Clinical trial NCT01493050: The Effects of Sevelamer Carbonate on Diabetic Nephropathy
Official title: Multi-Center Study of the Effect of Sevelamer Carbonate (Renvela®) on Metabolic/Inflammatory/ROS in Diabetics With Nephropathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetic Nephropathy
Keywords: Diabetic Nephropathy
Sevelamer Carbonate
Lead sponsor: Icahn School of Medicine at Mount Sinai
Sponsor class: OTHER
First posted: 2011-12-15
Enrollment: 117
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to see if taking a medication can lower the amount of oxidants from food that go into our body. Previous research shows that if the investigators lower the oxidants from food in people with diabetes, this simple change lowers different risks for heart disease and the worsening of kidney disease. The investigators focus on a specific type of oxidant, advanced glycation endproducts (AGEs). A previous, smaller study, conducted by our group showed that a drug, already approved by the FDA, will lower AGEs in the investigators compared Renvela® to Tums®. Both of these drugs have few side effects and have been used for a long time in patients with diabetes and kidney disease. While our previous study was interesting, it was just too small to be able to be sure that it will help all people with diabetes, or if the good effects the investigators found were simply due to chance. The investigators are doing this new study to confirm or deny the possibility that Renvela® can really help people with diabetes and kidney disease.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: glucose metabolism
timeFrame: baseline
measure: glucose metabolism
timeFrame: at 3 months
measure: glucose metabolism
timeFrame: at 6 months
Secondary outcomes:
measure: markers of inflammation and oxidative stress
timeFrame: baseline
measure: markers of inflammation and oxidative stress
timeFrame: at 3 months
measure: markers of inflammation and oxidative stress
timeFrame: at 6 months
measure: serum lipid levels
timeFrame: baseline
measure: serum lipid levels
timeFrame: at 3 months
measure: serum lipid levels
timeFrame: at 6 months
measure: serum phosphate level
timeFrame: at one week
measure: serum phosphate level
timeFrame: at two weeks
Other outcomes:
Locations:
city: New York
country: United States
facility: Beth Israel Medical Center
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: Gary Striker, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vlassara H, Uribarri J, Cai W, Goodman S, Pyzik R, Post J, Grosjean F, Woodward M, Striker GE. Effects of sevelamer on HbA1c, inflammation, and advanced glycation end products in diabetic kidney disease. Clin J Am Soc Nephrol. 2012 Jun;7(6):934-42. doi: 10.2215/CJN.12891211. Epub 2012 Mar 29.