IDNT

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Lewis EJ, et al. "Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes". The New England Journal of Medicine. 2001. 345(12):851-860.
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Clinical Question

In patients with type 2 diabetes and nephropathy, do irbesartan or amlodipine slow the progression of nephropathy independently of their antihypertensive effect, as compared to placebo?

Bottom Line

In patients with type 2 diabetes and nephropathy, irbesartan slows the progression of nephropathy independently of its antihypertensive effects when compared to placebo or amlodipine.

Major Points

ACE-inhibitors were shown to prevent progression of DM nephropathy in patients with T1DM in the 1993 CSG Captopril Trial. Irbesartan and amlodipine are antihypertensive agents which belong to the categories of angiotensin-II-receptor blocker (ARB) and dihydropyridine calcium-channel blockers (CCB), respectively. The Irbesartan Diabetic Nephropathy Trial (IDNT) examined if these agents slow the progression of nephropathy independently of their antihypertensive effect in patients with type 2 diabetes (T2DM).

IDNT randomized 1,715 T2DM patients with nephropathy and hypertension to receive irbesartan, amlodipine or placebo in a double-blind fashion. The primary outcome was a composite of doubling of baseline serum creatinine, development of end-stage renal disease (ESRD), or all-cause mortality. Irbesartan reduced the risk of the primary outcome by 20% as compared to placebo (P=0.02) and by 23% as compared to amlodipine (P=0.006). In contrast, amlodipine did not reduce the risk. Neither of the treatments reduced all-cause mortality significantly. Hyperkalemia occurred in 1.9% of the patients in the irbesartan group, as compared with 0.5% in the amlodipine group and 0.4% in the placebo group (P=0.01 for both comparisons).

RENAAL (2001) showed that losartan reduced the risk of the composite outcome of doubling of serum creatinine, ESRD, or death in a similar patient group. IRMA[1] (2001) showed that irbesartan had renoprotective effects independent of its antihypertensive effect in T2DM patients with microalbuminuria. The IDNT, IRMA and RENAAL trials were included in the a Cochrane subanalysis with a total of 3,251 patients. ARBs reduced the risk of ESRD (RR 0.78; 95% CI 0.67-0.91) and doubling of serum creatinine concentration (RR 0.79; 95% CI 0.67-0.93) as compared to placebo. The authors also concluded that ARBs did not reduce all-cause mortality risk significantly.[2]

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, randomized, placebo-controlled trial
  • N=1,715
    • Irbesartan (n=579)
    • Amlodipine (n=567)
    • Placebo (n=569)
  • Setting: 210 centers in the United States, Europe, Israel, Australasia, and Southeast Asia
  • Enrollment: 1996-1999
  • Median follow-up: 2.6 years
  • Analysis: Intention-to-treat
  • Primary outcome: Doubling of baseline serum creatinine, development of ESRD, or all-cause mortality

Population

Inclusion Criteria

Details are published elsewhere.[4]

  • Age 30-70 years; <30 in patients with biopsy-proven diabetic nephropathy
  • T2DM, either:
    • Hyperglycemia not requiring insulin
    • Hyperglycemia requiring insulin with either >1 year between diagnosis and commencement of insulin treatment or elevated fasting or stimulated C-peptide
  • Hypertension (>135/85 mm Hg or receiving antihypertensive treatment)
  • 24 hour protein excretion ≥900 mg/24 hr
  • Serum creatinine 1-3 mg/dl (88-265 μmol/l) in women and 1.2-3 mg/dl (106-265 μmol/l) in men.

Exclusion Criteria

  • Onset of T2DM <20 years
  • Type I DM
  • Absolute requirement for an ACE inhibitors, ARB, or CCB
  • Cardiovascular disease, defined by any of the following:
    • Unstable angina, MI, CABG or PTCA 3 months prior to enrollment
    • NYHA class III or IV heart failure
    • TIA in prior 6 months
    • Stroke in prior 3 months
  • Serum potassium outside of normal range

Baseline Characteristics

From patients in the irbesartan group or from all when if an asterix.[4]

  • Demographics: Age 59 years; Males 65%; non-Hispanic White race 76%; Non-Hispanic Black race 11%, Hispanic 5%, Asian or Pacific Islander 4%
  • BMI: 31 kg/m2
  • Duration of diabetes: 12 years
  • Insulin treatment: 57%
  • PMH: CVD 27%; retinopathy 69%
  • BP: 160/87 mm Hg
  • Labs: Serum creatinine 1.67 mg/dL; A1c 8.1%; Tchol* 229 mg/dL; K* 4.6 mEq/L
  • Urinary protein excretion: 2.9 g/24 hr; urinary albumin excretion 1.9 g/24 hr

Interventions

  • All ACE inhibitors, ARB, and CCB were discontinued >10 days before screening
  • Randomization to a group:
    • Irbesartan - Irbesartan 75 mg po qday initially, titrated up to 300 mg po qday
    • Amlodipine - Amlodipine 2.5 mg po qday initially, titrated up to 10 mg po qday
    • Placebo
  • Target BP was systolic ≤135 mm Hg and diastolic ≤85 mm Hg
    • If baseline SBP was >145 mm Hg, the goal was a 10 mm Hg reduction with a maximum goal of 160 mmHg
  • Antihypertensive agents other than ACE inhibitors, ARB, and CCB were used as needed

Outcomes

Presented as unadjusted relative risk. Table 3 on page 858 presents the adjusted relative risk.

Primary Outcome

Doubling of baseline serum creatinine, development of ESRD, or all-cause mortality
Irbesartan vs. placebo: 32.6% vs. 39.0% (RR 0.8; 95% CI 0.66-0.97; P=0.02)
Amlodipine vs. placebo: 41.1% vs. 39.0% (RR 1.04; 95% CI 0.86-1.25; P=0.69)
Irbesartan vs. amlodipine: 32.6% vs. 41.1% (RR 0.77; 95% CI 0.63-0.93; P=0.006)

Secondary Outcomes

CV mortality, nonfatal MI, HF hospitalization, permanent neurological from CVA, or lower limb amputation above the ankle
Irbesartan vs. placebo: 23.8% vs. 25.3% (RR 0.91; 95% CI 0.72-1.14; P=0.40)
Amlodipine vs. placebo: 22.6% vs. 25.3% (RR 0.88; 95% CI 0.69-1.12; P=0.29)
Irbesartan vs. amlodipine: 23.8% vs. 22.6% (RR 1.03; 95% CI 0.81-1.31; P=0.79)
Patients in the irbesartan group had a 23% lower rate of heart failure than the placebo group.
Patients in the amlodipine group had a 41% lower rate of nonfatal MI than the placebo group.
Doubling of baseline serum creatinine
Irbesartan vs. placebo: 16.9% vs. 23.7% (RR 0.67; 95% CI 0.52-0.87; P=0.003)
Amlodipine vs. placebo: 25.4% vs. 23.7% (RR 1.06; 95% CI 0.84-1.35; P=0.60)
Irbesartan vs. amlodipine: 16.9% vs. 25.4% (RR 0.63; 95% CI 0.48-0.81; P<0.001)
ESRD
Defined by the initiation of dialysis, renal transplantation, or a serum creatinine concentration of ≥6.0 mg/dl [530 μmol/l].
Irbesartan vs. placebo: 14.2% vs. 17.8% (RR 0.77; 95% CI 0.57-1.03; P=0.07)
Amlodipine vs. placebo: 18.3% vs. 17.8% (RR 1.00; 95% CI 0.76-1.32; P=0.99)
Irbesartan vs. amlodipine: 14.2% vs. 18.3% (RR 0.77; 95% CI 0.57-1.03; P=0.07)
All-cause mortality
Irbesartan vs. placebo: 15.0% vs. 16.3% (RR 0.92; 95% CI 0.69-1.23; P=0.57)
Amlodipine vs. placebo: 14.6% vs. 16.3% (RR 0.88; 95% CI 0.66-1.19; P=0.40)
Irbesartan vs. amlodipine: 15.0% vs. 14.6% (RR 1.04; 95% CI 0.77-1.40; P=0.80)

Additional Analyses

Mean BP during follow-up
Irbesartan vs. amlodipine vs. placebo: 140/77 vs. 141/77 vs. 144/80 mm Hg
MAP was lower (by 3.3 mm Hg) in irbesartan and amlodipine groups as compared to placebo (P=0.001 for both comparisons).
Glycemic control
The HbA1c values did not differ significantly among the treatment groups over time.
Change in serum creatinine
Irbesartan vs. amlodipine vs. placebo: 0.45±0.04 vs. 0.57±0.04 vs. 0.59±0.04 mg/dL/year
Serum creatinine increased 24% more slowly in the irbesartan group than placebo (P=0.008) and 21% more slowly than the amlodipine group (P=0.02).
Rate of change in creatinine clearance
Irbesartan vs. amlodipine vs. placebo: -5.5±0.36 vs. -6.8±0.37 vs. -6.5±0.37 ml/minute/1.73 m2/year
Percent reduction in urinary protein excretion
Irbesartan vs. amlodipine vs. placebo: 33% (-1.1±1.7 g/24 hr) vs. 6%(-0.1±2.9 g/24 hr) vs. 10% (-0.3±4.3 g/24 hr)

Adverse events

Hyperkalemia necessitating discontinuation of study medication
Irbesartan vs. placebo: 1.9% vs. 0.4% (P=0.01)
Amlodipine vs. placebo: 0.5% vs. 0.4%
Irbesartan vs. amlodipine: 1.9% vs. 0.5% (P=0.01)
Overall, patients in the irbesartan group had a lower rate of adverse events than those in the placebo and amlodipine groups (P=0.002).

Criticisms

  • The BP treatment target was higher than that recommended in the JNC-VI. (<130/85 mm Hg).[5][6]
  • When interpreting the relative risk reduction of ESRD, it is important to note that the study medications were stopped when serum creatinine doubled.[7]

Funding

  • Bristol-Myers Squibb Institute for Medical Research, the sellers of Avapro (brand name for Irbesartan)
  • Sanofi-Synthelabo
  • Authors with financial conflicts of interest

Further Reading

  1. Parving HH et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N. Engl. J. Med. 2001. 345:870-8.
  2. Strippoli GF et al. Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists for preventing the progression of diabetic kidney disease. Cochrane Database Syst Rev 2006. :CD006257.
  3. American Diabetes Association 9. Microvascular Complications and Foot Care. Diabetes Care 2016. 39 Suppl 1:S72-80.
  4. 4.0 4.1 Rodby RA et al. The Irbesartan type II diabetic nephropathy trial: study design and baseline patient characteristics. For the Collaborative Study Group. Nephrol. Dial. Transplant. 2000. 15:487-97.
  5. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch. Intern. Med. 1997. 157:2413-46.
  6. Walser M & Angiotensin-receptor blockers, type 2 diabetes, and renoprotection. N. Engl. J. Med. 2002. 346:705-7.
  7. Lewis EJ & Lewis JB Treatment of diabetic nephropathy with angiotensin II receptor antagonist. Clin. Exp. Nephrol. 2003. 7:1-8.