Renal Oxygenation, Oxygen Consumption and Hemodynamic Kinetics in Type 2 DIabetes: an Ertugliflozin Study.
Ключови думи
Резюме
Описание
Sodium-glucose cotransporter-2 inhibitors (SGLT2-i) are a relatively new class of drugs in the treatment of diabetes and improve glycemic control by blocking SGLT-2 in the proximal tubule, the main transporter of coupled sodium-glucose reabsorption Three large cardiovascular outcome trials (EMPA-REG, CANVAS, DECLARE- TIMI 58) showed SGLT-2 inhibition to have a renoprotective effect, including on renal outcomes. Moreover, the recently publicized CREDENCE trial concluded early after the planned interim analyses showed a striking renoprotective effect of SGLT-2 inhibition in patients with T2DM and CKD. The mechanisms underlying their beneficial effects remain to be elucidated, as the small SGLT-2 induced reduction in glucose level (0.5% HbA1c), bodyweight (about 3%), systolic blood pressure (about 4 mmHg), or uric acid (about 6%) are insufficient to fully account for the effect.
The pathological mechanisms underlying DKD involve complex interactions between metabolic and haemodynamic factors which are not fully understood. However, accumulating evidence of foremost animal studies indicates that a chronic state of renal tissue hypoxia is the final common pathway in the development and progression of diabetic kidney disease. Therefore several hypothesis have been proposed on the alleviation of chronic tissue hypoxia following SGLT-2 inhibition: (1) A decrease in workload by a decrease in GFR. (2) A shift in renal fuel energetics by increasing ketone body oxidation, which renders high ATP/oxygen consumption ratio's compared to glucose or free fatty acids. (3) An improvement of cardiac function and systemic hemodynamics to lead to an increase in renal perfusion, and (4) an increase in erythropoietin (EPO) levels to stimulate oxygen delivery.
Current study will examine the above hypothesis by researching renal oxygenation by BOLD-MRI, oxygen consumption by PET-CT, and hemodynamic kinetics by the Iohexol clearance method/contrast-enhance ultrasound/arterial spin labeling. Blood sampling will allow for the measurement of EPO and ketone bodies, as well as a resting energy expenditure will elucidate a shift in use of energy substrate metabolism. The research will be performed in T2DM without overt kidney disease (n=20) before and after a 4 week treatment with SGLT-2 inhibition (ertugliflozin), and will be compared the obtained results from healthy controls (n=20).
Дати
| Последна проверка: | 04/30/2020 |
| Първо изпратено: | 07/08/2019 |
| Очаквано записване подадено: | 07/15/2019 |
| Първо публикувано: | 07/21/2019 |
| Изпратена последна актуализация: | 05/18/2020 |
| Последна актуализация публикувана: | 05/19/2020 |
| Действителна начална дата на проучването: | 05/31/2020 |
| Приблизителна дата на първично завършване: | 04/30/2021 |
| Очаквана дата на завършване на проучването: | 11/30/2021 |
Състояние или заболяване
Интервенция / лечение
Drug: Ertugliflozin 15 mg
Фаза
Групи за ръце
| Arm | Интервенция / лечение |
|---|---|
| Experimental: Ertugliflozin 15mg once daily Once daily treatment with oral ertugliflozin (steglatro) 15mg for 4 consecutive weeks. | |
| Placebo Comparator: Placebo Once daily treatment with a placebo pill for 4 consecutive weeks. |
Критерии за допустимост
| Възрасти, отговарящи на условията за проучване | 18 Years Да се 18 Years |
| Полове, допустими за проучване | All |
| Приема здрави доброволци | Да |
| Критерии | Group 1: T2DM patients Inclusion criteria - Provision of signed and dated, written informed consent prior to any study specific procedures. - Caucasian*; female or male aged ≥18 years and <80 years. Females must be post-menopausal (defined as no menses >1 year and follicle stimulating hormone (FSH) >31 U/L)*. - Type 2 diabetes mellitus since at least 3 years with HbA1c ≥ 6.5% (≥57mmol/mol) and <10% (<94mmol/mol) - An appropriate stable dose of metformin and/or sulfonylurea as glucose-lowering therapy for the last 12 weeks - Maximum tolerated antihypertensive dose of an ARB for at least 6 weeks prior to randomization. - eGFR 60-90 ml/min/1.73m² - BMI 25-35 kg/m² * In order to increase homogeneity Exclusion criteria - Involvement in the planning and/or conduction of another study - Participation in another clinical study with an investigational product during the last 3 months - Diagnosis of type 1 diabetes mellitus - CKD defined as eGFR<60 ml/min/1.73m² or albuminuria (defined as an UACR > 2.5 mg/mol). - Cardiovascular disease event in the last 6 months prior to enrollment as assessed by the investigator, including: myocardial infarction, cardiac surgery or revascularization (CABG/PTCA), unstable angina, heart failure, transient ischemic attack (TIA) or significant cerebrovascular disease, unstable or previously undiagnosed arrhythmia. - Current/chronic use of the following medication: insulin, thiazolidinediones, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitors, oral glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), immune suppressants, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs), diuretics, and monoamine oxidase inhibitors. - Current urinary tract infection or active nephritis - History of ketoacidosis - History of allergy/hypersensitivity to any of the test agents. Group 2: Age-matched and eGFR-matched non-diabetic controls Inclusion criteria - Provision of signed and dated, written informed consent prior to any study specific procedures. - Caucasian*; female or male aged ≥18 years and <80 years. Females must be post-menopausal (defined as no menses >1 year and follicle stimulating hormone (FSH) >31 U/L)*. - Normal glucose tolerance at screening as confirmed by OGTT - Maximum tolerated antihypertensive dose of an ARB for at least 6 weeks prior to randomization in case of hypertension. - BMI 25-35 kg/m2 - eGFR 60-90ml/min * In order to increase homogeneity Exclusion criteria - Involvement in the planning and/or conduction of another study - Participation in another clinical study with an investigational product during the last 3 months - CKD defined as eGFR<60ml/min or macro-albuminuria or proteinuria - Cardiovascular disease event in the last 6 months prior to enrollment, as assessed by the investigator, including: myocardial infarction, cardiac surgery or revascularization (CABG/PTCA), unstable angina, heart failure, transient ischemic attack (TIA) or significant cerebrovascular disease, unstable or previously undiagnosed arrhythmia. - Use of medication that may interfere with study endpoints non-steroidal anti-inflammatory drugs (NSAIDs), immune suppressants, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs), diuretics, and monoamine oxidase inhibitors. - Current urinary tract infection and active nephritis - Any other condition that prevents participation as judged by investigator. |
Резултат
Първични изходни мерки
1. Renal oxygenation measured by BOLD-MRI (R2*) [After 4 week treatment with ertugliflozin 15mg QD versus placebo]
Вторични изходни мерки
1. Renal oxygen consumption by PET/CT-scan using 11C-Acetate [After 4 week treatment with active drug intervention versus placebo]
2. Renal hemodynamics [After 4 week treatment with active drug intervention versus placebo]
3. Renal efficiency [After 4 week treatment with active drug intervention versus placebo]
4. Cortical blood flow [After 4 week treatment with active drug intervention versus placebo]
5. Renal arterial blood flow [After 4 week treatment with active drug intervention versus placebo]
6. Acute 24-hour sodium and glucose excretion [After 2 days of treatment with active drug intervention versus placebo]
7. Chronic 24-hour sodium and glucose excretion [After 4 week treatment with active drug intervention versus placebo]
8. Renal tubular function: Urinary pH [After 4 week treatment with active drug intervention versus placebo]
9. Renal tubular function: Urine Osmolality [After 4 week treatment with active drug intervention versus placebo]
10. Renal tubular function: sodium transport [After 4 week treatment with active drug intervention versus placebo]
11. Renal damage markers [After 4 week treatment with active drug intervention versus placebo]
12. Changes in plasma energy substrate: glucose [After 4 week treatment with active drug intervention versus placebo]
13. Changes in plasma energy substrate: free fatty acids [After 4 week treatment with active drug intervention versus placebo]
14. Changes in plasma energy substrate: ketone bodies [After 4 week treatment with active drug intervention versus placebo]
15. Changes in plasma energy substrate:triglycerides [After 4 week treatment with active drug intervention versus placebo]
16. Energy expenditure [After 4 week treatment with active drug intervention versus placebo]
17. Changes in erythropoietin (EPO) levels [After 4 week treatment with active drug intervention versus placebo]
18. Insulin sensitivity [After 4 week treatment with active drug intervention versus placebo]
19. Beta-cell function [After 4 week treatment with active drug intervention versus placebo]
20. Peripheral insulin extraction [After 4 week treatment with active drug intervention versus placebo]
21. Total insulin extraction [After 4 week treatment with active drug intervention versus placebo]
