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About
The current study aims to explore the clinical effects and mechanistics of mono- and combination therapy with SGLT-2 inhibitor empagliflozin and DPP-4 inhibitor linagliptin on renal physiology and biomarkers in metformin-treated T2DM patients.
Full description
Sodium-glucose linked transporters (SGLT-2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors are relatively novel glucose-lowering drugs for the treatment of T2DM. These agents seem to exert pleiotropic actions 'beyond glucose control'. SGLT-2 inhibitors decrease proximal sodium reabsorption and decrease glomerular pressure and albuminuria in rodents and type 1 diabetes patients. In addition, SGLT-2 inhibitors reduce, blood pressure and body weight. In rodents, SGLT-2 inhibitors also improved histopathological abnormalities associated with DKD. DPP-4 inhibitors are considered weight neutral, improve lipid profiles and slight reductions in blood pressure have been reported. To date, the potential renoprotective effects and mechanisms of SGLT-2 inhibitors and combination therapy with SGLT-2 inhibitors have not been sufficiently detailed in human type 2 diabetes. The current study aims to explore the clinical effects and mechanistics of mono- and combination therapy with an SGLT-2 inhibitor and a DPP-4 inhibitor on renal physiology and biomarkers in metformin-treated T2DM patients.
66 patients with type 2 diabetes will undergo a 16-week intervention period with 8-week empagliflozin (SGLT-2 inhibitor) monotherapy, followed by 8-week empagliflozin and linagliptin (DPP-4 inhibitor) combination therapy or 8-week linagliptin monotherapy, followed by 8-week linagliptin and empagliflozin combination therapy or 8-week gliclazide (SU derivative), followed by 8-week gliclazide intensification therapy in order to assess changes in the outcome parameters.
Enrollment
Sex
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Volunteers
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: 7.0 - 9.5% Diabetes Control and Complications Trial (DCCT) or 53 - 80 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 adverse 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
Exclusion criteria
Estimated GFR <45 mL/min/1.73m2 (determined by the Modification of Diet in Renal Disease (MDRD) study equation)
Hemoglobin level < 7.0 mmol/L
Current urinary tract infection and active nephritis
History of unstable or rapidly progressing renal disease
Macroalbuminuria; defined as ACR of >300 mg/g.
Current/chronic use of the following medication: thiazolidinediones, sulfonylurea derivatives, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitor, oral glucocorticoids, immune suppressants, antimicrobial agents, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MOAIs).
Patients on diuretics will only be excluded when these drugs cannot be stopped 3 months prior randomization and for the duration of the study.
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
Pregnancy
History of or actual severe mental disease
History of or actual severe somatic disease (e.g. systemic disease)
History of or actual malignancy (except basal cell carcinoma)
History of or actual pancreatic disease
(Unstable) thyroid disease
Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN)
Recent (<6 months) history of cardiovascular disease, including
Complaints compatible with or established neurogenic bladder and/or incomplete bladder emptying (as determined by ultrasonic bladder scan)
Substance abuse (alcohol: defined as >3 units alcohol/day)
History of diabetic ketoacidosis (DKA) requiring medical intervention (e.g., emergency room visit and/or hospitalization) within 1 month prior to the Screening visit.
Recent blood donation (< 6 months)
Allergy to any of the agents used in the study
Inability to understand the protocol and/or give informed consent
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
Primary purpose
Allocation
Interventional model
Masking
66 participants in 3 patient groups
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Data sourced from clinicaltrials.gov
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