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Therapeutics

Irbesartan was renoprotective in patients with type 2 diabetes, hypertension, and microalbuminuria

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ACP J Club. 2002 May-Jun;136:82. doi:10.7326/ACPJC-2002-136-3-082

Related Content in the Archives
• Correction: Irbesartan was renoprotective in patients with type 2 diabetes, hypertension, and microalbuminuria


Source Citation

Parving HH, Lehnert H, Bröchner-Mortensen J, et al., for the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001 Sep 20;345:870-8. [PubMed ID: 11565519] (All 2002 articles were reviewed for relevancy, and abstracts were last revised in 2008.)


Abstract

Question

In patients with type 2 diabetes mellitus, hypertension, and persistent microalbuminuria, what is the effectiveness of the angiotensin-II–receptor antagonist (ARA) irbesartan for delaying or preventing the development of nephropathy?

Design

Randomized {allocation concealed*}†, blinded {clinicians, patients, and outcome assessors}†,* placebo-controlled trial with 2-year follow-up.

Setting

96 centers worldwide.

Patients

611 patients between 30 and 70 years of age who had type 2 diabetes; hypertension defined as systolic blood pressure > 135 mm Hg or diastolic blood pressure > 85 mg Hg or both; persistent microalbuminuria defined as an albumin excretion rate of 20 to 200 µg/min; and a serum creatinine level ≤ 133 µmol/L for men or ≤ 97 µmol/L for women. Exclusion criteria were nondiabetic kidney disease, cancer, fatal disease, or indication for angiotensin-converting enzyme (ACE) inhibitors or ARAs. 590 of 611 (97%) patients (mean age 58 y, 68% men) completed follow-up.

Intervention

Patients were allocated to receive irbesartan, 150 mg/d (n = 195) or 300 mg/d (n = 194), or placebo (n = 201). Patients were treated with antihypertensive drugs as needed, but ACE inhibitors were not allowed. Patients continued their usual diabetes care. Dietary salt and protein were not restricted.

Main outcome measure

Development of nephropathy, defined by a urinary albumin excretion rate > 200 µg/min that is at least 30% higher than the baseline rate.

Main results

Analysis was by intention to treat. At 2 years, unadjusted analyses showed that placebo was associated with a higher incidence of progression to nephropathy than was irbesartan, 300 mg/d (P < 0.001), but not irbesartan, 150 mg/d (P = 0.08). After adjusting for baseline microalbuminuria and blood pressure during the study, placebo was associated with a higher incidence of progression to nephropathy than was irbesartan, 300 mg/d (P < 0.001), and irbesartan, 150 mg/d (P = 0.05) (Table).

Conclusion

In patients with type 2 diabetes mellitus, hypertension, and persistent microalbuminuria, irbesartan delayed progression to nephropathy independent of its effect on blood pressure.

*See Glossary.

†Information provided by author.

Sources of funding: Sanofi-Synthelabo and Bristol-Myers Squibb.

For correspondence: Dr. H. Parving, Steno Diabetes Center, Gentofte, Denmark. E-mail hhp@novo.dk.


Table. Irbesartan vs placebo for progression to nephropathy in type 2 diabetes, hypertension, and persistent microalbuminuria at 2 years§

Irbesartan dose Irbesartan Placebo Adjusted hazard ratio (95% CI) NNT (CI)
150 mg/d 9.7% 14.9% 0.56 (0.31 to 0.99) 16 (10 to 728)
300 mg/d 5.2% 14.9% 0.32 (0.15 to 0.65) 11 (8 to 21)

§Abbreviations defined in Glossary; NNT and its CI calculated by using hazard ratios provided in the article; hazard ratios adjusted for baseline microalbuminuria and blood pressure during the study.


Commentary

[ACPJC-2002-136-3-083.htm]Irbesartan reduced progression of nephropathy caused by type 2 diabetes independent of the effect on blood pressure [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]