RACELINES: Renal Actions of Combined Empagliflozin and LINagliptin in Type 2 diabetES
Overview
- Phase
- Phase 4
- Intervention
- EMPA/LINA 10/5 mg QD (n=22)
- Conditions
- Type2 Diabetes
- Sponsor
- M.H.H. Kramer
- Enrollment
- 66
- Locations
- 1
- Primary Endpoint
- GFR
- Last Updated
- 4 years ago
Overview
Brief Summary
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
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.
Investigators
M.H.H. Kramer
Head of the Internal Medicine department
Amsterdam UMC, location VUmc
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: 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.
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
Arms & Interventions
LINA/EMPA 5/10 mg QD (N=22)
8w LINA followed by LINA/EMPA 5/10 mg QD (N=22)
Intervention: EMPA/LINA 10/5 mg QD (n=22)
EMPA/LINA 10/5 mg QD (n=22)
8w EMPA followed by 8w EMPA/LINA 10/5 mg QD (n=22)
Intervention: EMPA/LINA 10/5 mg QD (n=22)
EMPA/LINA 10/5 mg QD (n=22)
8w EMPA followed by 8w EMPA/LINA 10/5 mg QD (n=22)
Intervention: LINA/EMPA 5/10 mg QD (N=22)
LINA/EMPA 5/10 mg QD (N=22)
8w LINA followed by LINA/EMPA 5/10 mg QD (N=22)
Intervention: LINA/EMPA 5/10 mg QD (N=22)
Gliclazide 30 mg QD/BID (N=22)
8w Gliclazide 30 mg QD, followed by 8w Gliclazide BID (N=22)
Intervention: Gliclazide 30 mg QD/BID (N=22)
Outcomes
Primary Outcomes
GFR
Time Frame: 8 weeks
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)
Secondary Outcomes
- Renal Damage(2 weeks)
- Renal tubular function(8 weeks)
- Heart Rate (Dinamap®)(2 weeks)
- Blood Pressure (Dinamap®)(2 weeks)