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Therapeutics

Irbesartan reduced progression of nephropathy caused by type 2 diabetes independent of the effect on blood pressure

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ACP J Club. 2002 May-Jun;136:83. doi:10.7326/ACPJC-2002-136-3-083

Related Content in the Archives
• Correction: Irbesartan reduced progression of nephropathy caused by type 2 diabetes independent of the effect on blood pressure


Source Citation

Lewis EJ, Hunsicker LG, Clarke WR, et al., for the Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001 Sep 20;345:851-60. [PubMed ID: 11565517] (All 2002 articles were reviewed for relevancy, and abstracts were last revised in 2008.)


Abstract

Question

In patients with type 2 diabetes mellitus, diabetic nephropathy, and hypertension, what effect does the angiotensin-II–receptor antagonist (ARA) irbesartan and the calcium-channel blocker amlodipine have on renal disease?

Design

Randomized (allocation concealed*), blinded (clinicians, patients, outcome assessors, and statisticians),* placebo-controlled trial with mean follow-up of 2.6 years (the Irbesartan Diabetic Nephropathy Trial [IDNT]).

Setting

210 clinical centers worldwide.

Patients

1715 patients between 30 and 70 years of age (mean age 59 y, 66% men) who had type 2 diabetes, hypertension, proteinuria defined as a urinary protein excretion rate ≥ 900 mg/24 hours, and serum creatinine levels between 88 and 265 µmol/L in women and between 106 and 265 µmol/L in men. Follow-up was 99%.

Intervention

Patients were allocated to irbesartan, titrated to 300 mg/d (n = 579); amlodipine, titrated to 10 mg/d (n = 567); or placebo (n = 569). Treatment targeted a systolic blood pressure ≤ 135 mm Hg and a diastolic blood pressure ≤ 85 mm Hg by using drugs other than angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers, and calcium-channel blockers, if necessary.

Main outcome measures

The primary outcome was the composite of a doubling of the baseline serum creatinine level, onset of end-stage renal disease, or all-cause mortality. The secondary outcome was the composite of cardiovascular mortality, nonfatal myocardial infarction, heart failure resulting in hospitalization, neurologic deficit caused by a cerebrovascular event, or above-ankle lower-limb amputation.

Main results

Analysis was by intention to treat. After adjusting for mean blood pressure, irbesartan lowered the risk for the primary composite outcome more than did amlodipine (P = 0.005) or placebo (P = 0.03); this outcome did not differ for amlodipine and placebo (P = 0.47) (Table). The 3 groups did not differ for the secondary composite outcome.

Conclusion

In patients with type 2 diabetes, nephropathy, and hypertension, irbesartan was more effective in reducing progression of nephropathy independent of the effect on blood pressure than was amlodipine or placebo.

*See Glossary.

Sources of funding: Bristol-Myers Squibb Institute for Medical Research and Sanofi-Synthelabo.

For correspondence: Dr. E.J. Lewis, Rush–Presbyterian–St. Luke’s Medical Center, Chicago, IL, USA.


Table. Irbesartan, amlodipine, or placebo for risk for a composite outcome in diabetic nephropathy and hypertension at mean 2.6 y†

Comparisons Event rates Adjusted RRR (95% CI) NNT (CI)
Irbesartan vs amlodipine 33% vs 41% 24% (8 to 37) 12 (7 to 35)
Irbesartan vs placebo 33% vs 39% 19% (1 to 33) 16 (8 to 121)
Adjusted RRI (CI) NNH
Amlodipine vs placebo 41% vs 39% 7% (−11 to 29) Not significant

†Composite outcome = doubling of baseline serum creatinine level, end-stage renal disease, or all-cause mortality. Abbreviations defined in Glossary; RRR, RRI, and CI adjusted for mean arterial blood pressure; NNT, NNH, and CI calculated from data in article.


Commentary

[ACPJC-2002-136-3-082.htm]Irbesartan was renoprotective in patients with type 2 diabetes, hypertension, and microalbuminuria [ACPJC-2002-136-3-084.htm]Losartan was renoprotective in diabetic nephropathy independent of its effect on blood pressure

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 as retinopathy, neuropathy, and nephropathy. Diabetic nephropathy causes almost 40% of all incident dialysis cases in the United States. Once 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 and colleagues have shown that treating patients who have type 2 diabetes, hypertension, and microalbuminuria with irbesartan, 300 mg/d, reduced progression to overt nephropathy at 2 years; lower doses (e.g., 150 mg/d) were less effective. This beneficial effect of irbesartan was independent of blood pressure lowering and glycemic control. In addition, irbesartan was more likely than placebo to cause regression to normoalbuminuria. The findings support the role of renin-angiotensin system blockade with irbesartan in preventing progression to albuminuria.

The Microvascular Heart Outcomes Prevention Evaluation (MICRO-HOPE) study (2) 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 and colleagues (3) provides a preliminary assessment of the role of combination therapy 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-to-creatinine ratio than either drug given alone.

Once overt nephropathy develops, the goal of therapy 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 to 150 mm Hg, and diastolic blood pressure levels ranged from 74 to 77 mm Hg. A mean of 3 to 4 additional nonstudy medications were needed to achieve these blood pressure levels. Mean proteinuria levels 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 persons with type 2 diabetes, fatal and nonfatal cardiovascular events occur at a rate of 4% to 5% per year. The HOPE study (4) 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. Losartan was associated, however, with a lower rate of first hospitalization for congestive heart failure.

Patients and their clinicians must now consider using these 2 classes of drugs. Therapy 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 renin-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 renin-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 persons with type 2 diabetes.

Christian G. Rabbat, MD
McMaster University
Hamilton, Ontario, Canada


References

1. United States Renal Data System. USRDS 2000 Annual Data Report. 2000. Bethesda, Md.: National Institutes of Health; 2000. www.usrds.org/adr_2000.htm.

2. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253-59. [PubMed ID: 10675071]

3. Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ. 2000;321:1440-4. [PubMed ID: 11110735]

4. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145-53. [PubMed ID: 10639539]

5. Casas JP, Chua W, Loukogeorgakis S, et al. Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet. 2005;366:2026-33. [PubMed ID: 16338452]

6. Kunz R, Friedrich C, Wolbers M, Mann JF. Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med. 2008;148:30-48. [PubMed ID: 17984482]

7. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547-59. [PubMed ID: 18378520]