There are two fundamental understandings that underlie

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1 AJH 2003; 16:7S 12S Role for -Blockers in the Management of Diabetic Kidney Disease George L. Bakris Diabetes is the number one cause of end-stage renal disease in the United States. Most patients with diabetic renal disease also have hypertension and additional cardiovascular (CV) risk factors. The leading cause of death among these patients is CV events. Treatment of hypertension in patients with diabetes is therefore of particular relevance. The goals of antihypertensive therapy are to lower blood pressure (BP), to slow the progression of kidney disease, and to reduce the risk of CV events. The recommended target BP in patients with chronic kidney disease, with or without diabetes, is 130/80 mm Hg. The majority of these patients will require more than one antihypertensive agent to control their BP; most will need more than two There are two fundamental understandings that underlie selection of the optimal antihypertensive regimen for patients with diabetic nephropathy. First, diabetes is the most common cause of end-stage renal disease (ESRD) in the United States (US). 1 Second, declining levels of kidney function are recognized as an independent risk factor for cardiovascular (CV) events. 2 Importantly, CV events are the number one cause of death in hypertensive patients with diabetic kidney disease. 3 5 Cardiovascular events associated with the triad of hypertension, diabetes, and renal disease represent an enormous burden of disease, disability, and medical expenditures for patients, their families, and society. Because patients with ESRD require renal replacement therapy either dialysis or kidney transplantation this group uses a disproportionate amount of medical resources. Moreover, patients with ESRD and diabetes use an even greater share of resources than do ESRD patients without diabetes. In the US in 1997, the cost of treatment of diabetic patients with ESRD was in excess of $15.6 billion. 5 Among patients with diabetic nephropathy, most of whom also have hypertension and additional CV risk factors, the goals of antihypertensive therapy are to lower blood pressure (BP), to slow the progression of kidney disease, and to reduce the risk of CV events. The two most important interventions for preventing diabetic nephropathy in patients with either type 1 or type 2 diabetes are drugs. Data from numerous randomized clinical trials show that patients with diabetic kidney disease should receive an agent that blocks the renin-angiotensin system in combination with a diuretic, -blocker ( B), or calcium channel blocker. -Blockers have an important dual role to play in the management of patients with diabetic kidney disease: to help achieve target BP, and to provide optimal cardioprotection in these patients who are at high risk for cardiac events. Am J Hypertens 2003;16:7S 12S 2003 American Journal of Hypertension, Ltd. Key Words: Diabetes, renal disease, -blockers, hypertension, diabetic nephropathy. tight control of both blood glucose and BP; and attention should also be given to reducing hypercholesterolemia. 4,5 However, once renal disease is present, reduction of BP is the most important factor for slowing progression to renal failure and the need for dialysis. 6 There is a current consensus that patients with diabetic nephropathy or other forms of chronic renal insufficiency should have BP levels 130/80 mm Hg for maximal preservation of renal function and for slowing the progression of chronic renal disease. 4 8 It is also accepted that single-agent therapy will not achieve the level of BP control required in these extremely high-risk patients. Combination therapy, including two, three, or more agents, is generally required. The antihypertensive regimen should be individualized, based on the entire risk profile of the patient. This article examines treatment of hypertension and management of patients with diabetic nephropathy, with a focus on the role for -blocker ( B) therapy. Hypertension, Diabetes, and Kidney Disease: Interrelated Pathologies Hypertension and Renal Disease With or without diabetes, uncontrolled systolic hypertension is associated with a progressive loss of kidney func- Received June 10, First decision June 10, Accepted June 10, From the Rush-Presbyterian St. Luke s Medical Center, Chicago, Illinois. Address correspondence and reprint requests to Dr. George L. Bakris, Professor, Departments of Preventive and Internal Medicine, Vice Chairman, Department of Preventive Medicine, Rush-Presbyterian St Luke s Medical Center, Director, Rush Hypertension Clinical Research Center, 1700 West Van Buren Street, Suite 470, Chicago, IL 60612; George_L_Bakris@rsh.net 2003 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc /03/$30.00 doi: /s (03)

2 8S ROLE FOR -BLOCKERS IN DIABETIC KIDNEY DISEASE AJH September 2003 VOL. 16, NO. 9, PART 2 tion, decreasing glomerular filtration rate (GFR), 9 and development of ESRD. 10 Cardiovascular disease is twice as common and advances at 1.7 to 2.5 times the rate in patients with chronic renal disease compared with the general population without chronic renal disease. 1 The level of kidney function is recognized as an independent risk factor for CV disease. Among patients enrolled in the Heart Outcomes Prevention Evaluation (HOPE) study, the presence of microalbuminuria was found to be an independent risk factor for CV events in both diabetic and nondiabetic individuals, nearly doubling (relative risk [RR] 1.83) the risk of major CV events and tripling (RR 3.23) the risk of heart failure (HF). 11 Investigators for the prospective Atherosclerosis Risk in Communities (ARIC) study 2 found a linear, independent association between GFR and atherosclerotic CV events in 15,350 subjects aged 45 to 64 years. During a mean follow-up of 6.2 years, 965 subjects (6.3%) experienced CV events. Those with a GFR 90 ml/min/1.73m 2 had an increased risk of atherosclerotic CV events, compared with subjects with a GFR 90 ml/min/1.73m 2.Insubjects with a GFR of 60 to 89 ml/min/1.73m 2 (stage 2 kidney disease; n 7665), the RR of an event was 1.16; in patients with a GFR 15 to 59 ml/min/1.73 m 2 (stage 3 disease; n 444), the RR for an event was Hypertension, Diabetes, and the Kidney In concert, diabetes and hypertension are interrelated diseases that have a synergistic impact on the risk for ESRD as well as for coronary heart disease and stroke. Additionally, the risk of CV disease, retinopathy, and other diabetic complications is significantly greater in diabetic patients with kidney disease than in those without. Both CV and renal diseases reflect premature, accelerated atherosclerosis in both small and large blood vessels in patients with diabetes. Diabetic nephropathy is a renal microvascular complication of diabetes marked by the presence of increasing levels of albuminuria and a deteriorating course from normal renal function to ESRD. However, CV events are the more likely cause of death than renal failure in these patients. Approximately 30% to 40% of patients with type 1 diabetes develop nephropathy and related hypertension; in type 2 diabetes, hypertension is usually one of several important risk factors for CV disease, including obesity, hyperglycemia, and dyslipidemia. 4,5 FIG. 1. Incidence rates (per million persons) of end-stage renal disease in the United States between 1992and 2000, by diagnosis of primary cause of renal failure, adjusted for age, sex, and ethnicity. 1 Diabetes and ESRD The prevalence of diabetes in the US rose from 4.9% in 1990 to 6.5% in This 33% increase is primarily due to an increase in the rate of type 2 diabetes. The prevalence of individuals with ESRD in the US in 2000 was estimated to be about 380,000. Of these, approximately 131,000 cases (35%) were attributable to diabetes, 1 making diabetes the most common cause of ESRD. The prevalence continues to rise. Presently, diabetic nephropathy accounts for about 40% of new cases of ESRD 5 and about 50% of new patients entering dialysis. 1 Diabetes is responsible for a 9% increase in the prevalence of ESRD during the decade of the 1990s 1,12 (Fig. 1). In particular, ESRD due to diabetes has increased in the US in individuals of African American, Hispanic, and Native American ethnicity 1 (Fig. 2). More than 50% of current ESRD patients have diabetes, either as a primary cause of renal failure, or as a secondary complication. 1 Hypertension (defined as BP 140/90 mm Hg) is present in 20% to 60% of patients with diabetes. 4 Diabetes and hypertension may lead to the development of diabetic nephropathy and progression to ESRD. The rates of CV diseases, including HF, coronary artery disease, and peripheral vascular disease, which occur in the year after diagnosis of ESRD, were found to be substantially higher among patients with diabetes 1 (Fig. 3). In one study, 13 the overall prevalence of hypertension (defined as BP FIG. 2. Incidence rates (per million persons) of end-stage renal disease in the United States between 1991 and 1999 (Hispanic data, 1995 to 1999), by diagnosis of primary cause of renal failure and by ethnicity, adjusted for age and sex. 1

3 AJH September 2003 VOL. 16, NO. 9, PART 2 ROLE FOR -BLOCKERS IN DIABETIC KIDNEY DISEASE 9S FIG. 3. Comparison of the incidences of cardiovascular comorbidities between diabetic and nondiabetic patients with end-stage renal disease (ESRD). Data from inpatient hospitalization diagnosis codes in patients surviving 1 year after diagnosis of ESRD. CHF congestive heart failure; ISHD ischemic heart disease; PVD peripheral vascular disease /90 mm Hg, or on medication) in patients with chronic renal disease but without ESRD, was found to be 65%, whereas the prevalence among those with diabetic nephropathy was 87%. Although 5-year survival after a diagnosis of HF is generally very poor in patients on dialysis ( 25%), patients with diabetes as the primary cause of ESRD have even worse survival rates than those of ESRD patients with diabetes that is not the primary cause of ESRD. Both groups have worse survival than ESRD patients without diabetes. 1 Use of CV Medications in Renal Disease According to data from the US Renal Data System (USRDS), the use of CV medications is common among patients with chronic renal disease. Unfortunately, angiotensin-converting enzyme (ACE) inhibitors, B, and aspirin are used significantly less commonly among patients with ESRD than among patients with less severe stages of renal disease 14 (Fig. 4). Thus, the patients who need these medications the most are least likely to receive them. The FIG. 4. US Renal Data System (USRDS) data showing the use of cardiovascular medications by severity of kidney disease. 14 *P.01, for end-stage renal disease (ESRD) compared with use in normal patients or patients with stage 2, 3, or 4 kidney disease. USRDS 1 reports that ACE inhibitors are used by about 35% of patients with chronic renal disease, whereas B are included in the regimen of about 65% of patients. In other data regarding the specific use of antihypertensive regimens among patients with kidney disease, one survey 13 found that 45% were taking a single antihypertensive medication, 36% were taking two drugs, 13% were taking three drugs, and 2.5% were taking more than three drugs. In addition, 4% of patients were treated with diet only. Among the classes of drugs used as monotherapy in these patients were ACE inhibitors (39%), CCB (27%), diuretics (18%), and B (9%). Taken together, these data suggest that there is substantial room for improvement in selection of antihypertensive regimens among patients at all stages of kidney disease. Clinical Guidelines for Treating Hypertension in Diabetes Both the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), 7 and the most recent guidelines published by the American Diabetes Association (ADA) 4,5 recommend lowering BP in all patients with diabetes to 130/80 mm Hg with an antihypertensive regimen that includes ACE inhibitors or angiotensin II receptor blockers (ARB), plus diuretics, B, and/or CCB. The JNC 7 provides some general guidelines for patients with diabetes, while the ADA guidelines are more specific to the individualized patient s level of risk (Table 1). According to the ADA recommendations, initial drug therapy may be with a drug from any of these classes, although preference is given to ACE inhibitors, ARB, thiazide diuretics, and B as comprising the optimal regimen. 4 Calcium channel blockers (including dihydropyridine and nondihydropyridine CCB), -adrenergic blockers ( blockers), and loop diuretics are considered as second-line agents 15 (Table 2). In addition, ACE inhibitors are favored for patients with HF, and for patients with type 1 diabetes and albuminuria or nephropathy; ACE inhibitors or ARB are favored for patients with type 2 diabetes and microalbuminuria or renal insufficiency, and for patients with type 2 diabetic nephropathy; and B are favored for patients with a recent myocardial infarction. 4 -Blockers have been well established as important components of antihypertensive regimens, and have an important role in the treatment of patients with diabetes for helping to achieve BP goal, preserving renal function, slowing the progression of nephropathy, and reducing CV morbidity and mortality. Clinical Trial Data Effective BP reduction in hypertensive patients with type 2 diabetes is known to reduce albuminuria, to slow the development and progression of diabetic nephropathy, and to improve survival. These benefits have been demon-

4 10S ROLE FOR -BLOCKERS IN DIABETIC KIDNEY DISEASE AJH September 2003 VOL. 16, NO. 9, PART 2 Table 1. Recommendations for antihypertensive classes in patients with diabetes, according to risk level 4 7 Risk Level ACE ARB B CCB D ACE ARB B CCB D Initial therapy for hypertension x x x x x x x x Age 55 y, with one additional x CV risk factor, with or without hypertension Post-MI x x x Type 1 diabetic nephropathy x x x Type 2diabetes microalbuminuria x x x x Type 2diabetes x x x macroalbuminuria, nephropathy, renal insufficiency strated with a number of antihypertensive classes of agents including diuretics, B, CCB, ACE inhibitors, and ARB. A number of studies have confirmed that BP reduction reduces morbidity and mortality in high-risk patients, including those with diabetes and diabetic nephropathy. These studies include the Systolic Hypertension in Europe (Syst-Eur) trial, 16 Heart Outcomes Prevention Evaluation (HOPE) study, 11 Hypertension Optimal Treatment (HOT) study, 17 United Kingdom Prospective Diabetes Study Hypertension in Diabetes Study (UKPDS), 18 Appropriate Blood Pressure Control in Diabetes (ABCD) study, 19 Captopril Prevention Project (CAPPP), 20 Irbesartan Diabetic Nephropathy Trial (IDNT), 21 Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL), 22 and Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2). 23 Clinical trial results demonstrate that an average of two to three different antihypertensive medications are required to achieve adequate BP control. 6 In the trials noted above, encompassing more than 20,000 participants with diabetes, it has been clearly demonstrated that regimens JNC 7 ACE angiotensin-converting enzyme; ADA American Diabetes Association; ARB angiotensin II receptor blocker; B -blocker; CCB calcium channel blocker; CV cardiovascular; D diuretic; JNC 7 Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; MI myocardial infarction. ADA including a combination of ACE inhibitors, ARB, diuretics, or B offer an advantage over other possible combinations. In the UKPDS, 18 a B-based regimen had effects similar to those of an ACE inhibitor based regimen for reducing the risk of CV events and microvascular complications of diabetes. Dihydropyridine CCB have been associated with more controversial findings regarding slowing the progression of kidney disease in clinical trials; they have not proved to be as effective as other agents in slowing the decline of GFR, although nondihydropyridine CCB have been inadequately studied in this population. 24 However, CCB-based regimens have demonstrated significant CV benefits compared with placebo in elderly hypertensive patients with systolic hypertension, 16 and thus continue to have a role in effectively driving down BP as part of a multidrug regimen in patients at high risk for stroke and other CV events. In recently completed trials in patients with established diabetic renal disease (IRMA 2, IDNT, and RENAAL), ARB have proved to be beneficial in slowing the progression of diabetic renal disease , In these trials, B were Table 2. Antihypertensive agents and effects on adults with hypertension and diabetes demonstrated in randomized clinical trials 15,16 27 Class Effects on Progression of Renal Disease Effects on Coronary Events Rates Effect on Stroke First-line agents ACE inhibitors Beneficial Beneficial Beneficial ARB Beneficial Beneficial Beneficial B Beneficial Beneficial Beneficial Thiazide diuretics Unknown Beneficial Beneficial Second-line agents NDCCB Beneficial Unknown Unknown DCCB Controversial Controversial Beneficial -Blockers Unknown Controversial Unknown Loop diuretics Unknown Unknown Unknown ACE angiotensin-converting enzyme; ARB angiotensin II receptor blocker; B -blocker; DCCB dihydropyridine calcium channel blocker; NDCCB nondihydropyridine calcium channel blocker.

5 AJH September 2003 VOL. 16, NO. 9, PART 2 ROLE FOR -BLOCKERS IN DIABETIC KIDNEY DISEASE 11S commonly used as adjunct therapy after diuretics. In the IRMA 2 study, 23 B were prescribed in up to 38% of subjects with early diabetic renal disease to help achieve target BP. In IDNT, 21 patients with overt diabetic nephropathy required an average of three antihypertensive agents in addition to their assigned study drug to help achieve their BP goal. Diuretics and B were the most frequently added agents in each treatment group. Finally, in RENAAL, 22 in patients with diabetic nephropathy, a little more than one third of all patients in both treatment groups received B. Thus, B have a role as part of renoprotective antihypertensive regimens. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) 25 evaluated the effects of a treatment regimen using a thiazide diuretic (chlorthalidone), an ACE inhibitor (lisinopril), and a CCB (amlodipine besylate), and compared their effects on CV outcomes. All three treatment groups demonstrated similar results for the primary endpoint (fatal coronary heart disease or nonfatal myocardial infarction), although the diuretic-based regimen was superior with regard to some of the secondary endpoints such as HF and stroke. Unfortunately, optimal antihypertensive treatment and drug combinations for patients with diabetes or early diabetic renal disease (BP goal 130/80 mm Hg; drug regimen including a renin-angiotensin [RAS]-blocking agent plus a diuretic, with a B or CCB, as needed) were disallowed by the trial design. As in previous trials, many patients in all three groups were taking a B as part of their regimen; thus, B contributed to reduced CV events across all arms of the trial. The African American Study of Kidney Disease and Hypertension (AASK) trial 26 was performed in 1094 African American individuals with nondiabetic hypertensive renal disease to compare the effects of two levels of BP control and three antihypertensive drug classes. Patients were randomized to initial therapy with a B (extendedrelease metoprolol succinate), a CCB (amlodipine besylate), or an ACE inhibitor (ramipril), with a loop diuretic and other agents allowed as add-on therapy to achieve the assigned BP goals. The primary outcome measures were rate of change in GFR, and the composite endpoint of reduction in GFR by 50% (reduction or loss of 25 ml/min/1.73 m 2 ) from baseline, ESRD, or death. There was no significant difference among the three drug regimens for the primary analysis of decline in GFR. However, there were definitive benefits of ramipril versus amlodipine besylate and versus extended-release metoprolol succinate on the composite outcome, and some of the secondary analyses suggest that ramipril slows nondiabetic hypertensive kidney disease progression compared with the other two regimens. It also appeared that extended-release metoprolol succinate may improve renal outcome compared with amlodipine besylate, particularly among patients with higher levels of proteinuria. The composite endpoint was similar in the ramipril and extended-release metoprolol succinate groups, and was significantly worse in the amlodipine besylate group, among patients with macroalbuminuria at baseline. In addition, proteinuria increased on amlodipine besylate, whereas a sustained reduction in proteinuria was observed in both the ramipril and extended-release metoprolol succinate groups. Clinical Recommendations Patients who have developed or are at risk for developing chronic kidney disease, including all patients with diabetes, should be included in the highest-risk group for implementation of recommendations for antihypertensive therapy to reduce CV risk. Target BP in patients with diabetes or chronic kidney disease, with or without diabetes, should be 130/80 mm Hg. In addition, the antihypertensive regimen must be effective in lowering BP, slowing progression of kidney disease, and reducing the risk of CV events. Most patients will require two or more antihypertensive agents for BP control. The individual risk profile of a patient is the best guide to determining the most effective treatment regimen (Table 1). The best paradigm for creating an optimal antihypertensive regimen for patients will be served by efforts to reduce CV risk as much as possible. To this end, all patients with diabetic nephropathy should receive an ACE inhibitor or an ARB, as directed by their individual risk profile, for both renal and CV protection; serum potassium levels should be monitored for the development of hyperkalemia. 5 For reduction of BP as well as CV events, thiazide diuretics have not been surpassed 25 and thus should be included in the regimens of patients with less advanced kidney disease; patients with advanced disease will generally require a loop diuretic rather than a thiazide diuretic. 5 -Blockers should be prescribed for their established CV benefits. 4,7,15 Calcium channel blockers may also be useful for additional BP reduction. 4,7,15 Conclusions Most patients with diabetic kidney disease should receive a RAS-blocking agent (ACE inhibitor or ARB) in combination with a diuretic. 3,4,7,27 -Blockers clearly have a role in reducing CV risk in the treatment of patients with diabetic or nondiabetic kidney disease. Other agents such as CCB have a role in helping to achieve BP goals. Attention should also be directed toward control of hyperglycemia and dyslipidemia. References 1. United States Renal Data System 2002 Annual Data Report (ADR): Incidence and prevalence of ESRD; patient characteristics at the beginning of ESRD; chronic kidney disease in the Medicaid population. Available online at: Accessed May 30, 2003.

6 12S ROLE FOR -BLOCKERS IN DIABETIC KIDNEY DISEASE AJH September 2003 VOL. 16, NO. 9, PART 2 2. Manjunath G, Tighiouart H, Ibrahim H, MacLeod B, Salem DN, Griffith JL, Coresh J, Levey AS, Sarnak MJ: Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol 2003;41: Mailloux LU: Hypertension in chronic renal failure and ESRD: prevalence, pathophysiology, and outcomes. Semin Nephrol 2001; 21: American Diabetes Association: Treatment of hypertension in adults with diabetes. Diabetes Care 2003;26(suppl 1):S80 S American Diabetes Association: Diabetic nephropathy. Diabetes Care 2003;26(suppl 1):S94 S Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, Tuttle K, Douglas J, Hsueh W, Sowers J, for the National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group: Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis 2000; 36: Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ, and the National High Blood Pressure Education Program Coordinating Committee: The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289: McAlister FA, Zarnke KB, Campbell NR, Feldman RD, Levine M, Mahon J, Grover SA, Lewanczuk R, Leenen F, Tobe S, Lebel M, Stone J, Schiffrin EL, Rabkin SW, Ogilvie RI, Larochelle P, Jones C, Honos G, Fodor G, Burgess E, Hamet P, Herman R, Irvine J, Culleton B, Wright JM, for the Canadian Hypertension Recommendations Working Group: The 2001 Canadian recommendations for the management of hypertension: part two therapy. Can J Cardiol 2002;18: Bakris G, Sowers J, Epstein M, Williams M: Hypertension in patients with diabetes. Why is aggressive treatment essential? Postgrad Med 2000;107:53 56, Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL, Stamler J: End-stage renal disease in African-American and white men: 16-year MRFIT findings. JAMA 1997;277: Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, Halle JP, Young J, Rashkow A, Joyce C, Nawaz S, Yusuf S, for the HOPE Study Investigators: Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 2001;286: Mokdad AH, Ford ES, Bowman BA, Nelson DE, Engelgau MM, Vinicor F, Marks JS: Diabetes trends in the U.S: Diabetes Care 2000;23: Ridao N, Luno J, Garcia de Vinuesa S, Gomez F, Tejedor A, Valderrabano F: Prevalence of hypertension in renal disease. Nephrol Dial Transplant 2001;16(suppl 1): Abbott KC, Bakris GL: Kidney failure and cardiovascular disease. Circulation (in press). 15. American Diabetes Association/American College of Cardiology: Hypertension in diabetes. Diabetes and Cardiovascular Disease Review 2003;2: Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A, for The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators: Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997;350: Hansson L, Zanchetti A, Carruthers SG, Dahlöf B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S, for the HOT Study Group: Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet 1998;351: UK Prospective Diabetes Study Group: Efficacy of atenolol and captopril in reducing the risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. Br Med J 1998;317: Estacio RO, Schrier RW: Antihypertensive therapy in type 2 diabetes: implications of the appropriate blood pressure control in diabetes (ABCD) trial. Am J Cardiol 1998;82:9R 14R. 20. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, Luomanmaki K, Dahlöf B, de Faire U, Morlin C, Karlberg BE, Wester PO, Bjorck JE: Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomized trial. Lancet 1999;353: Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I, for the Collaborative Study Group: Renoprotective effect of the angiotensin receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345: Brenner BM, Cooper ME, DeZeeuw D, Keane WE, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S, for the RENAAL Study Investigators: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345: Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Anderson S, Arner P, for the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group: The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345: Tarif N, Bakris GL: Preservation of renal function: the spectrum of effects by calcium-channel blockers. Nephrol Dial Transplant 1997; 12: 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: Wright JT Jr, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, Cheek D, Douglas-Baltimore JG, Gassman J, Glassock R, Hebert L, Jamerson K, Lewis J, Phillips RA, Toto RD, Middleton JP, Rostand SG, for the African American Study of Kidney Disease and Hypertension Study Group: Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease. Results from the AASK trial. JAMA 2002;288: Kaplan NM: Management of hypertension in patients with type 2 diabetes mellitus: guidelines based on current evidence. Ann Intern Med 2001;135: