Impact of the PPAR-gamma2 Pro12Ala polymorphism and ACE inhibitor therapy on new-onset microalbuminuria in type 2 diabetes: evidence from BENEDICT

Abstract

Objective: Cross-sectional studies found less microalbuminuria in type 2 diabetic patients with the Ala12 allele of the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) Pro12Ala polymorphism. We prospectively evaluated the association between Pro12Ala polymorphism (rs1801282) and new-onset microalbuminuria.

Research design and methods: Pro12Ala polymorphism was genotyped by TaqMan-based assay in genomic DNA of 1,119 consenting patients from BErgamo NEphrologic DIabetic Complications Trial (BENEDICT)-a prospective, randomized trial evaluating ACE inhibition effect on new-onset microalbuminuria (albuminuria 20-200 microg/min in at least two of three consecutive overnight urine collections in two consecutive visits) in hypertensive type 2 diabetes with albuminuria <20 microg/min at inclusion.

Results: Baseline characteristics of Ala (Ala/Ala or Ala/Pro) carriers and Pro/Pro homozygotes were similar, with a nonsignificant trend to lower albuminuria (P = 0.1107) in the 177 Ala carriers. Over a median (interquartile range) of 44.0 (17.1-51.9) months, 7 (4%) Ala carriers and 86 (9.1%) Pro/Pro homozygotes developed microalbuminuria (hazard ratio [HR] 0.45 [95% CI 0.21-0.97]; P = 0.042). Final albuminuria was significantly lower in Ala carriers than Pro/Pro homozygotes (7.3 +/- 9.1 vs. 10.5 +/- 24.9 microg/min, respectively), even after adjustment for baseline albuminuria (P = 0.048). Baseline and follow-up blood pressure and metabolic control were similar in both groups. Incidence of microalbuminuria was significantly decreased by ACE versus non-ACE inhibitor therapy in Pro/Pro homozygotes (6.3 vs. 11.9%, respectively, HR 0.46 [0.29-0.72]; P < 0.001).

Conclusions: In type 2 diabetes, the Ala allele protects from worsening albuminuria and new-onset microalbuminuria, and ACE inhibition blunts the excess risk of microalbuminuria associated with the Pro/Pro genotype. Evaluating Pro12Ala polymorphism may help identifying patients at risk who may benefit the most from early renoprotective therapy.

FIG. 1.

Schematic diagram of the study. ACEi, ACE inhibitor therapy.

FIG. 2.

Kaplan-Meier curves for the percentages of Ala carriers or Pro/Pro homozygotes in subjects who developed persistent microalbuminuria throughout the study period.

FIG. 3.

Upper panels: Trough systolic and diastolic blood pressure throughout the study period in Ala carriers or Pro/Pro homozygotes (left), in Ala carriers according to ACE inhibitor therapy (ACEi) (yes or no) (middle), and in Pro/Pro homozygotes according to ACE inhibitor therapy (yes or no). *P < 0.05 (ACE inhibitor therapy yes vs. ACE inhibitor therapy no, without Bonferroni correction for multiple comparisons). Lower panels: A1C throughout the study period in Ala carriers or Pro/Pro homozygotes (left), in Ala carriers according to ACE inhibitor therapy (yes or no) (middle), and in Pro/Pro homozygotes according to ACE inhibitor therapy (yes or no). °P < 0.05 (Pro/Pro homozygotes vs. Ala carriers, without Bonferroni correction for multiple comparisons).

FIG. 4.

Urinary AER (geometric mean and 95% CI) at basal and final visits in Ala carriers or Pro/Pro homozygotes. The difference in urinary AER between the two genotype groups at final visit was significant after adjustment for baseline albumin excretion.

FIG. 5.

Kaplan-Meier curves for the percentages of Pro/Pro homozygotes considered according to concomitant ACE inhibitor therapy (ACEi) (yes or no) and of Ala carriers considered as a whole in subjects who developed persistent microalbuminuria throughout the study period.