Renal Actions of Combined Empagliflozin and LINagliptin in Type 2 diabetES

  • STATUS
    Recruiting
  • End date
    Dec 1, 2021
  • participants needed
    66
  • sponsor
    M.H.H. Kramer
Updated on 26 January 2021

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.

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.

Details
Condition Type2 Diabetes
Treatment EMPA/LINA 10/5 mg QD (n=22), LINA/EMPA 5/10 mg QD (N=22), Gliclazide 30 mg QD/BID (N=22)
Clinical Study IdentifierNCT03433248
SponsorM.H.H. Kramer
Last Modified on26 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age between 35 yrs and 75 yrs?
Gender: Male or Female
Do you have Type2 Diabetes?
Do you have any of these conditions: Do you have Type2 Diabetes??
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
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