[Clinical and health economic implications of early treatment with irbesartan of patients with type 2 diabetes mellitus, hypertension and nephropathy]. / Klinische und gesundheitsökonomische Auswirkungen einer frühen Irbesartan-Therapie bei Typ-2-Diabetes, Hypertonie und Nierenerkrankung.

BACKGROUND AND OBJECTIVE: It was the aim of this study to project the long-term clinical and cost outcomes of irbesartan treatment, based on data from the irbesartan in Reduction of Microalbuminuria-2 (IRMA-2) study and the irbesartan in Diabetic Nephropathy Trial (IDNT), in hypertensive patients with type 2 diabetes and renal disease in Germany. PATIENTS AND METHODS: A Markov model adapted to the German setting simulated progression of renal disease and associated changes in mortality in patients with hypertension, type 2 diabetes and microalbuminuria. Early irbesartan 300 mg daily (initiated at microalbuminuria) and late irbesartan (initiated at overt nephropathy) were compared to a control scheme of antihypertensive standard medications with comparable blood pressure control, initiated at microalbuminuria. Cumulative incidence of ESRD, time to onset of ESRD, life expectancy (LE), quality-adjusted life years (QALY) and costs were projected over 25 years for 1,000 simulated patients, from a third party payer perspective. Clinical and cost outcomes were discounted at 5% per annum. RESULTS: When compared to standard blood pressure control, both early and late treatment with irbesartan were projected to reduce the cumulative incidence of ESRD fromm23.80.3% to 9.10.6% and 19.83%, increase discounted LE by 0.670.04 and 0.030.00 years, and improve QALY by 0.750.04 and 0.070.01 years per treated patient, respectively. Early irbesartan treatment was associated with a cost savings of i 12,658825 per patient while late irbesartan treatment was associated with a cost savings of i 4,116575 per patient compared to control over the 25-year time horizon. CONCLUSIONS: Early irbesartan treatment was projected to improve LE and QALY, and reduce the onset of ESRD, with cost savings, in hypertensive patients with type 2 diabetes and microalbuminuria in Germany. Later use of irbesartan in overt nephropathy is also superior to standard care. These findings suggest that irbesartan should be started earlier and continued long-term.

[Cost-efectiveness of Ibersartan in type II diabetic nephropathy with hypertension. A Spanish perspective]. / Coste-efectividad de irbesartan en pacientes hipertensos con nefropatía diabética tipo II: una perspectiva española.

BACKGROUND: In the Irbesartan Diabetic Nephropathy Trial (IDNT), treatment with irbesartan demonstrated 23% and 20% reductions in the combined endpoint of doubling of serum creatinine (DSC), end-stage renal disease (ESRD) or death in patients with hypertension, type 2 diabetes and overt nephropathy compared to amlodipine and control respectively. A simulation model was developed to project long-term cost consequences of the IDNT in the Spanish setting. METHODS: A Markov model simulated progression from nephropathy to DSC, ESRD and death in patients with hypertension, type 2 diabetes and overt nephropathy. Treatment-specific probabilities were derived from IDNT. Country-specific ESRD-related data were retrieved from published sources. Delay in onset of ESRD, life expectancy and mean lifetime costs were calculated for patients with baseline age 59 years. Future costs were discounted at 6% per annum, and clinical benefits were discounted at 0% and 6% per annum. Extensive sensitivity analyses were performed. RESULTS: Onset of ESRD was delayed with irbesartan by 1.41 and 1.35 years versus amlodipine and control respectively. When a 25-year (lifetime) horizon was considered, delay in ESRD onset led to anticipated improvements in life expectancy (discounted at 6% shown in brackets) of 0.46 (0.21) years versus amlodipine and 0.75 (0.37) years versus control. Irbesartan was associated with cost savings of 13,673 Euro and 7,632 Euro patient versus amlodipine and control respectively. The results were robust under a wide range of plausible assumptions. CONCLUSIONS: Treating patients with hypertension, type 2 diabetes and overt nephropathy using irbesartan was both cost- and life-saving compared to amlodipine and control in the Spanish setting.

An economic evaluation of the Irbesartan in Diabetic Nephropathy Trial (IDNT) in a UK setting.

There are substantial healthcare costs associated with the provision of renal replacement therapy. Patients with diabetes mellitus are the largest and fastest growing group developing end-stage renal disease (ESRD) in the United Kingdom (UK). Treatment leading to a slowing of progression to ESRD in diabetic patients could lead to considerable cost savings. Using treatment-specific probabilities derived from the Irbesartan in Diabetic Nephropathy Trial (IDNT), the cost effectiveness of treating patients with hypertension, type II diabetes and nephropathy with irbesartan, amlodipine or control was calculated using a Markov model. UK-specific ESRD-related data were retrieved from published sources to reflect local management practices, ESRD outcomes and costs. Mean 10-year costs and changes in life expectancy due to ESRD delayed or avoided were calculated. Future costs and clinical benefits were discounted at 6.0 and 1.5% per annum and extensive sensitivity analyses were performed. Delay in the onset of ESRD with irbesartan led to cost savings of pound sterling 5125 and pound sterling 2919/patient and improvements in projected discounted life expectancy of 0.07 and 0.21 years over 10 years vs amlodipine and control, respectively. The costs of treatment of ESRD were the main contributor to the total costs. The cost of trial medications had only a minor impact. These results were robust in a wide range of plausible assumptions. Given that the IDNT efficacy results could be translated to a UK setting, treating patients with hypertension, type II diabetes and overt nephropathy with irbesartan was cost saving over a 10-year period compared to amlodipine and control.

[Health economic consequences of the use of irbesartan in patients in Germany with type 2 diabetes, nephropathy and hypertension]. / Gesundheitsökonomische Aspekte der Anwendung von Irbesartan bei Patienten mit Typ-2-Diabetes, Nephropathie und Hypertonie in Deutschland.

BACKGROUND AND AIMS: The "Irbesartan in Diabetic Nephropathy Trial" (IDNT), demonstrated a reduction in the combined endpoint of doubling of serum creatinine, end-stage renal disease (ESRD) or death compared to control or amlodipine arms in patients with hypertension, type 2 diabetes and overt nephropathy when treated with irbesartan. Aim of this study is to compare long-term consequences in costs and outcomes of IDNT treatment alternatives from the German health care system's perspective. METHODS: A Markov model simulated progression from overt nephropathy to doubling of serum creatinine, end-stage renal disease, and death in patients with hypertension, type 2 diabetes and overt nephropathy for the three treatment arms. Treatment-specific probabilities were derived from IDNT. German-specific ESRD-related data were retrieved from published sources to reflect local management practices, ESRD outcomes and costs. A time horizon of 10 years was used. Delay in onset of ESRD and mean costs per patient were calculated. Future costs were discounted at 5 % per annum. RESULTS: The cumulative incidence of ESRD after 10 years with irbesartan (36 %) is lower compared to amlodipine (49 %) or control (45 %). Irbesartan leads to cost savings of 14 424 EUR and 8 720 EUR per patient versus amlodipine or control respectively. CONCLUSION: Treating patients with hypertension, type 2 diabetes and nephropathy using irbesartan lowers the cumulative incidence of ESRD and is cost-saving compared to amlodipine or control.

A clinical trial in type 2 diabetic nephropathy.

A prospective, randomized, three-armed, double-blind, placebo-controlled clinical trial has been completed in 210 sites worldwide to determine whether the angiotensin II receptor blocker irbesartan or the calcium channel blocker amlodipine has a renoprotective effect in patients with overt type 2 diabetic nephropathy. A total of 1,715 subjects randomized during a 3-year period were followed a minimum of 2 years. The goal for all treatment groups was to achieve equivalent blood pressure control, with the blinded study drug (irbesartan, amlodipine, or placebo) as primary therapy with additional antihypertensive drugs, excluding angiotensin-converting enzyme inhibitors, calcium antagonists, and angiotensin II receptor antagonists, to achieve seated systolic blood pressure less than 135 mm Hg and diastolic blood pressure less than 85 mm Hg. The primary outcome was the combined endpoint of time to doubling of entry serum creatinine, end-stage renal disease, or death. Secondary outcomes included fatal and nonfatal cardiovascular events. A Clinical Management Committee monitored the conduct of the study. An Outcome Confirmation Committee classified all study outcome events in blinded fashion. An external Data Safety Monitoring Committee monitored unblinded data for interim safety and efficacy analyses of the study. Eligibility criteria included informed consent, age 30 to 70 years, adult-onset diabetes, hypertension, urine protein excretion greater than 900 mg/24 hours, and serum creatinine values of 90 to 265 micromol/L in women and 110 to 265 micromol/L in men. Baseline characteristics were age, 59 +/- 8 years; body mass index, 31 +/- 7 kg/m(2); 67% male; 73% white, 14% black, and 13% other; duration of diabetes, 15 +/- 9 years; retinopathy, 66%; neuropathy, 48%; congestive heart failure, 7.5%; screening seated systolic blood pressure, 156 +/- 18 mm Hg, and diastolic blood pressure, 85 +/- 11 mm Hg; urine protein excretion, 4.0 +/- 3.5 g/24 hours; serum creatinine, 150 +/- 53 micromol/L; serum potassium, 4.6 +/- 0.5 mEq/L; total cholesterol, 229 +/- 58 mg/dL; and hemoglobin A(1c), 8.1 +/- 1.7%. This large-scale international trial should help define the clinical course and standards of care for hypertensive adults with type 2 diabetes mellitus and nephropathy. Results available on May 19, 2001, will help in defining the current controversy of the risks and benefits of blockade of the renin-angiotensin system versus calcium channel blockade versus standard antihypertensive therapy in this large patient population.

The Irbesartan type II diabetic nephropathy trial: study design and baseline patient characteristics. For the Collaborative Study Group.

BACKGROUND: Diabetic nephropathy is the most common cause of end-stage renal disease in the developed world. Angiotensin-converting enzyme inhibitors have been demonstrated to be renoprotective in type I diabetes and are now the standard of care for both hypertensive and non-hypertensive type I diabetic patients with any level of proteinuria. The role of blockade of the renin-angiotensin system in type II diabetic patients is not defined. The Collaborative Study Group has initiated the Irbesartan Type II Diabetic Nephropathy Trial (IDNT), studying the effect of the angiotensin II receptor antagonist irbesartan on progression of renal disease and mortality in type II diabetic patients with overt nephropathy and hypertension. Here we report the study design and baseline patient characteristics. METHODS: To qualify, hypertensive type II patients, age 30-70 years, must have a 24 h urinary protein excretion of >900 mg and a serum creatinine 90-265 micromol/l (1.0-3. 0 mg/dl) in women and 110-265 micromol/l (1.2-3.0 mg/dl) in men. Three treatment arms include irbesartan, placebo and amlodipine, with every attempt made to achieve similar blood pressure levels in all treatment arms. A total of 1650 patients will be enrolled utilizing approximately 225 clinics worldwide. The primary outcome measure is time to event to the composite end-point of doubling of serum creatinine, end-stage renal disease or death. The secondary outcome measure is time to composite end-point of fatal or non-fatal cardiovascular events. The average length of patient follow-up is expected to be approximately 36 months. RESULTS: The baseline characteristics of the study subjects are: age 59+/-8 years, duration of diabetes 15+/-9 years, height 168+/-11 cm (5 ft 6 in), weight 87+/-19 kg (192 lb), body mass index 31+/-7 kg/m(2), blood pressure 156+/-18 mmHg/85+/-11 mmHg, serum creatinine 150+/-53 micromol/l (1.7+/-0.6 mg/dl), creatinine clearance 66+/-34 ml/min and 24 h urine protein 4.0+/-3.5 g/day.

Re-evaluation of solute transport groups using the peritoneal equilibration test.

OBJECTIVE: To determine if the previously described peritoneal equilibration test (PET)-determined solute transport groups, as defined by Twardowski, fit our patient population. DESIGN: We reviewed the 195 initial standardized PETs (on 195 patients) performed through our peritoneal dialysis program since 1989. Using the method originally defined by Twardowski using the means and standard deviations of the PET-determined dialysis/plasma ratio (D/P) of creatinine and dialysate-to-0 hour dialysate (D/D0) glucose values, transport groupings for our patient population were determined. Comparisons were then made between patient populations. RESULTS: The mean 4-hour D/P creatinine in our patients was 0.70 +/- 0.10. This compares to a mean of 0.65 +/- 0.15 as determined by Twardowski, and indicates that our patients have higher mean solute transport characteristics and tighter ranges within transport groups than previously reported. Only 2% of our patients fell into the previously described low (L) range, with 30% low average (LA), 51% high average (HA), and 17% high (H). Using our data, we would redefine the groups by a 4-hour D/P creatinine as L < 0.60, LA = 0.60-0.70, HA = 0.70-0.80, and HA > 0.80. Using these values, our population fits a Gaussian distribution with 17% L, 31% LA, 33% HA, and 19% H. CONCLUSION: Our patients have higher mean solute transport and tighter ranges within transport groups than previously reported. Using the previously defined PET-determined transport groupings, low transporters are particularly underestimated. If our population data are representative of the peritoneal dialysis population as a whole, these ranges should be redefined.

Free pentosidine and neopterin as markers of progression rate in diabetic nephropathy. Collaborative Study Group.

BACKGROUND: Patients with diabetic nephropathy experience a progressive and usually inexorable decline in renal function. The presence of the structurally defined advanced glycation end product (AGE) pentosidine on tissue and circulating proteins has been correlated with the severity of diabetic complications. METHODS: To delineate a role for this AGE in the progression of diabetic nephropathy, glycohemoglobin and free and protein-bound pentosidine were measured in baseline stored serum and urine from a subgroup of patients with diabetes mellitus and proteinuria originally followed by the Collaborative Study Group Trial. To delineate a potential role for an immune-activation response to AGEs, the inflammatory markers, interleukin-6 (IL-6), C-reactive protein (CRP), and the monocyte activation marker marker neopterin were also measured at baseline. The patients chosen represented 67 subjects whose creatinine levels had "doubled" over the course of the study whether or not they later were treated with captopril, and 67 paired "non-doublers." RESULTS: Baseline disease activity, as manifested by glycohemoglobin, serum creatinine and degree of proteinuria was equal in the two groups, as was protein-bound pentosidine and the immune-markers IL-6 and CRP. At baseline the "doublers" as compared to the "non-doublers" had elevated serum levels of free pentosidine and neopterin. Baseline increases in these two parameters were also associated with an increased rate of "doubling" of serum creatinine by the proportional hazards method. CONCLUSION: Differences in individual responsiveness to AGEs, as manifested by either the production of free pentosidine or its release from a protein-bound form, and by evidence of monocyte/macrophage activation, are associated with progression of diabetic nephropathy.

An 18-year-old man with Goodpasture's syndrome and ANCA-negative central nervous system vasculitis.

An 18-year-old man with Goodpasture's syndrome developed a recurrent seizure disorder refractory to anticonvulsant therapy spanning a full course of plasmapheresis and cytotoxic therapy. Status epilepticus developed during a taper of cytotoxic agents, with magnetic resonance imaging (MRI) findings consistent with multiple lacunar infarcts. Although the diagnosis of vasculitis was considered, anti-neutrophilic cytoplasmic antibody serology was consistently negative. A meningeal biopsy showed vasculitis, which was successfully treated with the reintroduction of high-dose steroids and cytotoxic agents in conjunction with anticonvulsants. Nearly 1 year later, with Goodpasture's disease in remission, he received a living-related renal transplant from his mother. He is currently leading a normal lifestyle. From an extensive review of the literature, this is the first case of anti-neutrophil cytoplasmic antibody-negative central nervous system (CNS) vasculitis in a patient with Goodpasture's syndrome.

Type II diabetic nephropathy: its clinical course and therapeutic implications.

Type II diabetes is responsible for more end-stage renal disease in the United States than any other single condition. Until recently, the majority of research in diabetic nephropathy has focused on patients with type I diabetes despite the fact that type II nephropathy is a more prevalent condition. The notion that there are major differences between the nephropathy of these two types of diabetes is not supported by recent literature. The biggest difference appears to be related to ethnic risk. Histopathologic differences are now being described as well. Clinical interventional trials are few compared to type I diabetes; however, it seems that maneuvers that improve renal prognosis in patients with type I diabetes (blood pressure control, blood glucose control, and the use of angiotensin-converting enzyme inhibitors) apply to the type II population as well. Some of the calcium channel blockers lower proteinuria to a degree that suggests renoprotection and may further improve outcome.

An economic analysis of captopril in the treatment of diabetic nephropathy. The Collaborative Study Group.

OBJECTIVE: The results of a recent clinical trial. The Effect of ACE inhibition on Diabetic Nephropathy, demonstrated that captopril reduced the rate of renal failure, end-stage renal disease (ESRD), and death in patients with IDDM and nephropathy. The purpose of this study was to determine the cost-benefit and cost-effectiveness of captopril as a therapy in patients with IDDM as well as the potential savings for all patients with diabetes and nephropathy. RESEARCH DESIGN AND METHODS: We used the results from a randomized, placebo-controlled trial comparing captopril (207 patients) with placebo (202 patients), whose purpose was to determine whether captopril has kidney-protecting properties independent of its effect on blood pressure in diabetic nephropathy to develop a model of medical treatment for patients before progression to ESRD. To model the course of illness after progression to ESRD and to extend the model to patients with NIDDM, we used data from the U.S. Renal Data System and published literature. Medical resource cost data were based predominantly upon Medicare reimbursement levels, published wholesale drug prices, and surveying health care providers. The economic model uses a payer perspective to estimate direct cost. The cost to society (indirect cost) associated with lost patient productivity due to ESRD was also estimated. Using this information, we predicted the costs incurred annually and over a lifetime if patients with IDDM and NIDDM and overt nephropathy were treated with either placebo or captopril. We also constructed a model of the overall prevalence of diabetic nephropathy to estimate the aggregate savings in total U.S. health care expenditures. RESULTS: Treatment with captopril resulted in an absolute direct cost savings or benefit of $32,550 per patient with IDDM over the course of a lifetime compared to treatment with placebo. For patients with NIDDM, the direct cost savings totaled $9,900 per patient. Absolute savings were found for indirect costs as well: $84,390 per patient with IDDM and $45,730 per patient with NIDDM. If captopril therapy were initiated in 1995 for patients with either IDDM or NIDDM and nephropathy, the aggregate health care cost savings (i.e. direct cost savings alone) would be $189 million a year for the year 1999 and $475 million a year in 2004, the present value of cumulative health care cost savings for these 10 years would be $2.4 billion. CONCLUSIONS: The use of captopril in diabetic nephropathy will provide significant savings in health care costs; in addition, it will result in savings in indirect cost, which reflects the broader societal benefit.

Reproducibility of studies of peritoneal dialysis adequacy.

To assess the variability and reproducibility of dialysis adequacy clearance measurements (weekly Kt/V and weekly creatinine clearance/1.73 m2 BSA) in a given patient, 42 patients underwent three clearance studies in a one week period. The dialysis prescription was kept constant. There were 21 males with a group mean age of 49 +/- 15 years; 37 patients performed CAPD and 5 DAPD; the dialysis prescription was 6 to 12 liters/day; and 17 patients were anuric. To assess test variability within each patient, the coefficient of variation (CV) and the range were determined for each patient's three clearance values, and for the factors that determine those values. These were averaged to determine the mean patient variability (CV and range) of those measurements. The mean patient CV of the weekly Kt/V was 8.1%. The mean patient range of the weekly Kt/V was 0.30. Of the determinants of total Kt/V, the greatest variability (GV) existed in residual renal urea clearance at 35.4%, with moderate variability seen for peritoneal dialysis urea clearance at 7.0%, which was more a function of variability in D/P urea (CV = 6.3%) than variability in drain volume (CV = 4.1%). There was little variability in V (CV = 0.6%). Similar results were seen for the variability in weekly creatinine clearance measurements. We found that the day-to-day reproducibility of Kt/V measurements is limited, especially in patients with residual renal function, although day-to-day variability in D/P urea also affects Kt/V reproducibility in all patients. Values that fall into the borderline "adequate" range may need to be repeated when considering a patient's dialysis prescription. In addition, research that involves the measurement of Kt/V should utilize more than one collection to increase the reliability of those measurements.

The urine protein to creatinine ratio as a predictor of 24-hour urine protein excretion in type 1 diabetic patients with nephropathy. The Collaborative Study Group.

The purpose of this study was to determine the usefulness of a random urine specimen protein to creatinine (P/C) ratio in predicting 24-hour urine protein excretion (24 UP) in type 1 diabetic patients with overt nephropathy. Two hundred twenty-nine outpatient diabetic subjects enrolled in the Collaborative Study Group's multicenter clinical trial of "Angiotensin-Converting Enzyme Inhibition in Type 1 Diabetic Nephropathy" provided specimens for study, which encompassed a wide range of proteinuria (0.05 to 13.3 g/d). Twenty-four hour urine collections for total protein and creatinine (g/d) were obtained in the outpatient setting. This was followed shortly thereafter by an untimed single urine specimen for protein and creatinine (mg/dL). For longitudinal analysis, 33 patients provided two 24-hour urine collections with concomitant random urine specimens, separated by at least a 3-month period. Across the range of proteinuria that we studied, the log random urine P/C ratio correlated to log 24 UP (r = 0.90). The regression line was almost identical to the line of unity, which indicates that a patient's 24 U/P (in g/d) can be predicted directly from the random urine specimen P/C ratio (P/C = 24 UP in g/d). However, the standard deviations associated with these predictions were large, especially at the higher 24 UP values. Of the 33 patients who provided two time-separated specimens, the direction of change in P/C ratio was discordant with the direction of change in 24 UP in 14 of the 33 repeat specimens.(ABSTRACT TRUNCATED AT 250 WORDS)

The study of the effect of intensity of blood pressure management on the progression of type 1 diabetic nephropathy: study design and baseline patient characteristics. Collaborative Study Group.

A randomized, prospective, clinical trial has been initiated to continue follow-up in a subset of the patients previously enrolled in the recently completed Study of Angiotensin-Converting Enzyme Inhibition (ACEi) in Type 1 Diabetic Nephropathy. In that study, the use of captopril was associated with a 48% reduction in the risk of doubling the serum creatinine and a 50% reduction in the risk of experiencing dialysis, transplantation, or death, compared with the use of placebo. These effects were independent of captopril's effect on the blood pressure. This study is designed to determine whether the level of mean arterial blood pressure (MAP), using the ACE inhibitor ramipril as the primary therapy, is associated with an improved prognosis of diabetic nephropathy with respect to (1) the rate of decline in renal function; (2) the rate of progression to end-stage renal failure; (3) the clinical course of proteinuria; (4) morbidity; and (5) mortality. Patients are randomized into one of two distinct blood pressure control groups, an Intensive Group #1, MAP < or = 92 mm Hg; and a Moderate Group #2, MAP 100 to 107 mm Hg. Patients previously enrolled in the "Study of ACEi in Type 1 Diabetic Nephropathy" whose serum creatinine was less than 4.0 mg/dL (354 mumol/L) were eligible for randomization into this study. All patients will receive ramipril (2.5 to 10.0 mg/day) as the primary therapy, with the addition or removal of other antihypertensive agents as needed to achieve the assigned blood pressure goal.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormal acyltransferase activities and accelerated cholesteryl ester transfer in patients with nephrotic syndrome.

To determine the effects of the nephrotic syndrome (NS) on atherogenic risk, we studied the lipoprotein composition and the activities of lecithin-cholesterol acyltransferase (LCAT), lysolecithin acyltransferase (LAT), and cholesteryl ester transfer (CET) in the plasma of 11 NS patients and 10 control subjects. NS plasma had lower ratios of high-density lipoprotein (HDL) to low-density lipoprotein (LDL) and HDL2/HDL3 and an elevated free cholesterol (FC) to phosphatidyl choline (PC) ratio (1.09 +/- 0.27 in NS and 0.72 +/- 0.21 in controls, P < .02), all of which indicate an increased atherogenic potential. LCAT activity was normal in NS plasma when assayed with an exogenous substrate, but was 40% lower than in control plasma when assayed with the endogenous substrates. However, in vitro addition of serum albumin to NS plasma failed to normalize the LCAT activity. The LAT reaction, which is catalyzed by LCAT protein in the presence of LDL, was 60% to 80% higher in NS plasma, and consequently the ratio of LAT/LCAT activities was increased twofold. CET activity was significantly increased (+160% of control), and this abnormality was attributable to changes in both the acceptor (very-low-density lipoprotein [VLDL] + LDL) and donor (HDL) lipoproteins and possibly in CET protein. These results suggest that the NS may increase the risk of atherosclerosis not only by adversely affecting the concentrations of lipoproteins, but also by altering their composition and function.