Trimox

* EVIDENCE-BASED ANSWER

Angiotensin receptor blockers (ARBs) have been shown to reduce the progression of nephropathy in several consistent studies. While ACE inhibitors have not been as well studied for the endpoint of nephropathy, patients with nephropathy exhibit reduced mortality when treated with an ACE inhibitor (strength of recommendation: A, based on randomized controlled trials).

* EVIDENCE SUMMARY

The RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) study (1)--a multicenter, randomized, double-blind, placebo-controlled trial--followed 1513 patients with type 2 diabetes and nephropathy over a mean of 3.4 years. Patients were randomized to receive losartan (Cozaar) or placebo, both taken in addition to conventional anti-hypertensive therapy (but not including renin-angiotensin-aldosterone system antagonist medications). The primary outcome was a composite of a doubling of serum creatinine, end-stage renal disease, or death. The number needed to treat (NNT) for the composite outcome was 34. The NNT for a doubling of the serum creatinine was 25, and for end-stage renal disease was 17.

The 2-year IRMA (Irbesartan Microalbuminuria) study, (2) a multicenter, randomized, double-blind, placebo-controlled trial, randomized 590 patients with type 2 diabetes, hypertension, and persistent microalbuminuria to receive 150 or 300 mg of irbesartan (Avapro) or placebo. Additional antihypertensive agents were allowed in each arm with the exception of ACE inhibitors, ARBs, and dihydropyridine calcium-channel blockers. The primary outcome was the development of overt nephropathy defined by a urinary albumin excretion rate >200 [micro]g/min that is at least 30% higher than the baseline rate. This trial showed that irbesartan delayed progression to nephropathy independent of its effect on blood pressure compared with conventional therapy (NNT = 16 at the 150-mg dose and NNT = 11 at the 300-mg dose).

A third double-blind, placebo-controlled trial--IDNT (Irbesartan Diabetic Nephropathy Trial (3)--randomized 1715 patients to irbesartan, amlodipine (Norvasc), or placebo for a median follow-up of 2.6 years. Each group could also use other conventional anti_hypertensive therapy (but again excluding ACE inhibitors, ARBs, and calcium-channel blockers). Irbesartan reduced progression of nephropathy (defined by doubling of the serum creatinine) and the onset of end-stage renal disease more effectively than amlodipine (NNT = 12) or placebo (NNT = 16). Irbesartan did not decrease cardiovascular mortality, nonfatal myocardial infarction, heart failure resulting in hospitalization, neurologic deficit caused by a cerebrovascular event, or above-ankle lower-limb amputation.

The mortality benefit with ARBs has not been as consistent as that shown with ACE inhibitors. Both classes of drugs conferred reduced mortality as seen with ramipril in the HOPE (Heart Outcomes Prevention Evaluation) trial (4) and losartan in the LIFE (Losartan Intervention For Life) trial. (5) However, a survival benefit was not seen with irbesartan in the RENAAL and IDNT trials.

* RECOMMENDATION FROM OTHERS

The American Diabetes Association recommends both ACE inhibitors and ARBs for the treatment of early nephropathy in hypertension to delay the progression of microalbuminuria to macroalbuminuria and overt nephropathy. (6)

* CLINICAL COMMENTARY

ARBs not yet shown to be as good as ACE inhibitors at reducing mortality

The evidence is good that ARBs delay the progression of type 2 diabetic nephropathy. Although more studies have looked at ARBs than ACE inhibitors in nephropathy from type 2 diabetes, ARBs have not been shown to be as good as ACE inhibitors at reducing all-cause mortality, the most important patient-oriented outcome.

REFERENCES

(1.) Brenner BM, Cooper ME, de Zeeuw D, et al, for the RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345:861-869.

(2.) Parring H-H, Lehnert H, Brochner-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; 345:870-878.

(3.) 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; 345:851-860.

(4.) Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICCRO-HOPE substudy. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Lancet 2000; 355:253.

(5.) Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002; 359:1004.

(6.) American Diabetes Association. Diabetic Nephropathy. Diabetes Care 2003; 26:S94-S98.

DRUG BRAND NAMES

Amlodipine * Norvasc Amoxicillin * Amoxil, Biomox, Polymox, Trimox, Wymox Azithromycin * Zithromax Cefaclor * Ceclor Cephalexin * Biocef, Keflex Clarithromycin * Biaxin Clindamycin * Cleocin, Dalacin Irbesartan * Avapro Losartan * Cozaar Ramipril * Altace Vancomycin * Vancocin Warfarin * Coumadin Xylometazoline * Otrivin

Brett H. Foreman, MD, M. Lee Chambliss, MD, MPH, Moses Cone Health System, Greensboro, NC

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