Clinical trial NCT03433248: Renal Actions of Combined Empagliflozin and LINagliptin in Type 2 diabetES
Official title: RACELINES: Renal Actions of Combined Empagliflozin and LINagliptin in Type 2 diabetES
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Type2 Diabetes
Keywords: Type 2 diabetes mellitus
Diabetic kidney disease
Diabetic nephropathy
Renoprotection
SGLT2 inhibitor
Empagliflozin
DPP-4 inhibitor
Linagliptin
SU derivative
Gliclazide
Lead sponsor: Amsterdam UMC, location VUmc
Sponsor class: OTHER
First posted: 2018-02-14
Enrollment: 66
Sex: ALL
Minimum age (years): 35
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

  * 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

Primary outcomes:
measure: GFR
timeFrame: 16 weeks
measure: GFR
timeFrame: 8 weeks
Secondary outcomes:
measure: Renal tubular function
timeFrame: 16 weeks
measure: Renal tubular function
timeFrame: 8 weeks
measure: Renal Damage
timeFrame: 16 weeks
measure: Renal Damage
timeFrame: 10 weeks
measure: Renal Damage
timeFrame: 8 weeks
measure: Renal Damage
timeFrame: 2 weeks
measure: Heart Rate (Dinamap®)
timeFrame: 16 weeks
measure: Heart Rate (Dinamap®)
timeFrame: 10 weeks
measure: Heart Rate (Dinamap®)
timeFrame: 8 weeks
measure: Heart Rate (Dinamap®)
timeFrame: 2 weeks
measure: Blood Pressure (Dinamap®)
timeFrame: 16 weeks
measure: Blood Pressure (Dinamap®)
timeFrame: 10 weeks
measure: Blood Pressure (Dinamap®)
timeFrame: 8 weeks
measure: Blood Pressure (Dinamap®)
timeFrame: 2 weeks
Other outcomes:
measure: Body anthropometrics: Body mass index
timeFrame: 16 weeks
measure: Body anthropometrics: Body mass index
timeFrame: 8 weeks
measure: Body anthropometrics: Body weight
timeFrame: 16 weeks
measure: Body anthropometrics: Body weight
timeFrame: 8 weeks
measure: Body anthropometrics: Height
timeFrame: 16 weeks
measure: Body anthropometrics: Height
timeFrame: 8 weeks
measure: Body anthropometrics: Waist circumference
timeFrame: 16 weeks
measure: Body anthropometrics: Waist circumference
timeFrame: 8 weeks
measure: Body anthropometrics: Hip circumference
timeFrame: 16 weeks
measure: Body anthropometrics: Hip circumference
timeFrame: 8 weeks
measure: Body fat content
timeFrame: 16 weeks
measure: Body fat content
timeFrame: 8 weeks
measure: Blood pressure (NexFin®)
timeFrame: 16 weeks
measure: Blood pressure (NexFin®)
timeFrame: 8 weeks
measure: Heart Rate (NexFin®)
timeFrame: 16 weeks
measure: Heart Rate (NexFin®)
timeFrame: 8 weeks
measure: Stroke Volume
timeFrame: 16 weeks
measure: Stroke Volume
timeFrame: 8 weeks
measure: Cardiac output
timeFrame: 16 weeks
measure: Cardiac output
timeFrame: 8 weeks
measure: Cardiac index
timeFrame: 16 weeks
measure: Cardiac index
timeFrame: 8 weeks
measure: Total systemic vascular resistance
timeFrame: 16 weeks
measure: Total systemic vascular resistance
timeFrame: 8 weeks
measure: Cardiac autonomic nervous system function
timeFrame: 16 weeks
measure: Cardiac autonomic nervous system function
timeFrame: 8 weeks
measure: Microvascular function
timeFrame: 16 weeks
measure: Microvascular function
timeFrame: 8 weeks
measure: Arterial stiffness
timeFrame: 16 weeks
measure: Arterial stiffness
timeFrame: 8 weeks
measure: Insulin sensitivity (M-value)
timeFrame: 16 weeks
measure: Insulin sensitivity (M-value)
timeFrame: 8 weeks
measure: Insulin sensitivity (OGIS)
timeFrame: 16 weeks
measure: Insulin sensitivity (OGIS)
timeFrame: 8 weeks
measure: Insulin sensitivity (Matsuda index)
timeFrame: 16 weeks
measure: Insulin sensitivity (Matsuda index)
timeFrame: 8 weeks
measure: Beta-cell function (insulinogenic index)
timeFrame: 16 weeks
measure: Beta-cell function (insulinogenic index)
timeFrame: 8 weeks
measure: Beta-cell function (HOMA-B)
timeFrame: 16 weeks
measure: Beta-cell function (HOMA-B)
timeFrame: 8 weeks
measure: Beta-cell function (ratio of postprandial glucose and C-peptide)
timeFrame: 16 weeks
measure: Beta-cell function (ratio of postprandial glucose and C-peptide)
timeFrame: 8 weeks
measure: Lipid spectrum
timeFrame: 16 weeks
measure: Lipid spectrum
timeFrame: 8 weeks
measure: DPP-4
timeFrame: 16 weeks
measure: DPP-4
timeFrame: 8 weeks
measure: ACE
timeFrame: 16 weeks
measure: ACE
timeFrame: 8 weeks
measure: HbA1c (%)
timeFrame: 16 weeks
measure: HbA1c (%)
timeFrame: 8 weeks
measure: Fasting plasma glucose (mmol/L)
timeFrame: 16 weeks
measure: Fasting plasma glucose (mmol/L)
timeFrame: 8 weeks
measure: Postprandial plasma glucose (mmol/L)
timeFrame: 16 weeks
measure: Postprandial plasma glucose (mmol/L)
timeFrame: 8 weeks
measure: Free Fatty Acids (FFA) (mmol/L)
timeFrame: 16 weeks
measure: Free Fatty Acids (FFA) (mmol/L)
timeFrame: 8 weeks
measure: Insulin (mg/L)
timeFrame: 16 weeks
measure: Insulin (mg/L)
timeFrame: 8 weeks
measure: Glucagon (mg/L)
timeFrame: 16 weeks
measure: Glucagon (mg/L)
timeFrame: 8 weeks
Locations:
city: Amsterdam
country: Netherlands
facility: VU University Medical Center
state: Noord-Holland
Study officials:
affiliation: Amsterdam UMC, location VUmc
name: Mark HH Kramer, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: