Cardiovascular Risk Profile Improves with Sevelamer Use in Diabetic Nephropathy

Markers of cardiovascular protection rose when diabetic patients with chronic kidney disease were treated with the phosphate binder sevelamer carbonate (sevelamer). In a randomized trial comparing sevelamer with the phosphate binder calcium carbonate, the group receiving sevelamer experienced increased levels of estrogen receptor-α (ER-α), two markers of antioxidant activity, and defenses against advanced glycation end products.

Phosphate is a component of diet and is absorbed in the small intestine. The kidneys excrete excess phosphate, but in the case of impaired renal function, they cannot maintain proper phosphate balance. Studies have shown that the resulting hyperphosphatemia correlates with increased mortality. Dietary restriction of phosphate intake and the use of oral phosphate binders can help control phosphate balance.

Sevelamer is a non–calcium-containing phosphate binder that may also have additional beneficial effects on other factors that promote cardiovascular disease, a major cause of mortality in chronic kidney disease.

Oxidative stress and inflammation are part of the process of cardiovascular disease. ER-α is known to reduce these factors in men and women, but ER-α activity is reduced in diabetic kidney disease, suggesting that decreased ER-α may contribute to the increased risk and prevalence of cardiovascular disease in this population. Simply put, less ER-α leads to more oxidative stress and inflammation, leading to more cardiovascular damage. In addition, advanced glycation end products, the result of hyperglycemia in diabetes, elevate the levels of oxidative stress and inflammation.

Besides binding phosphate, sevelamer is also thought to block the absorption of advanced glycation end products from food, further helping to limit oxidative stress and inflammation. Given that sevelamer does not contain calcium, it may also lower the progression of vascular calcification in comparison with calcium-containing phosphate binders.

Testing effect of sevelamer on cardiovascular risk factors

To test the hypothesis that sevelamer restores the levels of ER-α and has beneficial effects on other risk factors, Gary Striker, MD, research professor of geriatrics and medicine at the Mount Sinai School of Medicine in New York City, and colleagues compared the effects of sevelamer and calcium carbonate on the levels of ER-α and other markers of antioxidant and anti–advanced glycation end products in peripheral blood mononuclear cells (white blood cells). They presented their findings at the 50th Congress of the European Renal Association—European Dialysis and Transplant Association.

The trial randomly assigned men and women with type 2 diabetes to sevelamer 4800 mg/day (n = 56) or to calcium carbonate 1950 mg/day (n = 50) for 6 months. The inclusion criteria were hemoglobin A1c level greater than 6.5 percent, an estimated GFR of 25–80 mL/min per 1.73 m2, and albumin excretion greater than 300 mg/day. The mean ages of the men and women in the sevelamer and calcium carbonate groups ranged from 60.1 to 67.5 years.

In an analysis at 3 months assessing the amount of change from baseline in the biomarkers, the group as a whole (both men and women analyzed together) showed a marked increase in ER-α if they received sevelamer as opposed to calcium carbonate (p = 0.003). There were also significant increases in two biomarkers of antioxidant effects, Nrf2 and advanced glycated end-product receptor 1 (AGER1) (p = 0.009, p = 0.028, respectively). Nrf1 activates multiple pathways within cells to protect against oxidative stress and inflammation, and AGER1 suppresses oxidative stress caused by cellular oxidants.

The levels of two inflammatory markers predictive of cardiovascular disease and progression of diabetic kidney disease (tumor necrosis factor receptor 1 and RAGE) decreased in the group receiving sevelamer.

There were differences between men and women in some of the various markers when the sexes were analyzed separately, but the major finding of increased levels of ER-α was consistent regardless of sex.

The investigators concluded that sevelamer carbonate restored levels of ER-α in both men and women and that this effect was associated with a reduction in markers of oxidative stress, inflammation, progression of diabetic kidney disease, and risk factors for cardiovascular disease, as well as improvements in antioxidant defenses.

It is important to note that the study involved surrogate markers that indicate risk. It did not directly investigate clinical outcomes such as cardiovascular events or progression of kidney disease. Larger trials of longer duration are planned to see whether the findings in this trial will be reflected in a reduction in clinical events.

July 2013 (Vol. 5, Number 7)