Try the modernized ClinicalTrials.gov beta website. Learn more about the modernization effort.
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03433248
Recruitment Status : Active, not recruiting
First Posted : February 14, 2018
Last Update Posted : January 14, 2022
Sponsor:
Information provided by (Responsible Party):
M.H.H. Kramer, Amsterdam UMC, location VUmc

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.

Condition or disease Intervention/treatment Phase
Type2 Diabetes 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) Phase 4

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 66 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: RACELINES: Renal Actions of Combined Empagliflozin and LINagliptin in Type 2 diabetES
Actual Study Start Date : November 9, 2017
Actual Primary Completion Date : June 1, 2021
Estimated Study Completion Date : September 1, 2022

Resource links provided by the National Library of Medicine


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:
  • Tradjenta
  • Jardiance

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:
  • Tradjenta
  • Jardiance

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 Name: Gliclazide Sandoz




Primary Outcome Measures :
  1. GFR [ Time Frame: 16 weeks ]
    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)

  2. 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 Outcome Measures :
  1. Renal tubular function [ Time Frame: 16 weeks ]
    24-hour urine sodium-, potassium-, chloride-, calcium-, magnesium-, phosphate-, uric acid-, bicarbonate-, ammonium-, urea- and glucose excretion, urine osmolality and urinary pH

  2. Renal tubular function [ Time Frame: 8 weeks ]
    24-hour urine sodium-, potassium-, chloride-, calcium-, magnesium-, phosphate-, uric acid-, bicarbonate-, ammonium-, urea- and glucose excretion, urine osmolality and urinary pH

  3. Renal Damage [ Time Frame: 16 weeks ]
    24-hour urinary albumin excretion, albumin/creatinine ratio (UCR)

  4. Renal Damage [ Time Frame: 10 weeks ]
    24-hour urinary albumin excretion, albumin/creatinine ratio (UCR)

  5. Renal Damage [ Time Frame: 8 weeks ]
    24-hour urinary albumin excretion, albumin/creatinine ratio (UCR)

  6. Renal Damage [ Time Frame: 2 weeks ]
    24-hour urinary albumin excretion, albumin/creatinine ratio (UCR)

  7. Heart Rate (Dinamap®) [ Time Frame: 16 weeks ]
    Measured using an automated oscillometric blood pressure device (Dinamap®)

  8. Heart Rate (Dinamap®) [ Time Frame: 10 weeks ]
    Measured using an automated oscillometric blood pressure device (Dinamap®)

  9. Heart Rate (Dinamap®) [ Time Frame: 8 weeks ]
    Measured using an automated oscillometric blood pressure device (Dinamap®)

  10. Heart Rate (Dinamap®) [ Time Frame: 2 weeks ]
    Measured using an automated oscillometric blood pressure device (Dinamap®)

  11. Blood Pressure (Dinamap®) [ Time Frame: 16 weeks ]
    Measured using an automated oscillometric blood pressure device (Dinamap®)

  12. Blood Pressure (Dinamap®) [ Time Frame: 10 weeks ]
    Measured using an automated oscillometric blood pressure device (Dinamap®)

  13. Blood Pressure (Dinamap®) [ Time Frame: 8 weeks ]
    Measured using an automated oscillometric blood pressure device (Dinamap®)

  14. Blood Pressure (Dinamap®) [ Time Frame: 2 weeks ]
    Measured using an automated oscillometric blood pressure device (Dinamap®)


Other Outcome Measures:
  1. Body anthropometrics: Body mass index [ Time Frame: 16 weeks ]
    Body mass index

  2. Body anthropometrics: Body mass index [ Time Frame: 8 weeks ]
    Body mass index

  3. Body anthropometrics: Body weight [ Time Frame: 16 weeks ]
    Body weight

  4. Body anthropometrics: Body weight [ Time Frame: 8 weeks ]
    Body weight

  5. Body anthropometrics: Height [ Time Frame: 16 weeks ]
    Height

  6. Body anthropometrics: Height [ Time Frame: 8 weeks ]
    Height

  7. Body anthropometrics: Waist circumference [ Time Frame: 16 weeks ]
    Waist circumference

  8. Body anthropometrics: Waist circumference [ Time Frame: 8 weeks ]
    Waist circumference

  9. Body anthropometrics: Hip circumference [ Time Frame: 16 weeks ]
    Hip circumference

  10. Body anthropometrics: Hip circumference [ Time Frame: 8 weeks ]
    Hip circumference

  11. Body fat content [ Time Frame: 16 weeks ]
    Body fat content by bioimpedance analysis

  12. Body fat content [ Time Frame: 8 weeks ]
    Body fat content by bioimpedance analysis

  13. Blood pressure (NexFin®) [ Time Frame: 16 weeks ]
    Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)

  14. Blood pressure (NexFin®) [ Time Frame: 8 weeks ]
    Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)

  15. Heart Rate (NexFin®) [ Time Frame: 16 weeks ]
    Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)

  16. Heart Rate (NexFin®) [ Time Frame: 8 weeks ]
    Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)

  17. Stroke Volume [ Time Frame: 16 weeks ]
    Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)

  18. Stroke Volume [ Time Frame: 8 weeks ]
    Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)

  19. Cardiac output [ Time Frame: 16 weeks ]
    Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)

  20. Cardiac output [ Time Frame: 8 weeks ]
    Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)

  21. Cardiac index [ Time Frame: 16 weeks ]
    Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)

  22. Cardiac index [ Time Frame: 8 weeks ]
    Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)

  23. Total systemic vascular resistance [ Time Frame: 16 weeks ]
    Continuous beat-to-beat hemodynamic monitor (NexFin®)

  24. Total systemic vascular resistance [ Time Frame: 8 weeks ]
    Continuous beat-to-beat hemodynamic monitor (NexFin®)

  25. Cardiac autonomic nervous system function [ Time Frame: 16 weeks ]
    Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)

  26. Cardiac autonomic nervous system function [ Time Frame: 8 weeks ]
    Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)

  27. Microvascular function [ Time Frame: 16 weeks ]
    Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)

  28. Microvascular function [ Time Frame: 8 weeks ]
    Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)

  29. Arterial stiffness [ Time Frame: 16 weeks ]
    Assessed by radial artery applanation tonometry (SphygmoCor®)

  30. Arterial stiffness [ Time Frame: 8 weeks ]
    Assessed by radial artery applanation tonometry (SphygmoCor®)

  31. Insulin sensitivity (M-value) [ Time Frame: 16 weeks ]
    Derived from the glucose infusion rate during the euglycemic clamp (M-value)

  32. Insulin sensitivity (M-value) [ Time Frame: 8 weeks ]
    Derived from the glucose infusion rate during the euglycemic clamp (M-value)

  33. Insulin sensitivity (OGIS) [ Time Frame: 16 weeks ]
    Meal tolerance test (OGIS)

  34. Insulin sensitivity (OGIS) [ Time Frame: 8 weeks ]
    Meal tolerance test (OGIS)

  35. Insulin sensitivity (Matsuda index) [ Time Frame: 16 weeks ]
    Meal tolerance test (Matsuda index)

  36. Insulin sensitivity (Matsuda index) [ Time Frame: 8 weeks ]
    Meal tolerance test (Matsuda index)

  37. Beta-cell function (insulinogenic index) [ Time Frame: 16 weeks ]
    Meal tolerance test (insulinogenic index)

  38. Beta-cell function (insulinogenic index) [ Time Frame: 8 weeks ]
    Meal tolerance test (insulinogenic index)

  39. Beta-cell function (HOMA-B) [ Time Frame: 16 weeks ]
    HOMA-B

  40. Beta-cell function (HOMA-B) [ Time Frame: 8 weeks ]
    HOMA-B

  41. Beta-cell function (ratio of postprandial glucose and C-peptide) [ Time Frame: 16 weeks ]
    Meal tolerance test (ratio of postprandial glucose and C-peptide)

  42. Beta-cell function (ratio of postprandial glucose and C-peptide) [ Time Frame: 8 weeks ]
    Meal tolerance test (ratio of postprandial glucose and C-peptide)

  43. Lipid spectrum [ Time Frame: 16 weeks ]
    (triglycerides (TG), total-cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C)

  44. Lipid spectrum [ Time Frame: 8 weeks ]
    (triglycerides (TG), total-cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C)

  45. DPP-4 [ Time Frame: 16 weeks ]
    DPP-4 activity

  46. DPP-4 [ Time Frame: 8 weeks ]
    DPP-4 activity

  47. ACE [ Time Frame: 16 weeks ]
    ACE activity

  48. ACE [ Time Frame: 8 weeks ]
    ACE activity

  49. HbA1c (%) [ Time Frame: 16 weeks ]
    HbA1c (%)

  50. HbA1c (%) [ Time Frame: 8 weeks ]
    HbA1c (%)

  51. Fasting plasma glucose (mmol/L) [ Time Frame: 16 weeks ]
    Fasting plasma glucose (mmol/L)

  52. Fasting plasma glucose (mmol/L) [ Time Frame: 8 weeks ]
    Fasting plasma glucose (mmol/L)

  53. Postprandial plasma glucose (mmol/L) [ Time Frame: 16 weeks ]
    Postprandial plasma glucose (mmol/L)

  54. Postprandial plasma glucose (mmol/L) [ Time Frame: 8 weeks ]
    Postprandial plasma glucose (mmol/L)

  55. Free Fatty Acids (FFA) (mmol/L) [ Time Frame: 16 weeks ]
    Free Fatty Acids (FFA) (mmol/L)

  56. Free Fatty Acids (FFA) (mmol/L) [ Time Frame: 8 weeks ]
    Free Fatty Acids (FFA) (mmol/L)

  57. Insulin (mg/L) [ Time Frame: 16 weeks ]
    Insulin (mg/L)

  58. Insulin (mg/L) [ Time Frame: 8 weeks ]
    Insulin (mg/L)

  59. Glucagon (mg/L) [ Time Frame: 16 weeks ]
    Glucagon (mg/L)

  60. Glucagon (mg/L) [ Time Frame: 8 weeks ]
    Glucagon (mg/L)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   35 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03433248


Locations
Layout table for location information
Netherlands
VU University Medical Center
Amsterdam, Noord-Holland, Netherlands, 1081HV
Sponsors and Collaborators
M.H.H. Kramer
Investigators
Layout table for investigator information
Principal Investigator: Mark HH Kramer, MD PhD Amsterdam UMC, location VUmc
Layout table for additonal information
Responsible Party: M.H.H. Kramer, Head of the Internal Medicine department, Amsterdam UMC, location VUmc
ClinicalTrials.gov Identifier: NCT03433248    
Other Study ID Numbers: DC2017RACELINES01
First Posted: February 14, 2018    Key Record Dates
Last Update Posted: January 14, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by M.H.H. Kramer, Amsterdam UMC, location VUmc:
Type 2 diabetes mellitus
Diabetic kidney disease
Diabetic nephropathy
Renoprotection
SGLT2 inhibitor
Empagliflozin
DPP-4 inhibitor
Linagliptin
SU derivative
Gliclazide
Additional relevant MeSH terms:
Layout table for MeSH terms
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Empagliflozin
Gliclazide
Linagliptin
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors