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J Am Soc Nephrol 13:S224-S229, 2002
© 2002 American Society of Nephrology

Renal and Cardiovascular Protection in Type 2 Diabetes Mellitus: Angiotensin II Receptor Blockers

Giacomo Deferrari*, Maura Ravera*, Luca Deferrari{dagger}, Simone Vettoretti*, Elena Ratto* and Denise Parodi*

Department of Internal Medicine, *Section of Nephrology and Dialysis, and {dagger}Section of Cardiology, University of Genoa, Genoa, Italy.

Correspondence to Dr. Giacomo Deferrari, Department of Internal Medicine, Viale Benedetto XV, 6 16123 Genoa, Italy. Phone: 39-010-353-8959; Fax: 39-010-353-8959;


   Abstract
Top
 Abstract
Introduction
 Renal Protection
 Cardiovascular Protection
 Conclusions
 References
 
ABSTRACT. Aggressive treatment of hypertension is effective in reducing both microvascular and macrovascular complications in type 2 diabetes, and target BP less than 130/85 or 130/80 mmHg are now recommended. Inhibition of renin angiotensin aldosterone system (RAAS) plays an essential role in the treatment of hypertension and diabetes-related complications. Studies focusing on renal end-points suggest that angiotensin-converting enzyme inhibitors (ACE-I) are more effective than other traditional agents in reducing the onset of clinical proteinuria in both type 1 and type 2 diabetic patients with incipient nephropathy, mainly in normotensive ones (secondary prevention). However, several small trials in type 2 diabetic patients with overt nephropathy (tertiary prevention) failed to demonstrate a specific renoprotective role for ACE-I, at variance with type 1 diabetes. Three recent large trials address the question of whether angiotensin II receptor blockers (ARB) prevent the development of clinical proteinuria or delay the progression of nephropathy in type 2 diabetes. The IRMA study showed that irbesartan is more effective than conventional therapy in preventing the development of clinical proteinuria and in favoring the regression to normoalbuminuria for comparable BP control in patients with incipient nephropathy. The IDNT and RENAAL trials showed that ARB are more effective than traditional antihypertensive therapies in reducing progression toward end-stage renal failure (ESRF) in type 2 diabetic patients with overt nephropathy independently of changes in BP. Moreover, a reduction in hospitalizations for heart failure was demonstrated for ARB-treated patients compared with placebo. Furthermore, the LIFE study showed that losartan is more effective than conventional therapy in reducing cardiovascular morbidity and mortality in a cohort of diabetic patients with hypertension and left ventricular hypertrophy. In conclusion, ARB seem to be effective in both preventing renal damage and reducing progression toward ESRF in type 2 diabetic patients. Thus, the guidelines for the prevention and treatment of diabetic nephropathy are now changed. In type 1 diabetes ACE-I are the first-choice drug; in type 2 diabetes, ARB are considered first-choice drugs in secondary prevention as well as ACE-I and have been now elected the unique first-choice drug in tertiary prevention of ESRF. Finally, ARB should be considered as the first-choice drug in cardiovascular prevention too, as well as ACE-I. E-mail: gildaplm@unige.it


   Introduction
Top
 Abstract
 Introduction
Renal Protection
 Cardiovascular Protection
 Conclusions
 References
 
Hypertension is an extremely common comorbid condition in type 2 diabetes. Its prevalence is higher than in the general population, thus contributing to explain the increased risk of both microvascular and macrovascular complications observed in diabetic patients. Hypertension appears to play an important role in the development and progression of renal damage in type 2 diabetes (1,2). Furthermore, hypertension is a major risk factor for the increased cardiovascular morbidity and mortality associated with diabetes mellitus, as confirmed by epidemiologic studies demonstrating a two or three times increased risk of cardiovascular mortality in hypertensive compared with normotensive type 2 diabetic patients (1,2).

Randomized clinical trials have demonstrated the effectiveness of the BP reduction (3,4) and of the intensive antihypertensive treatment (5,6) in reducing both microvascular and macrovascular complications. Current treatment guidelines recommend a target BP less than 130/85 or 130/80 mmHg for hypertensive patients with diabetes (7–14).

Proteinuria is a well-known marker of glomerular damage, which has recently been considered an independent promoter of renal disease progression too (15). A strict relationship has been demonstrated between the degree of glomerular proteinuria and both the interstitial fibrosis and the rate of progression of chronic renal failure in diabetic nephropathy as well as in other glomerular disease (16). Furthermore, interventions able to slow the progression of diabetic nephropathy are associated with a reduction in proteinuria (17). Finally, proteinuria is a powerful independent predictor of cardiovascular morbidity and mortality (18).

Renin angiotensin aldosterone system (RAAS) plays an essential role in the pathophysiology of hypertension and diabetes-related complications. A physiologic clinical rationale, therefore, exists for RAAS blockade. Although angiotensin-converting enzyme inhibitors (ACE-I) suppress the RAAS, they are not able to block the production of angiotensin II (AngII) by non–ACE-mediated pathways. Furthermore, ACE is not a specific enzyme, and its inhibition reduces the degradation of bradykinin, which in turn may amplify the vasodilator effect of this substance and induce the class-specific side effects associated with this drug. On the other hand, the lack of suppression of the degradation of bradykinin and possibly the incomplete inhibition of aldosterone seem to be the main drawbacks of AngII receptor blockers (ARB) (19,20). However, ARB appear to have potential advantages over ACE-I. In fact, they can provide a more complete blockade of AngII effects by binding selectively to the AT1 receptors while offering better tolerance. Furthermore, additional benefits of ARB could arise from AT2 receptor stimulation, which could contribute to prevent hypertrophic effects and provide end organ protection (19,20). These findings may have potentially important pathophysiological and clinical implications. A recent study by Hollenberg (20) reported enhanced renal vasodilator response due to RAAS inhibition with ARB relative to that observed with ACE-I in healthy human volunteers maintained on a low-salt diet to activate RAAS. Thus, blocking the system with ARB could provide even a greater efficacy than ACE-I, particularly under conditions of disease, such as diabetes, in which overactivity of RAAS has been described (21).

In the following sections, we will analyze the impact of treatment with ARB compared with the effect of traditional therapy on renal and cardiovascular end points in hypertensive patients with type 2 diabetes.


   Renal Protection
Top
 Abstract
 Introduction
 Renal Protection
Cardiovascular Protection
 Conclusions
 References
 
Three recent large, randomized, blinded, clinical trials addressing the question whether ARB prevent the development of clinical proteinuria in microalbuminuric patients (secondary prevention) (22) or delay the progression of overt nephropathy to end-stage renal failure (ESRF) in proteinuric patients with type 2 diabetes were published (tertiary prevention) (23,24).

Available studies dealing with the role of traditional antihypertensive treatment, including ACE-I, on the same renal end points in type 2 diabetes provide controversial results.

Several studies performed in normotensive microalbuminuric patients showed that ACE-I markedly reduce the incidence of overt nephropathy ( relative risk reduction [RRR], approximately 70 to 100%) in type 2 diabetes independently of BP levels (25–27), according to results obtained in type 1 diabetes (28–32).

In hypertensive microalbuminuric type 2 diabetic patients, a recent study comparing placebo with an active treatment mainly based on calcium channel blockers (CCB) showed the effectiveness of the active therapy in reducing the incidence of overt nephropathy (33). Moreover, two other studies compared the effect of tight BP control with a moderate one. The intensive treatment reduced, even if not significantly, the incidence of nephropathy in the first study (34); no differences were observed in the second study (5). As far as the role of the individual class of drugs is concerned, the Microhope study (35) on a large population and two other smaller studies (36,37) confirm the efficacy of ACE-I compared with other treatment in reducing the incidence of overt nephropathy. By contrast, this effect was not found in two other studies (34,38). Thus ACE-I seem to be less clearly effective in hypertensive patients than in normotensive ones.

The IRMA study, a multicentric, randomized, double-blind, placebo-controlled trial, evaluated the effect of irbesartan in preventing the onset of clinical proteinuria in type 2 diabetic patients with hypertension and microalbuminuria (22). Five hundred ninety subjects were randomized to receive therapy with 150 mg of irbesartan, 300 mg of irbesartan, or placebo. Additional antihypertensive agents, ACE-I, ARB, and dihydropyridine CCB being excluded, were allowed in each arm of the study to achieve the goal BP of less than 135/85 mmHg. The primary end point of the study was the onset of overt nephropathy, which was defined as the occurrence of a urinary albumin excretion rate greater than 200 µg/min and at least 30% higher than baseline. The mean duration of follow-up was 2 yr. The average BP during the course of the study was 143/83 mmHg in the 150-mg group, 141/83 mmHg in the 300-mg group, and 144/83 mmHg in the placebo group. With respect to the primary end point, 150 and 300 mg of irbesartan showed, respectively, an adjusted RRR of 44% and 68% versus conventional therapy; in addition, the regression to normoalbuminuria was more frequent in the patients treated with the higher dose of irbesartan (17 in the 300-mg group, 12 in the 150-mg group, and 10.5/100 patients per yr in the control group; Figure 1). Taking into account all these data, irbesartan appears much more effective than conventional therapy in preventing the development of clinical proteinuria and in favoring the regression to normoalbuminuria for comparable BP control.



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  		Figure 1. Renoprotection in 590 hypertensive microalbuminuric patients with type 2 diabetes: effect of angiotensin receptor antagonist in IRMA Study (22). Conv.th, conventional therapy; NDCCB, non–dihydropyridine calcium channel blockers; aRRR, adjusted relative risk reduction. *P = 0.005 for the comparison of mean BP between the 300 mg irbesartan group and the conventional treatment group.

 
In type 2 diabetic patients with overt nephropathy, a strict control of BP does not seem significantly effective in reducing the decline of GFR, at least in the only study reported in the literature (34), and four out of five small trials evaluating the effects of different classes of drugs failed to demonstrate a specific renoprotective role for ACE-I at this stage of nephropathy (34,36,39–41) (Figure 2). By contrast, in proteinuric patients with type 1 diabetes, a strict BP control was deemed effective in slowing the progression of nephropathy independently of the drug used (42); moreover, ACE-I appear to be clearly more renoprotective than other drugs, at least in two of five studies (RRR, approximately 30 to 60%) (43–47).



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  		Figure 2. Renoprotection in proteinuric patients with type 2 diabetes: effect of traditional antihypertensive therapy. Conv. Th., conventional therapy; diur, diuretics; CCB, calcium channel blockers, ACE-I, angiotensin-converting enzyme inhibitors. *significant difference (P < 0.0001) in decline of GFR between {beta}-blocker and both ACE-I or CCB.

 
In type 2 diabetic patients with overt nephropathy, two recent large trials confer to ARB an important renoprotective role (23,24). Although the baseline characteristics of populations of the two studies were slighly different (in the IDNT study, the prevalence of white and European subjects, the baseline BP values, and the degree of proteinuria were slightly higher than in the RENAAL study), the design of both trials was similar. In the IDNT trial, 1715 patients were followed for approximately 2.6 yr after being randomized to irbesartan, amlodipine, or placebo, each one plus conventional therapy, excluding ACE-I, ARB, and CCB. The achieved BP was similar in the irbesartan and amlodipine group and little higher in the conventional treatment group (140/77, 141/77, and 144/80 mmHg, respectively). The treatment with irbesartan was associated with a risk of the primary composite end point (doubling of serum creatinine, ESRF, or death) significantly lower than in the placebo (adjusted RRR [aRRR] = 19%) and the amlodipine group (aRRR = 24%) (Figure 3A). The risk of a doubling of serum creatinine in the irbesartan group was lower than in the placebo group (aRRR = 29%) and the amlodipine group (aRRR = 39%) (23). In the RENAAL study, 1513 patients randomized to losartaan or placebo, both taken in addition to conventional antihypertensive therapy not including RAAS antagonist drugs, were followed for approximately 3.4 yr. Average BP values at the end of the study were 140/74 mmHg in the losartan group and 142/74 mmHg in the conventional treatment group. The treatment with losartan resulted in a reduction (aRRR =15%) in the risk of the same primary composite end-point as in the IDNT trial (Figure 3B). The risk of a doubling of serum creatinine in the losartan group was 25% lower than in the conventional treatment group (24). Interestingly, the benefit of the ARB exceeded that attributable to changes in BP in both studies.



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  		Figure 3. Time to primary composite end point (doubling of serum creatinine, end-stage renal disease, or death) in the IDNT study (A) and the RENAAL study (B) (23,24).

 
Finally, an important finding of the IDNT trial was that amlodipine appeared to be less effective than the RAAS blocking agents as far as renal end-points were concerned, which is in keeping with data from a report on a nondiabetic population (48).


   Cardiovascular Protection
Top
 Abstract
 Introduction
 Renal Protection
 Cardiovascular Protection
Conclusions
 References
 
Some studies on large populations have demonstrated that the reduction of BP is the main factor that is able to decrease the risk of cardiovascular events independently of the class of antihypertensive agent used (3,4). Moreover, tight BP control has been deemed as more effective than moderate control in two other large trials addressing the effects of antihypertensive treatment on the same cardiovascular end points (5,6).

Considering the role of the individual classes of drugs, most studies have demonstrated the superior effectiveness of ACE-I in cardioprotection. Some recent trials have shown that ACE-I—based antihypertensive regimens were more effective in reducing the risk of cardiovascular complications in type 2 diabetes than conventional therapy (35,49) or CCB (34,50,51). By contrast, the UKPDS and STOP 2 studies failed to demonstrate a specific cardiovascular protective role for ACE-I compared with conventional therapy in patients with type 2 diabetes (51,52).

Interesting results were obtained for ARB. The composite cardiovascular end point (death from cardiovascular causes, nonfatal myocardial infarction, stroke, and heart failure resulting in hospitalization) was similar in IDNT and RENAAL studies. The treatments with irbesartan and losartan resulted in a 9 and 10% reduction respectively in the risk of the composite cardiovascular end points compared with conventional therapy. These differences were not statistically significant. Nevertheless, a significant reduction in hospitalizations for heart failure was demonstrated for patients on irbesartan compared with placebo or amlodipine in the IDNT study (-23%), and for losartan compared with placebo in the RENAAL study (-32%).

Although the incidence of major cardiovascular events was elevated due to a higher risk for patients with diabetes and overt proteinuria, the absence of any difference in the secondary endpoint in both trials could be mainly the effect of a short follow-up period. The LIFE study showed that losartan was more effective than conventional therapy in reducing cardiovascular morbidity and mortality in a large cohort of diabetic patients with hypertension and left ventricular hypertrophy followed for a long period, approximately 5 yr (53).


   Conclusions
Top
 Abstract
 Introduction
 Renal Protection
 Cardiovascular Protection
 Conclusions
References
 
In conclusion, ARB seem to be effective in both preventing renal damage and reducing progression toward end-stage renal disease in type 2 diabetic patients. According to the new evidence from these three large clinical trials, the guidelines for the prevention and treatment of diabetic nephropathy have now been changed. In type 1 diabetes ACE-I are the first-choice drugs. In type 2 diabetes, ARB are now considered first-choice drugs in microalbuminuric patients, as are ACE-I (secondary prevention). Furthermore, ARB have been elected the unique first-choice drugs in patients with overt nephropathy (tertiary prevention). Finally, taking into account the results of recent trials, including the LIFE study, ARB should be considered first-choice drugs in cardiovascular prevention too, as should ACE-I. Additional studies are needed to address the role of ARB in lowering the incidence of microalbuminuria in normoalbuminuric subjects.


   References
Top
 Abstract
 Introduction
 Renal Protection
 Cardiovascular Protection
 Conclusions
 References
 

  1. Parving HH, Osterby R, Ritz E: Diabetic nephropathy. In: The Kidney, edited by Brenner BM, Philadelphia, W.B. Saunders, 2000, pp 1731–1773
  2. Viberti GC, Walker JD, Pinto J: Diabetic nephropathy. In: International Textbook of Diabetes Mellitus, edited by Alberti KGMM, DeFronzo RA, Keen H, Zimmet P, New York, John Wiley & Sons Ltd., 1992, pp 1267–1328
  3. Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, Black H, Camel G, Davis BR, Frost PH, Gonzalez N, Guthrie G, Oberman A, Rutan GH, Stamler J: Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. Systolic Hypertension in the Elderly Program Cooperative Research Group. JAMA 276: 1886–1892, 1996[Abstract]
  4. Tuomilehto J, Rastenyte D, Birkenhager WH, Thijs L, Antikainen R, Bulpitt CJ, Fletcher AE, Forette F, Goldhaber A, Palatini P, Sarti C, Fagard R: Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. Systolic Hypertension in Europe Trial Investigators. N Engl J Med 340: 677–684, 1999[Abstract/Free Full Text]
  5. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 317: 703–713, 1998;[Abstract/Free Full Text]
  6. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S: Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 351: 1755–1762, 1998[CrossRef][Medline]
  7. Kaplan NM: Management of hypertension in patients with type 2 diabetes mellitus. Guidelines based on current evidence. Ann Intern Med 135: 1079–1183, 2001[Abstract/Free Full Text]
  8. Mogensen CE, Keane WF, Bennet PH, Jerums G, Parving HH, Passa P, Steffes MW, Striker GE, Viberti GC: Prevention of diabetic renal disease with special reference to microalbuminuria. (Consensus report). Lancet 346: 1080–1084, 1995[CrossRef][Medline]
  9. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 157: 2413–2446, 1997[Abstract]
  10. Feldman RD: The 1999 Canadian Recommendations for the Management of Hypertension. On behalf of the Task Force for the Development of the 1999 Canadian Recommendation for the Management of Hypertension. Can J Cardiol 15SG: 57G–64G, 1999
  11. 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 36: 646–661, 2000[Medline]
  12. Kjeldsen SE, Erdine S, Farsang C, Sleight P, Mancia G: The 1999 WHO/ISH Hypertension Guidelines Subcommittee, 1999. WHO/ISH Hypertension Guidelines–highlights & ESH update. J Hypertens 20: 153–155, 2002[CrossRef][Medline]
  13. American Diabetes Association: Treatment of hypertension in adults with diabetes. Diabetes Care 25: 199–201, 2002[Free Full Text]
  14. Deferrari G, Cavallo Perin P, Di Paolo S, Locatelli R, Nosadini R, Penno G, Piccoli G, Ravera M: Linee guida della nefropatia diabetica. Giornale italiano di nefrologia, 2002, in press
  15. Jafar TH, Stark PC, Schmid CH, Landa M, Maschio G, Marcantoni C, De Jong PE, De Zeeuw D, Shahinfar S, Ruggenenti P, Remuzzi G, Levey AS for the AIPRD Study Group: Proteinuria as a modifiable risk factor for the progression of non diabetic renal disease. Kidney Int 60: 1131–1140, 2001[CrossRef][Medline]
  16. Hebert LA, Wilmer WA, Falkenhain ME, Ladson-Wofford SE, Nahman NS Jr, Rovin BH: Renoprotection One or many therapies? Kidney Int 59: 1211–1226, 2001[CrossRef][Medline]
  17. Parving HH: Renoprotection in diabetes: Genetic and non genetic risk factors and treatment. Diabetologia 41: 745–759, 1998[CrossRef][Medline]
  18. Miettinen H, Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M: Proteinuria predicts stroke and other atherosclerotic vascular disease events in nondiabetic and non-insulin-dependent diabetic subjects. Stroke 27: 2033–2039, 1996[Abstract/Free Full Text]
  19. Dinh DT, Frauman AG, Johnston CI, Fabiani ME: Angiotensin receptors: Distribution, signalling and function. Clin Sci 100: 481–492, 2001[Medline]
  20. Hollenberg NK: Renal implications of angiotensin receptors blockers. AJH 14: 237S–241S, 2001
  21. Hollenberg NK: Non-insulin-dependent diabetes mellitus, nephropathy, and the renin system. J Hypertens Suppl 15: S7–S13, 1997[Medline]
  22. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P, 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 345: 870–878, 2001[Abstract/Free Full Text]
  23. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I, Collaborative Study Group: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345: 851–860, 2001[Abstract/Free Full Text]
  24. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S, RENAAL Study Investigators: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345: 861–869, 2001[Abstract/Free Full Text]
  25. 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: 577–581, 1993[Abstract/Free Full Text]
  26. Sano T, Hotta N, Kawamura Tm Matsumae H, Chaya S, Sasaki H, Nakayama M Hara T, Matsuo S, Sakamoto N: Effects of long-term enalapril treatment on persistent microalbuminuria in normotensive type 2 diabetic patients: Result of a 4-year, prospective, randomized study. Diabet Med 13: 120–124, 1996[CrossRef][Medline]
  27. Ahmad J, Siddiqui MA, Ahmad H: Effective postponement of diabetic nephropathy with enalapril in normotensive type 2 diabetic patients with microalbuminuria. Diabetes Care 20: 1576–1581, 1997[Abstract]
  28. The Microalbuminuria Captopril Study Group: Captopril reduces the risk of nephropathy in IDDM patients with microalbuminuria. Diabetologia 39: 587–593, 1996[Medline]
  29. Crepaldi G, Carta Q, Deferrari G, Mangili R, Navalesi R, Santeusanio F, Spalluto A, Vanasia A, Villa GM, Nosadini R, The Italian Microalbuminuria Study Group in IDDM: Effects of lisinopril and nifedipine on the progression to overt albuminuria in IDDM patients with incipient nephropathy and normal blood pressure. Diabetes Care 21: 104–110, 1998[Abstract]
  30. Penno G, Chaturvedi N, Talmud PJ, Cotroneo P, Manto A, Nannipieri M, Luong L, Fuller J, the Euclid Study Group: Effect of angiotensin-converting enzyme (ACE) gene polymorphism on progression of renal disease and the influence of ace inhibition in IDDM patients. Findings from the EUCLID randomized controlled trials. Diabetes 47: 1507–1511, 1998[Abstract/Free Full Text]
  31. Mathiesen ER, Hommel E, Hansen HP, Smidt UM, Parving HH: Randomised controlled trial of long term efficacy of captopril on preservation of Kidney function in normotensive patients with insulin dependent diabetes and microalbuminuria. BMJ 319: 24–25, 1999[Free Full Text]
  32. The ATLANTIS Study Group: Low dose ramipril reduces microalbuminuria in type 1 diabetic patients without hypertension. Diabetes Care 23: 1823–1829, 2000[Abstract/Free Full Text]
  33. Voyaki SM, Staessen JA, Thijs L, Wang JG, Efstratopoulos AD, Birkenhager WH, de Leeuw PW, Leonetti G, Nachev C, Rodicio JL, Tuomilehto J, Fagard R, Systolic Hypertension in Europe (Syst-Eur) Trial Investigators: Follow-up of renal function in treated and untreated older patients with isolated systolic hypertension. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. J Hypertens 19: 511–519, 2001[CrossRef][Medline]
  34. Estacio RO, Jeffers BW, Gifford N, Shrier R: Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care 23 [Suppl 2]: B54–B64, 2000
  35. Heart Outcomes Prevention Evaluation Study Investigators: Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 355: 253–259, 2000[CrossRef][Medline]
  36. Lebovitz HE, Wiegmann TB, Cnaan A, Shahinfar S, Sica DA, Broadstone V, Schwartz SL, Mengel MC, Segal R, Versaggi JA: Renal protective effects of enalapril in hypertensive NIDDM: Role of baseline albuminuria. Kidney Int Suppl 45: S150–S155, 1994[Medline]
  37. Chan JC, Ko GT, Leung DH, Cheung RC, Cheung MY, So WY, Swaminathan R, Nicholls MG, Critchley JA, Cockram CS: Long term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients. Kidney Int 57: 590–600, 2000[Medline]
  38. Baba S, The J-Mind Study Group: Nifedipine and enalapril equally reduce the progresion of nephropathy in hypertensive type 2 diabetics. Diab Res 54: 191–201, 2001
  39. Bakris GL, Copley JB, Vicknair N, Sadler R, Leurgans S: Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int 50: 1641–1650, 1996[Medline]
  40. Nielsen FS, Rossing P, Gall MA, Skott P, Smidt UM, Parving HH: Long-term effect of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy. Diabetes 46: 1182–1188, 1997[Abstract]
  41. Fogari R, Zoppi A, Corradi L, Mugellini A, Lazzari P, Preti P, Lusardi P: Long-term effects of ramipril and nitrendipine on albuminuria in hypertensive patients with type II diabetes and impaired renal function. J Hum Hypertens 13: 47–53, 1999[CrossRef][Medline]
  42. Deferrari G, Cheli V, Robaudo C: Treatment of diabetic nephropathy in its early stages. Diabetes/Metab Rev 13: 51–61, 1997[CrossRef][Medline]
  43. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 329: 1456–1462, 1993[Abstract/Free Full Text]
  44. Bjorck S, Mulec H, Johnsen SA, Norden G, Aurell M: Renal protective effect of enalapril in diabetic nephropathy. Br Med J 304: 339–343, 1992
  45. Elving LD, Wetzels JF, van Lier HJ, de Nobel E, Berden JH: Captopril and atenolol are equally effective in retarding the progression of diabetic nephropathy. Diabetologia 37: 604–609, 1994[Medline]
  46. Tarnow L, Rossing P, Jensen C, Hansen BV, Parving HH: Long-term renoprotective effect of nisoldipine and lisinopril in type 1 diabetic patients with diabetic nephropathy. Diabetes Care 23: 1725–1730, 2000[Abstract/Free Full Text]
  47. Hovind P, Rossing P, Tarnow L, Smidt UM, Parving HH: Progression of diabetic nephropathy. Kidney Int 59: 702–709, 2001[CrossRef][Medline]
  48. Sica DA, Douglas JG: The African American Study of Kidney Disease and Hypertension (AASK): New findings. J Clin Hypertens 3: 244–251, 2001
  49. Hansson L: Recent intervention trials in hypertension initiated in Sweden–HOT, CAPPP and others. Hypertension Optimal Treatment Study. Captopril Prevention Project. Clin Exp Hypertens 21: 507–515, 1999
  50. 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: 597–603, 1998[Abstract]
  51. Lindholm LH, Hansson L, Ekbom T, Dahlof B, Lanke J, Linjer E, Schersten B, Wester PO, Hedner T, de Faire U: Comparison of antihypertensive treatments in preventing cardiovascular events in elderly diabetic patients: Results from the Swedish Trial in Old Patients with Hypertension-2. STOP Hypertension-2 Study Group. J Hypertens 18: 1671–1675, 2000[CrossRef][Medline]
  52. 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: 713–726, 1998[Abstract/Free Full Text]
  53. Lindholm LH, Ibsen H, Dahlof B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristiansson K, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wedel H, Aurup P, Edelman J, Snapinn S, The LIFE Study Group: Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint Reduction in Hypertension study (LIFE): A randomised trial against atenolol. Lancet 359: 1004–1010, 2002[CrossRef][Medline]



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S. Hoffmann, D. Podlich, B. Hahnel, W. Kriz, and N. Gretz
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