Renal Actions of Combined Empagliflozin and LINagliptin in Type 2 diabetES

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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RACELINES: Renal Actions of Combined Empagliflozin and LINagliptin in Type 2 diabetES

Conditions
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Type2 Diabetes

Intervention / Treatment
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* Drug: EMPA/LINA 10/5 mg QD (n=22)
* Drug: LINA/EMPA 5/10 mg QD (N=22)
* Drug: Gliclazide 30 mg QD/BID (N=22)


Participation Criteria
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Eligibility Criteria
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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 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 <8% at screening. Subsequently, patients will be eligible to enter the study, now using metformin monotherapy, provided that HbA1c still meets inclusion criteria. 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 Acute coronary syndrome Stroke or transient ischemic neurologic disorder or chronic heart failure (NYHA grade II-IV) 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

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EMPA/LINA 10/5 mg QD (n=22)<br>8w EMPA followed by 8w EMPA/LINA 10/5 mg QD (n=22) | Drug: EMPA/LINA 10/5 mg QD (n=22)<br>* Once daily treatment with oral empagliflozin (Jardiance) 10 mg Once daily treatment with oral linagliptin (Tradjenta) 5 mg<br>* Other names: Tradjenta;Drug: LINA/EMPA 5/10 mg QD (N=22)<br>* Once daily treatment with oral linagliptin (Tradjenta) 5 mg Once daily treatment with oral empagliflozin (Jardiance) 10 mg<br>* Other names: Jardiance;|
| Experimental: LINA/EMPA 5/10 mg QD (N=22)<br>8w LINA followed by LINA/EMPA 5/10 mg QD (N=22) | Drug: EMPA/LINA 10/5 mg QD (n=22)<br>* Once daily treatment with oral empagliflozin (Jardiance) 10 mg Once daily treatment with oral linagliptin (Tradjenta) 5 mg<br>* Other names: Tradjenta;Drug: LINA/EMPA 5/10 mg QD (N=22)<br>* Once daily treatment with oral linagliptin (Tradjenta) 5 mg Once daily treatment with oral empagliflozin (Jardiance) 10 mg<br>* Other names: Jardiance;|
| Active Comparator: Gliclazide 30 mg QD/BID (N=22)<br>8w Gliclazide 30 mg QD, followed by 8w Gliclazide BID (N=22) | Drug: Gliclazide 30 mg QD/BID (N=22)<br>* Once daily or twice daily treatment with oral glicazide MR 30mg<br>* Other names: Gliclazide Sandoz;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GFR | Changes from baseline following 16-week treatment on renal hemodynamics in both the fasting and postprandial state, measured as GFR (determined by the inulin-clearance technique) | 16 weeks | 
| GFR | Changes from baseline following 8-week treatment on renal hemodynamics in both the fasting and postprandial state, measured as GFR (determined by the inulin-clearance technique) | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal tubular function | 24-hour urine sodium-, potassium-, chloride-, calcium-, magnesium-, phosphate-, uric acid-, bicarbonate-, ammonium-, urea- and glucose excretion, urine osmolality and urinary pH | 16 weeks | 
| Renal tubular function | 24-hour urine sodium-, potassium-, chloride-, calcium-, magnesium-, phosphate-, uric acid-, bicarbonate-, ammonium-, urea- and glucose excretion, urine osmolality and urinary pH | 8 weeks | 
| Renal Damage | 24-hour urinary albumin excretion, albumin/creatinine ratio (UCR) | 16 weeks | 
| Renal Damage | 24-hour urinary albumin excretion, albumin/creatinine ratio (UCR) | 10 weeks | 
| Renal Damage | 24-hour urinary albumin excretion, albumin/creatinine ratio (UCR) | 8 weeks | 
| Renal Damage | 24-hour urinary albumin excretion, albumin/creatinine ratio (UCR) | 2 weeks | 
| Heart Rate (Dinamap®) | Measured using an automated oscillometric blood pressure device (Dinamap®) | 16 weeks | 
| Heart Rate (Dinamap®) | Measured using an automated oscillometric blood pressure device (Dinamap®) | 10 weeks | 
| Heart Rate (Dinamap®) | Measured using an automated oscillometric blood pressure device (Dinamap®) | 8 weeks | 
| Heart Rate (Dinamap®) | Measured using an automated oscillometric blood pressure device (Dinamap®) | 2 weeks | 
| Blood Pressure (Dinamap®) | Measured using an automated oscillometric blood pressure device (Dinamap®) | 16 weeks | 
| Blood Pressure (Dinamap®) | Measured using an automated oscillometric blood pressure device (Dinamap®) | 10 weeks | 
| Blood Pressure (Dinamap®) | Measured using an automated oscillometric blood pressure device (Dinamap®) | 8 weeks | 
| Blood Pressure (Dinamap®) | Measured using an automated oscillometric blood pressure device (Dinamap®) | 2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes mellitus, Diabetic kidney disease, Diabetic nephropathy, Renoprotection, SGLT2 inhibitor, Empagliflozin, DPP-4 inhibitor, Linagliptin, SU derivative, Gliclazide