Effects of Sevelamer Carbonate on Advanced Glycation End Products and Antioxidant/Pro-Oxidant Status in Patients with Diabetic Kidney Disease

Background and objectives The primary goals were to re-examine whether sevelamer carbonate (SC) reduces advanced glycation end products (AGEs) (methylglyoxal and carboxymethyllysine [CML]), increases antioxidant defenses, reduces pro-oxidants, and improves hemoglobin A1c (HbA1c) in patients with type 2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD). Secondary goals examined albuminuria, age, race, sex, and metformin prescription. Design, setting, participants, & measurements This two-center, randomized, intention-to-treat, open-label study evaluated 117 patients with T2DM (HbA1c >6.5%) and stages 2-4 DKD (urinary albumin/creatinine ratio >= 200 mg/g) treated with SC (1600 mg) or calcium carbonate (1200 mg), three times a day, without changing medications or diet. Statistical analyses used linear mixed models adjusted for randomization levels. Preselected subgroup analyses of sex, race, age, and metformin were conducted. Results SC lowered serum methylglyoxal (95% confidence interval [CI], -0.72 to -0.29; P<0.001), serum CML (95% CI, -5.08 to -1.35; P <= 0.001), and intracellular CML (95% CI, -1.63 to -0.28; P=0.01). SC increased anti-inflammatory defenses, including nuclear factor like-2 (95% CI, -0.58 to 1.29; P <= 0.001), AGE receptor 1 (95% CI,.0.23 to 0.96; P=0.001), NAD-dependent deacetylase sirtuin-1 (95% CI, 0.20 to 0.86; P=0.002), and estrogen receptor alpha (95% CI, 1.38 to 2.73; P <= 0.001). SC also decreased proinflammatory factors such as TNF receptor 1 (95% CI, -1.56 to -0.72; P <= 0.001) and the receptor for AGEs (95% CI, 0.58 to 1.53; P <= 0.001). There were no differences in HbAlc, GFR, or albuminuria in the overall group. Subanalyses showed that SC lowered HbAlc in women (95% CI, -1.71 to -0.27; P=0.01, interaction P=0.002), and reduced albuminuria in those aged <65 years (95% CI, -1.15 to -00.07; P=0.03, interaction P=0.02) and non-Caucasians (95% CI, -1.11 to -0.22; P=0.003, interaction P <= 0.001 ), whereas albuminuria increased after SC and calcium carbonate in Caucasians. Conclusions SC reduced circulating and cellular AGEs, increased antioxidants, and decreased pro-oxidants, but did not change HbAlc or the albumin/creatinine ratio overall in patients with T2DM and DKD. Because subanalyses revealed that SC may reduce HbAlc and albuminuria in some patients with T2DM with DKD, further studies may be warranted.