To print: Select File and then Print from your browser's menu --------------------------------------------------------------------------------------- Title: Cozaar (Losartan) Slows Progression of Kidney Disease in Type 2 Diabetes URL: http://www.pslgroup.com/dg/2068F6.htm Doctor's Guide September 19, 2001
MONTREAL, QUEBEC -- September 19, 2001 -- Results from a new clinical trial show that treatment with the effective antihypertensive Cozaar® (losartan) can dramatically delay the progression of kidney disease, including reducing the risk of developing end-stage renal disease (ESRD). The study, conducted in patients with Type 2 diabetes and kidney disease, appears in the September 20th issue of The New England Journal of Medicine. End-stage renal disease is a serious condition in which dialysis or transplantation is required for survival.
Losartan is approved to treat high blood pressure, also known as hypertension. In Canada, as else where in the world, losartan as well as other antihypertensive medications are not approved nor indicated for the treatment or prevention of ESRD in people with Type 2 diabetes.
The landmark study, called RENAAL (Reduction of Endpoints in Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan), which included 1,513 patients from 28 countries, is the first and only study to report that a drug reduces ESRD in Type 2 diabetic patients with kidney disease. Previous studies with angiotensin converting enzyme (ACE) inhibitors have not provided data on progression to ESRD in this growing patient population.
Losartan is a member of the most recent class of antihypertensives known as angiotensin II antagonists (AIIA). An advantage to AIIAs is their excellent tolerability, compared to other classes of antihypertensives.
"Delaying the development of end-stage renal disease, which essentially is death of the kidney, is an enormously important goal due to the limited and costly treatment options, such as dialysis or kidney transplant," said Dr. Marc Houde, nephrologist at Maisonneuve-Rosemont Hospital in Montreal. "Clearly, this study will help guide our treatment of hypertensive patients with Type 2 diabetes and kidney disease. This certainly is a major advance in our ability to help these patients control the course of their disease."
Approximately five million Canadians suffer from high blood pressure. Close to 40 percent of those or two million Canadians also have diabetes. Ninety to 95 percent of patients with diabetes have Type 2 diabetes. This form of diabetes usually occurs later in life and is often associated with increased body weight, hypertension and abnormalities of blood lipids. Diabetes and its complications use up one in seven health care dollars in Canada or approximately nine billion dollars annually.
Individually, diabetes and hypertension increase the risk of kidney disease, as well as cardiovascular disease; together, the risks rise dramatically. Diabetes and hypertension damage the tiny blood vessels in the kidney that act as filters to remove wastes from the blood. It is estimated that 20 to 30 percent of diabetic patients eventually develop kidney disease a leading cause of ESRD necessitating chronic dialysis or kidney transplantation.
In this randomized, placebo-controlled study, all patients had Type 2 diabetes, proteinuria and elevated serum creatinine, markers that are indicative of kidney disease. Approximately 94 percent of the patients had high blood pressure and were taking blood pressure medication at the start of the study.
Seven hundred and fifty-one patients were randomized to the group treated with losartan (50 mg to 100 mg once daily) and 762 to the placebo treatment group. Both treatment groups continued to receive conventional blood pressure medication as needed, including calcium channel-blockers (CCB), diuretics, beta-blockers, alpha-blockers or centrally-acting agents. Other AIIAs and ACE inhibitors were excluded from the study.
Simultaneous therapy with CCBs did not detract from the beneficial effects of losartan, despite the recent controversy regarding the role of CCBs in the protection of the kidneys and the heart. Standard medical care for managing diabetes was continued throughout the study.
Investigators followed patients for an average of 3.4 years(1). The primary endpoint of the study was a composite measure consisting of time to the first occurrence of either doubling of serum creatinine (a marker indicating more than 50 percent loss of kidney function), ESRD or death.
· Patients taking losartan once daily plus conventional blood pressure therapy had a significant reduction in the primary composite endpoint by 16 percent, p=0.024, compared to the placebo group plus conventional blood pressure therapy. This renal protective effect of losartan was found to be beyond its blood pressure lowering ability. · Losartan significantly reduced the risk of progression to ESRD requiring dialysis or kidney transplantation by 28 percent, p=0.002.
· Losartan significantly reduced the risk of doubling of serum creatinine by 25 percent, p=0.006.
· Losartan significantly reduced the risk of ESRD or death by 20 percent, p=0.010.
· The risk of death was not significantly different between study groups.
The study also examined the effects of treatment on cardiovascular events and changes in proteinuria. The following observations were made:
· Hospitlization for heart failure, a component of the cardiovascular composite endpoint, was significantly reduced by 32 percent, p=0.005, in the patient group treated with losartan. There were similar effects in both treatment groups for the composite endpoint of cardiovascular events. · Proteinuria was significantly reduced by 35 percent in the patient group treated with losartan plus conventional blood pressure therapy compared to the placebo plus conventional blood pressure therapy group, p<0.001.
Losartan also provided excellent tolerability in this population. Dropouts from the study due to clinical adverse events, not including deaths, were 17 percent in the group receiving losartan plus conventional blood pressure therapy versus 22 percent in the placebo plus conventional blood pressure therapy group. The most common clinical adverse events requiring discontinuation were heart failure, end-stage renal disease, heart attack, stroke and worsening renal insufficiency.
In RENAAL, losartan led to significant improvements in renal outcome beyond its effects on blood pressure control in patients with Type 2 diabetes and kidney disease.
Reference:
(1) The study was stopped 13 months early because of increasing evidence from other sources that therapy aimed at blockade of the renin-angiotensin system (RAS) may provide cardioprotective benefits in diabetic patients with renal impairment -- a patient population similar to that enrolled in the RENAAL trial.
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