Combined Angiotensin Inhibition for the Treatment of Diabetic

Nephropathy

Dr. Sandeep G HuilgolMBBS, DNB(Internal Medicine),

MMedSci(Nephro)

Original Article Combined Angiotensin Inhibition for the Treatment

of Diabetic Nephropathy

Linda F. Fried, M.D., M.P.H., Nicholas Emanuele, M.D., Jane H. Zhang, Ph.D., Mary Brophy, M.D., Todd A. Conner, Pharm.D., William Duckworth, M.D., David J. Leehey, M.D., Peter A. McCullough, M.D., M.P.H., Theresa

O'Connor, Ph.D., Paul M. Palevsky, M.D., Robert F. Reilly, M.D., Stephen L. Seliger, M.D., Stuart R. Warren, J.D., Pharm.D., Suzanne Watnick, M.D.,

Peter Peduzzi, Ph.D., Peter Guarino, M.P.H., Ph.D., for the VA NEPHRON-D Investigators

N Engl J MedVolume 369(20):1892-1903

November 14, 2013

Study Overview

• In this study, patients with type 2 diabetes, albuminuria, and mild-to-moderate renal dysfunction received losartan followed by lisinopril or placebo.

• The study was stopped early because of increased risks of hyperkalemia and acute kidney injury with combination therapy.

• Combination therapy with angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain

• Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD).

• Persons with diabetes and proteinuria are at high risk for progression to ESRD.

• Blockade of the renin–angiotensin system decreases the progression of proteinuric kidney disease, and the degree of reduction in proteinuria correlates with the extent to which the decrease in the glomerular filtration rate (GFR) is slowed.

ONTARGET

Questions:1.Is telmisartan “non-inferior” to ramipril? 2.Is the combination superior to ramipril?Outcome:3.Primary: CV death, MI, stroke, CHF hosp4.Key secondary: CV death, MI, stroke (HOPE trial outcome)

1. Telmisartan is clearly “non-inferior” to ramipril

• Primary composite outcome (p=0.0038)

2. Combination therapy does not reduce the primary outcome to a greater extent compared to ramipril alone

3. Higher rates of adverse events:•-hypotension related, including syncope•-renal dysfunction

• The ONTARGET study population had predominantly normal levels of albumin excretion or microalbuminuria.

Research question

• Is combination therapy of ARB and ACE safe?• Is the combination therapy efficacious in

slowing the progression of proteinuric diabetic nephropathy than monotherapy.

The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) study was

• Multicenter • Double- blind, • Randomized, controlled study designed• to test the efficacy of the combination of losartan (an ARB)

with lisinopril (an ACE inhibitor), as compared with standard treatment with losartan alone, in slowing the progression of proteinuric diabetic kidney disease.

Primary end point

• First occurrence of a decline in the estimated GFR (an absolute decrease of ≥30 ml per minute per 1.73 m2 if the estimated GFR was ≥60 ml per minute per 1.73 m2 at randomization or a relative decrease of ≥50% if the estimated GFR was <60 ml per minute per 1.73 m2).

• ESRD (defined by the initiation of maintenance dialysis or an estimated GFR of <15 ml per minute per 1.73 m2), or death.

Secondary renal end point

• First occurrence of a decline in the estimated GFR (as defined above) or ESRD.

• Changes in the estimated GFR were confirmed at least 4 weeks after treatment of potentially reversible factors.

• Patients who reached the primary end point on the basis of the estimated GFR continued to receive study medications until the occurrence of ESRD or death….???

• Tertiary end points included cardiovascular events (myocardial infarction, stroke, or hospitalization for congestive heart failure), the slope of change in the estimated GFR, and the change in albuminuria at 1 year.

• Between July 2008 and September 2012, a total of 4346 patients were screened,

• 1648 were enrolled,• 1448 underwent randomization (724 in each

group).

Baseline Characteristics of the Patients.

Fried LF et al. N Engl J Med 2013;369:1892-1903

Adverse Events and Safety

Kaplan–Meier Plot of Cumulative Probabilities of the Primary and Secondary End Points and Death.

Fried LF et al. N Engl J Med 2013;369:1892-1903

Kaplan–Meier Plot of Cumulative Probabilities of Acute Kidney Injury and Hyperkalemia.

Fried LF et al. N Engl J Med 2013;369:1892-1903

Efficacy End Points and Mortality.

Fried LF et al. N Engl J Med 2013;369:1892-1903

Safety Outcomes.

Fried LF et al. N Engl J Med 2013;369:1892-1903

Conclusions

• Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy.

Take home message

• In the VA NEPHRON-D trail, despite higher reductions in UACR in the combination arm, there was no demonstrable renal benefits.

• AKI was the major reason for the higher rate of serious adverse events in the combination arm of the VA NEPHRON-D trial;

• Regardless of the evidence base for renoprotection with ACEI or ARB in proteinuric CKD and diabetic nephropathies, it must be borne in mind by the practicing physician that the potential for iatrogenic renal failure with ACEi/ARBs