Effects of SGLT2 Inhibition Treatment on Different Levels of Albuminuria in Patients With Type 2 Diabetes

Effects of SGLT2 Inhibition Treatment on Different Levels of Albuminuria in Patients With Type 2 Diabetes: a Prospective Interventional Study

Diabetic kidney disease has become the leading cause for ESRD worldwide.Albuminuria is a major risk factor for progression of diabetic nephropathy. SGLT2 inhibitors are the first antiglycaemic drugs with direct renoprotection, which are thought to protect the kidneys by lowering albuminuria, stimulating urinary glucose excretion ,reducing systemic blood pressure, while simultaneously improving multiple other risk factors in a glucose-independent manner. However, the precise mechanisms behind the renal beneficial effect of SGLT2 inhibitors are not entirely elucidated, although ongoing outcome trials will confirm these findings. This study is to assess the impact of three months of treatment with SGLT2 Inhibitions on different levels of albuminuria in patients with type 2 diabetes and to evaluate the effects of SGLT2 inhibition treatment on markers for podocyte damage , renal fibrosis, inflammation，oxidative stress and renin-angiotensin- aldosterone system.

Study Overview

• Status: Unknown
• Conditions: Diabetic Nephropathy; Type 2 Diabetes
• Intervention / Treatment: Drug: SGLT2 Inhibition

Detailed Description

Objective: The primary objective is to assess the impact of three months of treatment with SGLT2 Inhibition on Different levels of Albuminuria in Patients With type 2 diabetes and to seek the relationship of this influences to relevant risk markers in the pathology of diabetic renal disease.

Design: prospective ，intervention， case-controlled , single center study. Treatment period: 12 weeks. Patient population: 60 patients with type 2 diabetes recruited from Zhongshan Hospital Xiamen University in accordance with the study in- and exclusion criteria.

Intervention: Dapagliflozine 10 mg once daily tablet treatment or Empagliflozin10 mg once daily tablet treatment or Canagliflozin 100 mg once daily tablet treatment. Endpoints: Primary outcome: evaluate the effects of SGLT2 inhibition treatment on on urinary albuminuria, kidney function and eGFR .

Secondary endpoints To assess the effect of SGLT2 inhibition on markers for podocyte damage , renal fibrosis, inflammation，oxidative stress and renin-angiotensin- aldosterone system。 Timeframe: Recruiting planned from October 2019, inclusion over the following 12 months. Last patient is expected to be completed October 2020. Data analysis completed December 2020, publication autumn 2021.

• Study Type: Interventional
• Enrollment (Anticipated): 70
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Fujian
    • Xiamen, Fujian, China, 361004
      • Recruiting
      • Zhongshan Hospital Xiamen University
      • Contact: Yi-lin Zhao, principle; Phone Number: 8613950085931
      • Principal Investigator: Xiao-min Chen, principle
      • Sub-Investigator: Yuan Tian, assistant

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female patients between 18 -80 years of age with a diagnosis of type 2 diabetes (WHO criteria).
2. HbA1c of 7-11 %
3. eGFR equal to or above 45 ml/min/1.73 m2
4. The Trial included 20 normal albuminuria (Urinary albumin creatinine ratio [UACR]< 30 mg/g, with 20 moderately increased albuminuria UACR 30~300 mg/g, and 20 severely increased albuminuria UACR>30 0mg/g (in ≥2 out 3 morning spot urine collections prior to enrolment ).at baseline.
5. Patients who agree to receive treatment with SGLT2 inhibitors.
6. Patients must be on current stable hemodynamic profile , without dehydration.
7. Patients must be on current stable antiglycaemic treatment with oral drugs (OAD) or insulin 4 weeks before start of study drug and throughout study duration.
8. Patients must be on stable antihypertensive treatment (not include renin-angiotensin system blocking treatment) 4 weeks before start of study drug and throughout study duration.

Exclusion Criteria:

1. type 1 diabetes
2. Patients who suffer from recent acute complications including diabetic ketoacidosis and hyperglycaemic hyperosmolar coma, which may be at risk for dehydration.
3. Patients with hypertension who are not on stable antihypertensive treatment
4. urinary tract or reproductive tract acute infection
5. impaired liver function, defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN
6. History of unstable or rapidly progressing renal disease
7. impaired renal function ,eGFR: <45 mL/min (calculated by MDRD formula)
8. Ongoing cancer treatment

9. Recent Cardiovascular Events in a patient:

   9.1. Acute Coronary Syndrome (ACS) within 2 months prior to enrolment 9.2.Hospitalization for unstable angina or acute myocardial infarction within 2 months prior to enrolment9. 3. Acute Stroke or TIA within two months prior to enrolment 9. 4. Less than two months post coronary artery revascularization

10. Congestive heart failure defined as New York Heart Association (NYHA) class IV, unstable or acute congestive heart failure..
11. Pregnant or breastfeeding patients
12. smoker.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: normal albuminuria; baseline urinary albumin creatinine ratio [UACR]< 30 mg/g	Drug: SGLT2 Inhibition; Dapagliflozine 5-10 mg once daily tablet treatment or Empagliflozin10 mg once daily tablet treatment or Canagliflozin 100 mg once daily tablet treatment; Other Names: Dapagliflozine,Empagliflozin,Canagliflozin
Experimental: moderately increased albuminuria; baseline UACR 30~300 mg/g	Drug: SGLT2 Inhibition; Dapagliflozine 5-10 mg once daily tablet treatment or Empagliflozin10 mg once daily tablet treatment or Canagliflozin 100 mg once daily tablet treatment; Other Names: Dapagliflozine,Empagliflozin,Canagliflozin
Experimental: severely increased albuminuria; baseline UACR>300mg/g	Drug: SGLT2 Inhibition; Dapagliflozine 5-10 mg once daily tablet treatment or Empagliflozin10 mg once daily tablet treatment or Canagliflozin 100 mg once daily tablet treatment; Other Names: Dapagliflozine,Empagliflozin,Canagliflozin
No Intervention: blank Comparator; normal participant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in urinary albuminuria	a clean-catch 24- hour urine sample and spot urine sample were collected to assess urinary albuminuria,which will be evaluated at week 0, and at end study week 12 (+/- 1 week)	Up to 12 weeks
Change in eGFR	eGFR was calculated by modified glomerular filtration rate estimating equation for Chinese patients with chronic kidney disease.	Up to 12 weeks
change in nephrin	To assess effect of SGLT2 inhibition intervention on glomerular podocyte injury by detecting the expression of renal nephrin.	Up to 12 weeks
change in TGF-β1	To assess effect of SGLT2 inhibition intervention on glomerular and tubulointerstitial fibrosis by detecting the expression of TGF-β1	Up to 12 weeks
change in IL-6	To assess effect of SGLT2 inhibition intervention on inflammation biomarkers by detecting the levels of interleukin-6.	Up to 12 weeks
change in TNFα	To evaluate the effects of SGLT2 inhibition treatment on inflammation, biomarkers by detecting the levels of tumor necrosis factor alpha.	Up to 12 weeks
changes of AGEs	To evaluate the effects of SGLT2 inhibition treatment on oxidative stress index, the changes of AGEs.	Up to 12 weeks
changes of 8-OH-dG	To evaluate the effects of SGLT2 inhibition treatment on oxidative stress index by detecting the levels of 8-OH-dG. Urinary 8-OH-dG concentrations were assayed using a competitive enzyme-linked immunosorbent assay	Up to 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in uric acid	To evaluate the levels of serum uric acid before and after SGLT2 inhibition treatment.	Up to 12 weeks
Change in aldosterone	To evaluate the levels of aldosterone before and after SGLT2 inhibition treatment.	Up to 12 weeks
Change in rennin	To evaluate the levels of rennin before and after SGLT2 inhibition treatment	Up to 12 weeks
Change in angiotensin	To evaluate the levels of angiotensin before and after SGLT2 inhibition treatment	Up to 12 weeks

Collaborators and Investigators

• Sponsor: Zhongshan Hospital Xiamen University
• Investigators: Study Director: Yi-lin Zhao, principal, Zhongshan Hospital Xiamen University

Publications and helpful links

General Publications

• Tian Y, Chen XM, Liang XM, Wu XB, Yao CM. SGLT2 inhibitors attenuate nephrin loss and enhance TGF-beta₁ secretion in type 2 diabetes patients with albuminuria: a randomized clinical trial. Sci Rep. 2022 Sep 20;12(1):15695. doi: 10.1038/s41598-022-19988-7.

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2019
• Primary Completion (Anticipated): October 1, 2020
• Study Completion (Anticipated): August 1, 2021

Study Registration Dates

• First Submitted: October 8, 2019
• First Submitted That Met QC Criteria: October 11, 2019
• First Posted (Actual): October 15, 2019

Study Record Updates

• Last Update Posted (Actual): October 21, 2019
• Last Update Submitted That Met QC Criteria: October 16, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: Type 2 diabetes; Albuminuria; SGLT2 inhibitor; Diabetic Nephropathy
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Urologic Diseases; Urological Manifestations; Endocrine System Diseases; Diabetes Complications; Urination Disorders; Proteinuria; Diabetes Mellitus; Diabetes Mellitus, Type 2; Kidney Diseases; Diabetic Nephropathies; Albuminuria; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin; Canagliflozin
• Other Study ID Numbers: 20191005

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No