BASED ON WORLD Health Organization

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1 Treating High-Risk Diabetic Hypertensive Patients With Comorbid Conditions Robert W. Schrier, MD Diabetes mellitus, a highly prevalent metabolic and vascular disease, affects 155 million people worldwide. Tight blood glucose control can significantly reduce the incidence of diabetic retinopathy, nephropathy, and neuropathy, but does not appear to significantly reduce its macrovascular complications. Several randomized clinical trials indicate that tight blood pressure control can reduce the risk of microvascular and macrovascular complications in patients with diabetes and hypertension. Blockade of the renin-angiotensin sytem (RAS) with angiotensinconverting enzyme (ACE) inhibitors has proven effective both in lowering blood pressure and in independently slowing the progression of nephropathy. If instituted early, ACE inhibitor therapy potentially may prevent progression to end-stage renal disease in normotensive patients with type 1 or 2 diabetes. Additionally, ACE inhibitors may reduce cardiovascular morbidity and mortality in this patient population. Angiotensin II (Ang II) receptor blockers (ARBs), which attenuate the deleterious effects of the RAS via blockade of the Ang II subtype 1 receptor, may also be beneficial. Clinical trials are under way to evaluate this possibility by the National Kidney Foundation, Inc. INDEX WORDS: Angiotensin II (Ang II); angiotensin II receptor blockers (ARBs); valsartan; angiotensin-converting enzyme (ACE) inhibitors; diabetes mellitus; diabetic nephropathy; end-stage renal disease (ESRD); hypertension. BASED ON WORLD Health Organization (WHO) statistics, the worldwide prevalence of diabetes is expected to increase from an estimated 155 million in the year 2000 to 300 million in 2025 (Fig 1). 1 In the United States, diabetes affects approximately 15.7 million Americans, 5.4 million of whom are currently undiagnosed and presumed to have type 2 diabetes. 2 This disorder in particular is nearing epidemic proportions and will only worsen, because the aging population will have an increased life expectancy as well as a substantial increase in obesity and sedentary lifestyle. 2 From the Department of Medicine, University of Colorado Health Sciences Center, Denver, CO. Address reprint requests to Robert W. Schrier, MD, University of Colorado Health Sciences Center, Campus Box B178, 4200 E 9th Ave, Denver, CO Robert.Schrier@ UCHSC.edu 2000 by the National Kidney Foundation, Inc /00/ $3.00/0 doi: /ajkd DIABETES CONTRIBUTES TO MICROVASCULAR AND MACROVASCULAR DISEASE Diabetes is often accompanied by vasculopathy, neurologic abnormalities, and other organspecific pathology. Microangiopathic complications manifest as thickened capillary basement membranes, particularly in the kidneys and retina. Diabetic retinopathy is the leading cause of new cases of blindness among American adults, claiming up to 24,000 victims annually. 2 Diabetic end-stage renal disease (ESRD) has also been increasing steadily since 1988 and accounts for more than 40% of all new cases of renal failure. 3 In tandem with peripheral vascular disease, diabetic sensorimotor polyneuropathy is responsible for more than 50% of nontraumatic lowerlimb amputation in adults. 4 Finally, diabetes increases the risk of heart disease 2- to 4-fold. 2 Major studies conducted within the last decade provide evidence that the morbidity and mortality associated with diabetic cardiovascular (CV) disease can be reduced. This article focuses on three therapeutic modalities: tight control of plasma glucose, tight blood pressure control, and blockade of the renin-angiotensin system (RAS). TIGHT PLASMA GLUCOSE CONTROL The Diabetes Control and Complications Trial (DCCT) was the first large-scale controlled study (mean follow-up, 6.5 years) in 1,441 patients with type 1 diabetes to unequivocally demonstrate that maintaining plasma glucose levels close to the normal range can decrease the incidence and severity of long-term microvascular and neurologic complications. 5 Compared with conventional insulin therapy (1 to 2 injections daily), tight glycemic control with intensive insulin therapy (3 or more injections daily or an insulin pump) reduced the risk for development of retinopathy by 76%, slowed the progression of pre-existing mild retinopathy by 54%, and reduced the development of proliferative or severe S10 American Journal of Kidney Diseases, Vol 36, No 3, Suppl 1 (September), 2000: pp S10-S17

2 TREATING DIABETIC HYPERTENSIVE PATIENTS Fig 1. Number of adults with diabetes in developed and developing countries and worldwide. Adapted and reprinted with permission from King et al. 1 nonproliferative retinopathy by 47%. Microalbuminuria ( 40 mg/24 h, but 300 mg/24 h) was reduced by 39%, albuminuria ( 300 mg/24 h) by 54%, and clinical neuropathy by 60% in the cohort treated with the intensive insulin regimen. Tight control of plasma glucose increased the risk for severe hypoglycemia, although not by enough to offset the benefits. Tight glucose control, however, did not significantly reduce the risk of macrovascular events compared with conventional control. 5 The persistent benefits of intensive treatment on microvascular disease were documented in a follow-up study. Four years after DCCT, the reduction in risk of progressive retinopathy and nephropathy seen in the intensive therapy cohort persisted despite increasing hyperglycemia. 6 The Kumamoto study was a prospective 6-year trial of 110 Japanese patients with type 2 diabetes and glycosylated hemoglobin levels similar to those in DCCT. Results of the study showed S11 that intensive glycemic control with multiple insulin injections also delayed the onset and progression of retinopathy, nephropathy, and neuropathy compared with conventional insulin therapy. 7 The United Kingdom Prospective Diabetes Study (UKPDS) evaluated the effects of differing degrees of metabolic control in 3,867 middle-aged patients (median age, 54 years) with newly diagnosed type 2 diabetes. After a median follow-up of 10 years, intensive control with either insulin or sulfonylurea therapy reduced the risk of microvascular end points by 25%; however, total mortality and macrovascular disease were not reduced (Fig 2). 1,8 TIGHT BLOOD PRESSURE CONTROL Hypertension is the second leading cause of ESRD in the United States, accounting for 25% of cases. 3 An estimated 60% to 65% of diabetic patients in the United States also have high blood pressure. 4 In the diabetic patient, elevated blood pressure leads to an even greater risk of renal deterioration. Studies in the 1980s demonstrated that aggressive antihypertensive therapy in patients with type 1 diabetes can decrease blood pressure, reduce albuminuria, and slow the progressive decline in glomerular function associated with diabetic nephropathy Based on data from these and other large-scale controlled clinical trials, the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, the WHO, and the International Society of Hypertension recommend a target blood pressure of less than 140/90 mm Hg for patients with uncomplicated hypertension. They further advise lower blood pressure levels Fig 2. UKPDS: relativerisk reduction with tight versus conventional blood glucose control. *P 0.010; P 0.015; P Data from UKPDS. 8

3 S12 of less than 130/85 mm Hg for patients with diabetes or renal disease and even lower target levels ( 125/75 mm Hg) in patients with greater than 1 g/d of proteinuria. 14,15 Data supporting these consensus decisions also come from more recent studies, such as UKPDS and Hypertension Optimal Treatment (HOT). After examining plasma glucose control, UK- PDS investigators examined the impact of blood pressure control in newly diagnosed patients with type 2 diabetes. The study involved 1,148 hypertensive patients with an average blood pressure at entry of 160/94 mm Hg. 16 The objective of this study was to determine whether tight control of blood pressure prevented macrovascular and microvascular complications in these diabetic patients. A total of 758 patients were assigned to tight blood pressure control of less than 150/85 mm Hg, with the remaining 390 patients assigned to less tight control of less than 180/105 mm Hg. The less tight control group received treatment for hypertension that specifically excluded angiotensin-converting enzyme (ACE) inhibitor or beta-blocker therapy, whereas the tight-control group received either captopril or atenolol. Follow-up for a median of 8.4 years showed that patients in the tight-control group, achieving a mean blood pressure of 144/82 mm Hg, had a 24% reduced risk in diabetic end points, 32% in diabetes-related deaths, 44% in stroke, and 37% in microvascular end points relative to the less tight control group, which achieved a mean blood pressure of 154/87 mm Hg. 16 In a separate analysis of the tight-control group that used captopril or atenolol as the initial ROBERT W. SCHRIER antihypertensive agent, to which other drugs could be added as necessary, no significant differences were seen between the two agents. 17 Overall, tight control of blood pressure in patients with type 2 diabetes and hypertension achieved important reductions in diabetes-related deaths, strokes, and microvascular complications (Fig 3). 16 In the HOT trial, which was designed to establish the effects of intensive blood pressure lowering, 18,790 hypertensive patients were randomized to diastolic blood pressure goals of 90, 85, and 80 mm Hg. 18 Felodipine was the first-line drug of choice, and other drugs were added as needed to reach target levels. The lowest incidence of major CV events in the entire study population occurred at a mean diastolic blood pressure of 82.6 mm Hg and for CV mortality, 86.5 mm Hg, over an average 3.8 years follow-up. The greatest benefits in the HOT trial occurred in the subset of 1,501 patients with diabetes. 18 These patients in the 80 mm Hg target group had a 51% lower risk of major CV events than the 90 mm Hg target group (P 0.005), and although the inclusion of silent myocardial infarction (MI) attenuated the difference, it remained significant (P 0.045). The risk for MI was also halved, and stroke was reduced by 30%, although not significantly. Reduction in CV mortality (but not overall mortality) significantly favored the tight-control group. BLOCKADE OF THE RAS Accumulating data on diabetes patients support the benefits of ACE inhibitors in diabetic patients that are distinct from their blood pres- Fig 3. UKPDS: relativerisk reduction with tight versus moderate blood pressure control. *P 0.009; P 0.019; P Data from UKPDS. 16

4 TREATING DIABETIC HYPERTENSIVE PATIENTS sure lowering effects. The Microalbuminuria, Cardiovascular, and Renal Outcomes (MICRO) substudy from the Heart Outcome Prevention Evaluation (HOPE) analyzed 3,577 patients with diabetes plus one other CV risk factor who were randomized to receive the ACE inhibitor ramipril or placebo. MICRO-HOPE showed that ramipril decreased the risk for the composite CV end point by 25% (P ) and for overt nephropathy by 24% (P 0.029). 19 The CV benefit of ramipril was greater than that attributable to the small reduction in blood pressure seen in the active treatment group. The Collaborative Study Group performed a randomized, placebo-controlled study of captopril in 409 patients with type 1 diabetes and proteinuria 500 mg/24 h. 13 Many patients, 59% of the placebo group and 60% of the captopril group, were receiving antihypertensive therapy at entry. Calcium channel blockers (CCBs) and nonstudy ACE inhibitors were discontinued in patients taking these drugs before the study. Patients were eligible if the blood pressure goals for the study could be met without these agents. Over a median follow-up of 3 years, the captopril group had a 50% lower risk of the combined end point of death, dialysis, and renal transplantation compared with the placebo group. Although the captopril group also had a slightly lower blood pressure (2 mm Hg systolic and 4 mm Hg diastolic) compared with the placebo group, this did not account for the large reduction in risk. The investigators suggested that captopril therapy protected against deteriorating renal function in type 1 diabetics beyond blood pressure reduction alone, possibly by beneficially affecting glomerular hemodynamics. 13 Analogous results were reported from a study that randomized 94 normotensive patients with type 2 diabetes to enalapril or placebo during early stages of diabetic nephropathy. 20 Albuminuria decreased from a mean of 143 mg/24 h to 122 mg/24 h in the enalapril group after 1 year and then gradually increased back to 140 mg/24 h after 5 years, whereas albuminuria gradually rose in the placebo group from 123 mg/24 h to 310 mg/24 h (P 0.05). Over the same time period, mean creatinine remained stable in the enalapril group but increased by 13% in the placebo group. ACE inhibition during the early S13 stages of diabetic nephropathy appears to have had a long-term stabilizing effect on proteinuria and creatinine clearance independent of its antihypertensive effect, considering that blood pressures were normal at the start of the study and did not increase significantly in either group. These findings persisted in a 7-year follow-up study. 21 Similar conclusions were reached in the Captopril Prevention Project (CAPPP) in Sweden, where 10,985 patients with hypertension were randomly assigned to captopril or conventional therapy including diuretics, beta blockers, or both. 22 The primary study end point was a composite of fatal and nonfatal MI and stroke, as well as other CV morbidity. Although the entire cohort had little difference between antihypertensive agents in terms of CV morbidity and mortality, 572 patients with diabetes at baseline had significantly lower rates of total mortality, MI, and CV events in the captopril group versus conventional treatment (Fig 4). 22 Development of diabetes, a secondary end point, was 14% lower in captopril-treated patients (P 0.039). It was concluded that this lower incidence should have beneficial implications for long-term CV prognosis. Moreover, the relative risk of developing diabetes during follow-up among patients previously untreated for hypertension was 22% lower in the captopril group than in the conventional treatment group (P 0.041). The Appropriate Blood Pressure Control in Diabetes (ABCD) study compared the effects of moderate (target diastolic blood pressure, 80 to 89 mm Hg) to intensive (75 mm Hg) control of blood pressure on the incidence and progression of diabetes complications in 470 hypertensive patients with type 2 diabetes. 23 The patients were randomized to treatment with either the CCB nisoldipine or the ACE inhibitor enalapril as first-line antihypertensive therapy, and other openlabel medications were added as necessary to reach target diastolic pressures. Interim analysis demonstrated that, although nisoldipine- and enalapril-treated patients had similar blood pressure control, nisoldipine was associated with a significantly higher incidence of fatal and nonfatal MI than enalapril, resulting in early discontinuation of the comparison between these two drugs in the hypertensive cohort. 23 Because CV morbidity

5 S14 ROBERT W. SCHRIER Fig 4. CAPPP: relativerisk reduction with captopril versus conventional therapy in diabetic patients. *P 0.034; P 0.030; P Data from Hansson et al. 22 and mortality were secondary end points, these results require confirmation. After 5 years of follow-up, the mean blood pressures achieved were 132/78 mm Hg and 138/86 mm Hg in the intensive and moderate control groups, respectively. No difference was seen in microvascular complications. Creatinine clearance stabilized in patients with baseline normoalbuminuria or microalbuminuria but gradually declined in patients with overt albuminuria, regardless of the level of blood pressure control or choice of antihypertensive agent. Additionally, no difference was apparent between interventions in the progression of retinopathy or neuropathy. However, intensive blood pressure control significantly reduced all-cause mortality compared with moderate control. 24 The Fosinopril versus Amlodipine Cardiovascular Events Trial (FACET) compared the effects of the ACE inhibitor fosinopril to the CCB amlodipine on serum lipids and diabetic control in 380 patients with hypertension and type 2 diabetes without nephropathy. 25 The comparative drug could be added to the original drug if blood pressure was not controlled, and patients were followed-up for 3.5 years. Both drugs had similar effects on biochemical measures and were effective in decreasing blood pressure. Similar to the ABCD study, however, patients receiving fosinopril alone or in combination with amlodipine had a significantly lower risk of major CV events than those receiving amlodipine monotherapy. RAS May Contribute to Vascular Complications in Diabetics The RAS has multiple effects on the kidneys and renal vasculature, including vasoconstriction, hypertrophy, and cellular proliferation mediated by its principal effector hormone, angiotensin II (Ang II). In pathologic states, Ang II activity may precipitate or exacerbate hypertension, endothelial dysfunction, left ventricular hypertrophy, glomerular dysfunction, and progressive proteinuria. ACE inhibitors limit the synthesis of Ang II and reduce degradation of the vasodilator bradykinin by interfering with the enzymatic actions of ACE. As discussed in the article by Dr Siragy in this supplement, Ang II has opposing AT 1 and AT 2 receptors in the kidneys and renal vasculature that form a counterregulatory homeostatic mechanism. ACE inhibition attenuates stimulation of both Ang II receptors, but Ang II may continue to be generated via alternate pathways during chronic ACE inhibitor therapy. Ang II receptor blockers (ARBs) selectively block AT 1 receptors, independent of the pathway of Ang II generation, while permitting continued stimulation of AT 2 receptors a mechanism of action that offers theoretic advantages over ACE inhibition. Although ARBs are approved for the treatment of hypertension, clinical data on their renoprotective effects are limited. In a study of rats with subtotal nephrectomy, the ACE inhibitor enalapril, the ARB losartan, or triple therapy with reserpine, hydralazine, and hydrochlorothiazide all reduced blood pressure; only enalapril or losartan markedly reduced proteinuria and reduced segmental glomerulosclerosis. 26 Similar renal benefits were found in a male MWF/Ztm rat model that spontaneously develops hypertension, proteinuria, and glomerulosclerosis with aging when treated with lisinopril or losartan. 27 An ACE inhibitor and ARB were also

6 TREATING DIABETIC HYPERTENSIVE PATIENTS effective in preventing renal injury in Sprague- Dawley rats with induced passive Heymann nephritis, a model of immune renal disease that closely resembles human membranous nephropathy. 28 Antihypertensive therapy with the ACE inhibitor benazepril or the ARB valsartan normalized systemic and glomerular capillary blood pressures, prevented proteinuria, and minimized glomerulosclerosis in male MWF rats with streptozotocin-induced diabetes. 29 These preclinical studies suggest that the renoprotective effects of ACE inhibitors and ARBs are similar and that this is probably a result of their inhibitory actions on Ang II. Although ARBs and ACE inhibitors appear to offer equivalent renoprotection in animal models, clinical trials are needed to confirm these benefits in humans. Promising results have been seen in several small clinical trials. In one study, losartan lowered blood pressure, stabilized glomerular filtration rate, increased effective renal plasma flow, and reduced urinary excretion of protein, albumin, and immunoglobulin G compared with placebo in 13 patients with nondiabetic, biopsy-proven renal disease and hypertension. 30 A study of 29 elderly Chinese patients with hypertension, 12 of whom had coexisting type 2 diabetes, showed comparable blood pressure reductions with losartan and the CCB felodipine but a greater reduction in albuminuria with losartan. 31 A study of 122 hypertensive and normotensive patients with type 2 diabetes and microalbuminuria compared the effects of the ARB valsartan to the ACE inhibitor captopril on renal function over 1 year. Valsartan decreased the albumin excretion rate with comparable efficacy and fewer adverse events than captopril (Table 1). 32 In a 12-week study of 47 hypertensive patients with type 2 diabetic nephropathy, the ARB irbesartan reduced proteinuria with fewer side effects than the CCB amlodipine. 33 Nevertheless, confirmatory results are needed from long-term trials in patients with diabetes. Three large, ongoing clinical trials are evaluating the effects of antihypertensive therapy with ARBs on diabetic complications. The Appropriate Blood Pressure Control in Diabetes Part 2 with Valsartan (ABCD-2V) trial, a continuation of ABCD, is evaluating the long-term effects of Table 1. Effect on Albumin Excretion Rate and Safety of Valsartan and Captopril in Patients With Type 2 Diabetes Placebo (n 27) Valsartan 80 mg/d (n 27) Valsartan 160 mg/d (n 31) Captopril 50 mg tid (n 29) AER ratio (end/base) * 0.79* 0.73* Total adverse events (%) 4 (13.8) 3 (9.7) 7 (22.6) 10 (34.5) *P 0.05 compared with placebo. Data from Muirhead et al. 32 S15 moderate and intensive blood pressure control on the progression of diabetic complications in hypertensive and normotensive patients with type 2 diabetes, using valsartan as initial antihypertensive therapy. 34 The Irbesartan Diabetic Nephropathy Trial (IDNT) is examining the effects of irbesartan, amlodipine, or placebo on morbidity, mortality, and renal function in hypertensive patients with type 2 diabetic nephropathy. 35 The Losartan Renal Protection Study (RENAAL) is evaluating the effects of losartan versus placebo in type 2 diabetic patients with nephropathy and no prior exposure to ACE inhibitor therapy. 36 These clinical trials will help elucidate the role of ARBs in delaying the progression of renal disease in patients with diabetes and may provide new insights into the management of this highrisk population. REFERENCES 1. King H, Aubert RE, Herman WH: Global burden of diabetes, Prevalence, numerical estimates, and projections. Diabetes Care 21: , American Diabetes Association: Diabetes facts and figures. Available at: Accessed on March 30, US Renal Data System: USRDS 1999 Annual Data Report. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease, Bethesda, MD, 1999, pp Centers for Disease Control and Prevention: National diabetes fact sheet. National estimates and general information on diabetes in the United States Available at: Accessed on October 28, The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329: , The Diabetes Control and Complications Trial/Epide-

7 S16 miology of Diabetes Interventions and Complications Research Group: Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med 342: , Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulindependent diabetes mellitus: A randomized prospective 6-year study. Diabetes Res Clin Pract 28: , UK Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352: , Mogensen CE: Long-term antihypertensive treatment inhibiting progression of diabetic nephropathy. BMJ 285: , Parving HH, Andersen AR, Smidt UM, Svendsen PA: Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet 1: , Parving HH, Andersen AR, Hommel E, Smidt U: Effects of long-term antihypertensive treatment on kidney function in diabetic nephropathy. Hypertension 7:II114- II117, 1985 (part 2) 12. Parving HH, Hommel E, Smidt UM: Protection of kidney function and decrease in albuminuria by captopril in insulin dependent diabetics with nephropathy. BMJ 297: , Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, for the Collaborative Study Group: The effect of angiotensinconverting enzyme inhibition on diabetic nephropathy. N Engl J Med 329: , Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 157: , Guidelines Subcommittee: 1999 World Health Organization International Society of Hypertension guidelines for the management of hypertension. J Hypertens 17: , UK Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 317: , UK Prospective Diabetes Study Group: Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 317: , Hansson L, Zanchetti A, Carruthers SG, Dahlöf B, Elmfeldt D, Julius S, Ménard 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) randomised trial. Lancet 351: , Heart Outcomes Prevention Evaluation Study Investigators: Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the ROBERT W. SCHRIER HOPE study and MICRO-HOPE substudy. Lancet 355: , Ravid M, Savin H, Jutrin I, Bental T, Katz B, Lishner M: Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med 118: , Ravid M, Lang R, Rachmani R, Lishner M: Longterm renoprotective effect of angiotensin-converting enzyme inhibition in non insulin-dependent diabetes mellitus. A 7-year follow-up study. Arch Intern Med 156: , Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, Luomanmaki K, Dahlof 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) randomised trial. Lancet 353: , 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 338: , Estacio RO, Jeffers BW, Gifford N, Schrier RW: Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care 23:B54-B64, 2000 (suppl 2) 25. Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco R, Strollo G, Strollo F: Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 21: , Lafayette RA, Mayer G, Park SK, Meyer TW: Angiotensin II receptor blockade limits glomerular injury in rats with reduced renal mass. J Clin Invest 90: , Remuzzi A, Malanchini B, Battaglia C, Bertani T, Remuzzi G: Comparison of the effects of angiotensinconverting enzyme inhibition and angiotensin II receptor blockade on the evolution of spontaneous glomerular injury in male MWF/Ztm rats. Exp Nephrol 4:19-25, Zoja C, Donadelli R, Corna D, Testa D, Facchinetti D, Maffi R, Luzzana E, Colosio V, Bertani T, Remuzzi G: The renoprotective properties of angiotensin-converting enzyme inhibitors in a chronic model of membranous nephropathy are solely due to the inhibition of angiotensin II: Evidence based on comparative studies with a receptor antagonist. Am J Kidney Dis 29: , Remuzzi A, Fassi A, Sangalli F, Malanchini B, Mohamed EI, Bertani T, Remuzzi G: Prevention of renal injury in diabetic MWF rats by angiotensin II antagonism. Exp Nephrol 6:28-38, Gansevoort RT, de Zeeuw D, Shahinfar S, Redfield A, de Jong PE: Effects of the angiotensin II antagonist losartan in hypertensive patients with renal disease. J Hypertens 12:S37-S42, 1994 (suppl 2) 31. Chan JCN, Critchley JAJH, Tomlinson B, Chan TYK, Cockram CS: Antihypertensive and anti-albuminuric effects of losartan potassium and felodipine in Chinese elderly hypertensive patients with or without non-insulin-dependent diabetes mellitus. Am J Nephrol 17:72-80, 1997

8 TREATING DIABETIC HYPERTENSIVE PATIENTS S Muirhead N, Feagan BF, Mahon J, Lewanczuk RZ, Rodger NW, Botteri F, Oddou-Stock P, Pecher E, Cheung R: The effects of valsartan and captopril on reducing microalbuminuria in patients with type 2 diabetes mellitus: A placebo-controlled trial. Curr Ther Res 60: , Pohl M, Cooper M, Ulrey J, Pauls J, Rohde R, for the Collaborative Study Group: Safety and efficacy of irbesartan in hypertensive patients with type II diabetes and proteinuria. Am J Hypertens 10:105A, 1997 (abstr, part 2) 34. Schrier RW, Estacio RO, Jeffers BW, Biggerstaff S, Krinsky E, Pincus JR, Bedigian MP: ABCD-2V: Appropriate Blood Pressure Control in Diabetes Part 2 With Valsartan. Am J Hypertens 12:141A, 1999 (abstr, part 2) 35. Porush JG, Berl T, Anzalone DA, Rohde R: Multicenter collaborative trial of angiotensin II receptor antagonism on morbidity, mortality and renal function in hypertensive type II diabetic patients with nephropathy. Am J Hypertens 11:73A, 1998 (abstr, part 2) 36. Dasbach EJ, Shahinfar S, Santanello NC, Simpson RL, Haffner SM, for the RENAL Investigators: Quality of life in patients with NIDDM and nephropathy at baseline: The losartan renal protection study (RENAAL). Diabetes 48:A389, 1999 (abstr, suppl 1)