The Effects of Sevelamer Carbonate on Diabetic Nephropathy

Advanced glycation end products (AGEs) levels are elevated in diabetic patients and in
patients with chronic kidney disease (CKD) and may contribute to the excessive cardiovascular
disease in this population, by promoting oxidant stress and chronic vascular inflammation. It
has recently been recognized that AGEs in the body originate not only endogenously, but also
from the ingestion of preformed AGEs in the diet. We have shown that reduction of dietary AGE
intake leads to significant reductions of circulating AGEs and insulin levels as well as
levels of markers of oxidative stress and inflammation in both diabetic and CKD patients.
Thus, the increased inflammation and oxidative stress (Infl/OS) in stable diabetes mellitus
(DM) are largely due to advanced glycation end products (AGEs) from food, and restricting
AGEs-intake reduces these risk factors in DM. High circulating AGEs and TNFR1/2 have been
shown to be associated with progression in diabetic nephropathy. Ideally, a compound that
binds food AGEs within the lumen of the intestine should have the same effect as dietary
restriction of AGEs and could become an important therapeutic tool in the clinical care of
these patients. We found that Sevelamer binds AGEs in vitro in a pH dependent manner. This
led us to hypothesize that sevelamer carbonate, but not calcium carbonate, would sequester
AGEs in the gut and reduce Infl/OS, including circulating AGEs and TNFα, in T2DM with Stage
2-4 CKD. This hypothesis was tested in a Pilot Study (GCO-08-0976) we designed as a
proof-of-concept trial to determine if a larger and longer trial is indicated. We conducted a
randomized, open-label, intention-to-treat, two-month crossover study to compare stable
diabetic patients with stage 2-4 CKD treated with either Sevelamer carbonate or calcium
carbonate for 2 months, a 1 week wash-out, and then the opposite drug for 2 months. There
were no changes in medications and food intake. We found that urinary phosphate excretion was
decreased by both Sevelamer carbonate and calcium carbonate. Serum AGEs, lipids, HbA1c,
FGF23, and 8-isoprostanes were reduced by Sevelamer carbonate compared to calcium carbonate.
In addition, PMNC levels of AGER1, SIRT1 and TNFα were also decreased by Sevelamer carbonate,
compared to calcium carbonate. We concluded that Sevelamer carbonate reduces HbA1c, FGF23,
lipids, and TNFα via reduced inflammation and OS in stage 2-4 diabetic CKD. These changes
were not seen with calcium carbonate. Since we found that sevelamer carbonate bound AGE-BSA
(but not BSA) at pH 7.0, but not at pH 1.0 in vitro, we proposed that the mechanism action is
sequestration of dietary AGEs and GI elimination. Based on these data, we concluded that a
larger and longer trial is indicated to confirm these results.

The current study proposes to confirm that Sevelamer Carbonate, an agent known to prevent the
gastrointestinal absorption of phosphates, is also able to block the absorption of AGEs and
improve certain aspects of diabetes and chronic renal disease in a larger group of patients
who will be followed for a longer period of time.

Inclusion Criteria:

- Age > 18 years

- Evidence of CKD Stages II, III or IV

- Stage II CKD; eGFR 60-89 ml/min

- Stage III CKD: eGFR 30-59 ml/min

- Stage IV CKD: eGFR 15-29 ml/min

- Proteinuria (>200 mg/day or 300 mg/gm creatinine on a spot urine) on urinalysis on two
occasions within 18 months of recruitment

- Diagnosis of diabetes and receiving at least one medication for diabetes mellitus

- HbA1c>6.5%

Exclusion criteria:

- Age <18

- Patients receiving active treatment for hyperphosphatemia

- Biopsy proven renal disease other than diabetic nephropathy

- Hypophosphatemia

- Hypercalcemia

- Any history of significant gastrointestinal disorders

- Any history of significant gastrointestinal surgery such as ileostomy, colostomy and
colectomy.