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Diabetic nephropathy occurs in 20-40% of all diabetic patients and is considered the leading cause of end stage renal disease (ESRD).1 Therefore, treatments are needed that slow the progression of kidney decline to prevent ESRD. Recent Standards of Care published by the American Diabetes Association (ADA) at the beginning of 2014 support the use of an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) to block the renin-angiotensin system to decrease proteinuria along with slowing the decline in glomerular filtration rate.1 Several studies exist that have evaluated the use of each drug class and have showed positive outcomes in slowing the progression of kidney decline.2-4 While the ONTARGET study showed that the ARB, telmisartan, was non-inferior to ramipril and offered no benefit of combination therapy, the primary focus of that trial was cardiovascular outcomes and <3% of the patient population had diabetic nephropathy. The study also used the same doses for monotherapy and combination therapy and found more adverse effects (e.g., hypotension and hyperkalemia) with combination therapy.5 There was a need to look at the synergistic effects of ACE inhibitor and ARB therapies in a focused patient population of those with diabetic nephropathy.

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Juarez and colleagues conducted a multicenter, open-label, randomized controlled trial with a median follow-up time of 32 months to examine the efficacy of combination of the ACE inhibitor, lisinopril, with the ARB, irbesartan, to monotherapy with each agent in slowing the progression of kidney disease in type 2 diabetic patients with nephropathy (clinical diagnosis of diabetic nephropathy, stage 2 or 3 chronic kidney disease, and a urine protein-creatinine ratio of >300mg/g on 2 occasions).6 Subjects included in the study were older than 35 years of age with type 2 diabetes with a hemoglobin A1c (A1c) <10%, proteinuria of <10g/24 hours, albumin >2g/dL, and potassium <5.5 mEq/L. Exclusion of subjects occurred if they had a previous myocardial infarction, cerebrovascular stroke, heart failure, myocardial vascularization in the last 3 months, or any condition limiting long term survival. All patients had a 4-week washout period where those on an ACE inhibitor or an ARB had their medications removed and replaced by alternative open-label medications to control blood pressure. Following the washout period, all patients were randomly assigned to receive lisinopril (goal dose 40mg), irbesartan (goal dose 600mg), or combination of lisinopril (goal dose 20mg) and irbesartan (goal dose 300mg) daily (1:1:2). The primary endpoint for all groups was the time to the first event of a composite end point of a 50% increase from baseline in serum creatinine concentration, ESRD, or death. Secondary endpoints analyzed were the change in urine protein-creatinine ratio and tolerance and safety of each treatment group.6

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A total of 133 patients were included in the study with 35 patients in the lisinopril group, 28 patients in the irbesartan group, and 70 patients in the combination of group. The intent to treat design allowed everyone who received a dose of their respective medication to be included in the analysis regardless of whether or not they remained to the end of the follow up period. There was no significant difference in blood pressure during follow-up. The primary endpoint was achieved in 29% of patients in the lisinopril group, 29% in the irbesartan group, and 30% in the combination group with no significant differences between the groups. Proteinuria decreased by 20%, 17%, and 19% for lisinopril, irbesartan, and combination therapy respectively with no significant differences between the groups. The adverse events experienced were similar among the three treatment groups with the predominant adverse event being hyperkalemia.6

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The results of the study showed there was no added benefit or harm of the combination of an ACE inhibitor and an ARB in delaying the progression of kidney decline or reduction of proteinuria when compared to monotherapy of each individual agent. However, the study may have been underpowered, so it cannot be excluded that a difference in benefit or harm does not exist. In addition, previous studies have found that the ...

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