NCT03423355

Dapagliflozin Effect on Erythropoiesis and Physical Fitness

Dapagliflozin Effect on Erythropoiesis and Physical Fitness in Patients With Type 2 Diabetes - a Randomized, Partly Double-blinded, Controlled, Three Armed, Parallel Group, Exploratory Study

• Status: Withdrawn
• Phase: Phase 4
• Study type: Interventional
• Enrollment: 0 (actual)
• Sponsor: University Hospital Tuebingen · Academic / Other
• Sex: All
• Age: 40 Years – 70 Years
• Healthy volunteers: Not accepted

Summary

Dapagliflozin effect on erythropoiesis and physical fitness in patients with type 2 diabetes - a randomized, partly double-blinded, controlled, three armed, parallel group, exploratory study

Detailed description

Many patients with diabetes present with hyperglycemia, hypertension, hypercholesterolemia and excess weight, which are associated with micro- and macrovascular complications. Therapies to alleviate the burden of these complications have traditionally focused on reducing glycemia and optimizing blood pressure and cholesterol concentration. However, despite the various available treatment options to improve glycemic control, many patients do not reach treatment and lifestyle targets, such as improving physical fitness. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the proximal tubule reabsorption of filtered glucose, thereby causing glucosuria and decreasing plasma glucose concentrations. When large quantities of glucose are pharmacologically forced into urinary excretion, whole-body metabolism undergoes adaptive changes, involving glucose fluxes, hormonal responses, fuel selection, and energy expenditure. SGLT2 inhibitors have been proven to be superior to conventional therapy by reducing cardiovascular mortality in patients with cardiovascular diseases (CVD). Many of the explained mechanisms contribute to this effect, and other, still unknown factors, need to be identified. In the present study, patients suffering from T2DM and hypertension will be treated with Dapagliflozin, an SGLT2 inhibitor, or matching Placebo, or HCT as reference drug with a diuretic and anti-hypertensive effect. There is evidence that SGLT2 inhibition positively affects the erythropoietin-RBC axis. By this mechanism, Dapagliflozin improves oxygen supply to tissues, an effect which can explain the positive cardiovascular (CV) outcome data of Dapagliflozin in recent registry data. The aim of the present study is to provide clinical endpoints related to this effect. Specifically, the effect of Dapagliflozin on erythropoietin, reticulocytes, and HIF related factors will be studied and related to physical fitness before and after treatment with Dapagliflozin. Providing evidence for an improvement in physical fitness and cardiac function by Dapagliflozin will be of great clinical benefit in patients with T2DM, since a large number of these patients have reduced physical activity and heart failure. The increasing effect of SGLT2 inhibitors on hematocrit was initially attributed to a relative hemoconcentration due to the diuretic effect elicited by the drug. However, studies comparing Dapagliflozin directly to diuretic treatment with HCT showed that the effect of Dapagliflozin was superior to diuretic treatment with HCT. Moreover, Dapagliflozin, and not HCT, also increased reticulocytes count and EPO concentrations \[1\]. Together, these data suggest that hemoconcentration is not mediating the effect of Dapagliflozin on hemopoiesis and that other mechanisms must contribute. Yet, reducing preload by diuretic properties may beneficially affect physical performance and may, thus, affect the secondary endpoint. Therefore, three treatments will be used in this study: Dapagliflozin and matching placebo, and HCT as reference treatment for the diuretic effect.

Conditions

• Type 2 Diabetes Mellitus (T2DM)

Interventions

Type	Name	Description
DRUG	Dapagliflozin (Forxiga®)	10mg p.o. daily
DRUG	Hydrochlorothiazide 25 mg	25mg p.o. daily
DRUG	Placebo matching Dapagliflozin	Placebo matching Dapagliflozin p.o. daily

Timeline

• Start date: 2021-09-01
• Primary completion: 2023-03-01
• Completion: 2023-12-01
• First posted: 2018-02-06
• Last updated: 2021-12-15

Locations

1 site across 1 country: Germany