RENAAL

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Brenner BM, et al. "Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy". The New England Journal of Medicine. 2001. 345(12):861-869.
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Clinical Question

Among patients with diabetic nephropathy, do ARBs reduce progression to end stage renal disease or death?

Bottom Line

Among patients with diabetic nephropathy, losartan reduced doubling of serum creatinine and progression to ESRD but provided no mortality benefit.

Major Points

Although the CSG Captopril Trial (1993) demonstrated the renoprotective efficacy of ACE inhibitors in patients with T1DM-associated nephropathy, there is more evidence for the renoprotective efficacy of ARBs in patients with T2DM-associated nephropathy. Two major trials, IDNT (2001) and RENAAL, compared ARBs to placebo and demonstrated that ARBs are effective in reducing proteinuria and slowing the progression to ESRD. About 80% of the renoprotective benefits of ARB therapy have been attributed to its antihypertensive effects,[1] with the remaining benefit likely related to inhibition of the proliferative effects of the renin-angiotensin-aldosterone system.[2]

The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial randomized 1,513 patients with non-insulin-dependent T2DM and nephropathy to losartan or placebo in addition to conventional antihypertensive therapy excluding ACE inhibitors. During a mean follow-up of 3.4 years, losartan was associated with a 25% reduction in the doubling of serum creatinine and 28% reduction in progression to ESRD compared to placebo. Treatment with losartan also resulted in a 35% reduction in the urinary albumin-to-creatinine ratio, whereas patients in the placebo group tended to have an increase in proteinuria. Although there were significant reductions in heart failure hospitalizations, there was no difference in morbidity and mortality from cardiovascular causes.

Guidelines

ADA Standards of Medical Care in Diabetes (2016, adapted)[3]

  • ACE-inhibitor or ARB therapy for nonpregnant patients with diabetes:
    • Elevated urinary albumin excretion (30-299 mg/day) (Level of evidence: B)
    • Elevated urinary albumin excretion ≥300 mg/day and/or eGFR <60 mL/min/1.73 m2 (Level of evidence: A)

Design

  • Multicenter, double-blind, parallel-group, randomized, placebo-controlled trial
  • N=1,513
    • Losartan (n=751)
    • Placebo (n=762)
  • Setting: 250 centers in 28 countries in Asia, Europe, Central America, South America, and North America
  • Enrollment: 2001-2005
  • Mean follow-up: 3.4 years
  • Analysis: Intention-to-treat
  • Primary outcome: Doubling of baseline serum creatinine, ESRD, death

Population

Inclusion Criteria

  • Age 31-70 years
  • T2DM complicated by nephropathy, defined by serum creatinine 1.3-3.0 mg/dl and urinary albumin:creatinine ratio of ≥300

Exclusion Criteria

  • T1DM
  • Nondiabetic renal disease, including renal artery stenosis
  • MI or CABG within prior month
  • CVA or PCI within prior 6 months
  • TIA within prior year
  • History of HF

Baseline Characteristics

  • Mean age: 60 years
  • Male: 63.2%
  • Ethnicity:
    • White: 48.7%
    • Black: 15.2%
    • Asian: 16.7%
    • Hispanic: 18.2%
  • Medical comorbidities:
    • MI: 11.2%
    • HL: 33.4%
    • Neuropathy: 49.8%
    • Retinopathy: 63.4%
    • Amputation: 8.9%
  • Current smoker: 18.4%
  • BMI: 29.5 kg/m2
  • BP 153/82, MAP 106
  • Serum creatinine: 1.9 mg/dl
  • Hgb: 12.5 g/dl
  • HbA1c: 8.4%
  • Baseline medications:
    • CCB: 71.2%
    • Diuretic: 54%
    • Alpha-blocker: 24.1%
    • Beta-blocker: 18.3%
    • Centrally acting agent: 10.9%
    • ACE inhibitor/ARB: 51.3%

Interventions

  • Stratified according to baseline proteinuria (urinary albumin:creatinine ratio <2000 or ≥2000)
  • Randomized to receive either losartan (50-100 mg) or placebo daily
  • All patients received standard antihypertensive therapy (except ACE inhibitors or ARBs) to achieve target BP
  • Follow-up every 3 months

Outcomes

Comparisons are losartan vs. placebo.

Primary Outcomes

Composite of doubling of serum creatinine, ESRD, or death
43.5% vs. 47.1% (RR 0.84; P=0.02; NNT=28)

Secondary Outcomes

Doubling of serum creatinine
21.6% vs. 26.0% (RR 0.75; P=0.006)
ESRD
19.6% vs. 25.5% (RR 0.72; P=0.002)
Defined by need for long-term dialysis or renal transplantation
Death
21% vs. 20.3% (P=0.88)
CV event
32.9% vs. 35.2% (RR 0.90; P=0.26)
First hospitalization for heart failure
11.9% vs. 16.7% (RR 0.68; P=0.005)
Change in proteinuria
Losartan reduced proteinuria by 35%, while placebo increased proteinuria (P<0.001)

Adverse Events

Discontinuations due to adverse events
17.2% vs. 21.7%

Criticisms

  • ARBs were not compared to ACE inhibitors.[2]

Funding

  • Merck and Company

Additional Resources

  1. Griffin KA, Bidani, AK. "Progression of Renal Disease: Renoprotective Specificity of Renin-Angiotensin System Blockade." CJASN. 2006. 1(5):1054-1065.
  2. 2.0 2.1 Hostetter TH. "Editorial: Prevention of End-Stage Renal Disease Due to Type 2 Diabetes." N Engl J Med. 2001; 345:910-912
  3. American Diabetes Association 9. Microvascular Complications and Foot Care. Diabetes Care 2016. 39 Suppl 1:S72-80.