- Email: [email protected]
The role of angiotensin II antagonism in type 2 diabetes mellitus: a review of renoprotection studies
CLINICAL THERAPEUTICS®/VOL. 24, NO. 7, 2002
The Role of Angiotensin II Antagonism in Type 2 Diabetes Mellitus: A Review of Renoprotection Studies Maria-Teresa Zanella, AID, and Artur B. Ribeiro, AID Divisions of Nephrology and Endocrinology, Hospital do Rim e Hipertensao, Federal University of Sao Paulo, Sao Paulo, Brazil
ABSTRACT
Background: Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in Western and Asian countries. Effective antihypertensive therapy reduces the rate of decline in renal function and postpones ESRD in patients with diabetic nephropathy. Objective: This review presents evidence from studies on how blood pressure control, plasma glucose control, and the presence of proteinuria determine outcomes in diabetic patients. The role of angiotensin II (AII) in the development of diabetic nephropathy and the reno- and cardiobeneficial effects of AII antagonism in patients with type 2 diabetes mellitus (DM-2) and diabetic nephropathy also are addressed. Methods: Articles included in this review were found using a MEDLINE search for studies published from 1991 to 2001 and including the search terms diabetic nephropathy, type 2 diabetes mellitus, microalbuminuria, proteinuria, angiotensin receptor blockade, angiotensin-converting enzyme inhibition, and cardiovascular disease. Articles reporting new data, new mechanisms, major clinical trials, and our own data were included. Results: Recently, the Reduction of Endpoints in NIDDM (non-insulin-dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan (RENAAL) trial provided sufficient data to conclude that the blockade of the AII AT1 receptor with losartan confers renoprotection in patients with DM-2 and nephropathy. Similar results were obtained with irbesartan in the Irbesartan Diabetic Nephropathy Trial (IDNT) and the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria study (IRMA 2). The results of RENAAL indicate that the renoprotective effects of losartan were attributable to effects beyond blood pressure control. In addition to the favorable impact of the AII blockade on blood pressure and renal hemodynamics, the blockade of the growthpromoting, profibrotic, nonhemodynamic actions of AII also may be important for renoprotection. Intensive blood pressure control also confers cardiovascular protection in paAccepted for publication May 16, 2002. Printed in the USA. Reproduction in whole or part is not permitted.
0149-2918/02/$19.00
1019
CLINICAL THERAPEUTICS ~
tients with DM-2. Some studies suggest that the blockade of the renin-angiotensin system confers superior cardioprotective effects in patients with DM-2. The RENAAL study also showed cardioprotection with losartan, with an important reduction in the risk for first hospitalization for heart failure. Conclusion: Evidence supports the importance of an effective blockade of AlI action for both reno- and cardioprotection in patients with DM-2. Key words: angiotensin II antagonists, diabetic nephropathy, microalbuminuria, type 2 diabetes mellitus, proteinuria, cardioprotection, renoprotection ( Clin Ther. 2002;24:1019-1034) INTRODUCTION Major clinical trials have been conducted to address the growing incidence of cardiovascular and renal morbidity and mortality in patients with type 2 diabetes mellitus (DM-2). The results of the United Kingdom Prospective Diabetes Study (UKPDS), 1 Reduction of Endpoints in NIDDM (non-insulin-dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan (RENAAL) trial, 2 Irbesartan Diabetic Nephropathy Trial (IDNT),3 Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria study (IRMA 2) 4 and the Heart Outcomes Prevention Evaluation (HOPE) and its substudy in patients with DM (MICRO-HOPE) 5 provide strong clinical evidence of the benefits of well-defined approaches to treat diabetic patients. From these studies, it is clear that targeting the parameters of blood pressure, plasma glucose control, proteinuria, and blockade of the renin-angiotensin system (RAS) is the most effective approach to delay or prevent diabetes-related complications. 1020
Persistent albuminuria, blood pressure elevation, a progressive decline in glomerular filtration rate (GFR), and a high risk for cardiovascular morbidity and mortality characterize diabetic nephropathy. 6 This microvascular complication of diabetes occurs in approximately one third of patients with DM-2 and is the leading cause of end-stage renal disease (ESRD), accounting for 40% of new patients receiving kidney dialysis or transplant in Western and Asian countries. 6,7 With the constant improvement in health care facilities allowing more patients to live longer, the number of diabetic patients needing renal dialysis or transplant is rising sharply. As a consequence, the costs associated with ESRD in the United States are expected to surpass $28 billion per year by 2010. 8 Thus, ESRD, as a consequence of diabetic nephropathy, represents a large economic burden. This review presents evidence from recent studies on how blood pressure control, plasma glucose control, and the presence of proteinuria determine outcomes in diabetic patients. The role of angiotensin II (AII) in the development of diabetic nephropathy and the reno- and cardiobeneficial effects of AII antagonism in patients with DM-2 and diabetic nephropathy also are addressed.
METHODS Articles included in this review were found using a MEDLINE search for studies published from 1991 to 2001 and including the search terms diabetic
nephropathy, type 2 diabetes mellitus, microalbuminuria, proteinuria, angiotensin receptor blockade, angiotensin-converting enzyme inhibition, and cardiovascular disease. Articles reporting new data, new
M.-T. ZANELLA AND A.B. RIBEIRO
mechanisms, major clinical trials, and our own data were included. DIABETES M E L L I T U S : THE P R O B L E M Types 1 and 2 diabetes mellitus affect an estimated 2.1% of the population of the world 9 and 6.5% of the population of the United States. ~° Most of these patients (97%) have DM-2, which has been recognized as a major public health concern worldwide. Its prevalence is increasing rapidly; the estimated number of diabetic patients worldwide in 1997 was 124 million, and this number is expected to reach 221 million in 2010. 9 Arterial blood pressure and albuminuria are strong predictors for a faster decline in GFR in patients with type 1 diabetes mellitus (DM-I) and DM-2. Conversely, antihypertensive treatment reduces the rate of decline in GFR and postpones ESRD in patients with diabetic nephropathy.]]-15 In patients with DM-I and macroalbuminuria, an angiotensinconverting enzyme inhibitor (ACEI), captopril, has been shown to slow the progression of renal disease more effectively than other blood pressure-lowering agents/6 This renoprotective action has been shown to be independent of blood pressure-lowering effects. Unlike for DM-1 overt nephropathy, for DM-2 overt nephropathy, evidence that ACEIs effectively reduce the progression to ESRD has never been demonstrated consistently. Thus, the question remained as to whether the blockade of AII production or action would result in similar benefits in DM-1 and DM-2. Recently, however, 3 large, prospective clinical trials, RENAAL 2 (N = 1513), IDNT 3 (N = 1715), and IRMA 24 (N = 590), which assessed the effects of
AII-receptor blockade in patients with microalbuminuria and proteinuria, have provided sufficient data to conclude that the blockade of the RAS with AII antagonists confers renoprotection in patients with DM-2 and nephropathy. PROTEINURIA Clinical proteinuria, defined as persistent urinary protein excretion (UPE) >300 mg/L or urinary albumin excretion (UAE) >200 ~g/min, is the hallmark of diabetic nephropathy and is associated with a progressive decline in GFR. 6 Several studies in animal models and humans suggest that proteinuria itself contributes to renal damage. 17 In Pima Indians and other populations, overt proteinuria has been shown to be a powerful predictor of ESRD/8-2° On the other hand, reductions in proteinuria by >40% following antihypertensive therapy in patients with diabetic nephropathy have been associated with a better renal outcome. 21 In fact, reductions in proteinuria have been observed with therapeutic strategies that reduce the progression of diabetic and nondiabetic renal disease. 22,23 In the Captopril Study, 24 108 patients with DM-1 and a nephrotic range of proteinuria (3.5 g/d) were assessed according to whether they remitted after therapy (UPE, <1.5 g/d). After a mean followup of 3.4 + 0.8 years, a more pronounced decrease in GFR was observed among those nonremitters (from 66 to 38 mL/ mini n = i00) than among the remitters (from 70 to 59 mL/min; n = 8). Thus, these results and other evidence point to the need to reduce protein excretion as much as possible for renoprotection. 25 In addition, monitoring protein excretion may have a clinical implication in the assessment of the efficacy 1021
CLINICAL THERAPEUTICS ®
of therapy in patients with diabetic nephropathy. Proteinuria in patients with DM-2 not only reflects advanced nephropathy but also is a strong predictor of cardiovascular disease (CVD) and may be considered a marker for advanced atherosclerosis. 18'19'26 In a prospective study in Finland, Miettinen et al 2v found that clinical proteinuria predicts stroke and other atherosclerotic vascular disease events independent of other CVD risk factors. The incidence of atherosclerotic vascular disease events during a 7-year follow-up of 1056 patients was almost 2-fold higher among patients with DM-2 with clinical proteinuria than among those without proteinuria. The incidence of stroke was 7.2% in patients without clinical proteinuria (<150 mg/L), 11.1% in those with borderline proteinuria (150-300 mg/L) and 23% in patients with clinical proteinuria (>300 mg/L). In addition, a stepwise association between different degrees of proteinuria and the risk for coronary heart disease (CHD) or lower-extremity amputation was observed in this population. In a more recent study, Valmadrid et a128 also found that the presence of proteinuria increases the risk for death, particularly CHD-related death, even after accounting for other known risk factors. They followed up 840 patients with late-onset DM-2 in the Wisconsin Epidemiologic Study of Diabetic Retinopathy from 1984 to 1996. After accounting for other cardiovascular risk factors, patients with gross proteinuria had an increased relative risk (RR) for CVDrelated death (RR, 2.6; 95% CI, 2.0-3.4). Clinical proteinuria not only increases the risk for CHD, as shown in this study, but also is associated with an adverse outcome in those who require coronary revas1022
cularization. This fact was demonstrated in an observational study of 2784 patients, including 537 diabetic patients who underwent percutaneous transluminal coronary angioplasty. 29 The 2-year mortality rate among these patients was higher among those with proteinuria (n = 217) than among those without it (n = 320) (20.3% vs 9.1%, P < 0.001). The diabetic group with proteinuria was further prospectively stratified into low (n = 182) and high (n = 35) urinary protein concentration subgroups, and the authors found that the increase in mortality was related to the degree of proteinuria. The 2-year mortality rates were 9.1%, 16.2%, and 43.1% for the groups without proteinuria and low and high urinary protein concentrations, respectively (P < 0.001). Microalbuminuria (UAE, 20-200 p~g/ min) antedates clinical proteinuria in both DM-1 and DM-2. 3°-32 More recent studies have shown that ~ 40% of patients with DM-2 and microalbuminuria progress to overt nephropathy over a decade, a rate of progression similar to that observed in patients with DM-1.32-34 Microalbuminuria in patients with DM-2 not only predicts nephropathy but also is a strong predictor of all causes of death, particularly from
CVD.32 The implication of the findings of all of these studies is that proteinuria/albuminuria may be the reflection of vascular damage that is not confined to the glomeruli but also affects the entire cardiovascular system. The Steno hypothesis postulates that increased UPE in diabetic patients would reflect a more widespread disturbance of endothelial cell barrier function in the macrocirculation, particularly in the coronary arteries, where the transudation of plasma protein into the vessel wall might promote the atherogenic process. 35 All of
M.-T. ZANELLA AND A.B. RIBEIRO
these observational studies also give rise to the question of whether the treatment or prevention of abnormal UAE values would also reduce the mortality rate among patients with diabetes.
BLOOD PRESSURE Increased arterial blood pressure is an early and common phenomenon in diabetic nephropathy, and a close correlation between blood pressure and the rate of decline in GFR has been documented in patients with DM-1 and DM-2. 36,37 Followup studies indicate that early, aggressive antihypertensive therapy effectively reduces both albuminuria and the rate of GFR decline in patients with established diabetic nephropathy. 1233 In patients with DM-1, the development of hypertension is closely linked to diabetic nephropathy and typically occurs in the presence of renal involvement. 38 The transition from normoalbuminuria to microalbuminuria is associated with slight increases in blood pressure. 34,38 This abnormality in arterial pressure can be detected easily during the night because the typical blood pressure decrease that occurs during sleep is not as apparent in microalbuminuric patients. 3s~° In patients with DM-2, the relationship between nephropathy and hypertension is more complex than in patients with DM-I because hypertension is not necessarily linked to the presence of renal disease and often precedes the diagnosis of diabetes. Hypertension is 2-fold as common among diabetic patients as among nondiabetic patients, and hypertension in diabetic patients is strongly related to increased body weight, insulin resistance, and hyperinsulinemia.41 In contrast to patients with DM-1 and microalbuminuria, who usually pre-
sent with elevated diastolic blood pressure ,38 systolic hypertension predominates in patients with DM-2. 42 Hypertension increases the risk for morbidity and mortality associated with CVD, especially when renal function starts to decline. 2s,43 The combination of diabetes and hypertension is associated with an ~4-fold increase in cardiovascular risk compared with the absence of diabetes and hypertension. Adler et a142 assessed the risk for diabetes-related complications associated with systolic blood pressure (SBP) in 3642 patients with newly diagnosed DM-2 (age range, 25-65 years) enrolled in the UKPDS. Patients were followed up over a median of 10.4 years for all-cause or diabetes-specific death, myocardial infarction, heart failure, stroke, lower extremity amputation, and microvascular complications. Increasing SBP was significantly associated with both death and complications (P < 0.001 ). The slope for increasing risk with increasing SBP was continuous and linear, showing no evidence of threshold for any diabetes-related complication or death. PLASMA G L U C O S E Evidence emerging from clinical trials has demonstrated the importance of plasma glucose control to reduce the risk for the development and progression of diabetic nephropathy. The UKPDS documented a progressive beneficial effect of intensive metabolic control on the development of microalbuminuria, overt proteinuria, and ESRD in newly diagnosed patients with DM-2, although no significant reductions in cardiovascular complications or diabetes-related death were observed, l In a recent study, 44 an even greater benefit was obtained with multifactorial interven1023
CLINICAL THERAPEUTICS ®
tion in patients with DM-2 and microalbuminuria, with the pharmacologic therapy targeting hyperglycemia, hypertension, dyslipidemia, and microalbuminuria. This therapy has proved to delay the progression to overt nephropathy, retinopathy, and autonomic neuropathy. ANGIOTENSIN II A N D DIABETIC NEPHROPATHY Studies on the activity of the RAS, first undertaken in diabetic patients, suggested that this system was suppressed in these patients, especially in those with diabetic nephropathy45,46; however, despite reduced plasma renin activity in patients with diabetes, multiple studies in animal models have shown that the renal tissue renin levels and renin production are normal or even increased with diabetes. 47 Thus, the measures of circulating renin activity or even AII can be misleading, providing little insight into the state of the intrarenal renin system. 48 AII is the principal mediator of the RAS and seems to be responsible for important pathologic effects at the cellular level by stimulation of the AII-ATl-receptor subtype. Clinical and experimental data support the hypothesis that increased glomerular capillary pressure occurs in patients with diabetes, in addition to increases in systemic arterial pressure. The increased intraglomerular pressure is determined not only by systemic blood pressure but also by altered glomerular hemodynamics characterized by preglomerular vasodilatation and postglomerular vasoconstriction. 49 The latter is strongly regulated by the activity of the RAS. Increased intraglomerular pressure leads to hyperfiltration, and in the presence of an altered endothelial permeabil1024
ity, these renal hemodynamic abnormalities favor increases in albumin/protein excretion. The ability to reduce intraglomerular pressure accounts for the antiproteinuric effect of ACEIs and AII antagonists shown in prospective, randomized end point trials that have documented delayed renal deterioration during the RAS blockade. 34 The benefit of ACEIs in diabetic nephropathy is thought to result, at least in part, from attenuation of AII effects on blood pressure and glomerular hemodynamics. 5° Indirect evidence indicates that the enhanced renal vasodilator response to ACEIs and AII antagonists in diabetic patients may be attributed to renal AII.51 By reducing the vasoconstrictor effects of AII on the efferent glomerular arteriole, ACEIs reduce the intraglomerular pressure, which seems to be an important determinant of the progression of diabetic nephropathy. In both healthy patients and hypertensive patients, the AII antagonists have effects identical to those of ACEIs on renal hemodynamics as a result of their direct action at the ATI receptors) 2 Andersen et a153 have shown that, in patients with DM-I and nephropatby, the AII antagonist losartan has the same ability to reduce blood pressure and albuminuria as does the ACEI enalapril. These results indicate that the reduction in albuminuria and blood pressure induced by an ACEI is primarily caused by the blockade of AII. It also has been shown that losartan can reduce the abnormally elevated size-selective property of the glomerular membrane, a mechanism also involved in the antiproteinuric effect of this agent) 4 Apart from its hemodynamic actions, AII also exerts effects on the kidney, which may contribute to enhancing extra-
M.-T. ZANELLA AND A.B. RIBEIRO
cellular matrix production and vascular permeability in patients with diabetic glomerulopathy) 5 AlI stimulates transforming growth factor (TGF)-beta-1 synthesis, which results in extracellular matrix deposition in the glomeruli through engagement of the AT1 receptor. 56 All also activates protein kinase C in mesangial and proximal tubular renal cells through AT1 receptors.57 These nonhemodynamic effects of AII are quite similar to those of hyperglycemia. Activation of the RAS in patients with diabetes may be caused, at least in part, by the effects of hyperglycemia. A study of healthy volunteers demonstrated an increase in renal plasma flow induced by glucose infusion. 51 When captopril was added to the hyperglycemic state, a more accentuated vasodilator response was observed. In addition, during glucose infusion, captopril therapy enhanced the renal vascular response to AII, reflecting a reduction in AII production. 5j Similar resuits with the AII antagonist eprosartan were obtained, indicating that hyperglycemia can activate the intrarenal renin system. 5J Also, it has been demonstrated that, in vitro, high plasma glucose concentrations stimulate AI1 production in mesangial cells and that the high blood glucose-induced TGF-beta-I synthesis and mesangial matrix accumulation are reversed by the AII antagonist losartan at the ATI receptors. 58 These observations indicate that AII, at least in part, mediates the effects of hyperglycemia on the mechanism that results in TGF-beta-1 synthesis and matrix expansion. Furthermore, these data give rise to the hypothesis that AII antagonist therapy may reduce some of the AII-mediated deleterious effects of hyperglycemia that would result in the development of diabetic nephropathy.
MECHANISMS OF ANGIOTENSIN II BLOCKADE
Blockade of the RAS can be accomplished by blocking All formation (inhibiting renin or angiotensin-converting enzyme) or blocking AII actions at the specific ATl-receptor subtype. In the clinical setting, ACEIs and AII antagonists are the most important agents used for this purpose. From their mechanism of actions, ACEIs accumulate bradykinin (BK), but AlI antagonists do not; however, these 2 agents have similar effects on kidney physiologic and pathologic characteristics, pointing to a major role for AII blockade, and not for BK accumulation, in their mechanism of action. 53 Another difference is that All antagonists, but not ACEIs, are able to block the action of All formed through non-ACE pathways. 59,6° Thus, All antagonists, through a more complete AII blockade, might have a more renoprotective effect than ACEIs. Another physiologic difference between these agents has been described by Hollenberg et al, 6j who suggested that All antagonists and renin inhibitors have a greater effect on renal blood flow compared with ACEIs. ANGIOTENSIN-CONVERTING ENZYME INHIBITORS In patients with DM-1 and microalbuminuria, ACEIs have been proved to confer renoprotection against progression to overt proteinuria and ESRD. 62'63 In patients with DM-2 and microalbuminuria but not hypertension, Ravid et a164,65 reported that, compared with placebo, ACE inhibition resulted in renal function preservation and a lower risk for progression to proteinuria. In patients with DM-2, 1025
CLINICAL THERAPEUTICS ®
microalbuminuria, and hypertension, however, long-term studies have shown similar beneficial effects between ACEIs, long-acting calcium channel blockers) t and beta-blockers 66 on progression to overt proteinuria. In 1993, the Captopril Collaborative Study Group 16 demonstrated that, in patients with DM-1 and overt proteinuria who received captopril, the risk reduction for doubling in serum creatinine concentration (P = 0.007) or the composite end point, ESRD, transplant, or death (P = 0.006), was significant. The placebo group in this study also received antihypertensire therapy, which did not include calcium channel blockers or ACEIs. The 2 groups did not show significant differences in blood pressure control so that the benefits observed in the captopril-treated group occurred independent of its antihypertensive effects. Because captopril potentiates BK, however, it was not possible from these results to conclude that the beneficial effects were due solely to the blockade of All synthesis. A N G I O T E N S I N I I ANTAGONISTS The question of whether blockade of AII in patients with DM-2 would result in the same beneficial effects observed for patients with DM-1 remained unanswered until recently, when the results of 2 major trials (RENAAL 2 and IDNT 3) were published. To determine the effects of All-receptor antagonists on clinical nephropathy in patients with DM-2, the RENAAL trial, 2 a prospective, randomized, double-blind, placebo-controlled trial, included 1513 patients with DM-2 and established nephropathy. Patients were randomized to receive either losartan (maximum dose, 1026
100 mg) or placebo added to conventional antihypertensive therapy (CT), excluding ACEIs or other All antagonists but including calcium channel blockers. The target blood pressure was <140/90 mm Hg. The principal hypothesis tested in RENAAL was that long-term therapy with losartan added to CT would reduce the incidence of the composite outcome of doubling of serum creatinine concentration, ESRD, or death compared with placebo added to CT. Additional hypotheses tested in RENAAL were that losartan would reduce proteinuria, decrease the rate of progression of renal disease, prolong the time to the first event, and reduce the incidence of CVD-related death and major nonfatal cardiovascular events. After a mean followup of 3.4 years, despite similar levels of blood pressure in the 2 groups, the losartantreated group showed a 16% risk reduction for the composite primary end point (P = 0.024). The study was also extremely successful in demonstrating a marked renoprotective effect of losartan. This agent reduced the incidence of a doubling of serum creatinine concentration (risk reduction, 25%; P = 0.006) and ESRD (risk reduction, 28%; P = 0.002). The risk for the combined end point of ESRD or death was 20% lower with losartan. In addition, losartan led to an average reduction in the level of proteinuria of 35%, whereas in the placebo-treated group the level of proteinuria tended to increase. Also, compared with placebo, losartan was associated with a 15.2% reduction in the estimated decline in the GFR. The results of RENAAL indicate that all of these renoprotective benefits of the blockade of the RAS with losartan were attributable to effects beyond blood pressure control. The IDNT trial 3 compared an AII antagonist with a calcium channel blocker
M.-T. ZANELLA AND A.B. RIBEIRO
in 1715 diabetic, hypertensive patients randomly assigned to receive placebo, irbesartan, or amlodipine. As in the RENAAL trial, the All antagonist was added to background CT other than ACEIs, other calcium channel blockers, or All antagonist to achieve blood pressure control. After a mean period of 2.6 years of therapy, despite similar blood pressure levels, the irbesartan-treated group showed a 20% (P = 0.02) risk reduction compared with placebo and a 23% (P = 0.006) risk reduction compared with amlodipine for the primary composite outcome of doubling serum creatinine concentration, ESRD, or death. No significant difference was found in the RR for the combined primary end point between the amlodipine- and placebo-treated groups. As in the RENAAL study, these results have proved that therapy with an AII antagonist imparts greater benefits in the treatment of established nephropathy in patients with DM-2 than merely its well-documented role in lowering blood pressure. The results of RENAAL confirm the importance of blood pressure control to delay the progression of diabetic nephropathy. It was observed that, during the first 36 months of the study, UAE remained unchanged in the placebo-treated group. Considering that proteinuria itself contributes to renal damage, the lack of increase in UPE, which occurs in the natural history of diabetic nephropathy, may be interpreted as a benefit of blood pressure control. In the RENAAL trial, the mean baseline plasma creatinine concentrations were 1.9 mg/dL in both the losartan- and placebo-treated groups. Despite these increased baseline values, early increases in plasma creatinine concentrations led to the discontinuation of treatment with
study medication in 1.5% of patients in the losartan-treated group compared with 1.2% of patients in the placebo-treated group. Clear benefits regarding progression to ESRD are obtained with the blockade of All because losartan significantly prolonged the time from doubling of serum creatinine concentrations to the development of ESRD (risk reduction, 30%; P = 0.013). These results indicate that the All antagonist therapy should not be discontinued even after the serum creatinine concentration has doubled. The concern that hyperkalemia may occur in patients with high plasma creatinine concentrations during ACEI therapy 67 was not supported in the RENAAL study. Only 1.1 % of patients in the losartantreated group compared with 0.5% in the placebo-treated group discontinued treatment with the study medication because of increases in plasma potassium levels. Although some evidence points to a lower incidence of hyperkalemia during All antagonist therapy compared with ACEIs, the low incidence observed may, in part, be attributable to diuretic therapy, adopted by 83.5% of the patients in the losartantreated group. The RENAAL and IDNT studies enrolled patients with overt proteinuria, but All antagonism has also been shown to be renoprotective in patients with less severe renal disease. In the IRMA 2 study,4 590 patients with DM-2, hypertension, microalbuminuria, and normal renal function were included in a double-blind, randomized, prospective trial. This study compared 150 and 300 mg of irbesartan with placebo, all added to CT (excluding ACEIs and other AII antagonists) to achieve blood pressure control in 3 subgroups of patients (irbesartan 150 mg, irbesartan 300 mg, and placebo). 1027
CLINICAL THERAPEUTICS®
After 2 years, despite all groups achieving similar levels of blood pressure, the risk for progression to diabetic nephropatby, the primary end point of the study, was reduced by 70% (P < 0.001) in the group treated with irbesartan 300 rag. This renoprotective effect, however, was observed only with 300 mg of irbesartan because the risk reduction of 39% in the group treated with irbesartan 150 mg did not reach statistical significance. These results clearly demonstrate that blockade of the RAS with an AII antagonist confers renoprotection, independent of its blood pressure-lowering effect; however, in these microproteinuric patients, blood pressure control was also important. In the placebo-treated group, intensive antihypertensive therapy resulted in stabilization of UAE levels throughout the study, with 20% of these patients showing restoration of normoalbuminuria. Preventing or delaying the progression of diabetic nephropathy is the main objective of therapy. The results of RENAAL and IDNT clearly suggest that AII antagonists are able to reduce the rate of the decline of GFR in patients with DM-2 and nephropathy. According to the IRMA 2 trial, overt diabetic nephropathy can even be prevented if high-risk patients are identified early in the course of the disease and receive an AII antagonist for renoprotection. The results of this study emphasize the need for routine urine screening for microalbuminuria yearly in all patients with DM-2, as also recommended by published guidelines for the treatment of diabetic kidney disease. 68 CARDIOPROTECTION Because CVD is responsible for most deaths among patients with DM-2 and hy1028
pertension, high blood pressure, as a major contributing factor to cardiac death, is a crucial component in the therapy for such patients. Lowering blood pressure is an important preventive measure to be taken in patients with diabetic nephropathy. Data emerging from the UKPDS 69 and the Hypertension Optimal Treatment (HOT) study 14 show that intensive blood pressure control reduces complications and deaths among patients with DM-2 and that no lower limit of blood pressure exists at which to stop treatment (the lower the blood pressure, the lower the rate of complications). Current recommendations in the United States by the National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group specify a blood pressure of 130/85 mm Hg as the treatment goal for most patients with hypertension, and it is highly recommended that this goal be aggressively pursued in all patients with diabetes. 7° However, whether the blood pressure reduction is more important than the antihypertensive agent used to achieve it, and whether the blockade of the RAS confers superior cardioprotective effects compared with other antihypertensive agents, remain areas of intense discussion and investigation. The Hypertension in Diabetes study within the UKPDS showed that blood pressurelowering intensive therapy using primarily either an ACEI or a beta-blocker resulted in significantly fewer strokes (44%; P = 0.013), less heart failure (37%; P = 0.009), and fewer diabetes-related deaths (32%; P = 0.019), but in the group with lower blood pressure, no significant differences were found between the 2 antihypertensive agents. 66 The Appropriate Blood Pressure Control in Diabetes Trial 71 and the Fosinopril Versus Amlodipine
M.-T. ZANELLA AND A.B. RIBEIRO
Cardiovascular Events Randomized Trial (FACET) 72 suggested that ACEI treatment was superior to treatment with calcium channel blockers in conferring cardiovascular protection. Also, in the Captopril Prevention Project (CAPPP) study, 73 within a diabetic subgroup, the ACEI captopril appeared to be superior to the diuretic/beta-blocker regimen, despite similar blood pressure reduction. More recently, the MICRO-HOPE study 5 found that an ACEI provided protection against cardiovascular events and early renal disease progression in patients with DM-2. The results seemed to be better than might be attributable to the antihypertensive effect of the ACEI, although some controversies remain regarding the potential contribution of blood pressure reduction in this study. Evidence also emerged from the RENAAL study on the cardioprotective benefit of AII blockade with losartan, with a 32% reduction in risk for first hospitalization for heart failure (P = 0.005). 2 RENAAL was the first demonstration that primary prevention of clinical cardiac failure can be achieved by reducing AII action. Heart failure in hypertensive patients is associated with fibrosis, which is an important contributor to its progression. AII stimulates TGF-beta-1 production and, in turn, the matrix protein accumulation in the heart, leading to impaired cardiac function and fibrosis. TM In hypertensive patients with left ventricular (LV) hypertrophy, AII blockade at the ATI receptors with losartan has been shown to exert antifibrotic effects, with consequent improvement in LV function. 75 These effects may be particularly important in hypertensive, diabetic patients in whom hyperglycemia also contributes to LV hypertrophy. 76 This antifibrotic action of
losartan might account for the reduction in the risk for hospitalization for heart failure observed in the RENAAL trial. CONCLUSIONS The scientific rationale and clinical trial data strongly suggest that effective blockade of angiotensin action is important for both reno- and cardioprotection in patients with DM-2, as demonstrated with losartan in the RENAAL study. 2 Some of the benefits are undoubtedly related to the associated blood pressure reduction and the favorable impact of the All blockade on microvascular hemodynamics. Nevertheless, the blockade of the growth-promoting, profibrotic, nonhemodynamic actions of All, which also seem to mediate some of the deleterious influences of hyperglycemia on the kidney and heart, may also be important for reno- and cardioprotection in patients with DM-2.
ACKNOWLEDGMENT Partial financial support for this publication was provided by an educational grant from Merck & Co, Inc, Whitehouse Station, New Jersey.
REFERENCES 1. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352: 837-853. 2. Brenner BM, Cooper ME, de Zeeuw D, et al, for the RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 1029
CLINICAL THERAPEUTICS®
diabetes and nephropathy. N Engl J Med. 2001 ;345:861-869. 3. Lewis EJ, Hunsicker LG, Clarke WR, et al, for the Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001 ;345:851-860. 4. Parving HH, Lehnert H, Br6chnerMortensen J, et al, 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;345:870878. 5. 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. 2000;355:253-259. 6. Parving HH, Osterby R, Ritz E. Diabetic nephropathy. In: Brenner BM, Levine S, eds. The Kidney. Philadelphia: WB Saunders; 2000:1731-1733. 7. National Institutes of Health. Excerpts from the United States Renal Data System's 2000 annual data report: Atlas of end stage renal disease in the United States: Incidence and prevalence of ESRD. Am J Kidney Dis. 2000;36(Suppl 2):$37- $54.
complications: Estimates and projections to the year 2010. Diabet Med. 1997;14 (Suppl 5):S1-$85. 10. Mokdad AH, Ford ES, Bowman BA, et al. Diabetes trends in the U.S.: 1990-1998. Diabetes Care. 2000;23:1278-1283. 11. 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. 2000;23: B54-B64. 12. Parving HH, Andersen AR, Smidt UM, Svendsen PA. Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet. 1983; 1: 1175-1179. 13. Parving HH, Smidt UM, Hommel E, et al. Effective antihypertensive treatment postpones renal insufficiency in diabetic nephropathy. Am J Kidney Dis. 1993;22: 188-195. 14. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: Principle results of the Hypertension Optimal Treatment (HOT) randomized trial. HOT Study Group. Lancet. 1998;351:1755-1762. 15. Kasiske BL, Kalil RS, Ma JZ, et al. Effect of antihypertensive therapy on the kidney in patients with diabetes: A meta-regression analysis. Ann lntern Med. 1993;118:129138.
8. National Institutes of Health. Excerpts from the United States Renal Data System's 2000 annual data report: Atlas of end stage renal disease in the United States: Economic costs of ESRD. Am J Kidney Dis. 2000;36(Suppl 2):S163-S176.
16. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, for the Collaborative Study Group. The effect of angiotensin-convertingenzyme inhibition on diabetic nephropathy. N Engl J Med. 1993;329:1456-1462.
9. Amos AF, McCarty DJ, Zimmet P. The rising global burden of diabetes and its
17. Remuzzi G, Bertani T. Is glomerulosclerosis a consequence of altered glomemlar
1030
M.-T. ZANELLA AND A.B. RIBEIRO
permeability to macromolecules? Kidney Int. 1990;38:384-394. 18. Nelson RG, Pettitt DJ, Carraher MJ, et al. Effect of proteinuria on mortality in NIDDM. Diabetes. 1988;37:1499-1504.
26. Stephenson JM, Kenny S, Stevens LK, et al, Proteinuria and mortality in diabetes: The WHO Multinational Study of Vascular Disease in Diabetes. Diabet Med. 1995;12:149-155.
19. Ballard DJ, Humphrey LL, Melton J 3rd, et al. Epidemiology of persistent proteinuria in type II diabetes mellitus: Populationbased study in Rochester, Minnesota. Diabetes. 1988;37:405-412.
27. Miettinen H, Haffner SM, Lehto S, et al, Proteinuria predicts stroke and other atherosclerotic vascular disease events in nondiabetic and non-insulin-dependent diabetic subjects. Stroke. 1996;27:20332039.
20. Nelson RG, Newman JM, Knowler WC, et al. Incidence of end-stage renal disease in type 2 (non-insulin-dependent)diabetes mellitus in Pima Indians. Diabetologia. 1988;31:730-736.
28. Valmadrid CT, Klein R, Moss SE, Klein BE. The risk of cardiovascular disease mortality associated with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus. Arch Intern Med. 2000; 160:1093-1100.
21. Rossing P, Hommel E, Smidt UM, Parving HH. Reduction in albuminuria predicts diminished progression in diabetic nephropathy. Kidney lnt Suppl. 1994;45: S145-S149.
29. Marso SP, Ellis SG, Tuzco M, et al. The importance of proteinuria as a determinant of mortality following percutaneous coronary revascularization in diabetics. J Am Coil Cardiol. 1999;33:1269-1277.
22. Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, proteinuria, and the progression of renal disease. The Modification in Diet in Renal Disease Study. Ann Intern Med. 1995;123:754-762.
30. Viberti GC, Hill RD, Jarrett RJ, et al. Microalbuminuria as a predictor of clinical nephropathy in insulin-dependentdiabetes mellitus. Lancet. 1982; 1: 1430-1432.
23. The GISEN Group. Randomised placebocontrolled 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. 24. Hebert LA, Bain RP, Verme D, et al. Remission of nephrotic range proteinuria in type I diabetes. Collaborative Study Group. Kidney Int. 1994;46:1688-1693. 25. De Jong PE, Navis G, de Zeeuw D. Renoprotective therapy: Titration against urinary protein excretion. Lancet. 1999;354: 352-353.
31. Mogensen CE, Christensen CK. Predicting diabetic nephropathy in insulindependent patients. N Engl J Med. 1984; 331:89-93. 32. Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med. 1984;310:356-360. 33. Esmail ZN, Loewen PS. Losartan as an alternative to ACE inhibitors in patients with renal dysfunction. Ann Pharmacother. 1998;32:1096-1098. 34. Parving HH. Diabetic nephropathy: Prevention and treatment. Kidney Int. 2001; 60:2041-2055.
1031
CLINICAL THERAPEUTICS ®
35. Deckert T. Nephropathy and coronary death--the fatal twins in diabetes mellitus. Nephrol Dial Transplant. 1994;9: 1069-1071.
senting type 2 diabetic patients and the association with risk factors for cardiovascular and diabetic complications. J Hypertens. 1993; 11:309-317.
36. Yokoyama H, Tomonaga O, Hirayama M, et al. Predictors of the progression of diabetic nephropathy and the beneficial effect of angiotensin-converting enzyme inhibitors in NIDDM patients. Diabetologia. 1997;40:405--411.
44. Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: The Steno type 2 randomised study. Lancet. 1999; 353:617-622.
37. Parving HH, Hommel E, Mathiesen E, et al. Prevalence of microalbuminuria, arterial hypertension, retinopathy and neuropathy in patients with insulin dependent diabetes. Br Med J. 1988;296:156--160.
45. Bj6rk S. The renin angiotensin system in diabetes mellitus: A physiological and therapeutic study. Scand J Urol Nephrol Suppl. 1990; 126:1-50.
38. Zanella MT, Freire MB, Milagres R, et al. Blood pressure disturbance in diabetes mellitus. J Hypertens Suppl. 1992;10: $59-$70. 39. Poulsen PL, Hansen KW, Mogensen CE. Ambulatory blood pressure in the transition from normo- to microalbuminuria: A longitudinal study in IDDM patients. Diabetes. 1994;43:1248-1253. 40. Monteagudo PT, Nobrega JC, Cezarini PR, et al. Altered blood pressure profile, autonomic neuropathy and nephropathy in insulin-dependent diabetic patients. Eur J Endocrinol. 1996;135:683-688. 41. Sowers JR, Epstein M, Frolich ED. Diabetes, hypertension, and cardiovascular disease: An update. Hypertension. 2001; 37:1053-1059. 42. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): Prospective observational study. Br Med J. 2000;321:412--419. 43. Hypertension in Diabetes Study (HDS). I. Prevalence of hypertension in newly pre-
1032
46. Christlieb AR, Kaldani YA, D'Elia JA. Plasma renin activity and hypertension in diabetes mellitus. Diabetes. 1976;25:969974. 47. Anderson S, Jung FF, Ingelfinger JR. Renal renin-angiotensin system in diabetes: Functional immunohistochemical and molecular biological correlations. Am J Physiol. 1993;265:F477-F486. 48. Navar LG, Harrison-Bernard LM, Imig JD, et al. Renal responses to AT1 receptor blockade. Am J Hypertens. 2000;13:45S54S. 49. Hostetter TH, Rennke GH, Brenner BM. The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies. Am J Med. 1982; 72:375-380. 50. Zatz R, Dunn BR, Meyer TW, et al. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest. 1986;77:1925-1930. 51. Hollenberg NK. ACE inhibition, angiotensin II receptor blockade and diabetic nephropathy. In: Mogensen CE, ed.
M.-T. ZANELLA AND A.B. RIBEIRO
The Kidney and Hypertension in Diabetes Mellitus. Boston: Kluwer Academic Publishers; 2000:417-422.
52. Deray G. Are the antagonists of angiotensin II AT1 receptors protectors of the kidney? [in French]. Arch Mal Coeur Vaiss. 1999;92:903-907. 53. Andersen S, Tarnow L, Rossing P, et al. Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy. Kidney Int. 2000;57:601-606. 54. Andersen S, Blouch K, Bialek J, et al. Glomerular permselectivity in early stages of overt diabetic nephropathy. Kidney Int. 2000 ;58:2129-2137. 55. Wolf G. Angiotensin II is involved in the progression of renal disease: Importance of non-hemodynamic mechanisms. Nephrologie. 1998;19:451-456. 56. Kagami S, Border WA, Miller DE, Noble NA. Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factorbeta expression in the rat glomerular mesangial cells. J Clin Invest. 1994;93: 2431-2437. 57. Wolf G, Ziyadeh FN. The role of angiotensin II in diabetic nephropathy: Emphasis on non-hemodynamic mechanisms. Am J Kidney Dis. 1997;29:153-163. 58. Singh R, Alavi N, Singh AK, Leehey DJ. Role of angiotensin II in glucose-induced inhibition of mesangial matrix degradation. Diabetes. 1999;48:2066-2073. 59. Nishimura H, Hoffmann S, Baltatic O, et al. Angiotensin I converting enzyme and chimase in cardiovascular tissues. Kidney lnt Suppl. 1996;55:S18-$23.
60. Urata H, Healy B, Stewart RW, et al. Angiotensin II-forming pathways in normal and failing human hearts. Circ Res. 1990;66:883-890. 61. Hollenberg NK, Fisher ND, 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. 62. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-convertingenzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med. 2001 ;134:370-379. 63. Mathiesen ER, Hommel E, Hansen HP, et al. Randomised controlled trial of longterm efficacy of captopril on preservation of kidney function in normotensive patients with insulin dependent diabetes and microalbuminuria. Br Med J. 1999;319: 24-25. 64. Ravid M, Lang R, Rachmani R, Lishner M. Long-term renoprotective effect of angiotensin-convertingenzyme inhibition in non-insulin-dependentdiabetes mellitus. Arch Intern Med. 1996;156:286-289. 65. Ravid M, Savin H, Jutrin l, et al. Longterm stabilizing effect of angiotensinconverting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med. 1993;118:577-581. 66. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. Br Med J. 1998;317:714720. 67. Zanella MT, Mattei E Jr, Draibe SA, et al. Inadequate aldosterone response to hyper-
1033
CLINICAL THERAPEUTICS ~
kalemia during angiotensin converting enzyme inhibition in chronic renal failure. Clin Pharmacol Ther. 1985;38:613--617. 68, Mogensen CE, Keane WF, Bennett PH, et al. Prevention of diabetic renal disease with special reference to microalbuminuria. Lancet. 2001 ;346:1080-1084. 69. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. Br Med J. 1998;317:703-713. 70. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: A consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36:646-661. 71. Estacio RO, Jeffers BW, Hiatt WR, et al. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med. 1998;338:645-652. 72. Tatti P, Pahlor M, Byington RP, et al. Outcome results of the Fosinopril Versus Am-
lodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care. 1998;21:597-603. 73. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-convertingenzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: The Captopril Prevention Project (CAPPP) randomised trial. Lancet. 1999;353: 611-616. 74. Williams B. The renin angiotensin system in the pathogenesis of diabetic complications. In: Mogensen CE, ed. The Kidney and Hypertension in Diabetes Mellitus. Boston: Kluwer Academic Publishers; 2000:645-654. 75. Lopez B, Querejeta R, Varo N, et al. Usefulness of serum carboxy-terminal propeptide of procollagen type I in assessment of the cardioreparative ability of antihypertensive treatment in hypertensive patients. Circulation. 2001 ;104:286-291. 76. Felicio JS, Ferreira SRG, Plavnik FL, et al. Effect of blood glucose on left ventricular mass in patients with hypertension and type 2 diabetes mellitus. Am J Hypertens. 2000; 13:1149-1154.
Address correspondence to: Maria-Teresa Zanella, MD, Hospital do Rim e Hipertens~o, Federal University of S~o Paulo, Rua Borges Lagoa 960, 04038-002 Sao Paulo, SP, Brasil. E-mail: [email protected]
1034
The Role of Angiotensin II Antagonism in Type 2 Diabetes Mellitus: A Review of Renoprotection Studies Maria-Teresa Zanella, AID, and Artur B. Ribeiro, AID Divisions of Nephrology and Endocrinology, Hospital do Rim e Hipertensao, Federal University of Sao Paulo, Sao Paulo, Brazil
ABSTRACT
Background: Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in Western and Asian countries. Effective antihypertensive therapy reduces the rate of decline in renal function and postpones ESRD in patients with diabetic nephropathy. Objective: This review presents evidence from studies on how blood pressure control, plasma glucose control, and the presence of proteinuria determine outcomes in diabetic patients. The role of angiotensin II (AII) in the development of diabetic nephropathy and the reno- and cardiobeneficial effects of AII antagonism in patients with type 2 diabetes mellitus (DM-2) and diabetic nephropathy also are addressed. Methods: Articles included in this review were found using a MEDLINE search for studies published from 1991 to 2001 and including the search terms diabetic nephropathy, type 2 diabetes mellitus, microalbuminuria, proteinuria, angiotensin receptor blockade, angiotensin-converting enzyme inhibition, and cardiovascular disease. Articles reporting new data, new mechanisms, major clinical trials, and our own data were included. Results: Recently, the Reduction of Endpoints in NIDDM (non-insulin-dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan (RENAAL) trial provided sufficient data to conclude that the blockade of the AII AT1 receptor with losartan confers renoprotection in patients with DM-2 and nephropathy. Similar results were obtained with irbesartan in the Irbesartan Diabetic Nephropathy Trial (IDNT) and the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria study (IRMA 2). The results of RENAAL indicate that the renoprotective effects of losartan were attributable to effects beyond blood pressure control. In addition to the favorable impact of the AII blockade on blood pressure and renal hemodynamics, the blockade of the growthpromoting, profibrotic, nonhemodynamic actions of AII also may be important for renoprotection. Intensive blood pressure control also confers cardiovascular protection in paAccepted for publication May 16, 2002. Printed in the USA. Reproduction in whole or part is not permitted.
0149-2918/02/$19.00
1019
CLINICAL THERAPEUTICS ~
tients with DM-2. Some studies suggest that the blockade of the renin-angiotensin system confers superior cardioprotective effects in patients with DM-2. The RENAAL study also showed cardioprotection with losartan, with an important reduction in the risk for first hospitalization for heart failure. Conclusion: Evidence supports the importance of an effective blockade of AlI action for both reno- and cardioprotection in patients with DM-2. Key words: angiotensin II antagonists, diabetic nephropathy, microalbuminuria, type 2 diabetes mellitus, proteinuria, cardioprotection, renoprotection ( Clin Ther. 2002;24:1019-1034) INTRODUCTION Major clinical trials have been conducted to address the growing incidence of cardiovascular and renal morbidity and mortality in patients with type 2 diabetes mellitus (DM-2). The results of the United Kingdom Prospective Diabetes Study (UKPDS), 1 Reduction of Endpoints in NIDDM (non-insulin-dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan (RENAAL) trial, 2 Irbesartan Diabetic Nephropathy Trial (IDNT),3 Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria study (IRMA 2) 4 and the Heart Outcomes Prevention Evaluation (HOPE) and its substudy in patients with DM (MICRO-HOPE) 5 provide strong clinical evidence of the benefits of well-defined approaches to treat diabetic patients. From these studies, it is clear that targeting the parameters of blood pressure, plasma glucose control, proteinuria, and blockade of the renin-angiotensin system (RAS) is the most effective approach to delay or prevent diabetes-related complications. 1020
Persistent albuminuria, blood pressure elevation, a progressive decline in glomerular filtration rate (GFR), and a high risk for cardiovascular morbidity and mortality characterize diabetic nephropathy. 6 This microvascular complication of diabetes occurs in approximately one third of patients with DM-2 and is the leading cause of end-stage renal disease (ESRD), accounting for 40% of new patients receiving kidney dialysis or transplant in Western and Asian countries. 6,7 With the constant improvement in health care facilities allowing more patients to live longer, the number of diabetic patients needing renal dialysis or transplant is rising sharply. As a consequence, the costs associated with ESRD in the United States are expected to surpass $28 billion per year by 2010. 8 Thus, ESRD, as a consequence of diabetic nephropathy, represents a large economic burden. This review presents evidence from recent studies on how blood pressure control, plasma glucose control, and the presence of proteinuria determine outcomes in diabetic patients. The role of angiotensin II (AII) in the development of diabetic nephropathy and the reno- and cardiobeneficial effects of AII antagonism in patients with DM-2 and diabetic nephropathy also are addressed.
METHODS Articles included in this review were found using a MEDLINE search for studies published from 1991 to 2001 and including the search terms diabetic
nephropathy, type 2 diabetes mellitus, microalbuminuria, proteinuria, angiotensin receptor blockade, angiotensin-converting enzyme inhibition, and cardiovascular disease. Articles reporting new data, new
M.-T. ZANELLA AND A.B. RIBEIRO
mechanisms, major clinical trials, and our own data were included. DIABETES M E L L I T U S : THE P R O B L E M Types 1 and 2 diabetes mellitus affect an estimated 2.1% of the population of the world 9 and 6.5% of the population of the United States. ~° Most of these patients (97%) have DM-2, which has been recognized as a major public health concern worldwide. Its prevalence is increasing rapidly; the estimated number of diabetic patients worldwide in 1997 was 124 million, and this number is expected to reach 221 million in 2010. 9 Arterial blood pressure and albuminuria are strong predictors for a faster decline in GFR in patients with type 1 diabetes mellitus (DM-I) and DM-2. Conversely, antihypertensive treatment reduces the rate of decline in GFR and postpones ESRD in patients with diabetic nephropathy.]]-15 In patients with DM-I and macroalbuminuria, an angiotensinconverting enzyme inhibitor (ACEI), captopril, has been shown to slow the progression of renal disease more effectively than other blood pressure-lowering agents/6 This renoprotective action has been shown to be independent of blood pressure-lowering effects. Unlike for DM-1 overt nephropathy, for DM-2 overt nephropathy, evidence that ACEIs effectively reduce the progression to ESRD has never been demonstrated consistently. Thus, the question remained as to whether the blockade of AII production or action would result in similar benefits in DM-1 and DM-2. Recently, however, 3 large, prospective clinical trials, RENAAL 2 (N = 1513), IDNT 3 (N = 1715), and IRMA 24 (N = 590), which assessed the effects of
AII-receptor blockade in patients with microalbuminuria and proteinuria, have provided sufficient data to conclude that the blockade of the RAS with AII antagonists confers renoprotection in patients with DM-2 and nephropathy. PROTEINURIA Clinical proteinuria, defined as persistent urinary protein excretion (UPE) >300 mg/L or urinary albumin excretion (UAE) >200 ~g/min, is the hallmark of diabetic nephropathy and is associated with a progressive decline in GFR. 6 Several studies in animal models and humans suggest that proteinuria itself contributes to renal damage. 17 In Pima Indians and other populations, overt proteinuria has been shown to be a powerful predictor of ESRD/8-2° On the other hand, reductions in proteinuria by >40% following antihypertensive therapy in patients with diabetic nephropathy have been associated with a better renal outcome. 21 In fact, reductions in proteinuria have been observed with therapeutic strategies that reduce the progression of diabetic and nondiabetic renal disease. 22,23 In the Captopril Study, 24 108 patients with DM-1 and a nephrotic range of proteinuria (3.5 g/d) were assessed according to whether they remitted after therapy (UPE, <1.5 g/d). After a mean followup of 3.4 + 0.8 years, a more pronounced decrease in GFR was observed among those nonremitters (from 66 to 38 mL/ mini n = i00) than among the remitters (from 70 to 59 mL/min; n = 8). Thus, these results and other evidence point to the need to reduce protein excretion as much as possible for renoprotection. 25 In addition, monitoring protein excretion may have a clinical implication in the assessment of the efficacy 1021
CLINICAL THERAPEUTICS ®
of therapy in patients with diabetic nephropathy. Proteinuria in patients with DM-2 not only reflects advanced nephropathy but also is a strong predictor of cardiovascular disease (CVD) and may be considered a marker for advanced atherosclerosis. 18'19'26 In a prospective study in Finland, Miettinen et al 2v found that clinical proteinuria predicts stroke and other atherosclerotic vascular disease events independent of other CVD risk factors. The incidence of atherosclerotic vascular disease events during a 7-year follow-up of 1056 patients was almost 2-fold higher among patients with DM-2 with clinical proteinuria than among those without proteinuria. The incidence of stroke was 7.2% in patients without clinical proteinuria (<150 mg/L), 11.1% in those with borderline proteinuria (150-300 mg/L) and 23% in patients with clinical proteinuria (>300 mg/L). In addition, a stepwise association between different degrees of proteinuria and the risk for coronary heart disease (CHD) or lower-extremity amputation was observed in this population. In a more recent study, Valmadrid et a128 also found that the presence of proteinuria increases the risk for death, particularly CHD-related death, even after accounting for other known risk factors. They followed up 840 patients with late-onset DM-2 in the Wisconsin Epidemiologic Study of Diabetic Retinopathy from 1984 to 1996. After accounting for other cardiovascular risk factors, patients with gross proteinuria had an increased relative risk (RR) for CVDrelated death (RR, 2.6; 95% CI, 2.0-3.4). Clinical proteinuria not only increases the risk for CHD, as shown in this study, but also is associated with an adverse outcome in those who require coronary revas1022
cularization. This fact was demonstrated in an observational study of 2784 patients, including 537 diabetic patients who underwent percutaneous transluminal coronary angioplasty. 29 The 2-year mortality rate among these patients was higher among those with proteinuria (n = 217) than among those without it (n = 320) (20.3% vs 9.1%, P < 0.001). The diabetic group with proteinuria was further prospectively stratified into low (n = 182) and high (n = 35) urinary protein concentration subgroups, and the authors found that the increase in mortality was related to the degree of proteinuria. The 2-year mortality rates were 9.1%, 16.2%, and 43.1% for the groups without proteinuria and low and high urinary protein concentrations, respectively (P < 0.001). Microalbuminuria (UAE, 20-200 p~g/ min) antedates clinical proteinuria in both DM-1 and DM-2. 3°-32 More recent studies have shown that ~ 40% of patients with DM-2 and microalbuminuria progress to overt nephropathy over a decade, a rate of progression similar to that observed in patients with DM-1.32-34 Microalbuminuria in patients with DM-2 not only predicts nephropathy but also is a strong predictor of all causes of death, particularly from
CVD.32 The implication of the findings of all of these studies is that proteinuria/albuminuria may be the reflection of vascular damage that is not confined to the glomeruli but also affects the entire cardiovascular system. The Steno hypothesis postulates that increased UPE in diabetic patients would reflect a more widespread disturbance of endothelial cell barrier function in the macrocirculation, particularly in the coronary arteries, where the transudation of plasma protein into the vessel wall might promote the atherogenic process. 35 All of
M.-T. ZANELLA AND A.B. RIBEIRO
these observational studies also give rise to the question of whether the treatment or prevention of abnormal UAE values would also reduce the mortality rate among patients with diabetes.
BLOOD PRESSURE Increased arterial blood pressure is an early and common phenomenon in diabetic nephropathy, and a close correlation between blood pressure and the rate of decline in GFR has been documented in patients with DM-1 and DM-2. 36,37 Followup studies indicate that early, aggressive antihypertensive therapy effectively reduces both albuminuria and the rate of GFR decline in patients with established diabetic nephropathy. 1233 In patients with DM-1, the development of hypertension is closely linked to diabetic nephropathy and typically occurs in the presence of renal involvement. 38 The transition from normoalbuminuria to microalbuminuria is associated with slight increases in blood pressure. 34,38 This abnormality in arterial pressure can be detected easily during the night because the typical blood pressure decrease that occurs during sleep is not as apparent in microalbuminuric patients. 3s~° In patients with DM-2, the relationship between nephropathy and hypertension is more complex than in patients with DM-I because hypertension is not necessarily linked to the presence of renal disease and often precedes the diagnosis of diabetes. Hypertension is 2-fold as common among diabetic patients as among nondiabetic patients, and hypertension in diabetic patients is strongly related to increased body weight, insulin resistance, and hyperinsulinemia.41 In contrast to patients with DM-1 and microalbuminuria, who usually pre-
sent with elevated diastolic blood pressure ,38 systolic hypertension predominates in patients with DM-2. 42 Hypertension increases the risk for morbidity and mortality associated with CVD, especially when renal function starts to decline. 2s,43 The combination of diabetes and hypertension is associated with an ~4-fold increase in cardiovascular risk compared with the absence of diabetes and hypertension. Adler et a142 assessed the risk for diabetes-related complications associated with systolic blood pressure (SBP) in 3642 patients with newly diagnosed DM-2 (age range, 25-65 years) enrolled in the UKPDS. Patients were followed up over a median of 10.4 years for all-cause or diabetes-specific death, myocardial infarction, heart failure, stroke, lower extremity amputation, and microvascular complications. Increasing SBP was significantly associated with both death and complications (P < 0.001 ). The slope for increasing risk with increasing SBP was continuous and linear, showing no evidence of threshold for any diabetes-related complication or death. PLASMA G L U C O S E Evidence emerging from clinical trials has demonstrated the importance of plasma glucose control to reduce the risk for the development and progression of diabetic nephropathy. The UKPDS documented a progressive beneficial effect of intensive metabolic control on the development of microalbuminuria, overt proteinuria, and ESRD in newly diagnosed patients with DM-2, although no significant reductions in cardiovascular complications or diabetes-related death were observed, l In a recent study, 44 an even greater benefit was obtained with multifactorial interven1023
CLINICAL THERAPEUTICS ®
tion in patients with DM-2 and microalbuminuria, with the pharmacologic therapy targeting hyperglycemia, hypertension, dyslipidemia, and microalbuminuria. This therapy has proved to delay the progression to overt nephropathy, retinopathy, and autonomic neuropathy. ANGIOTENSIN II A N D DIABETIC NEPHROPATHY Studies on the activity of the RAS, first undertaken in diabetic patients, suggested that this system was suppressed in these patients, especially in those with diabetic nephropathy45,46; however, despite reduced plasma renin activity in patients with diabetes, multiple studies in animal models have shown that the renal tissue renin levels and renin production are normal or even increased with diabetes. 47 Thus, the measures of circulating renin activity or even AII can be misleading, providing little insight into the state of the intrarenal renin system. 48 AII is the principal mediator of the RAS and seems to be responsible for important pathologic effects at the cellular level by stimulation of the AII-ATl-receptor subtype. Clinical and experimental data support the hypothesis that increased glomerular capillary pressure occurs in patients with diabetes, in addition to increases in systemic arterial pressure. The increased intraglomerular pressure is determined not only by systemic blood pressure but also by altered glomerular hemodynamics characterized by preglomerular vasodilatation and postglomerular vasoconstriction. 49 The latter is strongly regulated by the activity of the RAS. Increased intraglomerular pressure leads to hyperfiltration, and in the presence of an altered endothelial permeabil1024
ity, these renal hemodynamic abnormalities favor increases in albumin/protein excretion. The ability to reduce intraglomerular pressure accounts for the antiproteinuric effect of ACEIs and AII antagonists shown in prospective, randomized end point trials that have documented delayed renal deterioration during the RAS blockade. 34 The benefit of ACEIs in diabetic nephropathy is thought to result, at least in part, from attenuation of AII effects on blood pressure and glomerular hemodynamics. 5° Indirect evidence indicates that the enhanced renal vasodilator response to ACEIs and AII antagonists in diabetic patients may be attributed to renal AII.51 By reducing the vasoconstrictor effects of AII on the efferent glomerular arteriole, ACEIs reduce the intraglomerular pressure, which seems to be an important determinant of the progression of diabetic nephropathy. In both healthy patients and hypertensive patients, the AII antagonists have effects identical to those of ACEIs on renal hemodynamics as a result of their direct action at the ATI receptors) 2 Andersen et a153 have shown that, in patients with DM-I and nephropatby, the AII antagonist losartan has the same ability to reduce blood pressure and albuminuria as does the ACEI enalapril. These results indicate that the reduction in albuminuria and blood pressure induced by an ACEI is primarily caused by the blockade of AII. It also has been shown that losartan can reduce the abnormally elevated size-selective property of the glomerular membrane, a mechanism also involved in the antiproteinuric effect of this agent) 4 Apart from its hemodynamic actions, AII also exerts effects on the kidney, which may contribute to enhancing extra-
M.-T. ZANELLA AND A.B. RIBEIRO
cellular matrix production and vascular permeability in patients with diabetic glomerulopathy) 5 AlI stimulates transforming growth factor (TGF)-beta-1 synthesis, which results in extracellular matrix deposition in the glomeruli through engagement of the AT1 receptor. 56 All also activates protein kinase C in mesangial and proximal tubular renal cells through AT1 receptors.57 These nonhemodynamic effects of AII are quite similar to those of hyperglycemia. Activation of the RAS in patients with diabetes may be caused, at least in part, by the effects of hyperglycemia. A study of healthy volunteers demonstrated an increase in renal plasma flow induced by glucose infusion. 51 When captopril was added to the hyperglycemic state, a more accentuated vasodilator response was observed. In addition, during glucose infusion, captopril therapy enhanced the renal vascular response to AII, reflecting a reduction in AII production. 5j Similar resuits with the AII antagonist eprosartan were obtained, indicating that hyperglycemia can activate the intrarenal renin system. 5J Also, it has been demonstrated that, in vitro, high plasma glucose concentrations stimulate AI1 production in mesangial cells and that the high blood glucose-induced TGF-beta-I synthesis and mesangial matrix accumulation are reversed by the AII antagonist losartan at the ATI receptors. 58 These observations indicate that AII, at least in part, mediates the effects of hyperglycemia on the mechanism that results in TGF-beta-1 synthesis and matrix expansion. Furthermore, these data give rise to the hypothesis that AII antagonist therapy may reduce some of the AII-mediated deleterious effects of hyperglycemia that would result in the development of diabetic nephropathy.
MECHANISMS OF ANGIOTENSIN II BLOCKADE
Blockade of the RAS can be accomplished by blocking All formation (inhibiting renin or angiotensin-converting enzyme) or blocking AII actions at the specific ATl-receptor subtype. In the clinical setting, ACEIs and AII antagonists are the most important agents used for this purpose. From their mechanism of actions, ACEIs accumulate bradykinin (BK), but AlI antagonists do not; however, these 2 agents have similar effects on kidney physiologic and pathologic characteristics, pointing to a major role for AII blockade, and not for BK accumulation, in their mechanism of action. 53 Another difference is that All antagonists, but not ACEIs, are able to block the action of All formed through non-ACE pathways. 59,6° Thus, All antagonists, through a more complete AII blockade, might have a more renoprotective effect than ACEIs. Another physiologic difference between these agents has been described by Hollenberg et al, 6j who suggested that All antagonists and renin inhibitors have a greater effect on renal blood flow compared with ACEIs. ANGIOTENSIN-CONVERTING ENZYME INHIBITORS In patients with DM-1 and microalbuminuria, ACEIs have been proved to confer renoprotection against progression to overt proteinuria and ESRD. 62'63 In patients with DM-2 and microalbuminuria but not hypertension, Ravid et a164,65 reported that, compared with placebo, ACE inhibition resulted in renal function preservation and a lower risk for progression to proteinuria. In patients with DM-2, 1025
CLINICAL THERAPEUTICS ®
microalbuminuria, and hypertension, however, long-term studies have shown similar beneficial effects between ACEIs, long-acting calcium channel blockers) t and beta-blockers 66 on progression to overt proteinuria. In 1993, the Captopril Collaborative Study Group 16 demonstrated that, in patients with DM-1 and overt proteinuria who received captopril, the risk reduction for doubling in serum creatinine concentration (P = 0.007) or the composite end point, ESRD, transplant, or death (P = 0.006), was significant. The placebo group in this study also received antihypertensire therapy, which did not include calcium channel blockers or ACEIs. The 2 groups did not show significant differences in blood pressure control so that the benefits observed in the captopril-treated group occurred independent of its antihypertensive effects. Because captopril potentiates BK, however, it was not possible from these results to conclude that the beneficial effects were due solely to the blockade of All synthesis. A N G I O T E N S I N I I ANTAGONISTS The question of whether blockade of AII in patients with DM-2 would result in the same beneficial effects observed for patients with DM-1 remained unanswered until recently, when the results of 2 major trials (RENAAL 2 and IDNT 3) were published. To determine the effects of All-receptor antagonists on clinical nephropathy in patients with DM-2, the RENAAL trial, 2 a prospective, randomized, double-blind, placebo-controlled trial, included 1513 patients with DM-2 and established nephropathy. Patients were randomized to receive either losartan (maximum dose, 1026
100 mg) or placebo added to conventional antihypertensive therapy (CT), excluding ACEIs or other All antagonists but including calcium channel blockers. The target blood pressure was <140/90 mm Hg. The principal hypothesis tested in RENAAL was that long-term therapy with losartan added to CT would reduce the incidence of the composite outcome of doubling of serum creatinine concentration, ESRD, or death compared with placebo added to CT. Additional hypotheses tested in RENAAL were that losartan would reduce proteinuria, decrease the rate of progression of renal disease, prolong the time to the first event, and reduce the incidence of CVD-related death and major nonfatal cardiovascular events. After a mean followup of 3.4 years, despite similar levels of blood pressure in the 2 groups, the losartantreated group showed a 16% risk reduction for the composite primary end point (P = 0.024). The study was also extremely successful in demonstrating a marked renoprotective effect of losartan. This agent reduced the incidence of a doubling of serum creatinine concentration (risk reduction, 25%; P = 0.006) and ESRD (risk reduction, 28%; P = 0.002). The risk for the combined end point of ESRD or death was 20% lower with losartan. In addition, losartan led to an average reduction in the level of proteinuria of 35%, whereas in the placebo-treated group the level of proteinuria tended to increase. Also, compared with placebo, losartan was associated with a 15.2% reduction in the estimated decline in the GFR. The results of RENAAL indicate that all of these renoprotective benefits of the blockade of the RAS with losartan were attributable to effects beyond blood pressure control. The IDNT trial 3 compared an AII antagonist with a calcium channel blocker
M.-T. ZANELLA AND A.B. RIBEIRO
in 1715 diabetic, hypertensive patients randomly assigned to receive placebo, irbesartan, or amlodipine. As in the RENAAL trial, the All antagonist was added to background CT other than ACEIs, other calcium channel blockers, or All antagonist to achieve blood pressure control. After a mean period of 2.6 years of therapy, despite similar blood pressure levels, the irbesartan-treated group showed a 20% (P = 0.02) risk reduction compared with placebo and a 23% (P = 0.006) risk reduction compared with amlodipine for the primary composite outcome of doubling serum creatinine concentration, ESRD, or death. No significant difference was found in the RR for the combined primary end point between the amlodipine- and placebo-treated groups. As in the RENAAL study, these results have proved that therapy with an AII antagonist imparts greater benefits in the treatment of established nephropathy in patients with DM-2 than merely its well-documented role in lowering blood pressure. The results of RENAAL confirm the importance of blood pressure control to delay the progression of diabetic nephropathy. It was observed that, during the first 36 months of the study, UAE remained unchanged in the placebo-treated group. Considering that proteinuria itself contributes to renal damage, the lack of increase in UPE, which occurs in the natural history of diabetic nephropathy, may be interpreted as a benefit of blood pressure control. In the RENAAL trial, the mean baseline plasma creatinine concentrations were 1.9 mg/dL in both the losartan- and placebo-treated groups. Despite these increased baseline values, early increases in plasma creatinine concentrations led to the discontinuation of treatment with
study medication in 1.5% of patients in the losartan-treated group compared with 1.2% of patients in the placebo-treated group. Clear benefits regarding progression to ESRD are obtained with the blockade of All because losartan significantly prolonged the time from doubling of serum creatinine concentrations to the development of ESRD (risk reduction, 30%; P = 0.013). These results indicate that the All antagonist therapy should not be discontinued even after the serum creatinine concentration has doubled. The concern that hyperkalemia may occur in patients with high plasma creatinine concentrations during ACEI therapy 67 was not supported in the RENAAL study. Only 1.1 % of patients in the losartantreated group compared with 0.5% in the placebo-treated group discontinued treatment with the study medication because of increases in plasma potassium levels. Although some evidence points to a lower incidence of hyperkalemia during All antagonist therapy compared with ACEIs, the low incidence observed may, in part, be attributable to diuretic therapy, adopted by 83.5% of the patients in the losartantreated group. The RENAAL and IDNT studies enrolled patients with overt proteinuria, but All antagonism has also been shown to be renoprotective in patients with less severe renal disease. In the IRMA 2 study,4 590 patients with DM-2, hypertension, microalbuminuria, and normal renal function were included in a double-blind, randomized, prospective trial. This study compared 150 and 300 mg of irbesartan with placebo, all added to CT (excluding ACEIs and other AII antagonists) to achieve blood pressure control in 3 subgroups of patients (irbesartan 150 mg, irbesartan 300 mg, and placebo). 1027
CLINICAL THERAPEUTICS®
After 2 years, despite all groups achieving similar levels of blood pressure, the risk for progression to diabetic nephropatby, the primary end point of the study, was reduced by 70% (P < 0.001) in the group treated with irbesartan 300 rag. This renoprotective effect, however, was observed only with 300 mg of irbesartan because the risk reduction of 39% in the group treated with irbesartan 150 mg did not reach statistical significance. These results clearly demonstrate that blockade of the RAS with an AII antagonist confers renoprotection, independent of its blood pressure-lowering effect; however, in these microproteinuric patients, blood pressure control was also important. In the placebo-treated group, intensive antihypertensive therapy resulted in stabilization of UAE levels throughout the study, with 20% of these patients showing restoration of normoalbuminuria. Preventing or delaying the progression of diabetic nephropathy is the main objective of therapy. The results of RENAAL and IDNT clearly suggest that AII antagonists are able to reduce the rate of the decline of GFR in patients with DM-2 and nephropathy. According to the IRMA 2 trial, overt diabetic nephropathy can even be prevented if high-risk patients are identified early in the course of the disease and receive an AII antagonist for renoprotection. The results of this study emphasize the need for routine urine screening for microalbuminuria yearly in all patients with DM-2, as also recommended by published guidelines for the treatment of diabetic kidney disease. 68 CARDIOPROTECTION Because CVD is responsible for most deaths among patients with DM-2 and hy1028
pertension, high blood pressure, as a major contributing factor to cardiac death, is a crucial component in the therapy for such patients. Lowering blood pressure is an important preventive measure to be taken in patients with diabetic nephropathy. Data emerging from the UKPDS 69 and the Hypertension Optimal Treatment (HOT) study 14 show that intensive blood pressure control reduces complications and deaths among patients with DM-2 and that no lower limit of blood pressure exists at which to stop treatment (the lower the blood pressure, the lower the rate of complications). Current recommendations in the United States by the National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group specify a blood pressure of 130/85 mm Hg as the treatment goal for most patients with hypertension, and it is highly recommended that this goal be aggressively pursued in all patients with diabetes. 7° However, whether the blood pressure reduction is more important than the antihypertensive agent used to achieve it, and whether the blockade of the RAS confers superior cardioprotective effects compared with other antihypertensive agents, remain areas of intense discussion and investigation. The Hypertension in Diabetes study within the UKPDS showed that blood pressurelowering intensive therapy using primarily either an ACEI or a beta-blocker resulted in significantly fewer strokes (44%; P = 0.013), less heart failure (37%; P = 0.009), and fewer diabetes-related deaths (32%; P = 0.019), but in the group with lower blood pressure, no significant differences were found between the 2 antihypertensive agents. 66 The Appropriate Blood Pressure Control in Diabetes Trial 71 and the Fosinopril Versus Amlodipine
M.-T. ZANELLA AND A.B. RIBEIRO
Cardiovascular Events Randomized Trial (FACET) 72 suggested that ACEI treatment was superior to treatment with calcium channel blockers in conferring cardiovascular protection. Also, in the Captopril Prevention Project (CAPPP) study, 73 within a diabetic subgroup, the ACEI captopril appeared to be superior to the diuretic/beta-blocker regimen, despite similar blood pressure reduction. More recently, the MICRO-HOPE study 5 found that an ACEI provided protection against cardiovascular events and early renal disease progression in patients with DM-2. The results seemed to be better than might be attributable to the antihypertensive effect of the ACEI, although some controversies remain regarding the potential contribution of blood pressure reduction in this study. Evidence also emerged from the RENAAL study on the cardioprotective benefit of AII blockade with losartan, with a 32% reduction in risk for first hospitalization for heart failure (P = 0.005). 2 RENAAL was the first demonstration that primary prevention of clinical cardiac failure can be achieved by reducing AII action. Heart failure in hypertensive patients is associated with fibrosis, which is an important contributor to its progression. AII stimulates TGF-beta-1 production and, in turn, the matrix protein accumulation in the heart, leading to impaired cardiac function and fibrosis. TM In hypertensive patients with left ventricular (LV) hypertrophy, AII blockade at the ATI receptors with losartan has been shown to exert antifibrotic effects, with consequent improvement in LV function. 75 These effects may be particularly important in hypertensive, diabetic patients in whom hyperglycemia also contributes to LV hypertrophy. 76 This antifibrotic action of
losartan might account for the reduction in the risk for hospitalization for heart failure observed in the RENAAL trial. CONCLUSIONS The scientific rationale and clinical trial data strongly suggest that effective blockade of angiotensin action is important for both reno- and cardioprotection in patients with DM-2, as demonstrated with losartan in the RENAAL study. 2 Some of the benefits are undoubtedly related to the associated blood pressure reduction and the favorable impact of the All blockade on microvascular hemodynamics. Nevertheless, the blockade of the growth-promoting, profibrotic, nonhemodynamic actions of All, which also seem to mediate some of the deleterious influences of hyperglycemia on the kidney and heart, may also be important for reno- and cardioprotection in patients with DM-2.
ACKNOWLEDGMENT Partial financial support for this publication was provided by an educational grant from Merck & Co, Inc, Whitehouse Station, New Jersey.
REFERENCES 1. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352: 837-853. 2. Brenner BM, Cooper ME, de Zeeuw D, et al, for the RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 1029
CLINICAL THERAPEUTICS®
diabetes and nephropathy. N Engl J Med. 2001 ;345:861-869. 3. Lewis EJ, Hunsicker LG, Clarke WR, et al, for the Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001 ;345:851-860. 4. Parving HH, Lehnert H, Br6chnerMortensen J, et al, 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;345:870878. 5. 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. 2000;355:253-259. 6. Parving HH, Osterby R, Ritz E. Diabetic nephropathy. In: Brenner BM, Levine S, eds. The Kidney. Philadelphia: WB Saunders; 2000:1731-1733. 7. National Institutes of Health. Excerpts from the United States Renal Data System's 2000 annual data report: Atlas of end stage renal disease in the United States: Incidence and prevalence of ESRD. Am J Kidney Dis. 2000;36(Suppl 2):$37- $54.
complications: Estimates and projections to the year 2010. Diabet Med. 1997;14 (Suppl 5):S1-$85. 10. Mokdad AH, Ford ES, Bowman BA, et al. Diabetes trends in the U.S.: 1990-1998. Diabetes Care. 2000;23:1278-1283. 11. 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. 2000;23: B54-B64. 12. Parving HH, Andersen AR, Smidt UM, Svendsen PA. Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet. 1983; 1: 1175-1179. 13. Parving HH, Smidt UM, Hommel E, et al. Effective antihypertensive treatment postpones renal insufficiency in diabetic nephropathy. Am J Kidney Dis. 1993;22: 188-195. 14. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: Principle results of the Hypertension Optimal Treatment (HOT) randomized trial. HOT Study Group. Lancet. 1998;351:1755-1762. 15. Kasiske BL, Kalil RS, Ma JZ, et al. Effect of antihypertensive therapy on the kidney in patients with diabetes: A meta-regression analysis. Ann lntern Med. 1993;118:129138.
8. National Institutes of Health. Excerpts from the United States Renal Data System's 2000 annual data report: Atlas of end stage renal disease in the United States: Economic costs of ESRD. Am J Kidney Dis. 2000;36(Suppl 2):S163-S176.
16. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, for the Collaborative Study Group. The effect of angiotensin-convertingenzyme inhibition on diabetic nephropathy. N Engl J Med. 1993;329:1456-1462.
9. Amos AF, McCarty DJ, Zimmet P. The rising global burden of diabetes and its
17. Remuzzi G, Bertani T. Is glomerulosclerosis a consequence of altered glomemlar
1030
M.-T. ZANELLA AND A.B. RIBEIRO
permeability to macromolecules? Kidney Int. 1990;38:384-394. 18. Nelson RG, Pettitt DJ, Carraher MJ, et al. Effect of proteinuria on mortality in NIDDM. Diabetes. 1988;37:1499-1504.
26. Stephenson JM, Kenny S, Stevens LK, et al, Proteinuria and mortality in diabetes: The WHO Multinational Study of Vascular Disease in Diabetes. Diabet Med. 1995;12:149-155.
19. Ballard DJ, Humphrey LL, Melton J 3rd, et al. Epidemiology of persistent proteinuria in type II diabetes mellitus: Populationbased study in Rochester, Minnesota. Diabetes. 1988;37:405-412.
27. Miettinen H, Haffner SM, Lehto S, et al, Proteinuria predicts stroke and other atherosclerotic vascular disease events in nondiabetic and non-insulin-dependent diabetic subjects. Stroke. 1996;27:20332039.
20. Nelson RG, Newman JM, Knowler WC, et al. Incidence of end-stage renal disease in type 2 (non-insulin-dependent)diabetes mellitus in Pima Indians. Diabetologia. 1988;31:730-736.
28. Valmadrid CT, Klein R, Moss SE, Klein BE. The risk of cardiovascular disease mortality associated with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus. Arch Intern Med. 2000; 160:1093-1100.
21. Rossing P, Hommel E, Smidt UM, Parving HH. Reduction in albuminuria predicts diminished progression in diabetic nephropathy. Kidney lnt Suppl. 1994;45: S145-S149.
29. Marso SP, Ellis SG, Tuzco M, et al. The importance of proteinuria as a determinant of mortality following percutaneous coronary revascularization in diabetics. J Am Coil Cardiol. 1999;33:1269-1277.
22. Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, proteinuria, and the progression of renal disease. The Modification in Diet in Renal Disease Study. Ann Intern Med. 1995;123:754-762.
30. Viberti GC, Hill RD, Jarrett RJ, et al. Microalbuminuria as a predictor of clinical nephropathy in insulin-dependentdiabetes mellitus. Lancet. 1982; 1: 1430-1432.
23. The GISEN Group. Randomised placebocontrolled 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. 24. Hebert LA, Bain RP, Verme D, et al. Remission of nephrotic range proteinuria in type I diabetes. Collaborative Study Group. Kidney Int. 1994;46:1688-1693. 25. De Jong PE, Navis G, de Zeeuw D. Renoprotective therapy: Titration against urinary protein excretion. Lancet. 1999;354: 352-353.
31. Mogensen CE, Christensen CK. Predicting diabetic nephropathy in insulindependent patients. N Engl J Med. 1984; 331:89-93. 32. Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med. 1984;310:356-360. 33. Esmail ZN, Loewen PS. Losartan as an alternative to ACE inhibitors in patients with renal dysfunction. Ann Pharmacother. 1998;32:1096-1098. 34. Parving HH. Diabetic nephropathy: Prevention and treatment. Kidney Int. 2001; 60:2041-2055.
1031
CLINICAL THERAPEUTICS ®
35. Deckert T. Nephropathy and coronary death--the fatal twins in diabetes mellitus. Nephrol Dial Transplant. 1994;9: 1069-1071.
senting type 2 diabetic patients and the association with risk factors for cardiovascular and diabetic complications. J Hypertens. 1993; 11:309-317.
36. Yokoyama H, Tomonaga O, Hirayama M, et al. Predictors of the progression of diabetic nephropathy and the beneficial effect of angiotensin-converting enzyme inhibitors in NIDDM patients. Diabetologia. 1997;40:405--411.
44. Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: The Steno type 2 randomised study. Lancet. 1999; 353:617-622.
37. Parving HH, Hommel E, Mathiesen E, et al. Prevalence of microalbuminuria, arterial hypertension, retinopathy and neuropathy in patients with insulin dependent diabetes. Br Med J. 1988;296:156--160.
45. Bj6rk S. The renin angiotensin system in diabetes mellitus: A physiological and therapeutic study. Scand J Urol Nephrol Suppl. 1990; 126:1-50.
38. Zanella MT, Freire MB, Milagres R, et al. Blood pressure disturbance in diabetes mellitus. J Hypertens Suppl. 1992;10: $59-$70. 39. Poulsen PL, Hansen KW, Mogensen CE. Ambulatory blood pressure in the transition from normo- to microalbuminuria: A longitudinal study in IDDM patients. Diabetes. 1994;43:1248-1253. 40. Monteagudo PT, Nobrega JC, Cezarini PR, et al. Altered blood pressure profile, autonomic neuropathy and nephropathy in insulin-dependent diabetic patients. Eur J Endocrinol. 1996;135:683-688. 41. Sowers JR, Epstein M, Frolich ED. Diabetes, hypertension, and cardiovascular disease: An update. Hypertension. 2001; 37:1053-1059. 42. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): Prospective observational study. Br Med J. 2000;321:412--419. 43. Hypertension in Diabetes Study (HDS). I. Prevalence of hypertension in newly pre-
1032
46. Christlieb AR, Kaldani YA, D'Elia JA. Plasma renin activity and hypertension in diabetes mellitus. Diabetes. 1976;25:969974. 47. Anderson S, Jung FF, Ingelfinger JR. Renal renin-angiotensin system in diabetes: Functional immunohistochemical and molecular biological correlations. Am J Physiol. 1993;265:F477-F486. 48. Navar LG, Harrison-Bernard LM, Imig JD, et al. Renal responses to AT1 receptor blockade. Am J Hypertens. 2000;13:45S54S. 49. Hostetter TH, Rennke GH, Brenner BM. The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies. Am J Med. 1982; 72:375-380. 50. Zatz R, Dunn BR, Meyer TW, et al. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest. 1986;77:1925-1930. 51. Hollenberg NK. ACE inhibition, angiotensin II receptor blockade and diabetic nephropathy. In: Mogensen CE, ed.
M.-T. ZANELLA AND A.B. RIBEIRO
The Kidney and Hypertension in Diabetes Mellitus. Boston: Kluwer Academic Publishers; 2000:417-422.
52. Deray G. Are the antagonists of angiotensin II AT1 receptors protectors of the kidney? [in French]. Arch Mal Coeur Vaiss. 1999;92:903-907. 53. Andersen S, Tarnow L, Rossing P, et al. Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy. Kidney Int. 2000;57:601-606. 54. Andersen S, Blouch K, Bialek J, et al. Glomerular permselectivity in early stages of overt diabetic nephropathy. Kidney Int. 2000 ;58:2129-2137. 55. Wolf G. Angiotensin II is involved in the progression of renal disease: Importance of non-hemodynamic mechanisms. Nephrologie. 1998;19:451-456. 56. Kagami S, Border WA, Miller DE, Noble NA. Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factorbeta expression in the rat glomerular mesangial cells. J Clin Invest. 1994;93: 2431-2437. 57. Wolf G, Ziyadeh FN. The role of angiotensin II in diabetic nephropathy: Emphasis on non-hemodynamic mechanisms. Am J Kidney Dis. 1997;29:153-163. 58. Singh R, Alavi N, Singh AK, Leehey DJ. Role of angiotensin II in glucose-induced inhibition of mesangial matrix degradation. Diabetes. 1999;48:2066-2073. 59. Nishimura H, Hoffmann S, Baltatic O, et al. Angiotensin I converting enzyme and chimase in cardiovascular tissues. Kidney lnt Suppl. 1996;55:S18-$23.
60. Urata H, Healy B, Stewart RW, et al. Angiotensin II-forming pathways in normal and failing human hearts. Circ Res. 1990;66:883-890. 61. Hollenberg NK, Fisher ND, 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. 62. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-convertingenzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med. 2001 ;134:370-379. 63. Mathiesen ER, Hommel E, Hansen HP, et al. Randomised controlled trial of longterm efficacy of captopril on preservation of kidney function in normotensive patients with insulin dependent diabetes and microalbuminuria. Br Med J. 1999;319: 24-25. 64. Ravid M, Lang R, Rachmani R, Lishner M. Long-term renoprotective effect of angiotensin-convertingenzyme inhibition in non-insulin-dependentdiabetes mellitus. Arch Intern Med. 1996;156:286-289. 65. Ravid M, Savin H, Jutrin l, et al. Longterm stabilizing effect of angiotensinconverting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med. 1993;118:577-581. 66. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. Br Med J. 1998;317:714720. 67. Zanella MT, Mattei E Jr, Draibe SA, et al. Inadequate aldosterone response to hyper-
1033
CLINICAL THERAPEUTICS ~
kalemia during angiotensin converting enzyme inhibition in chronic renal failure. Clin Pharmacol Ther. 1985;38:613--617. 68, Mogensen CE, Keane WF, Bennett PH, et al. Prevention of diabetic renal disease with special reference to microalbuminuria. Lancet. 2001 ;346:1080-1084. 69. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. Br Med J. 1998;317:703-713. 70. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: A consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36:646-661. 71. Estacio RO, Jeffers BW, Hiatt WR, et al. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med. 1998;338:645-652. 72. Tatti P, Pahlor M, Byington RP, et al. Outcome results of the Fosinopril Versus Am-
lodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care. 1998;21:597-603. 73. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-convertingenzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: The Captopril Prevention Project (CAPPP) randomised trial. Lancet. 1999;353: 611-616. 74. Williams B. The renin angiotensin system in the pathogenesis of diabetic complications. In: Mogensen CE, ed. The Kidney and Hypertension in Diabetes Mellitus. Boston: Kluwer Academic Publishers; 2000:645-654. 75. Lopez B, Querejeta R, Varo N, et al. Usefulness of serum carboxy-terminal propeptide of procollagen type I in assessment of the cardioreparative ability of antihypertensive treatment in hypertensive patients. Circulation. 2001 ;104:286-291. 76. Felicio JS, Ferreira SRG, Plavnik FL, et al. Effect of blood glucose on left ventricular mass in patients with hypertension and type 2 diabetes mellitus. Am J Hypertens. 2000; 13:1149-1154.
Address correspondence to: Maria-Teresa Zanella, MD, Hospital do Rim e Hipertens~o, Federal University of S~o Paulo, Rua Borges Lagoa 960, 04038-002 Sao Paulo, SP, Brasil. E-mail: [email protected]
1034