Supra Rx Dose of ARBs

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  • The pie chart shows that diabetes is currently the most common cause of ESRD. The lower graph reveals that the number of patients with ESRD maintained on dialysis is predicted to double over present levels by 2010, and the major contributor to this exponential increase is chronic renal failure associated with diabetes.
  • Proteinuria, a window into blood vessel integrity, predicts poor survival. The impact of micro- and macroalbuminuria on mortality was evaluated prospectively in 328 white patients with type 2 diabetes who were followed for 5 years. Patients in the 3 study groups included 109 men and 82 women with normoalbuminuria (albumin excretion rates [AER] <30 mg/24 h), 50 men and 36 women with microalbuminuria (AER 30 to 299 mg/24 h), and 43 men and 8 women with macroalbuminuria (AER  300 mg/24 h). The mean age at entry was 54 (SD ± 9) years. From 1987 until January 1993 (or until death), 8% of patients with normoalbuminuria, 20% of patients with microalbuminuria, and 35% of patients with macroalbuminuria died, predominantly from CV disease (P<0.01 normo- vs micro- and macroalbuminuria and P<0.05 micro- vs macroalbuminuria). The researchers concluded that abnormal elevated urinary albumin excretion (UAE) increased all-cause (mainly cardiovascular) mortality risk in type 2 diabetes.
  • Risk of Ischemic Heart Disease Related to SBP and Microalbuminuria The purpose of this study was to analyze prospectively whether the urinary albumin-to-creatinine (A/C) ratio could independently predict ischemic heart disease (IHD) in a population-based cohort. In 1983, urinary albumin and creatinine levels were measured, along with the conventional atherosclerotic risk factors, in 2,085 consecutive participants without IHD, renal disease, urinary tract infection, or diabetes mellitus. The participants were followed up until death, emigration, or December 31, 1993. IHD was identified by hospital diagnosis or listed as a cause of death. Seventy-nine individuals developed IHD. Microalbuminuria (MA) was defined as an A/C ratio >90 percentile (>0.65 mg/mmol). When adjusted for other risk factors, the relative risk of IHD associated with MA was 2.3 (95% CI, 1.3 to 3.9, p=0.002), and the 10-year disease-free survival decreased from 97% to 91% ( p< 0.0001) when MA was present. An interaction between MA and smoking was observed, and the presence of MA more than doubled the predictive effect of the conventional atherosclerotic risk factors for development of IHD. It is concluded that MA is not only an independent predictor of IHD but also substantially increases the risk associated with other established risk factors.   Reference: Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS. Urinary albumin excretion. An independent predictor of ischemic heart disease. Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997.
  • Microalbuminuria Compared to Traditional Risk Factors for Ischemic Heart Disease The purpose of this study was to analyze prospectively whether the urinary albumin-to-creatinine (A/C) ratio can independently predict ischemic heart disease (IHD) in a population-based cohort. The cohort was characterized by a preponderance of males and higher age, body mass index, blood pressure, lipoproteins, and proportion of current smokers. When adjusted for other risk factors, the relative risk of IHD associated with MA was 2.3 (95% CI, 1.3 to 3.9, p=0.002), and the 10-year disease-free survival decreased from 97% to 91% ( p< 0.0001) when MA was present. An interaction between MA and smoking was observed, and the presence of MA more than doubled the predictive effect of the conventional atherosclerotic risk factors for development of IHD. MA is not only an independent predictor of IHD, but also substantially increases the risk associated with other established risk factors.   Reference: Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS. Urinary albumin excretion. An independent predictor of ischemic heart disease. Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997.
  • Definitions of Microalbuminuria and Macroalbuminuria Measurements of urinary albumin are made from either a timed (4 or 24 hours) urine collection or from a randomly voided “spot” urine. In the former case the urinary albumin concentration is divided by the time of the collection (in minutes) calculate the first parameter. In the latter case, both albumin and creatinine concentrations are measured in the same specimen and a ratio of albumin to creatinine calculated. Numerous studies have demonstrated that the values obtained from both timed and randomly collected specimens correlate well and have the same prognostic significance. Measurements of urine protein concentrations by “dipstick” chemistry are not sufficiently sensitive to identify urine albumin concentrations that meet the criteria for microalbuminuria. Protein in the urine is usually a combination of albumin, globulins, and Tamm-Horsfall protein derived from tubular secretion. References: Bianchi S, Bigazzi R, Campese VM. Microalbuminuria in essential hypertension: significance, pathophysiology, and therapeutic implications. Am J Kidney Dis. 1999;34(6):973-995. Keane WF. Proteinuria: its clinical importance and role in progressive renal disease. Am J Kidney Dis. 2000;35(4suppl1):S97-S105.
  • Pathways Leading to Progressive Renal Failure This slide summarizes the multiple mechanisms by which non-hypertensive and hypertensive insults lead to renal scarring that results in loss of nephrons and ultimately to renal failure. Both systemic hypertension and non-hypertensive injury that causes loss of single nephron units results in hypertension in the remaining glomeruli (glomerular hypertension). Glomerular hypertension can lead to injury to the glomerular basement membrane causing it to leak plasma proteins into the urine. Attempts by the proximal tubules to reabsorb this filtered protein causes injury to the tubular cells, activates an inflammatory response, and is associated with the development of lipid metabolic abnormalities that create further oxidative stress on the already compromised glomerulus. The resultant tubular inflammatory response and renal microvascular injury activate pathways that lead to fibrosis and scarring of both glomerular and tubular elements of the nephron. An additional consequence of glomerular hypertension and resultant reduction in glomerular filtration rate (GFR) activates growth factors and cytokines that promote an influx of monocytes and macrophages into the vessel wall and into the renal interstitium, and also causes the differentiation of renal cells into fibroblasts. Monocytes, macrophages and fibroblasts are capable of producing those growth factors and cytokines that activate pathways leading to expansion of extracellular matrix, fibrosis and loss of both tubular and glomerular structures.
  • Pathologic Processes Leading to Glomular Injury and Proteinuria When Ang II is increased, greater AT 1 receptor-mediated constriction of efferent than afferent arterioles increases single nephron glomerular filtration rate and raises intraglomerular pressure, causing glomerular hypertension. Sustained or severe increases in intraglomerular pressure can lead to glomerular basement membrane damage, glomerular endothelial dysfunction, and ultimately, extravasation of protein into Bowman’s capsule. In addition to hypertension, conditions like diabetes that are associated with increased oxidative stress (increased formation of reactive oxygen species) independent of hypertension and glyco-oxidative modification of proteins (advanced glycation endproducts or AGEs) comprising the glomerular basement membrane can lead to extravasation of protein.
  • Role of Angiotensin II in Chronic Renal Disease Angiotensin II plays a pivotal role in pathological processes in hypertension that ultimately leads to renal glomerular and tubular destruction and renal failure. Angiotensin II, acting either through signal transducing mechanisms (top left box) or directly on cells to stimulate the production or activation of mediators (top right box) causes infiltration of inflammatory cells, increased production of mesangial and interstitial matrix with resultant glomerular and tubular injury and destruction (nephron loss). The remaining normal nephrons are forced to compensate by increasing filtration rate which, in the presence of increased angiotensin II, increases glomerular capillary pressure and perpetuates this progressive spiral of deteriorating renal function. Abbreviations: TGF-  , transforming growth factor-beta, CTGF, connective tissue growth factor, PAI-1, plasminogen activator inhibitor-1
  • Slide 3: Clinical Endpoint Data for ESRD in Type 2 Diabetes with ACE Inhibitors Are Lacking ACE inhibitors have been shown to beneficially alter surrogate markers of progressive renal disease (reduce proteinuria) in patients with diabetic and non-diabetic renal disease. 7 ACE inhibitors have also been shown to beneficially alter endpoints (ESRD data) in diabetic (Type 1) and non-diabetic patients. 8 However, much less is known about the effects of ACE inhibitors and other therapies on ESRD in patients with Type 2 diabetes. 9-18 At the time when the RENAAL trial was initiated, there were no renal endpoint data with ACE inhibitors in patients with Type 2 diabetes. 1 Since that time, endpoint studies have been reported with ACE inhibitors in Type 2 diabetic patients. 19,20 The first was a small study (The Ramipril Efficacy in Nephropathy study) of 352 patients which included only 27 (8%) Type 2 diabetic patients. In this study, ramipril was shown to substantially reduce the risk of ESRD by almost 50% but, as the majority of these patients were not diabetic, the results should not be extrapolated to Type 2 patients. 19 Another endpoint study involving an ACE inhibitor and Type 2 diabetic patients was the Heart Outcomes Prevention Evaluation (HOPE) study. In this trial of 9541 participants, 3654 patients were diabetic (97% Type 2) at randomization, 3577 of whom were included in a pre-specified analysis reported as the MI croalbuminuria, C ardiovascular, and R enal O utcomes (MICRO)-HOPE substudy. 20 Patients in the HOPE trial were excluded if they had overt nephropathy at baseline. Only 32% (n=1140) of the diabetic subpopulation had microalbuminuria; therefore, the majority of the HOPE/MICRO-HOPE patients had little nephropathy. 20 Overt nephropathy as an outcome measure in HOPE/MICRO-HOPE was a secondary endpoint. 20 It is important to note that in MICRO-HOPE ramipril did not reduce the risk of dialysis (p=0.70) or heart failure (p=0.93) compared to placebo. 20 However, there was a 24% risk reduction for overt nephropathy (p=0.027) and a 16% risk reduction on the combined microvascular outcome of overt nephropathy, laser therapy, or dialysis (p=0.036). 20 The MICRO-HOPE data are consistent with a renoprotective effect of ACE inhibition in Type 2 diabetic patients with little or no nephropathy. 20 These limited beneficial effects of ramipril are in contrast to the greater significant renal (reduction in ESRD) and cardiac protective (reduction in hospitalization for heart failure) effects of losartan observed in the RENAAL trial in patients with Type 2 diabetes and overt nephropathy. 2
  • During the course of the study both treatment groups continued to receive conventional BP medication as appropriate. These agents included CCBs, diuretics, beta blockers, alpha blockers and centrally-acting agents. Other ARBs and ACE inhibitors were excluded from the study. Standard medical care for managing diabetes was continued throughout the study.
  • Slide 9: RENAAL: Study Design The RENAAL study began with an initial screening–treatment phase lasting six weeks. During this phase no placebo was administered. The majority (93.5%) of patients entered the study on prior antihypertensive therapy. Those hypertensive patients being treated with either an ACE inhibitor or an A II antagonist within six weeks of trial enrollment discontinued these medications and received an alternative conventional antihypertensive (open-label CT including CCBs, diuretics, beta or alpha blockers, or centrally acting agents) as appropriate, to control hypertension to a goal of <140/90 mmHg. 1,2 Hypertensive patients not being treated with an ACE inhibitor or an A II antagonist continued to receive their prior conventional antihypertensive therapy. 1,2 The screening–treatment phase was followed by a double-blind treatment phase designed to have a 3.5-year follow-up after the last patient had been randomized. However, the study was discontinued early by the steering committee, while blinded to all treatment assignments for external reasons. The mean follow-up time was 3.4 years. The double-blind phase began with the randomization of eligible patients into two treatment groups. The first group received losartan 50 mg once daily, alone or in combination with CT, excluding ACE inhibitors and other A II antagonists (losartan + CT). The second treatment group received placebo once daily, alone or in combination with CT, excluding ACE inhibitors and other A II antagonists (placebo + CT). The randomization was stratified based on the level of baseline proteinuria (urine albumin:creatinine ratio above or below 2000 mg/g). 1,2 Four weeks after randomization, or at any phase during the study, if the target trough sitting systolic/diastolic blood pressure of <140/90 mmHg was not achieved, the daily dose of losartan (or placebo) was increased to losartan 100 mg once daily or two placebo tablets once daily. However, if losartan 100 mg or the two placebo tablets were not sufficient to reduce trough blood pressures below the target values, additional open-label antihypertensives were added. The open-label antihypertensives were as described above. 1
  • Blood pressure was controlled to nearly the same extent in both study groups. Thus it was postulated that any renal protective effect of the ARB was largely independent of BP lowering in this study.
  • Slide 13: RENAAL: Primary Composite Endpoint and Components The primary composite endpoint of RENAAL was the time to the first event of doubling of serum creatinine (DsCr), ESRD, or death. By an intention-to-treat (ITT) analysis (which was the primary analysis approach of the study), the primary composite endpoint was reached in 327 (43.5%) patients receiving losartan + CT and 359 (47.1%) patients receiving placebo + CT. Losartan + CT treatment resulted in a significant decrease in risk reduction of 16% (p=0.02) in the primary composite endpoint. For those patients who remained on treatment throughout the protocol (per-protocol analysis), losartan + CT treatment conferred a 22% risk reduction (p=0.008) in the primary composite endpoint. 2 REF2 pp 863 B
  • Slide 14: RENAAL: Primary Components This slide shows the individual Kaplan-Meier plots for the components of the composite primary endpoint. Doubling of serum creatinine and ESRD are both important renal endpoints. Once-daily losartan + CT significantly reduced the risk of the development of doubling serum creatinine (25%; p=0.006) and ESRD (28%; p=0.002). 2 The composite endpoint of ESRD or death also showed a significant risk reduction (20%; p=0.010). There was no significant risk reduction of death alone with losartan + CT. 2
  • Slide 14: RENAAL: Components of the Primary Composite Endpoint This slide shows the individual Kaplan-Meier plots for the components of the composite primary endpoint. Doubling of serum creatinine and ESRD are both important renal endpoints. Once-daily losartan + CT significantly reduced the risk of the development of doubling serum creatinine (25%; p=0.006) and ESRD (28%; p=0.002). 2 The composite endpoint of ESRD or death also showed a significant risk reduction (20%; p=0.010). There was no significant risk reduction of death alone with losartan + CT. 2 REF2 pp 865 A REF2 pp 865 C
  • Slide 14: RENAAL: Components of the Primary Composite Endpoint This slide shows the individual Kaplan-Meier plots for the components of the composite primary endpoint. Doubling of serum creatinine and ESRD are both important renal endpoints. Once-daily losartan + CT significantly reduced the risk of the development of doubling serum creatinine (25%; p=0.006) and ESRD (28%; p=0.002). 2 The composite endpoint of ESRD or death also showed a significant risk reduction (20%; p=0.010). There was no significant risk reduction of death alone with losartan + CT. 2 REF2 pp 865 A REF2 pp 865 C
  • Slide 14: RENAAL: Components of the Primary Composite Endpoint This slide shows the individual Kaplan-Meier plots for the components of the composite primary endpoint. Doubling of serum creatinine and ESRD are both important renal endpoints. Once-daily losartan + CT significantly reduced the risk of the development of doubling serum creatinine (25%; p=0.006) and ESRD (28%; p=0.002). 2 The composite endpoint of ESRD or death also showed a significant risk reduction (20%; p=0.010). There was no significant risk reduction of death alone with losartan + CT. 2 REF2 pp 865 A REF2 pp 865 C
  • Slide 23: RENAAL: Change from Baseline in Proteinuria A key inclusion criterion of the RENAAL trial was proteinuria. In this study, proteinuria was defined by the urinary albumin: creatinine ratio determined from first morning specimens of urine. This slide shows the dramatic effects of losartan + CT in reducing proteinuria in patients with Type 2 diabetes. In the placebo + CT treatment group, proteinuria was not reduced. By contrast, once-daily losartan significantly reduced proteinuria throughout the study period. The magnitude of this reduction was approximately 40% by 36 months. Losartan + CT led to an average reduction in proteinuria of 35% (p<0.001 vs. placebo + CT). 2
  • Slide 24: RENAAL: Rate of Progression of Renal Disease (median 1/sCr slope) Losartan reduced the rate of decline in renal function, as assessed by the reciprocal of the serum creatinine concentration (median slope –0.056 dl/mg/year with losartan + CT versus –0.069 dl/mg/year with placebo + CT, p=0.01). Thus, losartan slowed the rate of loss of renal function by 18% relative to placebo. 2
  • In DETAIL, telmisartan demonstrated renoprotective potential that was comparable to that achieved with ARBs in other large outcome trials. 1,2 In RENAAL, IRbesartan in patients with type 2 diabetes and MicroalbuminuriA (IRMA2) and IDNT, GFR was estimated from patient’s serum creatinine levels. Patients in RENAAL and IDNT had more severe nephropathy at baseline than patients in DETAIL (median urinary albumin:creatinine ratio = 1,250 in RENAAL, median UAER = 1.9 g/24 hours in IDNT). Patients in IRMA2 were similar to those in DETAIL (baseline GFR = 109 ml/min/1.73m2, UAER 55 µg/min, SBP/DBP=153/90 mmHg). The mean treatment duration was 3.4 years in RENAAL and 2.6 years in IDNT. IRMA2 was a 2-year study. Barnett A, et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy . N Engl J Med 2004;351:1952–1961. Barnett AH. Preventing renal complications in diabetic patients: the Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) study. Acta Diabetol 2005;42 Suppl 1:S42–S49 .
  • The target BP goal for the majority of patients was a systolic BP < 135 mm Hg and for all patients a diastolic BP < 85 mm Hg was required. If the baseline seated SBP (at the first screening visit) was > 145 mm Hg the target was a decrease of at least 10 mm Hg in seated SBP with a maximum allowable seated SBP of 160 mm Hg. Of importance, antihypertensive therapy (excluding ACE inhibitors, ARBs, and CCBs) could be added to each study arm to achieve equivalent BP control.
  • Upon study entry the average IDNT patient was 59 years old and was diabetic for 15 years. About one half of the patients had a history of neuropathy and two-thirds had a history of retinopathy. Of note, 67% of patients were male, 73% were Caucasian, mean serum creatinine was 1.7 mg/dl, 24-hour urine protein was 4016 mg/day and 25% of patients enrolled had a history of some cardiovascular (CV) disease, stroke, myocardial infarction, coronary heart disease, etc. There were no statistically significant differences in baseline demographics among groups.
  • Blood pressure was controlled to nearly the same extent in the two treatment groups. Compared with the treatment groups there was a 3-4 mm Hg higher diastolic BP and a 3 mm Hg higher systolic BP in the placebo group.
  • Upon study entry the average IRMA 2 patient was 58 years old (range 30-70 yrs) and was diabetic for 10 years. Of note, 69% of the patients were male, 97% were Caucasian and the mean UAER was 55 mcg/min. There were no statistically significant differences in baseline demographics among groups.
  • Blood pressure was controlled to nearly the same extent in each study group. Thus it was postulated that any benefit observed was mainly independent of BP and most likely related to the mechanism of action of the ARB, i.e., blocking the effect of angiotensin II at the receptor site.
  • ARB (Losartan) Reduces Urinary Albumin and TGF-  1 in Type 2 Diabetes with Microalbuminuria In this study of type 2 diabetes with microalbuminuria, systolic and diastolic blood pressure fell equivalently with losartan following 4 and 8 weeks of treatment, as did urine albumin excretion and plasma levels of TGF-β, the profibrotic cytokine.   Reference: Esmatjes E, Flores L, Inigo P, Lario S, Ruilope LM, Campistol JM. Effect of losartan on TGF-beta1 and urinary albumin excretion in patients with type 2 diabetes mellitus and microalbuminuria. Nephrol Dial Transplant. 2001; 16(suppl1):90-93.  
  • In this study of 122 patients randomized to 52 weeks of treatment with either valsartan 80 mg once daily, valsartan 160 mg once daily, captopril 25 mg three times daily or placebo, albumin excretion rate at endpoint was significantly decreased in all active treatment groups vs. placebo (p<0.05). Compared with captopril, there were no statistically significant differences in reduction in AER for valsartan 80 mg or valsartan 160 mg.
  • This slide shows data from the MicroAlbuminuria Reduction with VALsartan (MARVAL) study. This study recruited 332 patients with type 2 diabetes and albuminuria, with or without hypertension. Patients were given valsartan 80–160 mg daily or amlodipine 5–10 mg daily for 24 weeks. The reduction from baseline urine albumin excretion was significantly greater with valsartan compared with amlodipine. This occurred despite similar reductions in blood pressure. 1. Viberti G, et al. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation 2002;106:672–678.
  • INNOVATION recruited 527 patients with type 2 diabetes and evidence of incipient nephropathy. 1,2 Hypertension was not an inclusion criterion. It was a placebo-controlled, prospective, randomised, double-blind, parallel-group study. Add-on antihypertensive therapy (  -blocker, CCB, non-potassium sparing diuretics) was allowed to ensure adequate control of blood pressure in both treatment arms. Transition rates to overt nephropathy were: telmisartan 80 mg ( n  = 168) 16.7% telmisartan 40 mg ( n  = 172) 22.6% placebo ( n  = 174) 49.9%. 1 This corresponded to a relative risk reduction (RRR) of 55% with telmisartan 40 mg, and 66% with telmisartan 80 mg. The number needed to treat (NNT) to prevent 1 transition to overt nephropathy was 3.7 with telmisartan 40 mg, and 3.0 with telmisartan 80 mg. Makino H, et al. Prevention of transition from incipient to overt nephropathy with telmisartan in patients with type 2 diabetes. Diabetes Care 2007; in press. Makino H, et al. The telmisartan renoprotective study from incipient nephropathy to overt nephropathy – rationale, study design, treatment plan and baseline characteristics of the incipient to overt: angiotensin II receptor blocker telmisartan, investigation on type 2 diabetic nephropathy (INNOVATION) Study. J Int Med Res 2005;33:677–686.
  • This slide shows data from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) and the Irbesartan Diabetic Nephropathy Trial (IDNT). 1,2 RENAAL recruited 1,513 patients with type 2 diabetes and evidence of albuminuria. Patients were given losartan 50–100 mg daily or placebo for up to 4 years. Significantly fewer patients in the losartan group experienced a doubling of serum creatinine concentrations compared with the placebo group. IDNT recruited 1,715 patients with hypertension and nephropathy due to type 2 diabetes. Patients were given irbesartan 300 mg daily, amlodipine 10 mg daily or placebo for a mean 2.6 years. Significantly fewer patients in the irbesartan group experienced a doubling of serum creatinine concentrations compared with either the amlodipine or the placebo groups. In addition, irbesartan was associated with a significantly lower incidence of ESRD. Brenner BM, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861–869. Lewis EJ, et al. 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.
  • The Candesartan And Lisinopril effect on Microalbuminuria (CALM) study compared candesartan cilexetil 16 mg, lisinopril 20 mg and the combination over 24 weeks in 199 patients with type 2 diabetes, hypertension and microalbuminuria. 1 Combination therapy significantly reduced blood pressure compared with either candesartan or lisinopril monotherapy. Combination therapy significantly reduced the albumin:creatinine ratio compared with either monotherapy. However, candesartan monotherapy was significantly less effective than lisinopril monotherapy on this outcome measure. As a result, the combination therapy was significantly superior to candesartan monotherapy (mean relative reduction 34%, P =0.04) but not lisinopril monotherapy (mean relative reduction 18%, P >0.2). Mogensen CE, et al. Randomised controlled trial of dual blockade of renin--angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 2000;321:1440–1444.
  • The Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) study assessed the decline in renal function over 5 years in 250 patients with type 2 diabetes, mild-to-moderate hypertension, and GFR that was either normal or only mildly impaired. 1,2 It employed a 1-month run-in period, followed by up-titration over a period of 1 month to either telmisartan 80 mg or enalapril 20 mg. Add-on antihypertensive therapy (  - or  -blocker, CCB, diuretic) was allowed after 2 months of double-blind treatment if seated DBP was >100 mmHg or SBP was >160 mmHg. There were no significant differences in GFR at 5 years, or in the change in GFR over 5 years. At endpoint, the difference (telmisartan minus enalapril) in GFR was –2.6 ml/min/1.73 m 2 , with 95% confidence intervals (CIs) –7.1 to +2.0. Telmisartan was comparable to enalapril (i.e. met the statistical test for non-inferiority), since the 95% confidence interval of the difference was <–10 mL/min/1.73 m 2 . Barnett A, et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy . N Engl J Med 2004;351:1952–1961. Erratum in: N Engl J Med 2005;352:1731. Barnett AH. Preventing renal complications in diabetic patients: the Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) study. Acta Diabetol 2005; 42 Suppl 1:S42-S49.
  • National Kidney Foundation Recommendations on Treatment of HTN and Diabetes The blood pressure treatment goal for diabetics with hypertension proposed by the National Kidney Foundation Hypertension and Diabetes Executive Committee consensus report is 130/80 mmHg. If the patient has proteinuria > 1gm/day, goal blood pressure should be reduced further to 125/75 mmHg. The goal of treatment is not only to reduce blood pressure to goal, but to reduce or eliminate proteinuria to the extent possible. Certain medications, such as the ACE inhibitors and the angiotensin receptor blockers, appear to be more effective in achieving this combined end point than other anti-hypertensive agents. A reduction in both blood pressure and proteinuria has been associated with a reduction in the incidence of ischemic heart disease or in its progression in diabetic patients with pre-treatment cardiac ischemic conditions or impaired renal function. Reference: Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, Tuttle K, Douglas J, Hsueh W, Sowers J. 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(3):646-661.
  • Supra Rx Dose of ARBs

    1. 2. Supratherapeutic Doses of Angiotensin Receptor Blockers Beneficial and Controversy Thitisak Kitthaweesin MD. Department of Medicine Phramongkutklao Hospital and College of Medicine
    2. 4. Adjusted incident rates & annual percent change Incident ESRD patients; rates adjusted for age, gender, & race. USRDS Annual Data Report 2007
    3. 5. International Comparison: Where we are …. Prevalence 2002 USRDS Yearly Incidence 2002 USRDS Thailand (2004) 236 pMp Thailand (2004) 121 pMp TRT Registry 2005 www.nephrothai.org
    4. 6. Prevalent counts & adjusted rates by primary diagnosis December 31 point prevalent ESRD patients; rates adjusted for age, gender, & race. USRDS Annual Data Report 2007
    5. 7. Diabetes: The Most Common Cause of ESRD Primary Diagnosis for Patients Who Start Dialysis United States Renal Data System. Annual data report. 2000. 1984 1988 1992 1996 2000 2004 2008 0 100 200 300 400 500 600 700 r 2 =99.8% 243,524 281,355 520,240 No. of dialysis patients (thousands) Diabetes 50.1% Hypertension 27% Glomerulonephritis 13% Other 10% No. of patients Projection 95% CI
    6. 8. Projected growth of incident & prevalent ESRD populations through 2020 , by primary diagnosis (Markov model) Counts projected using a Markov model. Original projection uses data through 2000; new projection uses data through 2005. USRDS Annual Data Report 2007
    7. 9. Proteinuria Is an Independent Risk Factor for Mortality in Type 2 Diabetes 1.0 0.9 0.8 0.7 0.6 0.5 0 1 2 3 4 5 6 Years Survival (all-cause mortality) Normoalbuminuria (n=191) Microalbuminuria (n=86) Macroalbuminuria (n=51) Gall, MA et al. Diabetes 1995;44:1303 P<0.01 normo vs. micro- and macroalbuminuria P<0.05 micro vs. macroalbuminuria
    8. 10. Proteinuria is an independent predictor of kidney disease progression
    9. 11. Copyright ©2005 American Society of Nephrology Zhang, Z. et al. J Am Soc Nephrol 2005;16:1775-1780 Figure 1. Risk associated with increasing proteinuria for (1) the primary endpoint of doubling of serum creatinine concentration, ESRD, or death; (2) ESRD or death; and (3) ESRD
    10. 12. Copyright ©2005 American Society of Nephrology Zhang, Z. et al. J Am Soc Nephrol 2005;16:1775-1780 Figure 3. Kaplan-Meier curves for ESRD for the total Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan study population by treatment group (original; A) and adjustment for proteinuria as a continuous variable (adjusted; B)
    11. 13. Urinary protein excretion rate is the best independent predictor of ESRF in non - diabetic proteinuric chronic nephropathies Progression to end - stage renal failure per tertile of baseline urinary protein excretion rate . Symbols are: ( ) lowest; ( ) middle; ( ) highest tertile. Ruggenenti et al. Kidney Inter 1998;53:1209-16 MDRD study
    12. 14. Urinary protein excretion rate is the best independent predictor of ESRF in non - diabetic proteinuric chronic nephropathies Progression to end - stage renal failure per tertile of baseline urinary protein excretion rate and mean arterial pressure ( MAP ). Ruggenenti et al. Kidney Inter 1998;53:1209-16
    13. 15. Proteinuria is a risk marker for cardiovascular disease
    14. 16. Urinary Albumin Excretion Predicts Cardiovascular and Noncardiovascular Mortality in General Population Crude Incidence Rates per 1000 Person - Years for All - Cause, CV, and Non - CV Mortality by UAC Hillege HL et al. PREVEND study group. Circulation 2002;106:1777-1782.
    15. 17. Risk of Ischemic Heart Disease Related to SBP and Microalbuminuria Borch-Johnsen K, et al. Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997. N=2,085; 10 year follow-up
    16. 18. Microalbuminuria Compared To Traditional Risk Factors For Ischemic Heart Disease N=2,085; 10 year follow-up Borch-Johnsen K, et al. Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997. A/C ratio > 0.65mg/mmol > 7.0 mmol/L > 160 mmHg
    17. 19. Monitoring and detection
    18. 20. Definitions of Microalbuminuria and Macroalbuminuria AER=Albumin excretion rate CR # =creatinine >300 30 - 300 < 30 Urine albumin/ Cr # ratio (mg/gm) >300 30 - 300 < 30 Urine AER (mg/24h) >200 20 - 200 < 20 Urine AER (  g/min) Macro-albuminuria Micro-albuminuria Normal Parameter
    19. 21. Reproducibility of Renal Function Measurement Protein excretion Protein/creatinine ratio Agarwal R. Am J Nephrol 2007;27:92-100
    20. 22. Strategies for Treatment
    21. 23. Pathways Leading To Progressive Renal Failure Renal growth factor & cytokine activation Fibrogenesis Systemic hypertension Progressive Loss of Filtration Surface Area GFR Renal injury  Nephron mass Glomerular hypertension Renal scarring Hyperlipidemia  Filtration of plasma proteins Proteinuria  Proximal tubule protein uptake Renal microvascular injury Influx of monocytes and macrophages Transdifferentiation of renal cells to fibroblast phenotype Brenner BM, Keane WF. 2001.
    22. 24. Pathologic Processes Leading to Glomerular Injury and Proteinuria Ang II Increased Glomerular Pressure Ang II Urinary protein Glucose AGEs Glycoxidation (glycation) Efferent arteriolar constriction =angiotensin AT 1 receptor
    23. 25. Role of Angiotensin II in Chronic Renal Disease  Adhesion molecules  Chemotactic factors  Cell growth  Apoptosis  TGF-  , CTGF  PAI-1  Glomerular capillary pressure  Single nephron GFR Macrophage infiltration Angiotensin II <ul><li>Mechanical stress </li></ul><ul><li>Mesangial changes </li></ul><ul><li>Oxidative stress </li></ul><ul><li>Proteinuria </li></ul><ul><li>NF-  B activation </li></ul>Glomerulosclerosis & Tubulo-interstitial fibrosis Renal disease Nephron loss
    24. 26. ACEI and ARB
    25. 27. Afferent arteriole, BP drop Renin Negative feedback Increased blood pressure Sodium retention Aldosterone Inactive fragments Bradykinin ACE Angiotensin II Angiotensinogen Angiotensin I Non-ACE pathway Tissue Chymase Cathepsin G AT 1 RECEPTORS ADRENAL GLAND AT 1 RECEPTORS BLOOD VESSELS VASOCONSTRICTION The Lancet; Vol 355, Feb 2000
    26. 28. K / DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease Am J Kidney Dis 2004; 43: S 65- S 223 (suppl 1 )
    27. 29. ACEI and ARB
    28. 30. Clinical Endpoint Data for ESRD in Type 2 Diabetes with ACE Inhibitors Are Lacking <ul><li> Endpoints Studied </li></ul><ul><li>ACE Inhibitor Trials </li></ul><ul><li>in Type 2 Diabetics Total Reduction of Reduction of Reduction in Risk with >1 Year Follow-Up Sample Proteinuria GFR Decline of ESRD * </li></ul><ul><li>Ravid et al Ann Intern Med 1993 94 Yes Yes  No </li></ul><ul><li>Lebovitz et al Kidney Int 1994 121 Yes Yes  No </li></ul><ul><li>Bakris et al Kidney Int 1996 52 Yes Yes  No </li></ul><ul><li>Ahmad et al Diabetes Care 1996 103 Yes Yes  No </li></ul><ul><li>Nielsen et al Diabetes Care 1997 36 Yes Yes  No </li></ul><ul><li>UKPDS et al Br Med J 1998 758 Yes No  No </li></ul><ul><li>Fogari et al J Hum Hypertens 1999 107 Yes No  No </li></ul><ul><li>ABCD Diabetes Care 2000 470 Yes Yes  No </li></ul><ul><li>Ruggenenti et al (REIN) 352 (27)** Yes Yes Yes** </li></ul><ul><li>Am J Kidney Dis 2000 MICRO-HOPE** Lancet 2000 3577 Yes No  Yes*** </li></ul>GFR=glomerular filtration rate *Reduction in the risk of end-stage renal disease (renal transplant or dialysis) **Only 27 (8%) of the 352 patients in this study were Type 2 diabetics ***In this study there was no reduction of risk for renal dialysis for ramipril compared to placebo (p=0.70)
    29. 31. Evidence for ARBs and Renoprotection in Diabetes ↓ transition to overt nephropathy, 55%, 66% in 40, 80 mg Telmisartan vs Placebo 675 1.0 yr INNOVATION <2007>  43% of baseline albuminuria Losartan < 140/90 422 0.5 yr Lozano <2001>  incidence of progression to macroal-buminuria ( hazard ratio = 0.30, 0.14-0.61 ) Irbesartan vs Placebo < 135/85 590 2.0 yrs IRMA-2 <2001>  baseline albuminuria, 56% vs 92% Valsartan vs Amlodipine < 135/85 332 0.5 yr MARVAL <2002> T2DM with microalbuminuria  24% of proteinuria with mono Rx  50% with combined Rx Candesartan vs lisinopril + both 199 0.5 yr CALM <2000> Major Findings Rx comparator BP goal Number Trial
    30. 32. Evidence for ARBs and Renoprotection in Diabetes ↓ proteinuria 29% vs 19% Telmisartan vs Losartan 800 1 yr AMADEO <2003> ↓ proteinuria , comparable Telmisartan vs Valsartan 800 1 yr VIVALDI <2003> No inferiority in the change in GFR from baseline Telmisartan vs Enalapril 199 5 yrs DETAIL <2004>  20-23% risk of composite end point (doubling SCr/ESRD/death)  29-39% risk of doubling SCr Irbesartan vs Amlodipine vs Placebo < 135/85 1715 2.6 yrs IDNT <2001> T2 DM with o vert nephropathy  16% risk of composite end point (doubling SCr/ESRD/death)  25% risk of doubling SCr, 28% ESRD Losartan vs Placebo < 140/90 1513 3.4 yrs RENAAL <2001> Major Findings Rx comparator BP goal Number Trial
    31. 33. RENAAL R eduction of E ndpoint in N IDDM with the A ngiotensin II A ntagonist L osartan Study
    32. 34. RENAAL : R eduction of E ndpoint in N IDDM with the A ngiotensin II A ntagonist L osartan Study <ul><li>1513 patients with type 2 diabetes </li></ul><ul><ul><li>Proteinuria (urine alb/cr >300 mg/g, >25 mg/mmol) </li></ul></ul><ul><ul><li>Serum Creatinine: 1.3-3.0 mg/dl </li></ul></ul><ul><ul><li>Mean age 60 years old </li></ul></ul><ul><li>Multicenter, randomized, double-blind, placebo-controlled </li></ul><ul><ul><li>Placebo +normal AHT </li></ul></ul><ul><ul><li>Losartan 50-100 mg OD + Normal AHT </li></ul></ul><ul><ul><li>AHT excluded ACEI and other ARB </li></ul></ul><ul><ul><li>Target BP: SBP<140 mm Hg, DBP<90 mm Hg </li></ul></ul><ul><li>Primary outcome measurement </li></ul><ul><ul><li>Doubling of serum creatinine </li></ul></ul><ul><ul><li>ESRD </li></ul></ul><ul><ul><li>ESRD and death </li></ul></ul>Brenner B et al. N Engl J Med. 2001;345:861-869.
    33. 35. RENAAL Study Design qd=once daily *CT=conventional therapy: Open-label calcium-channel blocker, diuretic, beta blocker, alpha blocker, or centrally acting agents. Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334. 4 wk Losartan 100 mg qd (+CT) Maintain conventional antihypertensive therapy (CT)* (excluding ACE inhibitors, A II antagonists) Losartan 100 mg qd (+CT) Placebo (+CT) Goal trough BP: <140/<90 mmHg n=1513 Placebo (+CT) Losartan 50 mg qd (+CT) Placebo (+CT) 8 wk 6 wk Mean follow-up 3.4 years
    34. 36. RENAAL: Inclusion/Exclusion Criteria <ul><li>Inclusion criteria </li></ul><ul><li>Type 2 diabetes </li></ul><ul><li>Age 31-70 years </li></ul><ul><li>Proteinuria: urine alb:cr >300 mg/g, >25 mg/mmol </li></ul><ul><li>Serum Creatinine: 1.3-3.0 mg/dl, 115-265 µmol/L* </li></ul><ul><li>Exclusion criteria </li></ul><ul><li>Type 1 diabetes </li></ul><ul><li>Known non-diabetic renal disease or renal artery stenosis </li></ul><ul><li>Recent history of MI, CABG, PTCA, CVA, TIA </li></ul><ul><li>History of heart failure </li></ul><ul><li>HbA1c >12% </li></ul>*Lower limit 1.5 mg/dl (133 µmol/L) in male patients >60 kg Brenner BM et al J Renin-Angio-Aldo System 2000;1(4):328-335.
    35. 37. RENAAL: Blood Pressure Changes Baseline Study End 152/82 mm Hg 140/74 mm Hg Losartan + usual AHT 153/82 mm Hg 142/74 mm Hg Placebo + usual AHT AHT = antihypertensive therapy (excluding ACEIs and other ARBs). Brenner B et al. N Engl J Med. 2001;345:861-869.
    36. 38. RENAAL : Primary Composite Endpoint and Components DsCr, ESRD, Death Doubling of sCr ESRD Death ESRD or Death Losartan (+CT) (n=751) n (%) 327 (43.5) 162 (21.6) 147 (19.6) 158 (21.0) 255 (34.0) 359 (47.1) 198 (26.0) 194 (25.5) 155 (20.3) 300 (39.4) P-Value 0.02 0.006 0.002 0.88 0.01 % Risk Reduction 16 25 28 -2 20 95% CI (2, 28) (8, 39) (11, 42) (-27, 19) (5, 32) Composite and Components Placebo (+CT) (n=762) n (%) Brenner BM et al New Engl J Med 2001;345(12):861-869.
    37. 39. RENAAL Primary Components ESRD Months % with event RR: 28% p=0.002 ESRD or Death Months % with event sCr=serum creatinine; RR=risk reduction Adapted from Brenner BM et al N Engl J Med 2001;345(12):861-869. Doubling of sCr Months % with event RR: 25% p=0.006 Placebo (+CT) 762 689 554 295 36 Losartan (+CT) 751 692 583 329 52 RR: 20% p=0.010 Placebo (+CT) 762 715 610 347 42 Losartan (+CT) 751 714 625 375 69 Placebo (+CT) 762 715 610 347 42 Losartan (+CT) 751 714 625 375 69 0 12 24 36 48 0 10 20 30 0 12 24 36 48 0 10 20 30 40 50 0 12 24 36 48 0 10 20 30
    38. 40. Primary Components : Doubling of Serum Creatinine Brenner BM et al . New Engl J Med 2001;345(12):861-869. RENAAL: R eduction of E ndpoint in N IDDM with the A ngiotensin II A ntagonist L osartan Study Months % with event p=0.006 Risk Reduction: 25% 751 692 583 329 52 762 689 554 295 36 P (+ CT) L (+ CT) 0 12 24 36 48 0 10 20 30 P L
    39. 41. RENAAL: Primary Components, ESRD Brenner BM et al . New Engl J Med 2001;345(12):861-869. Months % with event 0 12 24 36 48 0 10 20 30 p=0.002 Risk Reduction: 28% P L P (+ CT) L (+ CT) 751 714 625 375 69 762 715 610 347 42
    40. 42. RENAAL: Primary Components, ESRD or Death ESRD or Death P (+ CT) L (+ CT) Months % with event 0 12 24 36 48 0 10 20 30 40 50 751 714 625 375 69 762 715 610 347 42 P L p=0.010 Risk Reduction: 20% Brenner BM et al . New Engl J Med 2001;345(12):861-869.
    41. 43. RENAAL Change from Baseline in Proteinuria 0 12 24 36 48 Months Median % change – 60 – 40 – 20 0 20 40 35% Overall reduction p<0.001 Proteinuria measured as the urine albumin:creatinine ratio from a first morning void. Adapted from Brenner BM et al N Engl J Med 2001;345(12):861-869. Placebo (+CT) 762 632 529 390 130 Losartan (+CT) 751 661 558 438 167
    42. 44. RENAAL Rate of Progression of Renal Disease (median 1/sCr slope) Losartan (+CT) Placebo (+CT) 0 – 0.02 – 0.04 – 0.06 – 0.08 dl/mg/yr – 0.056 – 0.069 p=0.01 18% reduction Adapted from Brenner BM et al N Engl J Med 2001;345(12):861-869.
    43. 45. ARB renoprotection in type 2 diabetes GFR decline with ARB treatment RENAAL* GFR decline (mL/min/1.73m 2 /year) IDNT † DETAIL † § *Median; † Mean § Completers IRMA2 † Barnett et al. N Engl J Med 2004;351:1952–1961 Barnett et al. Acta Diabetol 2005; 42 Suppl 1:S42-S49 Treatment duration: 3.4 years 2.6 years 2 years 5 years
    44. 46. Optimal dose of Losartan for Renoprotection in Diabetic Nephropathy Anderson S et al. Nephrol Dial Transplant ( 2002 ) 17 : 1413-1418
    45. 47. Table 1.  Characteristics of 50 type 1 diabetic patients with diabetic nephropathy Mean (SEM); *Geometric mean (95% CI). Anderson S et al. Nephrol Dial Transplant ( 2002 ) 17 : 1413-1418 91 ( 3 ) Glomerular filtration rate ( ml / min / 1.73 m 2 ) 105 ( 2 ) 24-h mean arterial blood pressure ( mmHg ) 81 ( 2 ) 24-h diastolic blood pressure ( mmHg ) 155 ( 3 ) 24-h systolic blood pressure ( mmHg ) 1138 ( 904–1432 ) Albuminuria ( mg / 24 h )* 28/72 Retinopathy ( non - proliferative / proliferative ) (%) 32 ( 1 ) Diabetes duration ( years ) 44 ( 2 ) Age ( years ) 33/17 Sex ( m / f )
    46. 48. Table 2 .   Kidney function and systemic blood pressure in 50 type 1 diabetic patients with diabetic nephropathy Anderson S et al. Nephrol Dial Transplant ( 2002 ) 17 : 1413-1418 98 ( 2 ) 97 ( 2 ) 100 ( 2 ) 105 ( 2 ) 24-h mean arterial blood pressure ( mmHg ) 76 ( 2 ) 75 ( 2 ) 77 ( 2 ) 81 ( 2 ) 24-h diastolic blood pressure ( mmHg ) 145 ( 3 ) 143 ( 3 ) 148 ( 2 ) 155 ( 3 ) 24-h systolic blood pressure ( mmHg ) 87 ( 3 ) 87 ( 3 ) 89 ( 3 ) 91 ( 3 ) Glomerular filtration rate ( ml / min / 1.73 m 2 ) 66 ( 47–94 ) 67 ( 44–99 ) 79 ( 56–113 ) 108 ( 79–149 ) IgG fractional clearance ( ) ( 10 -6 ) 174 ( 123–247 ) 171 (121-241) 208 ( 148–291 ) 308 ( 234–405 ) Albumin fractional clearance ( ) ( 10 -6 ) 63 ( 47–85 ) 56 (40-79) 76 ( 56–104 ) 98 ( 74–130 ) U - IgG ( mg / 24 h ) 642 ( 467–882 ) 597 (438-814) 796 ( 607–1043 ) 1138 ( 904–1432 ) Albuminuria ( mg / 24 h )* Losartan 150 mg Losartan 100 mg Losartan 50 mg Baseline
    47. 49. Optimal dose of Losartan for Renoprotection in Diabetic Nephropathy Anderson S et al. Nephrol Dial Transplant ( 2002 ) 17 : 1413-1418 N=50, T1DM
    48. 50. Renoprotection of Optimal Antiproteinuric Doses ( ROAD ) Study : A Randomized Controlled Study of Benazepril and Losartan in Chronic Renal Insufficiency Hou, F. F. et al. J Am Soc Nephrol 2007;18:1889-1898
    49. 51. Copyright ©2007 American Society of Nephrology Hou, F. F. et al. J Am Soc Nephrol 2007;18:1889-1898 Figure 1. Study flow diagram N=167+172, non-DM CKD
    50. 52. Copyright ©2007 American Society of Nephrology Hou, F. F. et al. J Am Soc Nephrol 2007;18:1889-1898 Figure 2. Kaplan-Meier estimates of the percentage of patients who reached the primary composite end point of a doubling of the serum creatinine level, ESRD, or death according to intention-to-treat (A) or per-protocol principal (B)
    51. 53. Hou, F. F. et al. J Am Soc Nephrol 2007;18:1889-1898 Figure 3. Median of changes in urinary proteinuria excretion (A), median of creatinine clearance (B), estimated GFR (eGFR; C), BP in all patients (D), median of systolic BP in patients with decline of eGFR ({Delta}eGFR) >5 or <=5 ml/min per 1.73 m2 (E), and median of urinary excretion of urea and chloride (F) Urinary protein excretion Median CrCl Estimated GFR
    52. 54. Table 3 . Adverse events after randomization Hou, F. F. et al. J Am Soc Nephrol 2007;18:1889-1898 1 1 2 1      Hypotension 0 0 15 17      Dry cough 3 3 3 2      Acute decline in renal function 5 3 5 3      Hyperkalemia 1 1 1 1      Stroke 1 2 2 1      Heart failure 2 2 2 2      Myocardial infarction 4 5 5 4      Nonfatal cardiovascular event 9 7 25 23 Adverse events Group 4 ( n = 90 ) Group 3 ( n = 90 ) Group 2 ( n = 90 ) Group 1 ( n = 90 )
    53. 55. Enhanced renoprotective effects of ultrahigh doses of I rbesartan in patients with T2DM and microalbuminuria Rossing K et al. Kidney Int 2005;68:1190-1198 N=52, T2DM+microalbuminuria
    54. 56. Rossing K et al. Kidney Int 2005;68:1190-1198
    55. 57. Rossing K et al. Kidney Int 2005;68:1190-1198
    56. 58. Additional Antiproteinuric Effect of Ultrahigh Dose Candesartan : A Double - Blind, Randomized, Prospective Study Copyright ©2005 American Society of Nephrology Schmieder, R. E. et al. J Am Soc Nephrol 2005;16:3038-3045 N=32 Proteinuria 1-10 g/d
    57. 59. Copyright ©2005 American Society of Nephrology Schmieder, R. E. et al. J Am Soc Nephrol 2005;16:3038-3045 Figure 3. Proteinuria throughout the whole study period
    58. 60. Copyright ©2005 American Society of Nephrology Schmieder, R. E. et al. J Am Soc Nephrol 2005;16:3038-3045 Figure 4. Scatterplot of changes in proteinuria versus changes in BP
    59. 61. Studies of High Dose ARB Berl T. Nephrol Dial Transplant (August) 2008;23:2443-2447
    60. 63. Conclusion <ul><li>CKD is common progressive disease that lead to ESRD and CVD </li></ul><ul><li>DM and HT are most common cause of CKD </li></ul><ul><li>Proteinuria is predictor of CKD progression and cardiovascular risk marker </li></ul><ul><li>Targeting at RAAS is strategy for CKD treatment </li></ul><ul><li>ARB and ACEi are beneficial in proteinuric nephropathy (DM/non-DM) </li></ul><ul><li>High dose ARB is one of options for maximize inhibition of RAAS to retard renal progression </li></ul>
    61. 64. Thank you
    62. 65. Safety
    63. 66. Hyperkalemia in ARB and ACEI Bakris et al. Val-K study group. Kidney Int Nov 2000;58:2084-92
    64. 67. Hyperkalemia in ARB and ACEI Baseline Week 4 Bakris et al.Val-K study group. Kidney Int Nov 2000 ;58:2084-92 .
    65. 68. Effects of ACEI Compared to ARB in Patient with Hypertension and GFR>60 Bakris et al.Val-K study group. Kidney Int Nov 2000 ;58:2084-92 .
    66. 69. Effects of ACEI Compared to ARB in Patient with Hypertension and GFR < 60 Bakris et al. Val-K study group. Kidney Int Nov 2000;58:2084-92 * * * p<0.05 compared to baseline
    67. 70. Albuminuria Response to Very High Dose Valsartan in T2DM Hollenberg et al. J Hypertens 2007;25:1921-6
    68. 71. Hollenberg et al. J Hypertens 2007;25:1921-6
    69. 72. Long-Term Renoprotective Effects of Standard Versus High Doses of Telmisartan in Hypertensive Nondiabetic Nephropathies Arandra P. et al. Am J Kidney Dis 2005;46:1074-1079
    70. 73. Arandra P. et al. Am J Kidney Dis 2005;46:1074-1079
    71. 74. Studies of High Dose ACEi
    72. 75. IDNT I rbesartan D iabetic N ephropathy T rial
    73. 76. IDNT: Irbesartan Diabetic Nephropathy Trial <ul><li>1715 patients with type 2 diabetes (>15 years) </li></ul><ul><ul><li>24-hour urine protein excretion >900 mg (mean 4,016 mg) </li></ul></ul><ul><ul><li>Serum creatinine 1.0-3.0 mg/dl (mean 1.7 mg/dl) </li></ul></ul><ul><ul><li>Mean age 59 years old </li></ul></ul><ul><li>210 centers, prospective, randomized, double-blind </li></ul><ul><ul><li>Irbesartan 75-300 mg OD + AHT </li></ul></ul><ul><ul><li>Amlodipine 2.5-10 mg OD + AHT </li></ul></ul><ul><ul><li>Placebo + AHT (BP target = 135/85 mmHg) </li></ul></ul><ul><li>Primary outcome measurement </li></ul><ul><ul><li>Doubling of serum creatinine </li></ul></ul><ul><ul><li>ESRD </li></ul></ul><ul><ul><li>All cause mortality </li></ul></ul>Lewis E et al. N Engl J Med. 2001;345:851-860.
    74. 77. IDNT: Irbesartan Diabetic Nephropathy Trial <ul><li>Inclusions </li></ul><ul><ul><li>Type 2 hypertensive diabetic subjects </li></ul></ul><ul><ul><li>30-70 years of age </li></ul></ul><ul><ul><li>24-hour urine protein excretion >900 mg </li></ul></ul><ul><ul><li>Serum creatinine 1.0-3.0 mg/dL </li></ul></ul><ul><li>Exclusions </li></ul><ul><ul><li>Age of onset of diabetics <20 years </li></ul></ul><ul><ul><li>Type 1 diabetes </li></ul></ul><ul><ul><li>Absolute requirement for ACEI, ARB, or CCB </li></ul></ul><ul><ul><li>CV disease </li></ul></ul><ul><ul><li>Abnormal serum potassium </li></ul></ul>Lewis E et al. N Engl J Med. 2001;345:851-860.
    75. 78. IDNT: Blood Pressure Changes Baseline Study End 160/88 mm Hg 140/77 mm Hg Irbesartan + AHT 158/87 mm Hg 141/77 mm Hg Amlodipine + AHT 158/87 mm Hg 144/80 mm Hg Placebo + AHT AHT = other antihypertensive therapy (excluding ACEIs, ARBs, and CCBs). Lewis E et al. N Engl J Med. 2001;345:851-860.
    76. 79. IDNT: Irbesartan Diabetic Nephropathy Trial Lewis EJ et al. N Engl J Med 2001;345:851-860. Primary End Point: Time to Doubling of Serum Creatinine Subjects (%) 0 6 12 18 24 30 36 42 48 54 Follow-up (mo) 60 0 10 20 30 40 50 60 70 Irbesartan Amlodipine Control RRR 33% P =0.003 P =NS RRR 37% P <0.001
    77. 80. IDNT: Primary Endpoint Time to Doubling of Serum Creatinine, ESRD, or Death Subjects (%) 0 6 12 18 24 30 36 42 48 54 Follow-up (mo) 60 Irbesartan Amlodipine Control RRR 20% P =0.02 P =NS RRR 23% P =0.006 Lewis EJ et al. N Engl J Med 2001;345:851-860. 0 10 20 30 40 50 60 70
    78. 81. IRMA 2 I rbesatan R educe M icro A lbuminuria in Type 2 Diabetes
    79. 82. IRMA 2: Irbesatan Reduce MicroAlbuminuria in Type 2 Diabetes <ul><li>590 patients with type 2 diabetics </li></ul><ul><ul><li>Hypertensive (DBP>85 mmHg or SBP>135 mmHg) </li></ul></ul><ul><ul><li>Microalbuminuria (UAER 20-200 µg/min, mean 55 µg/min) </li></ul></ul><ul><ul><li>Normal kidney function (serum creatinine <1.6 mg/dl in men <1.2 mg/dl in women) </li></ul></ul><ul><li>Randomization </li></ul><ul><ul><li>Irbesartan 150 mg + AHT* </li></ul></ul><ul><ul><li>Irbesartan 300 mg + AHT* </li></ul></ul><ul><ul><li>Placebo + AHT (excluding ACEIs, other ARBs, and DHP CCBs) </li></ul></ul><ul><li>Primary outcome measurement </li></ul><ul><ul><li>Development of overt proteinuria </li></ul></ul>Parving HH et al. N Engl J Med. 2001;345:870-878.
    80. 83. IRMA 2: Blood Pressure Changes Baseline Study End 153/90 mm Hg 143/84 mm Hg Irbesartan 150 mg + usual AHT 153/91 mm Hg 142/84 mm Hg Irbesartan 300 mg + usual AHT 153/90 mm Hg 145/84 mm Hg Placebo + usual AHT Parving HH et al. N Engl J Med. 2001;345:870-878.
    81. 84. IRMA 2: Irbesatan Reduce MicroAlbuminuria in Type 2 Diabetes Parving H-H, et al. N Engl J Med 2001;345:870-878. Primary Endpoint : Development of Overt Proteinuria 14 18 16 12 10 8 6 4 2 0 Subjects (%) Control (n=201) 150 mg (n=195) 300 mg (n=194) Irbesartan 9.7 5.2 14.9 RRR=39% P =0.08 RRR=70% P<0.001 NNT = 10
    82. 85. ARB (Losartan) Reduces Urinary Albumin and TGF-  1 in Type 2 Diabetes with Microalbuminuria Esmatjes E, et al. Nephrol Dial Transplant. 2001;16(Suppl1):90-93. 160 140 130 120 24-hour Systolic BP P <0.01 vs baseline mmHg 4 Weeks 90 80 70 60 24-hour Diastolic BP P <0.03 vs baseline Baseline 8 Weeks mmHg 50 Urinary Albumin Excretion P<0 .01 vs baseline 100 90 80 70 60 mcg/min 6 5 4 3 2 1 TGF-  P<0 .005 vs baseline Baseline 4 Weeks 8 Weeks ng/mL www.hypertensiononline.org
    83. 86. Effect of ARB vs ACE-I in Reduction in Progression of Urinary Albumin Excretion in Type 2 Diabetic Patients Muirhead N, et al. Curr Ther Research 1999;60(12):650-660 -16.7 -10.8 11.5 -30 -20 -10 0 10 20 Valsartan 80mg (n=27) Captopril 25mg tid (n=29) Placebo (n=28) %Change in AER from baseline (µg/min)
    84. 87. Effects of ARB vs ACEI: Progression to Proteinuria Muirhead et al, J Am Coll Cardiol, 1999. Prospective study 122 patients Type 2 DM Microalbuminuria FU for 52 weeks Progression to proteinuria (two AER > 300 ug/min within 6 mo)
    85. 88. Effects of ARB on GFR: Non-DM Castelao et al, JASN, 1999. Double blind Placebo control multicenter study 56 patients HT + CRF FU 6 months
    86. 89. Morbidity and Mortality Along the Renal Continuum Adapted from Burgess Risk Factors Diabetes Hypertension Endothelial Dysfunction Micro- Albuminuria Macro- Proteinuria Nephrotic Proteinuria, End-Stage Renal Disease Death
    87. 90. Morbidity and Mortality Along the Renal Continuum Risk Factors Diabetes Hypertension Endothelial Dysfunction Micro- Albuminuria Macro- Proteinuria Nephrotic Proteinuria, End-Stage Renal Disease Death Adapted from Burgess IDNT RENAAL MARVAL IRMA-2
    88. 91. ARBs prevent diabetic renal disease progression Albumin excretion in patients with microalbuminuria Viberti et al. Circulation 2002;106:672–678 p<0.001 MARVAL
    89. 92. Telmisartan renoprotection in type 2 diabetic nephropathy Reduced transition to overt nephropathy (INNOVATION) Month 0 3 6 9 12 15 18 21 24 27 30 0 0.2 0.4 0.6 0.8 Transition rate p<0.0001 RRR: 66% NNT: 3.0 p<0.0001 RRR: 55% NNT: 3.7 Patients with and without hypertension RRR: relative risk reduction NNT: number needed to treat to prevent 1 transition Makino et al. Diabetes Care 2007 Telmisartan 80 mg Telmisartan 40mg Placebo 16.7% 22.6% 49.9%
    90. 93. ARBs prevent diabetic renal disease progression Serum creatinine in patients with macroproteinuria Brenner et al. N Engl J Med 2001;345:861–869. , Lewis et al. N Engl J Med 2001;345:851–860 RENAAL IDNT p=0.003 p<0.001 p=0.006
    91. 94. Combination therapy provides additive benefit – CALM study Mogensen et al. BMJ 2000;321:1440–1444
    92. 95. Telmisartan renoprotection in type 2 DM Reduces long-term decline in GFR (DETAIL) Barnett et al. N Engl J Med 2004;351:1952–1961. Erratum in: N Engl J Med 2005;352:1731 Barnett. Acta Diabetol 2005; 42 Suppl 1:S42–S49 Total GFR † p = NS, telmisartan vs enalapril p = NS † Change in GFR p = NS † Baseline After 5 years ml/min/1.73m 2 ml/min/1.73m 2
    93. 96. National Kidney Foundation Recommendations on Treatment of HTN and Diabetes <ul><li>Blood pressure goal: 130/80 mmHg </li></ul><ul><li>Target blood pressure: 125/75 for patients with >1 gram/day proteinuria </li></ul><ul><li>Blood pressure lowering medications should reduce both blood pressure + proteinuria </li></ul><ul><li>Therapies that reduce both blood pressure and proteinuria have been known to reduce renal disease progression and incidence of ischemic heart disease </li></ul>Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661. www.hypertensiononline.org

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