Hematocrit improvement with SGLT2 inhibitor: Not just a diuretic effect?

BOSTON – The SGLT2 inhibitor dapagliflozin may increase red blood cell production by suppressing plasma levels of hepcidin, a proinflammatory inhibitor of iron transport, according to results of a randomized study.

This reduction in hepcidin provides a new mechanistic explanation for the improvement in hematocrit seen with SGLT2 inhibitor treatment and suggests a role for use of these drugs beyond their current indications, according to researcher Husam A. Ghanim, PhD, of the State University of New York at Buffalo.

“While the common knowledge is that SGLT2 inhibitors increase hematocrit through hemoconcentration, it is possible that the other mechanisms are involved, including the anti-inflammatory effect that suppresses hepcidin, as well as increased erythropoiesis due to kidney function improvement,” Dr. Ghanim said in a presentation at the annual meeting of the American Association of Clinical Endocrinologists.

To see whether there were other mechanisms involved beyond hemoconcentration caused by diuretic effects of the drugs, Dr. Ghanim and his colleagues investigated the possibility that dapagliflozin might suppress concentrations of hepcidin concentrations, thereby increasing erythropoiesis.

Their study included 22 patients with type 2 diabetes and normal renal function randomized to dapagliflozin 10 mg daily or placebo for 12 weeks.

They found that the plasma concentration of hepcidin fell significantly over that time period, from 265 to 215 ng/mL in dapagliflozin-treated patients. They also saw significant decreases in hemoglobin A_1c, hemoglobin concentration, and hematocrit, as well as an increase in transferrin, the major transporter of iron in the circulation, over 12 weeks.

 

No such significant changes in those measures were seen in the placebo group, Dr. Ghanim said.

There was a modest but nonsignificant increase in erythropoietin concentrations in the dapagliflozin-treated group, according to the researcher.

Circulating ferritin also fell by about 40% over the course of the study. “Circulating ferritin doesn’t have a clear indication or implication on iron transport,” Dr. Ghanim said. “However, it gets secreted from macrophages and from the liver, and it gets used as a marker for inflammation, and it’s also used as a marker of liver function. So a reduction in ferritin levels may have some clinical implication to what’s going on in the liver.”

On the basis of these findings, it appears that SGLT2 inhibition might increase hematocrit via anti-inflammatory effects and increased erythropoiesis, Dr. Ghanim said.

 

The increase in oxygenated blood available to tissues might contribute to the beneficial effects of SGLT2 inhibitors on cardiovascular disease, he added.

Also, it’s possible that SGLT2 inhibitors could have a “major impact” on the liver since hepcidin and ferritin are secreted mainly by the liver: “This could also lead us to think that it is possible that we could use SGLT2 inhibitors in conditions of liver inflammation like nonalcoholic steatohepatitis and fatty liver disease,” Dr. Ghanim said in his presentation. “These are future ideas we could explore, based on our data.”

Dr. Ghanim had no disclosures to report.

SOURCE: Ghanim HA et al. AACE 2018, Abstract 228.

BOSTON – The SGLT2 inhibitor dapagliflozin may increase red blood cell production by suppressing plasma levels of hepcidin, a proinflammatory inhibitor of iron transport, according to results of a randomized study.

This reduction in hepcidin provides a new mechanistic explanation for the improvement in hematocrit seen with SGLT2 inhibitor treatment and suggests a role for use of these drugs beyond their current indications, according to researcher Husam A. Ghanim, PhD, of the State University of New York at Buffalo.

“While the common knowledge is that SGLT2 inhibitors increase hematocrit through hemoconcentration, it is possible that the other mechanisms are involved, including the anti-inflammatory effect that suppresses hepcidin, as well as increased erythropoiesis due to kidney function improvement,” Dr. Ghanim said in a presentation at the annual meeting of the American Association of Clinical Endocrinologists.

To see whether there were other mechanisms involved beyond hemoconcentration caused by diuretic effects of the drugs, Dr. Ghanim and his colleagues investigated the possibility that dapagliflozin might suppress concentrations of hepcidin concentrations, thereby increasing erythropoiesis.

Their study included 22 patients with type 2 diabetes and normal renal function randomized to dapagliflozin 10 mg daily or placebo for 12 weeks.

They found that the plasma concentration of hepcidin fell significantly over that time period, from 265 to 215 ng/mL in dapagliflozin-treated patients. They also saw significant decreases in hemoglobin A_1c, hemoglobin concentration, and hematocrit, as well as an increase in transferrin, the major transporter of iron in the circulation, over 12 weeks.

 

No such significant changes in those measures were seen in the placebo group, Dr. Ghanim said.

There was a modest but nonsignificant increase in erythropoietin concentrations in the dapagliflozin-treated group, according to the researcher.

Circulating ferritin also fell by about 40% over the course of the study. “Circulating ferritin doesn’t have a clear indication or implication on iron transport,” Dr. Ghanim said. “However, it gets secreted from macrophages and from the liver, and it gets used as a marker for inflammation, and it’s also used as a marker of liver function. So a reduction in ferritin levels may have some clinical implication to what’s going on in the liver.”

On the basis of these findings, it appears that SGLT2 inhibition might increase hematocrit via anti-inflammatory effects and increased erythropoiesis, Dr. Ghanim said.

 

The increase in oxygenated blood available to tissues might contribute to the beneficial effects of SGLT2 inhibitors on cardiovascular disease, he added.

Also, it’s possible that SGLT2 inhibitors could have a “major impact” on the liver since hepcidin and ferritin are secreted mainly by the liver: “This could also lead us to think that it is possible that we could use SGLT2 inhibitors in conditions of liver inflammation like nonalcoholic steatohepatitis and fatty liver disease,” Dr. Ghanim said in his presentation. “These are future ideas we could explore, based on our data.”

Dr. Ghanim had no disclosures to report.

SOURCE: Ghanim HA et al. AACE 2018, Abstract 228.

BOSTON – The SGLT2 inhibitor dapagliflozin may increase red blood cell production by suppressing plasma levels of hepcidin, a proinflammatory inhibitor of iron transport, according to results of a randomized study.

This reduction in hepcidin provides a new mechanistic explanation for the improvement in hematocrit seen with SGLT2 inhibitor treatment and suggests a role for use of these drugs beyond their current indications, according to researcher Husam A. Ghanim, PhD, of the State University of New York at Buffalo.

“While the common knowledge is that SGLT2 inhibitors increase hematocrit through hemoconcentration, it is possible that the other mechanisms are involved, including the anti-inflammatory effect that suppresses hepcidin, as well as increased erythropoiesis due to kidney function improvement,” Dr. Ghanim said in a presentation at the annual meeting of the American Association of Clinical Endocrinologists.

To see whether there were other mechanisms involved beyond hemoconcentration caused by diuretic effects of the drugs, Dr. Ghanim and his colleagues investigated the possibility that dapagliflozin might suppress concentrations of hepcidin concentrations, thereby increasing erythropoiesis.

Their study included 22 patients with type 2 diabetes and normal renal function randomized to dapagliflozin 10 mg daily or placebo for 12 weeks.

They found that the plasma concentration of hepcidin fell significantly over that time period, from 265 to 215 ng/mL in dapagliflozin-treated patients. They also saw significant decreases in hemoglobin A_1c, hemoglobin concentration, and hematocrit, as well as an increase in transferrin, the major transporter of iron in the circulation, over 12 weeks.

 

No such significant changes in those measures were seen in the placebo group, Dr. Ghanim said.

There was a modest but nonsignificant increase in erythropoietin concentrations in the dapagliflozin-treated group, according to the researcher.

Circulating ferritin also fell by about 40% over the course of the study. “Circulating ferritin doesn’t have a clear indication or implication on iron transport,” Dr. Ghanim said. “However, it gets secreted from macrophages and from the liver, and it gets used as a marker for inflammation, and it’s also used as a marker of liver function. So a reduction in ferritin levels may have some clinical implication to what’s going on in the liver.”

On the basis of these findings, it appears that SGLT2 inhibition might increase hematocrit via anti-inflammatory effects and increased erythropoiesis, Dr. Ghanim said.

 

The increase in oxygenated blood available to tissues might contribute to the beneficial effects of SGLT2 inhibitors on cardiovascular disease, he added.

Also, it’s possible that SGLT2 inhibitors could have a “major impact” on the liver since hepcidin and ferritin are secreted mainly by the liver: “This could also lead us to think that it is possible that we could use SGLT2 inhibitors in conditions of liver inflammation like nonalcoholic steatohepatitis and fatty liver disease,” Dr. Ghanim said in his presentation. “These are future ideas we could explore, based on our data.”

Dr. Ghanim had no disclosures to report.

SOURCE: Ghanim HA et al. AACE 2018, Abstract 228.