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Combination Therapy Has Increased Risk in Diabetic Patients

No benefit seen from the combination therapy of an ACE inhibitor and ARB….

The leading cause of end-stage renal disease (ESRD) is diabetic nephropathy. People are at a high risk for progression to ESRD if they have diabetes and proteinuria. With the blockade of the renin-angiotensin system and reduction in proteinuria, there is a correlation with the decrease in glomerular filtration rate (GFR). So it has been hypothesized that an intervention that further lowers proteinuria will reduce the risk of ESRD progression even more.

This study was a multicenter, double-blind, randomized, and controlled study to observe the efficacy of the combination of an angiotensin-converting-enzyme (ACE) inhibitor and an angiotensin II-receptor blocker (ARB). The combination of losartan (an ARB) and lisinopril (an ACE inhibitor) was used to compare with monotherapy of losartan in slowing the progression of proteinuric diabetic kidney disease. The primary end point was the first incidence of change in the estimated GFR, ESRD, or death. The secondary renal end point was the first incidence of decline in the estimated GFR or ESRD. The tertiary end points were cardiovascular events, slope of change in the estimated GFR and the change in albuminuria at 1 year.

Out of 1,448 randomly assigned patients, 182 died or had progression to ESRD, while 143 patients exited the study before it was done. When looking at the primary end point, there was no significant difference between the monotherapy group and combination therapy group. In both groups, changes in estimated GFR, ESRD, and death were all observed. There was no significant difference between the groups in mortality or rate of cardiovascular events.

Overall major differences that were seen were an increased in the risk of hyperkalemia (6.3 events per 100 person-years with combination therapy vs. 2.6 events per 100 person-years with monotherapy) and acute kidney injury (12.2 events with combination therapy vs. 6.7 events with monotherapy).

Practice Pearls:
  • Diabetic nephropathy is the leading cause of ESRD
  • Increased risk of hyperkalemia and acute kidney injury with the use of combination therapy
  • Combination therapy shows no significant benefit in regards to mortality or cardiovascular disease.
New England Journal of Medicine 2013