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Losartan was renoprotective in diabetic nephropathy independent of its effect on blood pressure
  1. Christian G Rabbat, MD
  1. McMaster University
 Hamilton, Ontario, Canada

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 QUESTION: In patients with type 2 diabetes mellitus and nephropathy, what is the renoprotective effect of the angiotensin II receptor antagonist (ARA) losartan?

    Design

    Randomised (allocation concealed*), blinded (clinicians, patients, outcome assessors, and statisticians),* placebo controlled trial with mean follow up of 3.4 years (the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan [RENAAL] Study).

    Setting

    250 centres worldwide.

    Patients

    1513 patients between 31 and 70 years of age (mean age 60 y, 63% men) who had type 2 diabetes and nephropathy defined as a urinary albumin : creatinine ratio ≥ 300 mg/g and a serum creatinine concentration between 115 and 265 μmol/l (≥ 133 μmol/l for men weighing > 60 kg). Exclusion criteria included type 1 diabetes and non-diabetic renal disease. Follow up was 99.8%.

    Intervention

    After stratification by baseline level of proteinuria, patients were allocated to receive losartan, 50 to 100 mg/day (n=751), or placebo (n=762). Conventional antihypertensive treatment (excluding angiotensin I converting enzyme inhibitors and ARAs) was adjusted to target a systolic and diastolic blood pressure < 140 and < 90 mm Hg, respectively.

    Main outcome measures

    The primary outcome was the composite of a doubling of the baseline serum creatinine concentration, end stage renal disease (ESRD), or death. The secondary outcome was the composite of cardiovascular morbidity or mortality.

    Main results

    Analysis was by intention to treat. Losartan reduced the risk for the primary composite outcome (unadjusted p=0.02; p=0.03 after adjustment for blood pressure), doubling of the baseline serum creatinine concentration (unadjusted p=0.006), and ESRD (unadjusted p=0.002) more than did placebo (table). However, losartan and placebo did not differ for incidence of death (unadjusted p=0.88) (table) or the secondary composite outcome of cardiovascular morbidity or mortality (p=0.26).

    Losartan v placebo for type 2 diabetes and nephropathy at 3.4 years†

    Conclusions

    Losartan was renoprotective in patients with type 2 diabetes mellitus and nephropathy. This effect was beyond that attributable to blood pressure control.

    
 
 QUESTION: In patients with type 2 diabetes mellitus and nephropathy, what is the renoprotective effect of the angiotensin II receptor antagonist (ARA) losartan?

    Commentary

    Type 2 diabetes mellitus causes microvascular and macrovascular complications that pose public health concerns worldwide. The end organ damage resulting from microvascular complications clinically manifests itself as retinopathy, neuropathy, and nephropathy. Diabetic nephropathy causes almost 40% of all incident dialysis cases in the USA. Once end stage renal disease (ESRD) has developed, the median survival of patients with type 2 diabetes is 2 years, and most of these deaths are from cardiovascular disease.1

    In the spectrum of renal disease complicating diabetes, microalbuminuria precedes overt diabetic nephropathy. This stage is readily detectable, is associated with an increased risk for progression to diabetic nephropathy, and is potentially reversible.

    Parving et al have shown that treating patients who have type 2 diabetes, hypertension, and microalbuminuria with irbesartan, 300 mg/day, reduced progression to overt nephropathy at 2 years; lower doses (150 mg/d) were less effective. This beneficial effect of irbesartan was independent of blood pressure lowering and glycaemic control. In addition, irbesartan was more likely than placebo to cause regression to normoalbuminuria. The findings support the role of rennin–angiotensin system blockade with irbesartan in preventing progression to albuminuria.

    The Microvascular Heart Outcomes Prevention Evaluation (MICRO-HOPE) study2 enrolled 3577 patients with diabetes, 32% of whom had microalbuminuria. The rate of progression to overt nephropathy was lower in the ramipril group than in the placebo group (relative risk reduction [RRR] 24%). Although the effects of irbesartan (RRR 66%) seemed to be greater in preventing progression to overt nephropathy, no study exists with clinically important outcomes comparing ARAs to ACE inhibitors.

    The study of Mogensen et al 3 provides a preliminary assessment of the role of combination treatment with ARAs and ACE inhibitors in the candesartan and lisinopril microalbuminuria (CALM) study. Candesartan combined with lisinopril for 24 weeks resulted in greater reductions in blood pressure and in the albumin : creatinine ratio than either drug given alone.

    Once overt nephropathy develops, the goal of treatment is to slow the rate of progression to ESRD. The IDNT and the RENAAL trials, which used irbesartan and losartan, respectively, showed that patients treated with ARAs had a lower incidence of the composite outcome of doubling of serum creatinine, ESRD, or death. The effect of amlodipine on progression to the composite end point was neutral. After the baseline visit, mean systolic blood pressure levels ranged from 140 mm to 150 mm Hg, and diastolic blood pressure levels ranged from 74 mm to 77 mm Hg. A mean of 3 to 4 additional non-study medications were needed to achieve these blood pressure levels. Mean proteinuria concentrations decreased by 33% to 35% in the ARA treated groups. These trials provide convincing evidence that irbesartan and losartan reduce the risk for progression of renal disease.

    Preventing progression of diabetic nephropathy should not be considered in isolation from macrovascular complications associated with type 2 diabetes. In middle aged and elderly people with type 2 diabetes, fatal and non-fatal cardiovascular events occur at a rate of 4% to 5% per year. The HOPE study4 strongly supports a protective effect of ramipril (RRR 22%) on future cardiovascular events in high risk patients, including those with diabetes and ≥ 1 additional cardiovascular risk factor. Although the HOPE trial excluded patients with overt proteinuria, patients with proteinuria and type 2 diabetes would probably have a similar benefit.

    Both the IDNT and RENAAL studies used prespecified secondary outcome clusters to measure morbidity and mortality from cardiovascular causes. Secondary outcomes occurred in 24% of patients in the IDNT study and 34% of patients in the RENAAL study. Neither losartan nor irbesartan reduced the risk for this composite outcome; however, losartan was associated with a lower rate of first admission to hospital for congestive heart failure.

    Patients and their clinicians must now consider using these 2 classes of drugs. Treatment for individual patients should consider the risk for progression of renal disease, risk for future cardiovascular events, and blood pressure.

    The treatment of type 2 diabetes should start early in the course of the disease process. At the normoalbuminuric or microalbuminuric stage, ACE inhibitors should be considered first line agents because of their proven efficacy in preventing progression to overt nephropathy and reducing cardiovascular events. Attention should also focus on blood pressure control and modification of other risk factors for cardiovascular disease.

    Once nephropathy has developed, the importance of rennin–angiotensin system blockade persists, but the choice of drug is less clear. Clinicians should expect to use 3 to 4 different drugs to achieve a good blood pressure reading. Although further research using clinically important outcomes is required, dual blockade of the rennin–angiotensin system with a combined ACE inhibitor and ARA seems promising. This combination may offer the best of both treatment strategies and result in lower incidence rates of devastating microvascular and macrovascular complications in people with type 2 diabetes.

    References

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    Footnotes

    • * See glossary.

    • Source of funding: Merck and Company.

    • For correspondence: Dr B M Brenner, Brigham and Women's Hospital, Boston, MA, USA. bbrenner{at}partners.org.

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