Phase 4
N=44
Renoprotective Effects of Dapagliflozin in Type 2 Diabetes
Diabetes Mellitus, Type 2 · Diabetic Nephropathies
Bottom Line
View on ClinicalTrials.gov: NCT02682563 ↗Enrolled (actual)
44
Serious AEs
0.0%
Results posted
Jul 2020
Primary outcome: Primary: Glomerular Filtration Rate (GFR) in ml/Min — 104; 109 ml/min
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 4
- Interventions
- Dapagliflozin 10mg QD (Drug); Gliclazide 30mg QD (Drug)
- Age
- Adult, Older Adult · 35+ yrs
- Sex
- All
- Sponsor
- M.H.H. Kramer
- Primary completion
- Sep 2018
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Glomerular Filtration Rate (GFR) in ml/Min |
104; 109 | — |
| PRIMARY Effective Renal Plasma Flow (ERPF) in ml/Min |
639; 678 | — |
| SECONDARY Fractional Excretion of Sodium in % of Filtered Sodium |
0.74; 0.66 | — |
| SECONDARY Fractional Excretion of Potassium in % of Filtered Potassium |
13.6; 11.8 | — |
| SECONDARY Fractional Excretion of Glucose in % of Filtered Glucose |
31.1; 0.6 | — |
| SECONDARY Urinary Albumin-Creatinine Ratio in mg/mmol |
0.88; 0.54 | — |
| SECONDARY Neutrophil Gelatinase-associated Lipocalin (NGAL) |
3.76; 3.79 | — |
| SECONDARY Kidney Injury Molecule-1 (KIM-1) in ng/mmol |
0.25; 0.265 | — |
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.
Eligibility Criteria
Inclusion Criteria
- 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)
- Treatment with a stable dose of oral antihyperglycemic agents for at least 3 months prior to inclusion
- 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
- In order to increase homogeneity ** In order to accelerate inclusion, patients using combined metformin/SU derivative will be considered. In these patients, a 12 week wash-out period of the SU derivative will be observed, only when combined use has led to a HbA1c 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
- History of or actual malignancy (except basal cell carcinoma)
- History of or actual severe mental disease
- Substance abuse (alcohol: defined as >4 units/day)
- Allergy to any of the agents used in the study
- Individuals who are investigator site personnel, directly affiliated with the study, or are immediate (spouse, parent, child, or sibling, whether biological or legally adopted) family of investigator site personnel directly affiliated with the study
- Inability to understand the study protocol or give informed consent
Data sourced from ClinicalTrials.gov (NCT02682563). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.