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The role of angiotensin II receptor blockers in preventing the progression of renal disease in patients with type 2 diabetes
AJH
2002; 15:123S–128S
The Role of Angiotensin II Receptor Blockers in Preventing the Progression of Renal Disease in Patients With Type 2 Diabetes Edmund J. Lewis Diabetes mellitus is the most common cause of end-stage renal disease in the United States, accounting for about 50% of all new cases. Although we previously established the renoprotective benefits of angiotensin converting enzyme (ACE) inhibitors in patients with coexisting hypertension and type 1 diabetes, evidence of the renoprotective effect of ACE inhibitors in patients with type 2 diabetes is less clear. We conducted the Irbesartan Diabetic Nephropathy Trial (IDNT) to determine whether the angiotensin II receptor blocker (ARB) irbesartan slows the progression of nephropathy in patients with type 2 diabetes independently of its blood pressure (BP)-lowering effect. In this randomized, controlled trial, we found that irbesartan was associated with a 20% reduction in the risk for the primary composite end point (doubling of the baseline serum creatinine concentration, development of end-stage renal disease, or death from any cause) compared with placebo (P ⫽ .02) and a 23% reduction compared with amlodipine
D
therapy (P ⫽ .006). These results were not explained by differences in the BP that was achieved. In a separate study, losartan was shown to reduce the risk for progression of renal disease in patients with type 2 diabetic nephropathy. Angiotensin II receptor blocker therapy has also been demonstrated to slow the progression to overt nephropathy when initiated early in the course of type 2 diabetic renal disease (ie, in patients with microalbuminuria). Based on these studies, ARBs are clearly effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of their BP-lowering effect. Preclinical studies with the newest ARB, olmesartan medoxomil, suggest that this agent may provide renoprotective benefits as well. Am J Hypertens 2002;15:123S–128S © 2002 American Journal of Hypertension, Ltd. Key Words: Angiotensin II receptor blockers, diabetic nephropathy, hypertension, irbesartan, olmesartan medoxomil.
iabetes mellitus is the most common cause of end-stage renal disease (ESRD) in the United States, accounting for approximately half of all new cases.1 The majority of patients with diabetes who develop ESRD, defined as the need for renal dialysis or transplantation, have type 2 diabetes. Moreover, the number of ESRD patients maintained on dialysis is projected to double by the year 2010. The main factor behind this increase is the dramatic rise in the prevalence of diabetes and diabetic nephropathy, as well as the improved survival of patients with type 2 diabetes.1 Hypertension is diagnosed in about 50% of patients who have type 2 diabetes and is a major pathophysiologic mechanism for the arterial damage leading to diabetic nephropathy and cardiovascular (CV) disease.2,3 Hypertension in patients with type 2 diabetes markedly accelerates the progression of diabetic nephropathy; con-
versely, antihypertensive therapy has been shown to slow the decline in the glomerular filtration rate (GFR).4 The principal treatment for slowing the progression of diabetic renal disease, therefore, is aggressive antihypertensive therapy in addition to glycemic control and a low-protein diet.4,5 Hypertension treatment guidelines recommend antihypertensive therapy as early as possible (as soon as microalbuminuria becomes apparent) in patients with diabetes, with a goal blood pressure (BP) of ⬍130/85 mm Hg.6 The preferred antihypertensive treatment strategy for patients who have diabetes with renal involvement is inhibition or blockade of the renin-angiotensin-aldosterone system (RAAS) using angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs).4,6 An agent that prevents or retards the progression of renal disease in a manner independent of systemic effects such as BP lowering is defined as renoprotective. Al-
Received July 3, 2002. First decision July 9, 2002. Accepted July 9, 2002. From Rush-Presbyterian–St. Luke’s Medical Center, Chicago, Illinois.
Address correspondence and reprint requests to Dr. Edmund J. Lewis, Director, Department of Nephrology, Rush-Presbyterian–St. Luke’s Medical Center, 1653 West Congress Parkway, Suite 301, Jones Building, Chicago, IL 60612.
© 2002 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.
0895-7061/02/$22.00 PII S0895-7061(02)03007-8
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FIG. 1. A meta-analysis of 100 trials in 2494 subjects with diabetes showed that angiotensin converting enzyme (ACE) inhibitors produced the greatest reductions in urine albumin and protein excretion compared with other antihypertensive agents (*P ⬍ .05 v calcium channel blockers; †P ⬍ .05 v control). Only ACE inhibitors achieved these beneficial effects on renal function independent of changes in blood pressure. (Reprinted with permission from Kasiske BL, et al: Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med 1993;118:129 –138, Lippincott Williams & Wilkins©.10)
though the renoprotective effects of ACE inhibitors in patients with type 1 diabetes are well established, the benefits of ACE inhibitors in patients with type 2 diabetes are less clear. Research findings indicating that ARBs have antihypertensive efficacy similar to that of other drug classes, with superior tolerability, suggest that these agents could play an important role in the treatment of patients with diabetic nephropathy, not only as effective antihypertensive drugs, but also as renoprotective agents.7,8
Effects of Antihypertensive Drug Classes on Proteinuria Microalbuminuria has been shown to be an early sign of renal disease and a risk factor for CV disease.9 A sustained decrease in proteinuria is frequently associated with a slower progression of nephropathy and may be a useful indicator for evaluating therapeutic response.5 Different classes of antihypertensive agents may vary in their ability to reduce proteinuria.10 In a meta-analysis of 100 controlled and uncontrolled trials, the relative effect of several types of antihypertensive agents on proteinuria and renal function in patients with diabetes was assessed.10 Although therapy with ACE inhibitors, calcium channel blockers (CCBs), and -blockers had similar effects on mean arterial pressure, their effects on indicators of renal function were disparate. Subjects who were given ACE inhibitors experienced the greatest reduction in urine albumin and protein excretion (Fig. 1). Angiotensin converting enzyme inhibitors and CCBs also appeared to have a more favorable effect on GFR than did the other agents. Multiple linear regression analysis indicated that only ACE inhibitors decreased proteinuria and increased the GFR to a greater extent than would have been expected if the improvements had been derived from BP reduction alone.
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In several placebo-controlled trials, ACE inhibitors have demonstrated significant beneficial effects on the progression of nephropathy.11–13 In a randomized, placebo-controlled trial in 409 subjects with type 1 diabetes, the ACE inhibitor captopril reduced the risk of a doubling in serum creatinine by 48% (P ⫽ .007).13 Captopril was associated with a 50% reduced risk for the combined end points of death, dialysis, and transplantation independent of the small difference in BP between treatment groups. Similar data, however, are lacking for ACE inhibitors in type 2 diabetic nephropathy. Few studies have compared the effect of ARBs in reducing proteinuria with that of ACE inhibitors, but preliminary research suggests that these classes of drugs may provide similar antiproteinuric benefits. In one study, the ARB losartan was found to be as effective as enalapril in lowering proteinuria, reducing BP, and increasing renal plasma flow.14 In another study, the effect of the ACE inhibitor enalapril was compared with that of the ARB irbesartan on urinary protein excretion and renal hemodynamics in 20 patients with IgA glomerulonephritis.15 In this double-blind study, subjects were randomized to treatment with enalapril 20 mg once daily or irbesartan 10 mg once daily for 28 days. Enalapril and irbesartan produced similar reductions in proteinuria and comparable renal hemodynamic changes.15
Effect of ARBs on Diabetic Nephropathy Following up on research findings showing the significant renoprotective benefits provided by RAAS interference using ACE inhibitors in type 1 diabetes, a number of recent studies have investigated the effects of angiotensin II blockade using ARBs in type 2 diabetic nephropathy. The Irbesartan Microalbuminuria in Hypertensive Patients with Type 2 Diabetes (IRMA 2) trial evaluated the effect of the ARB irbesartan on the rate of progression to overt diabetic nephropathy in patients with hypertension at an early stage of type 2 diabetic renal disease.16 In this multicenter, randomized, double-blind, placebocontrolled trial, 590 subjects with type 2 diabetes, persistent microalbuminuria (albumin excretion rate of 20 to 200 g/min or 30 to 300 mg/day), and normal renal function were randomized to receive irbesartan 150 mg/day, irbesartan 300 mg/day, or placebo and followed for 2 years. Additional antihypertensive agents (excluding ACE inhibitors, other ARBs, and dihydropiridine CCBs) could be added to help achieve the BP goal of ⬍135/85 mm Hg. The primary end point was the time to the occurrence of clinical proteinuria or overt diabetic nephropathy, which was defined as an overnight urinary albumin excretion rate (UAER) of ⬎200 g/min (300 mg/day) and an increase in UAER from baseline of at least 30% at two successive 3-month evaluations. Secondary end points included changes in overnight UAER, regression to normoalbuminuria (⬍20 g/min), and change in creatinine clearance.
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FIG. 2. In the Irbesartan Microalbuminuria in Hypertensive Patients with type 2 Diabetes (IRMA 2) trial, a clear dose response was observed for the primary end point of time to clinical proteinuria (urinary albumin excretion rate ⬎200 g/min, or 300 mg/day). Although the irbesartan 150-mg group (n ⫽ 195) achieved a 39% relative risk reduction (RRR) versus placebo (P ⫽ .08), the irbesartan 300-mg group (n ⫽ 194) demonstrated a significant (70%; P ⬍ .001) RRR versus placebo (n ⫽ 201). (Reprinted with permission from Parving H-H, et al: The effects of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870 – 878. Copyright © 2001, Massachusetts Medical Society; All rights reserved.16)
A clear dose response was observed for the primary end point (Fig. 2).16 The irbesartan 150-mg group demonstrated a 39% relative risk reduction (RRR) versus placebo in the development of clinical proteinuria (UAER ⬎200 g/min, or 300 mg/day; P ⫽ .08). The irbesartan 300-mg group demonstrated a significant RRR (70%) versus placebo (P ⬍ .001). The UAER was reduced at 24 months in both the irbesartan 150-mg and 300-mg groups (24% and 38%, respectively), but remained unchanged in the control group compared with baseline (P ⬍ .001, irbesartan groups combined v placebo). Creatinine clearance remained in the normal range in all three groups. Regression to normoalbuminuria at the last visit was more frequent in subjects treated with irbesartan 300 mg than in the placebo group (34% v 21%, respectively; P ⫽ .006). Blood pressure reduction was
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similar in the three groups. Renin-angiotensin-aldosterone system blockade using irbesartan thus provided renoprotection, even at an early stage of diabetic renal disease and independent of its BP-lowering effect. The Irbesartan Diabetic Nephropathy Trial (IDNT) was conducted to evaluate the effect of irbesartan and amlodipine on the rate of progression of diabetic nephropathy in patients at a late stage of type 2 diabetic renal disease, independent of the BP-lowering effects of the drugs.17 This multicenter, randomized, double-blind, placebo-controlled trial enrolled 1715 subjects with proteinuria ⱖ900 mg/day and mild-to-moderate renal insufficiency (serum creatinine 1.0 to 3.0 mg/dL in women and 1.2 to 3.0 mg/dL in men). Subjects were randomized to treatment with irbesartan or placebo. As in the IRMA 2 trial, additional antihypertensive agents (excluding ACE inhibitors, other ARBs, or CCBs) could be added to help achieve the BP goal of ⬍135/85 mm Hg. The primary end point was the composite of the time from randomization to the time at which doubling of the baseline serum creatinine concentration, development of ESRD (defined as renal transplantation, renal dialysis, or serum creatinine level ⱖ6.0 mg/dL), or death (from any cause) occurred. In IDNT, irbesartan demonstrated a 20% RRR versus placebo (P ⫽ .02) and a 23% RRR versus amlodipine (P ⫽ .006) for the primary composite end point, despite similar reductions in BP levels (Table 1).17 Within the composite result, irbesartan achieved a 33% RRR for doubling of baseline serum creatinine versus placebo (P ⫽ .003) and a 37% RRR versus amlodipine (P ⬍ .001) (Fig. 3). There were no significant differences between the three groups for overall mortality or for CV events. The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial was conducted to assess the effects of the ARB losartan on type 2 diabetic nephropathy.18 In this randomized, doubleblind, placebo-controlled multinational trial, 1513 subjects with type 2 diabetes, proteinuria ⱖ500 mg/day, and serum creatinine between 1.3 and 3.0 mg/dL were randomized to receive losartan or placebo and followed for a mean of
Table 1. IDNT and RENAAL study results RRR (%) IDNT End points Composite end point (doubling of SCr, ESRD, or death) Doubling of: SCr ESRD Death Cardiovascular morbidity and mortality
Irbesartan v Placebo
RENAAL
Irbesartan v Amlodipine
Losartan v Placebo
20 (P ⫽ .02)
23 (P ⫽ .006)
16 (P ⫽ .02)
33 23 8 9
37 23 ⫺4 ⫺3
25 28 ⫺2 10
(P (P (P (P
⫽ ⫽ ⫽ ⫽
.003) .07) .57) .4)
(P (P (P (P
⬍ ⫽ ⫽ ⫽
.001) .07) .8) .79)
(P (P (P (P
⫽ ⫽ ⫽ ⫽
.006) .002) .88) .26)
IDNT ⫽ Irbesartan Diabetic Nephropathy Trial; RENAAL ⫽ Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; RRR ⫽ relative risk reduction; SCr ⫽ serum creatinine; ESRD ⫽ end-stage renal disease.
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FIG. 3. In the Irbesartan Diabetic Nephropathy Trial (IDNT), subjects treated with irbesartan had a 33% relative risk reduction (RRR) for time to doubling of baseline serum creatinine versus subjects in the control group (placebo plus other nonexcluded antihypertensive therapies) (P ⫽ .003) and a 37% RRR versus those in the amlodipine group (P ⬍ .001). (Reprinted with permission from Lewis EJ, et al: Renoprotective effect of the angiotension receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851– 860. Copyright © 2001, Massachusetts Medical Society. All rights reserved.17)
3.4 years. Additional antihypertensive agents (excluding ACE inhibitors and other ARBs) could be added to help achieve the BP goal of ⬍140/90 mm Hg. The primary end point was the composite of the time from randomization to the first occurrence of doubling of baseline serum creatinine, ESRD (defined as renal transplantation or long-term dialysis), or death from any cause. The results from RENAAL mirrored those from IDNT (Table 1). Losartan significantly reduced the risk of the primary composite end point by 16% versus placebo (P ⫽ .02).18 Taken together, the RENAAL and IDNT results indicate an important role for ARBs in the management of patients with type 2 diabetic nephropathy.
Potential of ARBs and ACE Inhibitors in Combination Although ACE inhibitors have been demonstrated to provide significant renoprotection, angiotensin II may be produced through pathways involving enzymes other than ACE (eg, chymase).19,20 Preliminary research has therefore investigated renoprotection with the use of combined ACE inhibitor and ARB therapy. The Candesartan and Lisinopril Microalbuminuria (CALM) study was a randomized, double-blind, 24-week trial that compared the effects of the ARB candesartan, the ACE inhibitor lisinopril, and the combination of these agents on BP and urinary albumin excretion in hypertensive subjects with coexisting type 2 diabetes and microalbuminuria.19 For the first 12 weeks of this trial, the 199 enrolled subjects were randomized to once-daily treatment with either candesartan 16 mg or lisinopril 20 mg. During the second 12 weeks, subjects were again randomized to candesartan 16 mg or lisinopril 20 mg, or their combination, once daily. After the first 12 weeks, both monotherapies demonstrated significant reductions from
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baseline in BP and urinary albumin:creatinine ratio (P ⬍ .001), with no significant differences in these parameters between the two treatment groups. After 24 weeks, all three treatments had achieved significant reductions in BP (P ⬍ .001) and in urinary albumin:creatinine ratio (P ⬍ .001 for combination therapy and lisinopril monotherapy; P ⫽ .05 for candesartan monotherapy). The greatest reductions were observed in the group taking combination therapy.19 Mean reduction in diastolic BP was significantly greater with combination therapy (16.3 mm Hg) than with candesartan monotherapy (10.4 mm Hg; P ⫽ .003) or with lisinopril monotherapy (10.7 mm Hg; P ⫽ .005). Mean reduction in systolic BP was significantly greater with combination therapy (25.3 mm Hg) than with candesartan monotherapy (14.1 mm Hg; P ⫽ .002) or lisinopril monotherapy (16.7 mm Hg; P ⫽ .02). The reduction in urinary albumin: creatinine ratio with combination therapy was significantly greater than with candesartan (50% v 24%, respectively; P ⫽ .04) and numerically greater than with lisinopril (39%). It is important to recognize that this was a small, short-term study. The more profound decrease in BP in subjects receiving ARB plus ACE inhibitor therapy could account for the improved lowering of albumin excretion. Whether this combination of agents provides increased renoprotection is not yet known.
Renoprotective Effects of Olmesartan Medoxomil The newest ARB, olmesartan medoxomil, has been shown to provide antihypertensive efficacy similar to that of other classes of antihypertensive agents and superior to that of the other leading ARB.21,22 In animal studies, olmesartan medoxomil has also demonstrated the potential to provide renoprotection. The renoprotective benefits of olmesartan medoxomil were examined in the Zucker diabetic fatty (ZDF) rat, a model of type 2 diabetes that develops progressive hyperglycemia, glomerulosclerosis, and proteinuria.23 Beginning at 12 weeks of age, the ZDF rats were given olmesartan medoxomil (0.001% or 0.01%) or vehicle in their diet. Untreated, lean nondiabetic rats were used as controls. Urine and plasma samples were taken and BP was measured every 2 weeks during treatment. After 19 weeks of treatment, the rats were killed and their kidneys histologically examined. The ZDF rats developed progressive hypertension and hyperglycemia over the course of the study, compared with the lean, nondiabetic control rats.23 The ZDF rats also developed progressive proteinuria, which was not observed in the lean control rats. Treatment with olmesartan medoxomil 0.01% reduced BP in the ZDF rats, but had no effect on the development of progressive obesity and hyperglycemia. Olmesartan medoxomil therapy also produced a dose-dependent reduction in proteinuria that was statistically significant with both doses compared with
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olmesartan medoxomil may provide renoprotection independent of its BP-reducing effect, as is the case with other agents in this class.
Conclusions
FIG. 4. In the Zucker diabetic fatty (ZDF) rat model, olmesartan medoxomil resulted in a dose-dependent reduction in urinary protein excretion (UPE) that was statistically significant with both doses (P ⬍ .01, vehicle [n ⫽ 10] v the 0.001% dose [n ⫽ 9] and v the 0.01% dose [n ⫽ 10]) and independent of changes in blood pressure and glycemic state.23
vehicle (Fig. 4), even though the lower dose (0.001%) did not significantly reduce BP. In addition, histologic examination of ZDF rat kidneys after completion of the study showed extensive glomerulosclerosis and tubular damage in vehicle-treated rats compared with the lean, nondiabetic control rats (Fig. 5). This renal damage was clearly reduced, upon histologic examination, in the ZDF rats treated with olmesartan medoxomil (Fig. 5). The renoprotective effects of olmesartan medoxomil were also studied in aged spontaneously hypertensive rats (SHRs). In this study, 32-week-old SHR and age-matched Wistar-Kyoto (WKY) normotensive control rats were both administered oral olmesartan medoxomil (3 and 10 mg/kg) for 6 weeks.24 At the end of the treatment period, olmesartan medoxomil had produced dose-dependent reductions in BP and in urinary protein excretion and tended to reduce blood creatinine and blood urea nitrogen (indices of renal dysfunction) compared with the untreated SHRs. These results in ZDF rats and SHRs demonstrate the involvement of angiotensin II in the development and progression of hypertensive nephropathy and suggest that
Blood pressure control is a crucial component of treatment to prevent the development of diabetic nephropathy or slow its progression. Angiotension II receptor blockers are safe and effective in combination with other drugs for the control of BP in this difficult population. Substantial evidence indicates that RAAS inhibition or blockade has an independent renoprotective effect. The renoprotective benefits of RAAS inhibition appear to be independent of BP reduction. Based on available data, ACE inhibitors are recommended for initial antihypertensive therapy in hypertensive or nonhypertensive patients with type 1 diabetes accompanied by microalbuminuria or proteinuria, and ARBs are the preferred initial agents for hypertensive patients with coexisting type 2 diabetes accompanied by microalbuminuria and proteinuria.4 Based on their demonstrated efficacy and tolerability profiles, ARBs are expected to play an important role in the management of renal disease. The newest ARB, olmesartan medoxomil, has been shown to have superior BPlowering efficacy compared with that of other leading ARBs. Animal studies indicate that olmesartan medoxomil may also provide renoprotective benefits.
References 1.
2.
3.
4. 5.
6.
7. 8. FIG. 5. Histologic slides of the kidneys of Zucker diabetic fatty (ZDF) rats showed extensive glomerulosclerosis and tubular damage in vehicle-treated rats compared with controls (nondiabetic rats). Treatment with olmesartan medoxomil 0.01% prevented much of the kidney damage.24
9.
United States Renal Data System: USRDS-2001 Annual Data Report: Atlas of End Stage Renal Disease in the United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2001. 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(9B):9R–14R. 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; 36:646 –661. American Diabetes Association: Diabetic nephropathy. Diabetes Care 2002;25(Suppl 1):S85–S89. Keane WF, Eknoyan G: Proteinuria, albuminuria, risk, assessment, detection, elimination (PARADE): a position paper of the National Kidney Foundation. Am J Kidney Dis 1999;33:1004 –1010. 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 1997;157: 2413–2446. Burnier M: Angiotensin II type I receptor blockers. Circulation 2001;103:904 –912. Elliott HL: Angiotensin II antagonists: efficacy, duration of action, comparison with other drugs. J Hum Hypertens 1998;12:271–274. Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS: Urinary albumin excretion: an independent predictor of ischemic heart disease. Arterioscler Thromb Vasc Biol 1999;19: 1992–1997.
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10. Kasiske BL, Kalil RSN, Ma JZ, Liao M, Keane WF: Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med 1993;118:129 –138. 11. Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN Group): Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997;349:1857–1863. 12. Maschio G, Alberti D, Janin G, Locatelli F, Mann JFE, Motolese M, Ponticelli C, Ritz E, Zuchelli Z, for the Angiotensin-ConvertingEnzyme Inhibition in Progressive Renal Insufficiency Study Group: Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 1996; 334:939 –945. 13. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, for the Collaborative Study Group: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456 –1462. 14. Gansevoort RT, de Zeeuw D, de Jong PE: Is the antiproteinuric effect of ACE inhibition mediated by interference in the reninangiotensin system? Kidney Int 1994;45:861–867. 15. Perico N, Remuzzi A, Sangalli F, Azzollini N, Mister M, Ruggenenti P, Remuzzi G: The antiproteinuric effect of angiotensin antagonism in human IgA nephropathy is potentiated by indomethacin. J Am Soc Nephrol 1998;9:2308 –2317. 16. Parving H-H, Lehnert H, Bro¨ chner-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;345:870 –878. 17. 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
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irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851–860. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving H-H, 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;345:861–869. Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, Cooper ME, for the CALM Study Group: Randomized controlled trial of renin-angiotensin system in patients with hypertension, microalbuminuria, and noninsulin dependent diabetes. The Candesartan and Lisinopril Microalbuminuria (CALM) study. BMJ 2000;321:1440 –1444. Hollenberg NK, Fisher NDL, Price DA: Pathways for angiotensin II generation in intact human tissue. Evidence from comparative pharmacological interruption of the renin system. Hypertension 1998; 32:387–392. Ball KJ, Williams PA, Stumpe KO: Relative efficacy of an angiotensin II antagonist compared with other antihypertensive agents: olmesartan medoxomil versus antihypertensives. J Hypertens 2001; 19(Suppl):S49 –S56. Oparil S, Williams D, Chrysant SG, Marbury TC, Neutel JM: Comparative efficacy of olmesartan, losartan, valsartan, and irbesartan in the control of essential hypertension. J Clin Hypertens 2001; 3:283–291, 318. Koike H: New pharmacologic aspects of CS-866, the newest angiotensin II receptor antagonist. Am J Cardiol 2001;87(Suppl):33C– 36C. Koike H, Sada T, Mizuno M: In vitro and in vivo pharmacology of olmesartan medoxomil, an angiotensin II type AT1 receptor antagonist. J Hypertens 2001;19(Suppl 1):S3–S14.
2002; 15:123S–128S
The Role of Angiotensin II Receptor Blockers in Preventing the Progression of Renal Disease in Patients With Type 2 Diabetes Edmund J. Lewis Diabetes mellitus is the most common cause of end-stage renal disease in the United States, accounting for about 50% of all new cases. Although we previously established the renoprotective benefits of angiotensin converting enzyme (ACE) inhibitors in patients with coexisting hypertension and type 1 diabetes, evidence of the renoprotective effect of ACE inhibitors in patients with type 2 diabetes is less clear. We conducted the Irbesartan Diabetic Nephropathy Trial (IDNT) to determine whether the angiotensin II receptor blocker (ARB) irbesartan slows the progression of nephropathy in patients with type 2 diabetes independently of its blood pressure (BP)-lowering effect. In this randomized, controlled trial, we found that irbesartan was associated with a 20% reduction in the risk for the primary composite end point (doubling of the baseline serum creatinine concentration, development of end-stage renal disease, or death from any cause) compared with placebo (P ⫽ .02) and a 23% reduction compared with amlodipine
D
therapy (P ⫽ .006). These results were not explained by differences in the BP that was achieved. In a separate study, losartan was shown to reduce the risk for progression of renal disease in patients with type 2 diabetic nephropathy. Angiotensin II receptor blocker therapy has also been demonstrated to slow the progression to overt nephropathy when initiated early in the course of type 2 diabetic renal disease (ie, in patients with microalbuminuria). Based on these studies, ARBs are clearly effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of their BP-lowering effect. Preclinical studies with the newest ARB, olmesartan medoxomil, suggest that this agent may provide renoprotective benefits as well. Am J Hypertens 2002;15:123S–128S © 2002 American Journal of Hypertension, Ltd. Key Words: Angiotensin II receptor blockers, diabetic nephropathy, hypertension, irbesartan, olmesartan medoxomil.
iabetes mellitus is the most common cause of end-stage renal disease (ESRD) in the United States, accounting for approximately half of all new cases.1 The majority of patients with diabetes who develop ESRD, defined as the need for renal dialysis or transplantation, have type 2 diabetes. Moreover, the number of ESRD patients maintained on dialysis is projected to double by the year 2010. The main factor behind this increase is the dramatic rise in the prevalence of diabetes and diabetic nephropathy, as well as the improved survival of patients with type 2 diabetes.1 Hypertension is diagnosed in about 50% of patients who have type 2 diabetes and is a major pathophysiologic mechanism for the arterial damage leading to diabetic nephropathy and cardiovascular (CV) disease.2,3 Hypertension in patients with type 2 diabetes markedly accelerates the progression of diabetic nephropathy; con-
versely, antihypertensive therapy has been shown to slow the decline in the glomerular filtration rate (GFR).4 The principal treatment for slowing the progression of diabetic renal disease, therefore, is aggressive antihypertensive therapy in addition to glycemic control and a low-protein diet.4,5 Hypertension treatment guidelines recommend antihypertensive therapy as early as possible (as soon as microalbuminuria becomes apparent) in patients with diabetes, with a goal blood pressure (BP) of ⬍130/85 mm Hg.6 The preferred antihypertensive treatment strategy for patients who have diabetes with renal involvement is inhibition or blockade of the renin-angiotensin-aldosterone system (RAAS) using angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs).4,6 An agent that prevents or retards the progression of renal disease in a manner independent of systemic effects such as BP lowering is defined as renoprotective. Al-
Received July 3, 2002. First decision July 9, 2002. Accepted July 9, 2002. From Rush-Presbyterian–St. Luke’s Medical Center, Chicago, Illinois.
Address correspondence and reprint requests to Dr. Edmund J. Lewis, Director, Department of Nephrology, Rush-Presbyterian–St. Luke’s Medical Center, 1653 West Congress Parkway, Suite 301, Jones Building, Chicago, IL 60612.
© 2002 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.
0895-7061/02/$22.00 PII S0895-7061(02)03007-8
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FIG. 1. A meta-analysis of 100 trials in 2494 subjects with diabetes showed that angiotensin converting enzyme (ACE) inhibitors produced the greatest reductions in urine albumin and protein excretion compared with other antihypertensive agents (*P ⬍ .05 v calcium channel blockers; †P ⬍ .05 v control). Only ACE inhibitors achieved these beneficial effects on renal function independent of changes in blood pressure. (Reprinted with permission from Kasiske BL, et al: Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med 1993;118:129 –138, Lippincott Williams & Wilkins©.10)
though the renoprotective effects of ACE inhibitors in patients with type 1 diabetes are well established, the benefits of ACE inhibitors in patients with type 2 diabetes are less clear. Research findings indicating that ARBs have antihypertensive efficacy similar to that of other drug classes, with superior tolerability, suggest that these agents could play an important role in the treatment of patients with diabetic nephropathy, not only as effective antihypertensive drugs, but also as renoprotective agents.7,8
Effects of Antihypertensive Drug Classes on Proteinuria Microalbuminuria has been shown to be an early sign of renal disease and a risk factor for CV disease.9 A sustained decrease in proteinuria is frequently associated with a slower progression of nephropathy and may be a useful indicator for evaluating therapeutic response.5 Different classes of antihypertensive agents may vary in their ability to reduce proteinuria.10 In a meta-analysis of 100 controlled and uncontrolled trials, the relative effect of several types of antihypertensive agents on proteinuria and renal function in patients with diabetes was assessed.10 Although therapy with ACE inhibitors, calcium channel blockers (CCBs), and -blockers had similar effects on mean arterial pressure, their effects on indicators of renal function were disparate. Subjects who were given ACE inhibitors experienced the greatest reduction in urine albumin and protein excretion (Fig. 1). Angiotensin converting enzyme inhibitors and CCBs also appeared to have a more favorable effect on GFR than did the other agents. Multiple linear regression analysis indicated that only ACE inhibitors decreased proteinuria and increased the GFR to a greater extent than would have been expected if the improvements had been derived from BP reduction alone.
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In several placebo-controlled trials, ACE inhibitors have demonstrated significant beneficial effects on the progression of nephropathy.11–13 In a randomized, placebo-controlled trial in 409 subjects with type 1 diabetes, the ACE inhibitor captopril reduced the risk of a doubling in serum creatinine by 48% (P ⫽ .007).13 Captopril was associated with a 50% reduced risk for the combined end points of death, dialysis, and transplantation independent of the small difference in BP between treatment groups. Similar data, however, are lacking for ACE inhibitors in type 2 diabetic nephropathy. Few studies have compared the effect of ARBs in reducing proteinuria with that of ACE inhibitors, but preliminary research suggests that these classes of drugs may provide similar antiproteinuric benefits. In one study, the ARB losartan was found to be as effective as enalapril in lowering proteinuria, reducing BP, and increasing renal plasma flow.14 In another study, the effect of the ACE inhibitor enalapril was compared with that of the ARB irbesartan on urinary protein excretion and renal hemodynamics in 20 patients with IgA glomerulonephritis.15 In this double-blind study, subjects were randomized to treatment with enalapril 20 mg once daily or irbesartan 10 mg once daily for 28 days. Enalapril and irbesartan produced similar reductions in proteinuria and comparable renal hemodynamic changes.15
Effect of ARBs on Diabetic Nephropathy Following up on research findings showing the significant renoprotective benefits provided by RAAS interference using ACE inhibitors in type 1 diabetes, a number of recent studies have investigated the effects of angiotensin II blockade using ARBs in type 2 diabetic nephropathy. The Irbesartan Microalbuminuria in Hypertensive Patients with Type 2 Diabetes (IRMA 2) trial evaluated the effect of the ARB irbesartan on the rate of progression to overt diabetic nephropathy in patients with hypertension at an early stage of type 2 diabetic renal disease.16 In this multicenter, randomized, double-blind, placebocontrolled trial, 590 subjects with type 2 diabetes, persistent microalbuminuria (albumin excretion rate of 20 to 200 g/min or 30 to 300 mg/day), and normal renal function were randomized to receive irbesartan 150 mg/day, irbesartan 300 mg/day, or placebo and followed for 2 years. Additional antihypertensive agents (excluding ACE inhibitors, other ARBs, and dihydropiridine CCBs) could be added to help achieve the BP goal of ⬍135/85 mm Hg. The primary end point was the time to the occurrence of clinical proteinuria or overt diabetic nephropathy, which was defined as an overnight urinary albumin excretion rate (UAER) of ⬎200 g/min (300 mg/day) and an increase in UAER from baseline of at least 30% at two successive 3-month evaluations. Secondary end points included changes in overnight UAER, regression to normoalbuminuria (⬍20 g/min), and change in creatinine clearance.
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FIG. 2. In the Irbesartan Microalbuminuria in Hypertensive Patients with type 2 Diabetes (IRMA 2) trial, a clear dose response was observed for the primary end point of time to clinical proteinuria (urinary albumin excretion rate ⬎200 g/min, or 300 mg/day). Although the irbesartan 150-mg group (n ⫽ 195) achieved a 39% relative risk reduction (RRR) versus placebo (P ⫽ .08), the irbesartan 300-mg group (n ⫽ 194) demonstrated a significant (70%; P ⬍ .001) RRR versus placebo (n ⫽ 201). (Reprinted with permission from Parving H-H, et al: The effects of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870 – 878. Copyright © 2001, Massachusetts Medical Society; All rights reserved.16)
A clear dose response was observed for the primary end point (Fig. 2).16 The irbesartan 150-mg group demonstrated a 39% relative risk reduction (RRR) versus placebo in the development of clinical proteinuria (UAER ⬎200 g/min, or 300 mg/day; P ⫽ .08). The irbesartan 300-mg group demonstrated a significant RRR (70%) versus placebo (P ⬍ .001). The UAER was reduced at 24 months in both the irbesartan 150-mg and 300-mg groups (24% and 38%, respectively), but remained unchanged in the control group compared with baseline (P ⬍ .001, irbesartan groups combined v placebo). Creatinine clearance remained in the normal range in all three groups. Regression to normoalbuminuria at the last visit was more frequent in subjects treated with irbesartan 300 mg than in the placebo group (34% v 21%, respectively; P ⫽ .006). Blood pressure reduction was
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similar in the three groups. Renin-angiotensin-aldosterone system blockade using irbesartan thus provided renoprotection, even at an early stage of diabetic renal disease and independent of its BP-lowering effect. The Irbesartan Diabetic Nephropathy Trial (IDNT) was conducted to evaluate the effect of irbesartan and amlodipine on the rate of progression of diabetic nephropathy in patients at a late stage of type 2 diabetic renal disease, independent of the BP-lowering effects of the drugs.17 This multicenter, randomized, double-blind, placebo-controlled trial enrolled 1715 subjects with proteinuria ⱖ900 mg/day and mild-to-moderate renal insufficiency (serum creatinine 1.0 to 3.0 mg/dL in women and 1.2 to 3.0 mg/dL in men). Subjects were randomized to treatment with irbesartan or placebo. As in the IRMA 2 trial, additional antihypertensive agents (excluding ACE inhibitors, other ARBs, or CCBs) could be added to help achieve the BP goal of ⬍135/85 mm Hg. The primary end point was the composite of the time from randomization to the time at which doubling of the baseline serum creatinine concentration, development of ESRD (defined as renal transplantation, renal dialysis, or serum creatinine level ⱖ6.0 mg/dL), or death (from any cause) occurred. In IDNT, irbesartan demonstrated a 20% RRR versus placebo (P ⫽ .02) and a 23% RRR versus amlodipine (P ⫽ .006) for the primary composite end point, despite similar reductions in BP levels (Table 1).17 Within the composite result, irbesartan achieved a 33% RRR for doubling of baseline serum creatinine versus placebo (P ⫽ .003) and a 37% RRR versus amlodipine (P ⬍ .001) (Fig. 3). There were no significant differences between the three groups for overall mortality or for CV events. The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial was conducted to assess the effects of the ARB losartan on type 2 diabetic nephropathy.18 In this randomized, doubleblind, placebo-controlled multinational trial, 1513 subjects with type 2 diabetes, proteinuria ⱖ500 mg/day, and serum creatinine between 1.3 and 3.0 mg/dL were randomized to receive losartan or placebo and followed for a mean of
Table 1. IDNT and RENAAL study results RRR (%) IDNT End points Composite end point (doubling of SCr, ESRD, or death) Doubling of: SCr ESRD Death Cardiovascular morbidity and mortality
Irbesartan v Placebo
RENAAL
Irbesartan v Amlodipine
Losartan v Placebo
20 (P ⫽ .02)
23 (P ⫽ .006)
16 (P ⫽ .02)
33 23 8 9
37 23 ⫺4 ⫺3
25 28 ⫺2 10
(P (P (P (P
⫽ ⫽ ⫽ ⫽
.003) .07) .57) .4)
(P (P (P (P
⬍ ⫽ ⫽ ⫽
.001) .07) .8) .79)
(P (P (P (P
⫽ ⫽ ⫽ ⫽
.006) .002) .88) .26)
IDNT ⫽ Irbesartan Diabetic Nephropathy Trial; RENAAL ⫽ Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; RRR ⫽ relative risk reduction; SCr ⫽ serum creatinine; ESRD ⫽ end-stage renal disease.
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FIG. 3. In the Irbesartan Diabetic Nephropathy Trial (IDNT), subjects treated with irbesartan had a 33% relative risk reduction (RRR) for time to doubling of baseline serum creatinine versus subjects in the control group (placebo plus other nonexcluded antihypertensive therapies) (P ⫽ .003) and a 37% RRR versus those in the amlodipine group (P ⬍ .001). (Reprinted with permission from Lewis EJ, et al: Renoprotective effect of the angiotension receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851– 860. Copyright © 2001, Massachusetts Medical Society. All rights reserved.17)
3.4 years. Additional antihypertensive agents (excluding ACE inhibitors and other ARBs) could be added to help achieve the BP goal of ⬍140/90 mm Hg. The primary end point was the composite of the time from randomization to the first occurrence of doubling of baseline serum creatinine, ESRD (defined as renal transplantation or long-term dialysis), or death from any cause. The results from RENAAL mirrored those from IDNT (Table 1). Losartan significantly reduced the risk of the primary composite end point by 16% versus placebo (P ⫽ .02).18 Taken together, the RENAAL and IDNT results indicate an important role for ARBs in the management of patients with type 2 diabetic nephropathy.
Potential of ARBs and ACE Inhibitors in Combination Although ACE inhibitors have been demonstrated to provide significant renoprotection, angiotensin II may be produced through pathways involving enzymes other than ACE (eg, chymase).19,20 Preliminary research has therefore investigated renoprotection with the use of combined ACE inhibitor and ARB therapy. The Candesartan and Lisinopril Microalbuminuria (CALM) study was a randomized, double-blind, 24-week trial that compared the effects of the ARB candesartan, the ACE inhibitor lisinopril, and the combination of these agents on BP and urinary albumin excretion in hypertensive subjects with coexisting type 2 diabetes and microalbuminuria.19 For the first 12 weeks of this trial, the 199 enrolled subjects were randomized to once-daily treatment with either candesartan 16 mg or lisinopril 20 mg. During the second 12 weeks, subjects were again randomized to candesartan 16 mg or lisinopril 20 mg, or their combination, once daily. After the first 12 weeks, both monotherapies demonstrated significant reductions from
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baseline in BP and urinary albumin:creatinine ratio (P ⬍ .001), with no significant differences in these parameters between the two treatment groups. After 24 weeks, all three treatments had achieved significant reductions in BP (P ⬍ .001) and in urinary albumin:creatinine ratio (P ⬍ .001 for combination therapy and lisinopril monotherapy; P ⫽ .05 for candesartan monotherapy). The greatest reductions were observed in the group taking combination therapy.19 Mean reduction in diastolic BP was significantly greater with combination therapy (16.3 mm Hg) than with candesartan monotherapy (10.4 mm Hg; P ⫽ .003) or with lisinopril monotherapy (10.7 mm Hg; P ⫽ .005). Mean reduction in systolic BP was significantly greater with combination therapy (25.3 mm Hg) than with candesartan monotherapy (14.1 mm Hg; P ⫽ .002) or lisinopril monotherapy (16.7 mm Hg; P ⫽ .02). The reduction in urinary albumin: creatinine ratio with combination therapy was significantly greater than with candesartan (50% v 24%, respectively; P ⫽ .04) and numerically greater than with lisinopril (39%). It is important to recognize that this was a small, short-term study. The more profound decrease in BP in subjects receiving ARB plus ACE inhibitor therapy could account for the improved lowering of albumin excretion. Whether this combination of agents provides increased renoprotection is not yet known.
Renoprotective Effects of Olmesartan Medoxomil The newest ARB, olmesartan medoxomil, has been shown to provide antihypertensive efficacy similar to that of other classes of antihypertensive agents and superior to that of the other leading ARB.21,22 In animal studies, olmesartan medoxomil has also demonstrated the potential to provide renoprotection. The renoprotective benefits of olmesartan medoxomil were examined in the Zucker diabetic fatty (ZDF) rat, a model of type 2 diabetes that develops progressive hyperglycemia, glomerulosclerosis, and proteinuria.23 Beginning at 12 weeks of age, the ZDF rats were given olmesartan medoxomil (0.001% or 0.01%) or vehicle in their diet. Untreated, lean nondiabetic rats were used as controls. Urine and plasma samples were taken and BP was measured every 2 weeks during treatment. After 19 weeks of treatment, the rats were killed and their kidneys histologically examined. The ZDF rats developed progressive hypertension and hyperglycemia over the course of the study, compared with the lean, nondiabetic control rats.23 The ZDF rats also developed progressive proteinuria, which was not observed in the lean control rats. Treatment with olmesartan medoxomil 0.01% reduced BP in the ZDF rats, but had no effect on the development of progressive obesity and hyperglycemia. Olmesartan medoxomil therapy also produced a dose-dependent reduction in proteinuria that was statistically significant with both doses compared with
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olmesartan medoxomil may provide renoprotection independent of its BP-reducing effect, as is the case with other agents in this class.
Conclusions
FIG. 4. In the Zucker diabetic fatty (ZDF) rat model, olmesartan medoxomil resulted in a dose-dependent reduction in urinary protein excretion (UPE) that was statistically significant with both doses (P ⬍ .01, vehicle [n ⫽ 10] v the 0.001% dose [n ⫽ 9] and v the 0.01% dose [n ⫽ 10]) and independent of changes in blood pressure and glycemic state.23
vehicle (Fig. 4), even though the lower dose (0.001%) did not significantly reduce BP. In addition, histologic examination of ZDF rat kidneys after completion of the study showed extensive glomerulosclerosis and tubular damage in vehicle-treated rats compared with the lean, nondiabetic control rats (Fig. 5). This renal damage was clearly reduced, upon histologic examination, in the ZDF rats treated with olmesartan medoxomil (Fig. 5). The renoprotective effects of olmesartan medoxomil were also studied in aged spontaneously hypertensive rats (SHRs). In this study, 32-week-old SHR and age-matched Wistar-Kyoto (WKY) normotensive control rats were both administered oral olmesartan medoxomil (3 and 10 mg/kg) for 6 weeks.24 At the end of the treatment period, olmesartan medoxomil had produced dose-dependent reductions in BP and in urinary protein excretion and tended to reduce blood creatinine and blood urea nitrogen (indices of renal dysfunction) compared with the untreated SHRs. These results in ZDF rats and SHRs demonstrate the involvement of angiotensin II in the development and progression of hypertensive nephropathy and suggest that
Blood pressure control is a crucial component of treatment to prevent the development of diabetic nephropathy or slow its progression. Angiotension II receptor blockers are safe and effective in combination with other drugs for the control of BP in this difficult population. Substantial evidence indicates that RAAS inhibition or blockade has an independent renoprotective effect. The renoprotective benefits of RAAS inhibition appear to be independent of BP reduction. Based on available data, ACE inhibitors are recommended for initial antihypertensive therapy in hypertensive or nonhypertensive patients with type 1 diabetes accompanied by microalbuminuria or proteinuria, and ARBs are the preferred initial agents for hypertensive patients with coexisting type 2 diabetes accompanied by microalbuminuria and proteinuria.4 Based on their demonstrated efficacy and tolerability profiles, ARBs are expected to play an important role in the management of renal disease. The newest ARB, olmesartan medoxomil, has been shown to have superior BPlowering efficacy compared with that of other leading ARBs. Animal studies indicate that olmesartan medoxomil may also provide renoprotective benefits.
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7. 8. FIG. 5. Histologic slides of the kidneys of Zucker diabetic fatty (ZDF) rats showed extensive glomerulosclerosis and tubular damage in vehicle-treated rats compared with controls (nondiabetic rats). Treatment with olmesartan medoxomil 0.01% prevented much of the kidney damage.24
9.
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