Renal Actions of Combined Empagliflozin and LINagliptin in Type 2 diabetES (RACELINES)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Type2 Diabetes
• Intervention / Treatment: 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)

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.

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1081HV
      • VU University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: EMPA/LINA 10/5 mg QD (n=22); 8w EMPA followed by 8w EMPA/LINA 10/5 mg QD (n=22)	Drug: 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; Other Names: Jardiance; Tradjenta; 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; Other Names: Jardiance; Tradjenta
EXPERIMENTAL: LINA/EMPA 5/10 mg QD (N=22); 8w LINA followed by LINA/EMPA 5/10 mg QD (N=22)	Drug: 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; Other Names: Jardiance; Tradjenta; 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; Other Names: Jardiance; Tradjenta
ACTIVE_COMPARATOR: Gliclazide 30 mg QD/BID (N=22); 8w Gliclazide 30 mg QD, followed by 8w Gliclazide BID (N=22)	Drug: Gliclazide 30 mg QD/BID (N=22); Once daily or twice daily treatment with oral glicazide MR 30mg; Other Names: Gliclazide Sandoz

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body anthropometrics: Body mass index	Body mass index	16 weeks
Body anthropometrics: Body mass index	Body mass index	8 weeks
Body anthropometrics: Body weight	Body weight	16 weeks
Body anthropometrics: Body weight	Body weight	8 weeks
Body anthropometrics: Height	Height	16 weeks
Body anthropometrics: Height	Height	8 weeks
Body anthropometrics: Waist circumference	Waist circumference	16 weeks
Body anthropometrics: Waist circumference	Waist circumference	8 weeks
Body anthropometrics: Hip circumference	Hip circumference	16 weeks
Body anthropometrics: Hip circumference	Hip circumference	8 weeks
Body fat content	Body fat content by bioimpedance analysis	16 weeks
Body fat content	Body fat content by bioimpedance analysis	8 weeks
Blood pressure (NexFin®)	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	16 weeks
Blood pressure (NexFin®)	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	8 weeks
Heart Rate (NexFin®)	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	16 weeks
Heart Rate (NexFin®)	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	8 weeks
Stroke Volume	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	16 weeks
Stroke Volume	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	8 weeks
Cardiac output	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	16 weeks
Cardiac output	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	8 weeks
Cardiac index	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	16 weeks
Cardiac index	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	8 weeks
Total systemic vascular resistance	Continuous beat-to-beat hemodynamic monitor (NexFin®)	16 weeks
Total systemic vascular resistance	Continuous beat-to-beat hemodynamic monitor (NexFin®)	8 weeks
Cardiac autonomic nervous system function	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	16 weeks
Cardiac autonomic nervous system function	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	8 weeks
Microvascular function	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	16 weeks
Microvascular function	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	8 weeks
Arterial stiffness	Assessed by radial artery applanation tonometry (SphygmoCor®)	16 weeks
Arterial stiffness	Assessed by radial artery applanation tonometry (SphygmoCor®)	8 weeks
Insulin sensitivity (M-value)	Derived from the glucose infusion rate during the euglycemic clamp (M-value)	16 weeks
Insulin sensitivity (M-value)	Derived from the glucose infusion rate during the euglycemic clamp (M-value)	8 weeks
Insulin sensitivity (OGIS)	Meal tolerance test (OGIS)	16 weeks
Insulin sensitivity (OGIS)	Meal tolerance test (OGIS)	8 weeks
Insulin sensitivity (Matsuda index)	Meal tolerance test (Matsuda index)	16 weeks
Insulin sensitivity (Matsuda index)	Meal tolerance test (Matsuda index)	8 weeks
Beta-cell function (insulinogenic index)	Meal tolerance test (insulinogenic index)	16 weeks
Beta-cell function (insulinogenic index)	Meal tolerance test (insulinogenic index)	8 weeks
Beta-cell function (HOMA-B)	HOMA-B	16 weeks
Beta-cell function (HOMA-B)	HOMA-B	8 weeks
Beta-cell function (ratio of postprandial glucose and C-peptide)	Meal tolerance test (ratio of postprandial glucose and C-peptide)	16 weeks
Beta-cell function (ratio of postprandial glucose and C-peptide)	Meal tolerance test (ratio of postprandial glucose and C-peptide)	8 weeks
Lipid spectrum	(triglycerides (TG), total-cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C)	16 weeks
Lipid spectrum	(triglycerides (TG), total-cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C)	8 weeks
DPP-4	DPP-4 activity	16 weeks
DPP-4	DPP-4 activity	8 weeks
ACE	ACE activity	16 weeks
ACE	ACE activity	8 weeks
HbA1c (%)	HbA1c (%)	16 weeks
HbA1c (%)	HbA1c (%)	8 weeks
Fasting plasma glucose (mmol/L)	Fasting plasma glucose (mmol/L)	16 weeks
Fasting plasma glucose (mmol/L)	Fasting plasma glucose (mmol/L)	8 weeks
Postprandial plasma glucose (mmol/L)	Postprandial plasma glucose (mmol/L)	16 weeks
Postprandial plasma glucose (mmol/L)	Postprandial plasma glucose (mmol/L)	8 weeks
Free Fatty Acids (FFA) (mmol/L)	Free Fatty Acids (FFA) (mmol/L)	16 weeks
Free Fatty Acids (FFA) (mmol/L)	Free Fatty Acids (FFA) (mmol/L)	8 weeks
Insulin (mg/L)	Insulin (mg/L)	16 weeks
Insulin (mg/L)	Insulin (mg/L)	8 weeks
Glucagon (mg/L)	Glucagon (mg/L)	16 weeks
Glucagon (mg/L)	Glucagon (mg/L)	8 weeks

Collaborators and Investigators

• Sponsor: M.H.H. Kramer
• Investigators: Principal Investigator: Mark HH Kramer, MD PhD, Amsterdam UMC, location VUmc

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 9, 2017
• Primary Completion (ACTUAL): June 1, 2021
• Study Completion (ANTICIPATED): September 1, 2022

Study Registration Dates

• First Submitted: November 22, 2017
• First Submitted That Met QC Criteria: February 7, 2018
• First Posted (ACTUAL): February 14, 2018

Study Record Updates

• Last Update Posted (ACTUAL): January 14, 2022
• Last Update Submitted That Met QC Criteria: January 13, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Empagliflozin; Type 2 diabetes mellitus; Diabetic kidney disease; SGLT2 inhibitor; Diabetic nephropathy; Renoprotection; Linagliptin; DPP-4 inhibitor; Gliclazide; SU derivative
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Sodium-Glucose Transporter 2 Inhibitors; Dipeptidyl-Peptidase IV Inhibitors; Empagliflozin; Linagliptin; Gliclazide
• Other Study ID Numbers: DC2017RACELINES01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No