Effects of sevelamer on HbA1c, inflammation, and advanced glycation end products in diabetic kidney disease

Abstract

Background and objectives: Increased inflammation and oxidative stress may be caused by proteins and lipids modified by cytotoxic advanced glycation end products (AGEs) in food. Restricting food containing elevated AGEs improves these risk factors in diabetic CKD. Because diet adherence can be problematic, this study aimed to remove cytotoxic AGEs from food already ingested and to determine whether sevelamer carbonate sequesters cytotoxic AGEs in the gut, preventing their uptake and thereby reducing AGE-induced abnormalities.

Design, setting, participants, & measurements: This single-center, randomized, 2-month, open-label, intention-to-treat, crossover study compared sevelamer carbonate with calcium carbonate treatment in stage 2-4 diabetic CKD. Participants received 2 months of treatment with one drug, had a 1-week washout, and then received the opposite drug for 2 months.

Results: Sevelamer carbonate reduced HbA1c, serum methylglyoxal, serum (ε)N-carboxymethyl-lysine, triglycerides, and 8-isoprostanes. Total cholesterol and fibroblast growth factor 23 were reduced by sevelamer carbonate, relative to calcium carbonate. AGE receptor 1 and sirtuin 1 mRNA were increased and PMNC TNFα levels were decreased by sevelamer carbonate, but not calcium carbonate. Medications and caloric and AGE intake remained unchanged. Sevelamer carbonate reversibly bound AGE-BSA at intestinal, but not stomach, pH.

Conclusions: Sevelamer carbonate significantly reduces HbA1c, fibroblast growth factor 23, lipids, and markers of inflammation and oxidative stress, and markedly increases antioxidant markers, independently of phosphorus in patients with diabetes and early kidney disease. These novel actions of sevelamer carbonate on metabolic and inflammatory abnormalities in type 2 diabetes mellitus may affect progression of early diabetic CKD.

Trial registration: ClinicalTrials.gov NCT01493050.

Figure 1.

Effect of sevelamer on metabolic, AGE, oxidant, and antioxidant factors. The differential effects of calcium carbonate and sevelamer carbonate on (A) metabolic factors, (B) AGEs and oxidized lipids, and (C) antioxidant status and markers of inflammation. Changes are expressed as the mean percentage change from baseline to the end of the 8-week treatment period for individual patients. An asterisk denotes a significant change (P<0.05). AGE, advanced glycation end product; trig, triglycerides; LDL-Chol, LDL cholesterol; total chol, total cholesterol; sCML, serum carboxymethyllysine; sMG, serum methylglyoxal; 8-iso, 8-isoprostanes; AGER1, AGE receptor 1; SIRT1, sirtuin 1; FGF23, fibroblast growth factor 23.

Figure 2.

The percentage of ¹²⁵I-AGE-BSA or ¹²⁵I-AGE-BSA at either pH 1.0 or 7.0 is shown. Sevelamer carbonate beads (25 mg) were incubated with 5 µg of ¹²⁵I-AGE-BSA or ¹²⁵I-AGE-BSA at pH 1.0 or 7.0 at room temperature for 12 hours. The radioactivity bound to the beads was determined and expressed as the percentage of the added amount of radioactivity that was retained on the beads. ¹²⁵I-AGE-BSA was bound to sevelamer carbonate beads at pH 7.0 but not at pH 1.0. The binding was reversible. Less than 5% of ¹²⁵I-AGE-BSA bound to sevelamer carbonate beads at either pH 1.0 or 7.0. AGE, advanced glycation end product.