the majority of patients did not have hypertension at baseline (according to conventional definitions) and the mean reduction in blood pressure with treatment was extremely small (3/ mm Hg). 6 However, the results do show the potential benefits in reducing blood pressure in patients with diabetes, even if their blood pressures are within the normal range. 6 It is also interesting to note that ACE inhibition was associated with a 34% reduction in the risk (P <.00) of new-onset diabetes in this patient population. 7 Results from the Losartan Intervention for Endpoint Reduction Study (LIFE) mirrored that of the HOPE/micro-HOPE study. In the LIFE study, losartan (an ARB) was compared to atenolol (a β blocker) in 993 patients with hypertension and left ventricular hypertrophy. 8 The efficacy of losartan was superior to that of atenolol in all cardiovascular outcomes (the primary endpoint, a composite of cardiovascular mortality, stroke, and myocardial infarction, and the individual endpoints). Blood pressure reductions were similar in both treatment groups, again pointing to the benefits beyond blood pressure reduction of addressing the RAAS. 8 When the results from patients with type diabetes were analyzed in a subanalysis, significant cardiovascular benefits were again observed with the ARB versus the β blocker. 9 Moreover, ARB treatment reduced the risk of newonset diabetes by 5% compared to the β blocker. 0 More recently, results from the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) not only validated the benefits observed with an ARB in the LIFE study, but also highlighted the need for early and aggressive intervention. In the VALUE study (a double-blind, active-controlled, parallel-group trial), an ARB (valsartan) was compared to a calcium channel blocker (amlodipine) in 5 45 high-risk hypertensive subjects. Study participants were randomized to receive either of the drugs, with a 5-step monthly titration (over 6 months total) to achieve the target blood pressure of lower than 40/90 mm Hg. The original goal of the study was to compare cardiovascular outcomes between treatments that were expected to give similar reductions in blood pressure. However, amlodipine produced greater reductions in blood pressure, especially early in the study (ie, the first 3 months) 4.0/. mm Hg lower in the amlodipine group than the valsartan group after Johns Hopkins Advanced Studies in Medicine 373

3 month;.5/.3 mm Hg after year (P <.00) between groups. Thus, any differences in cardiovascular outcomes may be due to differences in blood pressure lowering, confounding the results. The VALUE study design also called for the addition of hydrochlorothiazide (a diuretic), followed by other antihypertensive drugs, if the target blood pressure was not reached after 6 months of treatment. Of the total study population, 46.4% remained on monotherapy after 6 months. Two analyses were performed events occurring in patients while on monotherapy and all events, regardless of drug regimen at the time of the event. Significantly reduced hazard ratios for heart failure were observed with valsartan compared to amlodipine (hazard ratio, 0.63; P =.004, and hazard ratio, 0.78; P =.045, for the analyses, respectively). Moreover, valsartan reduced the risk of developing new-onset diabetes mellitus in high-risk hypertensive patients (odds ratio, 0.77; 95% confidence interval, ; P <.000). 3 These study results form the basis of the recommendation for ACEIs and ARBs in patients with type diabetes, and for early and aggressive intervention for the prevention or management of hypertension in type diabetes. SAFETY CONSIDERATIONS Although thiazide diuretics are often a first-line treatment for hypertension in the general population, they are recommended as second-line treatment in patients with diabetes. This drop in recommendation is due to the apparent link between this class of drugs and an increase in risk of diabetes with their chronic use. Specifically, in the ALLHAT study, which compared a diuretic (chlorthalidone), a calcium channel blocker (amlodipine), and an ACEI (lisinopril), diabetes incidence after 4 years of therapy was.8% with diuretic therapy, 9.6% with the calcium channel blocker, and 8.% with the ACEI. 4 Although those differences did not translate to fewer cardiovascular events for the ACEI or calcium channel blocker groups, and other studies in the elderly have underscored the overall safety with diuretics, the differences in glucose metabolism in ALLHAT relegated diuretics to second-line treatment for patients with type diabetes. 4 The relegation of calcium channel blockers to second-line treatment in patients with diabetes has recently been called into question. In 999, the Syst-Euro study, which compared a calcium channel blocker (nitrendipine) to placebo (with the possible addition of enalapril or hydrochlorothiazide), showed that active treatment reduced overall mortality by 55%, mortality from CVD by 76%, all cardiovascular events combined by 69%, fatal and nonfatal strokes by 73%, and all cardiac events combined by 63% in the subset of patients with diabetes, after adjustment for possible confounders. 5 The Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm compared an amlodipine-based regimen to an atenololbased regimen (ie, calcium channel blocker vs β blocker) in 9 57 patients with hypertension. The amlodipine-based regimen prevented more major cardiovascular events and induced less diabetes than the atenolol-based regimen. These effects might not be explained entirely by better blood pressure control. 6 The Blood Pressure Trialists analysis showed that calcium channel blockers are as, if not more, effective than diuretics for elderly patients with diabetes. 5 In short, there appears to be no evidence that calcium channel blockers are harmful in patients with diabetes. The only exceptions are heart failure, in which the evidence suggests that calcium channel blockers should not be used in systolic heart failure, and in proteinuric kidney disease. 5 In the latter case, calcium channel blockers can be used in concert with a RAAS blocker, but not alone. 3,7 A recent meta-analysis of clinical trials involving patients showed that the association of antihypertensive drugs with incident diabetes is lowest for ARBs and ACEIs, followed by calcium channel blockers and placebo, β blockers, and diuretics, in rank order. 8 Interestingly, the recent update by the British Hypertension Society to hypertension management guidelines in the United Kingdom state that ACEIs and ARBs are recommended first-line therapy in patients younger than 55 years or who are black (ie, Black African and Black Caribbean patients, not Asian, Chinese, mixed-race, or other ethnic groups), but calcium channel blockers and diuretics should be first-line therapy for those 55 years and older. The only diabetes-related compelling indication is diabetic nephropathy, which would warrant an ARB. 9,0 Based on outcome data, it is clear that RAAS blockade at appropriately high doses should be the cornerstone of therapy. Diuretics or calcium channel blockers may be added if additional blood pressure lowering is needed. One should avoid use of dihydropyridine calcium channel blockers alone in the absence of adequate RAAS blockade. 374 Vol. 7, No. October 007

4 DOSING CONSIDERATIONS As mentioned in the article earlier in this monograph, most patients will require at least medications to achieve their target blood pressure; on average, clinical trial experience tells us that patients will require at least 3 different medications (Tables and )., Although some of the large, randomized studies of antihypertensive drugs have used or allowed combination therapy, it has not been hitherto studied in a systematic way. The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension trial, which will end this year, is comparing morbidity and mortality outcomes between high-risk patients with hypertension randomized to of initial combination regimens a calcium channel blocker plus ACEI versus ACEI plus diuretic. The Bergamo Nephrologic Diabetes Complications Trial is evaluating the effect of an ACEI plus calcium channel blocker on reducing the incidence of microalbuminuria. The British Hypertension Society recently concluded that, Pathophysiological reasoning suggests that adding an ACEI to a [calcium channel blocker] or a diuretic (or vice versa in the younger group) are logical combinations. Beyond this point there is even less evidence to guide practice but the most straightforward choice is to recommend a 3-drug combination of ACEI (or ARB) plus [calcium channel blocker] plus diuretic, although this recommendation is not specific to patients with diabetes. 0 Achieving the optimal dose with each drug is essential for the best chances of achieving target blood pressure. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) recommends, for patients with type diabetes, follow-up at monthly intervals until the target blood pressure is achieved. More frequent follow-up may be necessary for those with diabetes, perhaps every 3 weeks. Serum potassium and creatinine should be monitored at least to times per year. Once the target blood pressure is reached, follow-up at 3- to 6-month intervals should be sufficient. As discussed by Dr White earlier in this monograph, treating other cardiovascular risk factors is also paramount to achieving the best possible clinical outcomes. The JNC-7 indicates that low-dose aspirin therapy should be considered only when blood pressure is controlled because of the increased risk of hemorrhagic stroke when hypertension is not controlled. The British Hypertension Society recommends aspirin (75 mg daily) for patients with diabetes aged 50 years or older and blood pressure less than 50/90 mm Hg. 9 PATIENT EDUCATION: IMPROVING COMPLIANCE AND ADHERENCE There is a rapidly growing literature on the importance of and challenges with adherence in long-term illnesses. Unfortunately, not much progress has been made in studies to improve adherence, in part because there may be as many reasons for nonadherence as there are nonadherers. The JNC-7 has identified some critical elements that can have an important impact on adherence to antihypertensive medication patient attitudes, patient trust of clinician, involvement of the entire healthcare team, use of multiple tools, resisting clinical inertia, patient understanding of the disease and its sequelae, and eliminating cost barriers. Note that patients with type diabetes are already challenged by adherence issues with their diabetes medications; they are also most likely taking other medications to reduce their cardiovascular risk factors (eg, statins or fibrates). The JNC-7 provides numerous useful ideas for addressing these barriers to adherence. They are summarized in Table 3. NONPHARMACOLOGIC STRATEGIES The lifestyle modifications recommended at each stage of hypertension, including as a preventive measure in normotensive patients, include weight loss, reduced alcohol intake, stopping smoking, increased exercise, and adoption of the Dietary Approaches to Stop Hypertension (DASH) eating plan. Although lifestyle modifications are some of the most challenging treatments to prescribe, they have a multiplicative effect on the cardiovascular risk factors beyond hypertension, thus they are worth pursuing with alacrity. Table 4 lists the expected reduction in systolic blood pressure with each of these behaviors. The DASH eating plan does not prohibit specific foods, but rather focuses the patient onto healthier choices that are high in magnesium, potassium, and calcium (which are thought to help moderate blood pressure) and away from higher-fat and higher-sodium foods. The DASH plan does not require specific diet foods or require a specific amount of sodium restriction. In brief, the plan includes 8 to 0 servings per Johns Hopkins Advanced Studies in Medicine 375

5 Table. Oral Antihypertensive Drugs Class Drug Usual Dose Range, mg Usual Daily Frequency Thiazide diuretics Chlorthalidone Chlorothiazide Hydrochlorothiazide Indapamide Metolazone Polythiazide or.5 5* 4 Loop diuretics Bumetanide Furosemide Torsemide Potassium-sparing diuretics Amiloride Triamterene Aldosterone receptor blockers Eplerenone Spironolactone β blockers Atenolol Betaxolol Bisoprolol Metoprolol Metoprolol extended release Nadolol Propranolol Propranolol long acting Timolol β blockers with intrinsic sympathomimetic activity Acebutolol Penbutolol Pindolol Combined α and β blockers Carvedilol Carvedilol extended release Labetalol Nebivolol Expected to be approved by US FDA in November 007 NA ACEIs Benazepril Captopril Enalapril Fosinopril Lisinopril Moexipril Continued on page Vol. 7, No. October 007

6 Table. Oral Antihypertensive Drugs Continued from page 376 Class Drug Usual Dose Range, mg Usual Daily Frequency Perindopril Quinapril Ramipril Trandolapril Angiotensin II antagonists Candesartan Eprosartan Irbesartan Losartan Olmesartan Telmisartan Valsartan Calcium channel blockers (nondihydropyridines) Diltiazem extended release Verapamil immediate release Verapamil long acting Verapamil or 5 540* (both) Calcium channel blockers (dihydropyridines) Amlodipine Felodipine Isradipine Nicardipine sustained release Nifedipine long acting Nisoldipine α blockers Doxazosin Prazosin Terazosin Central α agonists and other centrally acting drugs Clonidine Clonidine patch Guanfacine Methyldopa Reserpine weekly Direct vasodilators Hydralazine Minoxidil *Depending on the brand. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval (trough effect). Blood pressure should be measured just prior to dosing to determine if satisfactory blood pressure control is obtained. Accordingly, an increase in dosage or frequency may need to be considered. ACEI = angiotensin-converting enzyme inhibitor; US FDA = US Food and Drug Administration. Data from US Department of Health and Human Services. Johns Hopkins Advanced Studies in Medicine 377

7 Table. Combination Drugs for Hypertension Combination Type Drug Names Fixed-Dose Combination ACEIs and calcium channel blockers Amlodipine-benazepril hydrochloride Enalapril-felodipine Trandolapril-verapamil.5/0, 5/0, 5/0, 0/0 5/5 /80, /40, /40, 4/40 ACEIs and diuretics Benazepril-hydrochlorothiazide Captopril-hydrochlorothiazide Enalapril-hydrochlorothiazide Fosinopril-hydrochlorothiazide Lisinopril-hydrochlorothiazide Moexipril-hydrochlorothiazide Quinapril-hydrochlorothiazide 5/6.5, 0/.5, 0/.5, 0/5 5/5, 5/5, 50/5, 50/5 5/.5, 0/5 0/.5, 0/.5 0/.5, 0/.5, 0/5 7.5/.5, 5/5 0/.5, 0/.5, 0/5 ARBs and diuretics Candesartan-hydrochlorothiazide Eprosartan-hydrochlorothiazide Irbesartan-hydrochlorothiazide Losartan-hydrochlorothiazide Olmesartan-hydrochlorothiazide Telmisartan-hydrochlorothiazide Valsartan-hydrochlorothiazide 6/.5, 3/.5 600/.5, 600/5 50/.5, 300/.5 50/.5, 00/5 0/.5, 40/.5, 40/5 40/.5, 80/.5 40/.5, 60/.5, 60/5 ARBs and calcium channel blockers Valsartan-amlodipine Olmesartan-amlodipine 60/5, 60/0, 30/5, 30/0 Expected to be approved by November 007 β blockers and diuretics Atenolol-chlorthalidone Bisoprolol-hydrochlorothiazide Metoprolol-hydrochlorothiazide Nadolol-bendroflumethiazide Propranolol long acting-hydrochlorothiazide Timolol-hydrochlorothiazide 50/5, 00/5.5/6.5, 5/6.5, 0/6.5 50/5, 00/5 40/5, 80/5 40/5, 80/5 0/5 Centrally acting drug and diuretic Methyldopa-hydrochlorothiazide Reserpine-chlorothiazide Reserpine-chlorthalidone Reserpine-hydrochlorothiazide 50/5, 50/5, 500/30, 500/50 0.5/50, 0.5/ /5, 0.5/50 0.5/5, 0.5/50 Diuretic and diuretic Amiloride-hydrochlorothiazide Spironolactone-hydrochlorothiazide Triamterene-hydrochlorothiazide 5/50 5/5, 50/ /5, 75/50 ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker. Data from US Department of Health and Human Services. 378 Vol. 7, No. October 007

8 Table 3. Strategies for Improving Adherence to Antihypertensive Medications Provide Empathetic Reinforcement Clinician Awareness and Monitoring Organize Care Delivery Systems Patient Education About Treatment Adopt an attitude of concern coupled with hope and interest in the patient s future. Provide positive feedback for blood pressure and behavioral improvement. Ask about behaviors to achieve blood pressure control. Hold exit interviews to clarify regimen. Schedule more frequent appointments and healthcare personnel contact Anticipate adherence problems for young men. Consider nonadherence as a cause of: Failure to reach goal blood pressure Resistant hypertension Sudden loss of control. Ask patients to bring in all medications (prescription, complementary, or OTC) to each visit to rule out iatrogenic causes. Ask what the patient takes for pain. Recognize and treat depression and other psychiatric illnesses, including panic attacks. Be willing to change unsuccessful regimens and search for those more likely to succeed. Schedule next appointment before patient leaves office. Use appointment reminders; contact patients to confirm appointments. Follow up with patients who missed appointments. Use an office-based system approach for monitoring and follow-up (eg, educate staff to provide patient encouragement, computer or chart reminders, and disease management aids). Assess the patient s understanding and acceptance of the diagnosis. Discuss patient s concerns, clarify misunderstandings. Tell the patient the blood pressure reading, and provide a written copy. Come to agreement with the patient on goal blood pressure. Ask the patient to rate from to 0 his or her chance of staying on treatment. Inform the patient about recommended treatment, and provide specific written information about the role of lifestyle, including diet, physical activity, dietary supplements, and alcohol intake; use standard brochures when available. Elicit concerns and questions, and provide opportunities for the patient to state specific behaviors to carry out treatment recommendations. Emphasize: Need to continue treatment Control does not mean cure One cannot tell if blood pressure is elevated by feeling or symptoms ; blood pressure must be measured. Collaborate with Other Health Professionals Use complementary skills and knowledge of nurses, physician assistants, pharmacists, registered dietitians, optometrists, dentists, and podiatrists. Refer selected patients for more intensive counseling. Individualize the Regimen Include patient in decision making. Simplify the regimen to once-daily dosing, if possible. Incorporate treatment into patient s daily lifestyle (eg, take medications just before or after brushing teeth). Agree with the patient on realistic short-term objectives for specific components of the medication and lifestyle modification plan. Encourage discussion of diet and physical activity. Encourage discussion of adverse drug effects and concerns. Encourage self-monitoring with validated blood pressure devices. Minimize the cost of therapy; recognize financial issues and enlist local community and national programs to assist in affording medications. Indicate that adherence to the regimen will be a subject of discussion at each visit. Encourage gradual sustained weight loss. Promote Social Support Systems With full permission of the patient, involve caring family members or other social support (eg, faith-based or community organizations) in the treatment process. Suggest common interest group activities (eg, a walking group) to enhance mutual support and motivation. OTC = over the counter. Data from US Department of Health and Human Services. Johns Hopkins Advanced Studies in Medicine 379

9 day of fruits and vegetables and to 3 servings per day of low-fat dairy foods. 3 Perhaps the biggest challenges to most American patients is educating them on serving size (most overestimate the serving size for fruits and vegetables, thus they feel overwhelmed by the idea of incorporating 8 to 0 servings per day) and reintroducing dairy products to their daily diet. However, the DASH plan lowers blood pressure in hypertensive and normotensive patients, thus it can be used for both prevention and treatment a key message for patients and healthcare professionals. 4,5 Just recently, results from the long-term (0 5 years) follow-up from the Trials of Hypertension Prevention Trials (TOHP I [n = 744] and TOHP II [n = 38]) have been published. These randomized trials evaluated the effect on cardiovascular outcomes for TOHP I, 7 nonpharmacologic interventions to reduce blood pressure (weight loss, sodium reduction, stress management, and nutritional supplements of calcium, magnesium, potassium, and fish oil) and, for TOHP II, weight loss alone, sodium reduction alone, or the combination. The TOHP I study lasted 8 months; TOHP II lasted 36 to 48 months. Patients in the active treatment group for both studies received dietary and behavioral counseling (individual and weekly group sessions during the first 3 months, and less frequently during the remainder of the study). Long-term follow-up showed a 5% reduction in cardiovascular events (adjusted for trial, clinic, age, race, and sex) in the active intervention group. 6 However, the cardiovascular benefits may vary depending on the patient population. Those with higher average daily salt intake may benefit more from reduction of dietary salt intake. 7 COMORBIDITY CONSIDERATIONS The most common comorbidities with diabetes and hypertension are coronary disease, vascular disease, and renal disease. Data on patients with comorbid coronary or vascular disease are currently limited. However, the effect of antihypertensive therapy on patients with renal disease is now well known. COMORBID RENAL DISEASE The kidney is the most vascular organ in the body, and nephropathy is a well-known microvascular complication of both diabetes and hypertension. 8 In diabetes, there is a reduced kidney filtration rate caused by ischemia in the renal tubule, which leads to a reduced renal mass, increased glomerular blood flow, and increased glomerular capillary pressure, which in turn leads to glomerular damage and albuminuria. Therefore, hypertension can be a cause or consequence of chronic kidney disease.,9 There is strong evidence to show the relationship between nephropathy and hypertension. Twenty years ago, follow-up of screened potential participants for the Multiple Risk Factor Intervention Trial showed a significant, graded association between blood pressure and rate of renal dysfunction, independent of associa- Table 4. Recommended Lifestyle Modifications and Expected Reduction in Systolic Blood Pressure: JNC-7 Modification Weight reduction Adopt DASH eating plan Dietary sodium restriction Physical activity Moderation of alcohol consumption Recommendation Maintain normal body weight (BMI kg/m ) Consume a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat Reduce dietary sodium intake to no more than 00 µmol per day (.4 g sodium or 6 g sodium chloride) Engage in regular aerobic physical activity, such as brisk walking (at least 30 minutes per day, most days of the week) Limit consumption to no more than drinks ( oz or 30 ml ethanol; eg, 4-oz beer, 0-oz wine, or 3-oz 80-proof whiskey) Approximate SBP Reduction (Range) 5 0 mm Hg/0 kg weight loss 8 4 mm Hg 8 mm Hg 4 9 mm Hg 4 mm Hg The effects of implementing these modifications are dose and time dependent, and could be greater for some individuals. BMI = body mass index; DASH = Dietary Approaches to Stop Hypertension; JNC-7 = Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; SBP = systolic blood pressure. Reprinted with permission from US Department of Health and Human Services. 380 Vol. 7, No. October 007

10 tions between the disease and age, race, income, use of medication for diabetes mellitus, history of myocardial infarction, serum cholesterol concentration, and cigarette smoking. 30 Currently, microalbuminuria is considered to be a marker for abnormal vascular function and a risk factor for CVD. 3,3-35 Microalbuminuria is the presence of albumin in the urine at concentrations between 30 and 300 mg/d on or more occasions. Proteinuria is a sign of overt nephropathy. 34 Without intervention, 0% to 40% of patients with type diabetes and microalbuminuria will progress to macroalbuminuria in 0 to 5 years. 34,36 The relationship between hypertension and abnormal urinary protein excretion differs between patients with type and type diabetes. For patients with type diabetes, hypertension usually precedes abnormal urinary protein excretion. Also, urinary albumin excretion relates primarily to atherosclerotic vascular damage in type diabetes, rather than renal damage as in type diabetes. 34 The JNC-7 recommends annual screening for microalbuminuria in all patients with diabetes. 35 (The reader is referred to a useful review of microalbuminuria. 35 ) As discussed earlier in this monograph, firstline therapies in patients with diabetes and hypertension are ARBs and ACEIs. These recommendations also extend to patients with renal dysfunction because these agents target the RAAS. However, as reviewed by Sarafidis et al, ACEIs may hold a slight advantage in patients with proteinuria and advanced kidney disease. 34 It appears that the higher the degree of baseline urine protein excretion and proteinuria decrease, the more pronounced the renoprotective effect. 34 Also, for this patient population, lifestyle changes remain critically important. In particular, a low-protein diet is recommended, but this must be balanced with the difficulties in following this diet long-term, especially for patients with diabetes who are also trying to limit fat and carbohydrate intake. 34 CONSIDERATIONS FOR SPECIAL POPULATIONS WOMEN The only special recommendations for management of hypertension in women are a preference for β blockers in pregnant women and avoidance of ACEIs and ARBs during pregnancy because of the potential for fetal defects. ACEI and ARBs should also be avoided in women who are likely to become pregnant. The British Hypertension Society recommends that β blockers should be considered for all women of childbearing potential. 0 MINORITIES As discussed earlier in this monograph by Dr White, African Americans have a higher rate of hypertension than other ethnicities. In fact, the prevalence, severity, and impact of hypertension are increased in African Americans. The JNC-7 notes that African Americans also have a somewhat reduced response to monotherapy with β blockers, ACEIs, or ARBs compared to diuretics or calcium channel blockers. ACEIinduced angioedema occurs to 4 times more frequently in African American patients with hypertension than in other groups. However, these differential responses are largely eliminated by drug combinations that include adequate doses of a diuretic. ELDERLY Any hypertension management plan for elderly patients should follow the same principles outlined for the general care of hypertension. However, lower initial drug doses may be necessary to avoid adverse effects. Also, use of diuretics in elderly patients may carry a higher risk of hypokalemia, which can affect the likelihood of cardiovascular benefit. 4 However, ultimately, standard doses and polypharmacy will most likely be required by most older patients to reach target blood pressure levels. CONCLUSIONS Despite the wide range of treatment options for hypertension, there are many considerations for the patient with type diabetes. It is important for clinicians to understand why ARBs and ACEIs are preferred therapies to be included in the antihypertensive armamentarium for this patient population. However, it is also important to examine the evidence for other therapies, which will most likely need to be added to achieve blood pressure targets. Treating or preventing hypertension in patients with type diabetes cannot be done with a cookie cutter approach; treatment must be tailored to each individual patient s comorbidities, risk factors, medical history, and personal situations. Throughout all considerations in a treatment plan must be the recognition and continued reinforcement of lifestyle modifications, which address every cardiovascular risk factor, not just hypertension. Johns Hopkins Advanced Studies in Medicine 38

11 REFERENCES. US Department of Health and Human Services. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Complete Report. NIH publication ; August Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular disease in people with diabetes mellitus. A scientific statement from the American Heart Association and the American Diabetes Association. Circulation. 007;5: National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis. 007;49(suppl ):S-S The 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). 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