Albuminuria and Blood Pressure, Independent Targets for Cardioprotective Therapy in Patients With Diabetes and Nephropathy: A Post Hoc Analysis of the Combined RENAAL and IDNT Trials

Study Questions:

The long-term cardioprotective effect of angiotensin-receptor blockers (ARBs) is associated with the short-term lowering of its primary target blood pressure, but also with the lowering of albuminuria. How does the variability and discordance in systolic blood pressure (SBP) and albuminuria response to ARB therapy affect long-term cardiovascular (CV) outcomes?


The combined data of the placebo-controlled RENAAL (losartan) and IDNT (irbesartan) trials in type 2 diabetics with nephropathy were used in this analysis. The extent of variability and discordance in SBP and albuminuria response (baseline to 6 months) was assessed initially, and followed by an analysis of the combined impact of residual month 6 SBP and albuminuria level with CV outcome.


A total of 2,900 patients were included. Mean age was 59.5 years; 34.8% were female; mean SBP was 154 mm Hg and diastolic BP was 84 mm Hg; glycated hemoglobin was 8.3%; estimated glomerular filtration rate was 43.6, serum creatinine was 1.8 mg/dl, and urine albumin-to-creatinine ratio was 1344 mg/g. In ARB-treated patients, 421 patients (34.5%) either had a reduction in SBP but no reduction in albuminuria, or vice versa, indicating substantial discordance in response in these parameters. The initial reduction in SBP and albuminuria independently correlated with CV protection: hazard ratio [HR] per 5 mm Hg SBP reduction, 0.97 (95% confidence interval [CI], 0.94-0.99), and HR per decrement log albuminuria, 0.87 (95% CI, 0.76-0.99). Across all SBP categories at month 6, a progressively lower CV risk was observed with a lower albuminuria level. This was particularly evident in patients who reached the guideline-recommended SBP target of ≤130 mm Hg.


The authors concluded that SBP and albuminuria response to ARB therapy is variable and discordant. Therapies intervening in the renin-angiotensin-aldosterone system with the aim of improving CV outcomes may therefore require a dual approach, targeting both blood pressure and albuminuria.


Whilst the data clearly demonstrate that the benefits of ARBs on CV risk reduction are related to both on-treatment SBP and reduction in albuminuria, it is a long stretch to suggest that each should be a target. The decrease in CV events with decrease in albuminuria may be an epiphenomenon. Of course, increasing ARB dosing in individuals to target albuminuria could result in modest or severe lowering of blood pressures and result in CV events and renal failure.

Clinical Topics: Heart Failure and Cardiomyopathies

Keywords: Angiotensin Receptor Antagonists, Biphenyl Compounds, Risk Reduction Behavior, Diabetes Mellitus, Type 2, Renin-Angiotensin System, Blood Pressure, Diabetic Nephropathies, Tetrazoles

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