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Valsartan Delays the Incidence of Microalbuminuria in Prediabetes Patients

Valsartan associated with reduction in new onset diabetes in patients with impaired glucose tolerance

Diabetic nephropathy (DN) is an important cause of chronic kidney disease (CKD) that frequently leads to end stage renal disease (ESRD)3. DN is one of the main complications of diabetes and early detection of DN is of utmost importance to provide appropriate therapy that prevents or slows the occurrence of ESRD. Although there are many biomarkers to diagnose DN, microalbuminuria is the ‘gold standard’ for early diagnosis and for assessing associated conditions. Renin-angiotensin system blockers reduce the incidence and progression of microalbuminuria and subsequent development of ESRD in patients with type 2. Therefore, the purpose of the study is to examine the effect of valsartan on kidney outcomes in patients with impaired glucose tolerance (IGT).

This study was a randomized, double-blinded, placebo-controlled, forced-titration, 2 x 2 factorial design. The study assessed the efficacy and safety of long-term administration of valsartan in the prevention of diabetes and cardiovascular outcomes in subjects with Impaired Glucose Tolerance (IGT). It included patients with risk factors associated with ≥1 cardiovascular disease (CVD) if ≥55 years or with known CVD if ≥50 years and confirmed impaired glucose tolerance (IGT). Also, fasting plasma glucose (FPG) levels of ≥5.3 mmol/L upto 7.0 mmol/L was required. However, the study excluded patients who were using an ACE inhibitor or ARB for hypertension, using antidiabetic medication within the last 5 years, or if their SCr >2.5 mg/dL.

Patients were either given placebo compared to valsartan 80 mg once daily with an increase to 160 mg once daily after 2 weeks, but not if larger doses were not tolerated. Subjects were followed-up after 2 and 4 weeks during the initial therapy and then every 6 months for 6 years. During follow-up, serum was collected, but serum creatinine (SCr) was measured yearly and estimated GFR (eGFR) was calculated using the 4-variable modified diet in renal disease formula. The primary endpoint was comprised of incidence of diabetes mellitus, an “extended” cardiovascular composite of time to first occurrence of cardiovascular death, and a “core” cardiovascular composite of cardiovascular death. Renal outcomes were prespecified and all biochemical outcomes were confirmed by a second measurement. Post-baseline microalbuminuria was expressed as urine albumin-to-creatinine ratio (UACR) >30 mg/g and macroalbuminuria as UACR >300 mg/g.

The study found that valsartan was associated with reduced incidence of diabetes, but not cardiovascular events. Twenty-five patients (0.5%) out of 4,631 subjects in the valsartan group versus 26 patients (0.6%) out of 4675 in the placebo groups, respectively, developed ESRD or experienced doubling of SCr (Hazards Ratio = 0.96; 95% Confidence Interval, 0.55 to 1.66; P = 0.87). Moreover, few patients developed an eGFR of ≤30 mL/min/1.73 m2 or had a renal hospitalization. In addition, fewer patients on valsartan; 237 out of 4,084 (5.8%) versus placebo; 342 out of 4,092 (8.4%) developed microalbuminuria (Hazards Ratio = 0.68; 95% Confidence Interval: 0.57 to 0.80; P<0.0001), and macroalbuminuria developed in even fewer valsartan-treated patients. Overall, urinary albumin-to-creatinine ratio (UACR) was 11% lower with valsartan (95% CI 8–13%) and 9% lower after adjusting (95% CI 6–11%) for both glucose and blood pressure (both P<0.0001).

The benefit of using RAS blockers during the earliest signs of DN has proven to reduce the incidence of microalbuminuria leading to complications in patients with T2D and normal urinary albumin excretion (UAE). The trial lacked consistency where elevated UAE had been linked with the risk of progressive kidney disease and CVD, even at acceptable normal ranges. Adjustments in blood pressure had little to no effect on UACR and plasma glucose that was lowered by valsartan resulted in little attenuated effect of ARB.

In conclusion, the effect of valsartan on urinary albumin-to-creatinine ratio was not wholly explained by a change in blood pressure or glucose. However, valsartan reduced the incidence of microalbuminuria in IGT without increasing the incidence of hyperkalemia or renal dysfunction compared with placebo.

However, it is uncertain whether reduction in microalbuminuria translates into protection against decline in GFR. Thus, further studies are required for a longer term to assess whether an ARB can produce a true renoprotective action.

Practice Pearls:

  • The earliest clinically detectable sign of diabetic kidney dysfunction is the development of microalbuminuria.
  • Valsartan reduced the incidence of microalbuminuria in patients with IGT.
  • Valsartan did not reduce the risk of cardiovascular events or death.

References:

  1. “Diabetic Nephropathy.” Diabetic Nephropathy, www.cleavelandclinicmeded.com/medicalpubs/diseasemanagement/nephrology/diabetic-nephropathy/. Accessed 16 Feb. 2017.
  2. Currie G, Bethel MA, Holzhauer B, Haffner SM, Holman RR, McMurray JV. Effect of valsartan on kidney outcomes in people with impaired glucose tolerance. Diabetes, Endocrinology, and Metabolism. Accepted manuscript online: 17 Jan 2017, DOI: 10.1111/dom.12877
  3. Gluhovschi C, Gluhovschi G, Petrica L, Timar R. Velciov S, Ionita I, et al. Urinary biomarkers in the assessment of early diabetic nephropathy. Journal of Diabetes Research.  2016 Jun 16. 2016: 4626125. www.ncbi.nlm.nih.gov/pmc/articles/PMC4927990/. Accessed 16 Feb. 2017.