Angiotensin II receptor blockers and nephropathy trials.
نویسنده
چکیده
This is the first of a series of reports on the American Diabetes Association (ADA) 61st Scientific Sessions held in Philadelphia in June 2001. It covers topics related to angiotensin II receptor blockers (ARBs) and nephropathy. At a symposium at the 61st Scientific Sessions of the ADA in June 2001, the results of three recent diabetic nephropathy trials with angiotensin II subtype 1 receptor antagonists were presented. Hans-Henrik Parving, Gentofte, Denmark, pointed out that kidney disease develops in 40% of patients with type 2 diabetes, with 25% of patients in Europe and 46% in the U.S. with end-stage renal disease (ESRD) having diabetes. In the latter population, the proportion increases annually by 1.5%. In type 2 diabetes, microalbuminuria is associated with a 5–10% lifetime risk of progression to overt nephropathy, while patients with normoalbuminuria have a 10to 20-fold lower risk. In the Irbesartan for MicroAlbuminuria in Type 2 Diabetes (IRMA) study, 590 patients with 20–200 g/min albuminuria with normal serum creatinine and with blood pressure (BP) 135/85 mm Hg were randomized to placebo or 150 or 300 mg irbesartan daily for 2 years. The mean age was 58 years; 70% were male; all were Caucasian; baseline BP was 153/90 mm Hg; baseline albuminuria was 55 g/min; baseline glomerular filtration rate (GFR) was 110 ml/min; and baseline HbA1c was 7.2%. Patients treated with aspirin in a dose exceeding 325 mg daily were excluded because of the effect on proteinuria and renal function. The mean trough BP (measured 24 h after the last dose of medication) during the study was 145/84, 143/ 84, and 142/84 mm Hg with placebo and 150 and 300 mg irbesartan daily, respectively. Progression to macroalbuminuria occurred in 15, 10, and 5%, respectively, of the three groups at 2 years, with adjusted risk reduction of 68% with 300 mg and 44% with 150 mg irbesartan daily. Overall, albuminuria increased 9% with placebo and decreased 6 and 46% at 2 years with 150 and 300 mg irbesartan daily, with a trend for albuminuria to increase after 1 year with 150 mg; albuminuria continued to decrease with 300 mg through 2 years. Two patients treated with 150 mg irbesartan developed K 5.5 mEq/l. The GFR decreased to 100 ml/min with irbesartan 300 mg and remained at 110 ml/min with placebo and 150 mg irbesartan daily. There were 8.7 vs. 4.5% cardiovascular disease (CVD) events with placebo versus 300 mg irbesartan—not a significant difference in view of the relatively small study size. Parving concluded, “What is the take home message? If you want to prevent diabetic kidney disease you need screening for microalbuminuria—it is mandatory. When you have documented [that] the patient has microalbuminuria, you start lifelong treatment with agents interfering with the renin-angiotensin system.” When asked how often to check for microalbuminuria once detected, he suggested that assessment should occur approximately every 3 months “for the rest of [the patient’s] life.” Barry Brenner, Boston, MA, discussed the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial of 1,513 patients with type 2 diabetes and nephropathy from 250 centers in 29 countries. Losartan had already been shown to be renal protective in animals and to reduce proteinuria (proportional to basal proteinuria levels) in patients with both diabetic and nondiabetic renal disease at the time of initiation of the study. What was not available in 1993 was “hard end point data” in type 2 diabetic subjects with nephropathy that showed losartan could slow the progression of advancing renal disease to nephropathy. The hypothesis was that longterm treatment would increase the time to primary end point, defined as the doubling of serum creatinine, reaching ESRD, or death. The secondary hypotheses were decreased time to first event and decreased CVD mortality. The vast majority of patients entering the trials were treated with multiple BP medications at study onset, with ACE inhibitor (ACEI) or ARB stopped at entry, and another drug (either or -blocker, centrally acting agent, calcium channel blocker [CCB], or diuretic) substituted to lower the BP to 140/90 mm Hg. Patients were treated initially with 50 mg losartan or placebo daily, with BP elevation at 4 weeks leading to an increase in dose to 100 mg daily. The study was discontinued 1 year early because of the accumulating evidence that ACEI were shown to be cardioprotective [particularly in the Heart Outcomes Prevention Evaluation (HOPE) substudy of patients with creatinine 1.4 mg/dl (1)]. Thus, 3.4 years of follow-up is available. Patients had onset of diabetes after age 30 years, with urine albumin 300 mg/g creatinine (mean 4 g/day proteinuria), serum creatinine between 1.3 and 3.0 mg/dl (mean 1.9), and HbA1c 12%. Patients with recent myocardial infarction, coronary intervention, or any history of congestive heart failure (CHF) were excluded. Of these patients, 38% were female and 48% were Caucasian; the mean age was 60 years; 27 and 71% of the losartan patients were treated with 50 and 100 mg daily, respectively. The BP fell progressively during the study, from ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
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ورودعنوان ژورنال:
- Diabetes care
دوره 24 10 شماره
صفحات -
تاریخ انتشار 2001