Renoprotective Effects of Dapagliflozin in Type 2 Diabetes

NCT02682563 | Completed Phase 4 Results

• 2 other identifiers: DC 2015 RED 012015-003818-24
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Worldwide, diabetic nephropathy or Diabetic Kidney Disease (DKD), is the most common cause of chronic and end-stage kidney disease. With the increasing rates of obesity and type 2 diabetes (T2DM), many more patients with DKD may be expected in the coming years. Large-sized prospective randomized clinical trials suggest that intensified glucose and blood pressure control, may halt the progression of DKD, both in type 1 diabetes and T2DM. However, despite the wide use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, a considerable amount of patients develop DKD during the course of diabetes, indicating an unmet need for renoprotective therapies. Sodium-glucose linked transporters (SGLT-2) inhibitors are novel glucose-lowering drugs for the treatment of T2DM. These agents seem to exert pleiotropic actions 'beyond glucose control', including reduction of blood pressure and body weight. In addition, SGLT-2 inhibitors decrease proximal sodium reabsorption and decrease glomerular pressure and albuminuria in rodents and type 1 diabetes patients. In rodents, SGLT-2 inhibitors also improved histopathological abnormalities associated with DKD. To date, the potential renoprotective effects and mechanisms of these agents have not been sufficiently detailed in human type 2 diabetes. The current study aims to explore the clinical effects and mechanistics of SGLT-2 inhibitors on renal physiology and biomarkers in metformin-treated T2DM patients with normal kidney function. Study Design: Randomized, double-blind, comparator-controlled, intervention trial Study Endpoints: Renal hemodynamics, i.e. measured glomerular filtration rate (GFR, ml/min) and effective renal plasma flow (ERPF, ml/min); 24-hour urinary solute excretion; markers of renal damage ; blood pressure; body anthropometrics; systemic hemodynamic variables (including stroke volume, cardiac output and total peripheral resistance); arterial stiffness will be assessed by applanation tonometry, (SphygmoCor®); insulin sensitivity and beta-cell function. Expected results: Treatment with the SGLT-2 inhibitor dapagliflozin, as compared to the sulfonylurea (SU) derivative gliclazide, may confer renoprotection by improving renal hemodynamics, and decreasing blood pressure and body weight in type 2 diabetes.

Conditions

Diabetes Mellitus, Type 2; Diabetic Nephropathies

Keywords

SGLT-2 inhibition, Renal, Cardiovascular, Type 2 diabetes

Outcome Measures

Primary Outcomes (2)

• Glomerular Filtration Rate (GFR) in ml/Min

  Calculated from urinary and plasma inulin concentrations, GFR in ml/min

  12 weeks

• Effective Renal Plasma Flow (ERPF) in ml/Min

  Calculated from urinary and plasma para-aminohippurate concentrations, ERPF in ml/min

  12 weeks

Secondary Outcomes (6)

• Fractional Excretion of Sodium in % of Filtered Sodium

  12 weeks

• Fractional Excretion of Potassium in % of Filtered Potassium

  12 weeks

• Fractional Excretion of Glucose in % of Filtered Glucose

  12 weeks

• Urinary Albumin-Creatinine Ratio in mg/mmol

  12 weeks

• Neutrophil Gelatinase-associated Lipocalin (NGAL)

  12 weeks

Other Outcomes (2)

• Body Weight

  12 weeks

• Systolic Blood Pressure

  12 weeks

Study Arms (2)

Dapagliflozin 10mg once daily

EXPERIMENTAL

Once daily treatment with oral dapagliflozin (forxiga) 10mg for 12 consecutive weeks.

Drug: Dapagliflozin 10mg QD

Gliclazide modified release 30mg once daily

ACTIVE COMPARATOR

Once daily treatment with oral gliclazide MR 30mg for 12 consecutive weeks.

Drug: Gliclazide 30mg QD

Interventions

Dapagliflozin 10mg QD DRUG

Dapagliflozin 10mg once daily for 12 weeks

Also known as: forxiga

Dapagliflozin 10mg once daily

Gliclazide 30mg QD DRUG

Gliclazide30mg once daily for 12 weeks

Also known as: Diamicron

Gliclazide modified release 30mg once daily

Eligibility Criteria

• Age: 35 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Caucasian\*
• Both genders (females must be post-menopausal; no menses \>1 year; in case of doubt, Follicle-Stimulating Hormone (FSH) will be determined with cut-off defined as \>31 U/L)
• Age: 35 - 75 years
• BMI: \>25 kg/m2
• HbA1c: 6.5 - 9.0% Diabetes Control and Complications Trial (DCCT) or 48 - 86 mmol/mol International Federation of Clinical Chemistry (IFCC)
• Metformin monotherapy
• Combination of metformin and low dose SU derivative\*\*
• Hypertension should be controlled, i.e. ≤140/90 mmHg, and treated with an ACE-I or ARB (unless prevented by side effect) for at least 3 months.
• Albuminuria should be treated with a RAAS-interfering agent (ACE-I or ARB) for at least 3 months.
• Written informed consent

You may not qualify if:

• History of unstable or rapidly progressing renal disease
• Macroalbuminuria; defined as albumin-creatinine ratio of 300mg/g.
• Estimated GFR \<60 mL/min/1.73m2 (determined by the Modification of Diet in Renal Disease (MDRD) study equation)
• Current/chronic use of the following medication: thiazolidinedione (TZD), SU derivative, Glucagon like peptide 1 receptor agonist (GLP-1RA), (dipeptidyl peptidase 4 inhibitor) DPP-4I, SGLT-2 inhibitors, glucocorticoids, immune suppressants, antimicrobial agents, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Subjects on diuretics will only be excluded when these drugs cannot be stopped for the duration of the study.
• Volume depleted patients. Patients at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics should have careful monitoring of their volume status.
• Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) will not be allowed, unless used as incidental medication (1-2 tablets) for non-chronic indications (i.e. sports injury, head-ache or back ache). However, no such drugs can be taken within a time-frame of 2 weeks prior to renal-testing
• History of diabetic ketoacidosis (DKA) requiring medical intervention (eg, emergency room visit and/or hospitalization) within 1 month prior to the Screening visit.
• Current urinary tract infection and active nephritis
• Recent (\<6 months) history of cardiovascular disease, including:
• Acute coronary syndrome
• Chronic heart failure (New York Heart Association grade II-IV)
• Stroke or transient ischemic neurologic disorder
• Complaints compatible with neurogenic bladder and/or incomplete bladder emptying (as determined by ultrasonic bladder scan)
• Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) \>3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) \>3x ULN
• (Unstable) thyroid disease; defined as free thyroxine (fT4) outside of laboratory reference values or change in treatment within 3 months prior to screening visit

Sponsors & Collaborators

• M.H.H. Kramer: lead
• AstraZeneca: collaborator

Study Sites (1)

VU University Medical Center

Amsterdam, North Holland, 1081 HV, Netherlands

Location

Related Publications (7)

• Natale P, Tunnicliffe DJ, Toyama T, Palmer SC, Saglimbene VM, Ruospo M, Gargano L, Stallone G, Gesualdo L, Strippoli GF. Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors for people with chronic kidney disease and diabetes. Cochrane Database Syst Rev. 2024 May 21;5(5):CD015588. doi: 10.1002/14651858.CD015588.pub2.

  PMID: 38770818 DERIVED

• Suijk DLS, van Baar MJB, van Bommel EJM, Iqbal Z, Krebber MM, Vallon V, Touw D, Hoorn EJ, Nieuwdorp M, Kramer MMH, Joles JA, Bjornstad P, van Raalte DH. SGLT2 Inhibition and Uric Acid Excretion in Patients with Type 2 Diabetes and Normal Kidney Function. Clin J Am Soc Nephrol. 2022 May;17(5):663-671. doi: 10.2215/CJN.11480821. Epub 2022 Mar 23.

  PMID: 35322793 DERIVED

• van Baar MJB, van Bommel EJM, Smits MM, Touw DJ, Nieuwdorp M, Ten Kate RW, Joles JA, van Raalte DH. Whole-body insulin clearance in people with type 2 diabetes and normal kidney function: Relationship with glomerular filtration rate, renal plasma flow, and insulin sensitivity. J Diabetes Complications. 2022 Apr;36(4):108166. doi: 10.1016/j.jdiacomp.2022.108166. Epub 2022 Feb 20.

  PMID: 35221224 DERIVED

• van Bommel EJM, Geurts F, Muskiet MHA, Post A, Bakker SJL, Danser AHJ, Touw DJ, van Berkel M, Kramer MHH, Nieuwdorp M, Ferrannini E, Joles JA, Hoorn EJ, van Raalte DH. SGLT2 inhibition versus sulfonylurea treatment effects on electrolyte and acid-base balance: secondary analysis of a clinical trial reaching glycemic equipoise: Tubular effects of SGLT2 inhibition in Type 2 diabetes. Clin Sci (Lond). 2020 Dec 11;134(23):3107-3118. doi: 10.1042/CS20201274.

  PMID: 33205810 DERIVED

• van Bommel EJM, Smits MM, Ruiter D, Muskiet MHA, Kramer MHH, Nieuwdorp M, Touw DJ, Heerspink HJL, Joles JA, van Raalte DH. Effects of dapagliflozin and gliclazide on the cardiorenal axis in people with type 2 diabetes. J Hypertens. 2020 Sep;38(9):1811-1819. doi: 10.1097/HJH.0000000000002480.

  PMID: 32516291 DERIVED

• van Bommel EJM, Lytvyn Y, Perkins BA, Soleymanlou N, Fagan NM, Koitka-Weber A, Joles JA, Cherney DZI, van Raalte DH. Renal hemodynamic effects of sodium-glucose cotransporter 2 inhibitors in hyperfiltering people with type 1 diabetes and people with type 2 diabetes and normal kidney function. Kidney Int. 2020 Apr;97(4):631-635. doi: 10.1016/j.kint.2019.12.021. No abstract available.

  PMID: 32200854 DERIVED

• van Bommel EJM, Herrema H, Davids M, Kramer MHH, Nieuwdorp M, van Raalte DH. Effects of 12-week treatment with dapagliflozin and gliclazide on faecal microbiome: Results of a double-blind randomized trial in patients with type 2 diabetes. Diabetes Metab. 2020 Apr;46(2):164-168. doi: 10.1016/j.diabet.2019.11.005. Epub 2019 Dec 6.

  PMID: 31816432 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Diabetic Nephropathies

Interventions

dapagliflozin; Gliclazide

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Complications

Intervention Hierarchy (Ancestors)

Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Sulfonylurea Compounds; Urea; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds

Limitations and Caveats

For GFR measurements, iohexol was used instead of inulin because inulin was retracted for human use during the trial. This did not alter our findings.

Results Point of Contact

• Title: Erik van Bommel
• Organization: AmsterdamUMC

e.vanbommel@amsterdamumc.nl

+31 20 444 2264

Study Officials

• Mark HH Kramer, MD/PhD

  Amsterdam UMC, location VUmc

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Head of the Internal Medicine department

Study Record Dates

• First Submitted: February 5, 2016
• First Posted: February 15, 2016
• Study Start: February 1, 2016
• Primary Completion: September 1, 2018
• Study Completion: September 1, 2018
• Last Updated: July 7, 2020
• Results First Posted: July 7, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)