By Harold L. Karpman, MD, FACC, FACP

Clinical Professor of Medicine, UCLA School of Medicine

Dr. Karpman reports no financial relationships relevant to this field of study.

SYNOPSIS: Although no blood pressure-lowering strategy prolonged survival in adults with diabetes and kidney disease in this meta-analysis, angiotensin-converting enzyme and angiotensin-receptor blockers, alone or in combination, were the most effective pharmacological strategies to prevent the development of end-stage renal disease.

SOURCE: Palmer SC, et al. Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: A network meta-analysis. Lancet 2015;385:2047-2056.

Diabetes mellitus effects 3-4% of adults worldwide, and chronic kidney disease occurs in 25-40% of patients with diabetes within 20-25 years of onset.¹ Diabetes is now the leading cause of end-stage renal disease,² and the combination of diabetes and renal disease is associated with a four-fold increase in the prevalence of atherosclerotic vascular disease and death.³ Blood pressure lowering with pharmacological agents has been central to the treatment of diabetic kidney disease for decades and has contributed enormously to the decreased prevalence of end-stage renal disease over the past 10 years.⁴ Surprisingly, the comparative efficacy and safety of available drugs is largely unknown, mainly because of an absence of published head-to-head clinical trials.⁵

In an attempt to assess the comparative effects of all blood pressure-lowering agents in adults with diabetes and renal disease, Palmer et al performed a worldwide network meta-analysis of randomized trials comparing blood pressure-lowering agents in adults with diabetic kidney disease.⁶ They found and evaluated 157 studies comprised of 43,256 participants, most with type II diabetes and chronic kidney disease. No blood pressure-lowering strategy resulted in prolonged survival of adults with diabetes and kidney disease; however, compared with placebo, end-stage renal disease was significantly less likely to occur after dual treatment with an angiotensin-receptor blocker (ARB) and an angiotensin-converting-enzyme (ACE) inhibitor or after ARB monotherapy. ACE inhibitors and ARBs alone or in combination were the most effective strategies against the development of end-stage renal disease. In their analysis, the authors excluded all study participants who underwent renal transplantation and/or dialysis.

COMMENTARY

In clinical practice, the functional equivalence of ACE inhibitors and ARBs has been assumed; however, appropriate concerns exist regarding the risk of acute kidney injury and hyperkalemia with dual therapy. These concerns led to the premature termination of the Veterans Affairs Nephropathy in Diabetes trial.7 The Palmer meta-analysis included clinical trials that compared the effect of any orally administered blood pressure lowering-agents (ACE inhibitors, ARBs, calcium channel blockers, beta-blockers, alpha-blockers, diuretics, renin inhibitors, aldosterone antagonists, or endothelin inhibitors) alone or in combination with a second blood pressure-lowering agent to placebo or control. They found little evidence that blood pressure-lowering in adults with diabetes and kidney disease increased survival. However, they did find that administration of ACE inhibitors and ARBs alone or in combination were the most effective hypertension treatment strategies for prevention of end-stage renal disease. Despite the proven clinical benefits of hypertensive drug therapy, clinicians should consider the potential harms of these treatments in individual patients. Constant surveillance for treatment-related acute kidney injury and/or hyperkalemia is mandatory.

Because of scant primary data, the effects of blood pressure treatment on cardiovascular events and related mortality were very uncertain in this very large meta-analysis,6 which did not support the use of beta-blockers, calcium channel blockers, renin inhibitors, or diuretic monotherapy for treatment of hypertension in patients with diabetes and renal disease. However, the use of ACE inhibitors or ARBs alone or in combination proved to be the most effective treatment strategies for prevention of end-stage renal disease. When these drugs are administered, patients should be carefully followed to be certain that deteriorating renal function and/or hyperkalemia are promptly discovered and treated if either of these drug-related complications were to occur. Clinicians should continue to appropriately treat hypertension, whether a patient has diabetes or not, to reduce the incidence of coronary artery disease and its complications. However, as indicated above, careful clinical follow-up is indicated, especially in hypertensive patients who have associated diabetes and/or renal disease.

REFERENCES

1. Wild S, et al. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27:1047-1053.
2. Ritz E, Orth SR. Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med 1999;341:1127-1133.
3. Foley RN, et al. Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the U.S. Medicare population,1998 to 1999. J Am Soc Nephrol 2005;16:489-495.
4. Burrows NR, et al. Incidence of treatment for end-stage renal disease among individuals with diabetes in the United States continues to decline. Diabetes Care 2010;33:73-77.
5. Strippoli GF, et al. Effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: Systematic review. BMJ 2004;229:828.
6. Palmer SC, et al. Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: A network meta-analysis. Lancet 2015;385:2047-2056.
7. Fried LF, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013;369:1892-1903.