Renal Actions of Combined Empagliflozin and LINagliptin in Type 2 diabetES

NCT ID: NCT03433248

Last Updated: 2022-01-14

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 66 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-11-09
• Study Completion Date: 2022-09-01

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.

Conditions

Type2 Diabetes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

EMPA/LINA 10/5 mg QD (n=22)

8w EMPA followed by 8w EMPA/LINA 10/5 mg QD (n=22)

Group Type: EXPERIMENTAL

EMPA/LINA 10/5 mg QD (n=22)

Intervention Type: DRUG

Once daily treatment with oral empagliflozin (Jardiance) 10 mg Once daily treatment with oral linagliptin (Tradjenta) 5 mg

LINA/EMPA 5/10 mg QD (N=22)

Intervention Type: DRUG

Once daily treatment with oral linagliptin (Tradjenta) 5 mg Once daily treatment with oral empagliflozin (Jardiance) 10 mg

LINA/EMPA 5/10 mg QD (N=22)

8w LINA followed by LINA/EMPA 5/10 mg QD (N=22)

Group Type: EXPERIMENTAL

EMPA/LINA 10/5 mg QD (n=22)

Intervention Type: DRUG

Once daily treatment with oral empagliflozin (Jardiance) 10 mg Once daily treatment with oral linagliptin (Tradjenta) 5 mg

LINA/EMPA 5/10 mg QD (N=22)

Intervention Type: DRUG

Once daily treatment with oral linagliptin (Tradjenta) 5 mg Once daily treatment with oral empagliflozin (Jardiance) 10 mg

Gliclazide 30 mg QD/BID (N=22)

8w Gliclazide 30 mg QD, followed by 8w Gliclazide BID (N=22)

Group Type: ACTIVE_COMPARATOR

Gliclazide 30 mg QD/BID (N=22)

Intervention Type: DRUG

Once daily or twice daily treatment with oral glicazide MR 30mg

Interventions

EMPA/LINA 10/5 mg QD (n=22)

Once daily treatment with oral empagliflozin (Jardiance) 10 mg Once daily treatment with oral linagliptin (Tradjenta) 5 mg

Intervention Type: DRUG

LINA/EMPA 5/10 mg QD (N=22)

Once daily treatment with oral linagliptin (Tradjenta) 5 mg Once daily treatment with oral empagliflozin (Jardiance) 10 mg

Intervention Type: DRUG

Gliclazide 30 mg QD/BID (N=22)

Once daily or twice daily treatment with oral glicazide MR 30mg

Intervention Type: DRUG

Other Intervention Names

Jardiance; Tradjenta; Tradjenta; Jardiance; Gliclazide Sandoz

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.
• 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

• 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

• Minimum Eligible Age: 35 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

M.H.H. Kramer

OTHER

Sponsor Role: lead

Responsible Party

M.H.H. Kramer

Head of the Internal Medicine department

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Mark HH Kramer, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Amsterdam UMC, location VUmc

Locations

VU University Medical Center

Amsterdam, North Holland, Netherlands

Countries

Netherlands

Other Identifiers

DC2017RACELINES01

Identifier Type: -

Identifier Source: org_study_id