Renal Actions of Combined Empagliflozin and LINagliptin in Type 2 diabetES

Type2 Diabetes Clinical Trial

— RACELINES  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03433248
• Other study ID #: DC2017RACELINES01
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: November 9, 2017
• Est. completion date: September 1, 2022

Study information

• Verified date: January 2022
• Source: VU University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 66
• Est. completion date: September 1, 2022
• Est. primary completion date: June 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 35 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Type2 Diabetes

Intervention

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
• 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
• Gliclazide 30 mg QD/BID (N=22)
Once daily or twice daily treatment with oral glicazide MR 30mg

Locations

Country	Name	City	State
Netherlands	VU University Medical Center	Amsterdam	Noord-Holland

Sponsors (1)

Lead Sponsor	Collaborator
M.H.H. Kramer

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Body anthropometrics: Body mass index	Body mass index	16 weeks
Other	Body anthropometrics: Body mass index	Body mass index	8 weeks
Other	Body anthropometrics: Body weight	Body weight	16 weeks
Other	Body anthropometrics: Body weight	Body weight	8 weeks
Other	Body anthropometrics: Height	Height	16 weeks
Other	Body anthropometrics: Height	Height	8 weeks
Other	Body anthropometrics: Waist circumference	Waist circumference	16 weeks
Other	Body anthropometrics: Waist circumference	Waist circumference	8 weeks
Other	Body anthropometrics: Hip circumference	Hip circumference	16 weeks
Other	Body anthropometrics: Hip circumference	Hip circumference	8 weeks
Other	Body fat content	Body fat content by bioimpedance analysis	16 weeks
Other	Body fat content	Body fat content by bioimpedance analysis	8 weeks
Other	Blood pressure (NexFin®)	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	16 weeks
Other	Blood pressure (NexFin®)	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	8 weeks
Other	Heart Rate (NexFin®)	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	16 weeks
Other	Heart Rate (NexFin®)	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	8 weeks
Other	Stroke Volume	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	16 weeks
Other	Stroke Volume	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	8 weeks
Other	Cardiac output	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	16 weeks
Other	Cardiac output	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	8 weeks
Other	Cardiac index	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	16 weeks
Other	Cardiac index	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	8 weeks
Other	Total systemic vascular resistance	Continuous beat-to-beat hemodynamic monitor (NexFin®)	16 weeks
Other	Total systemic vascular resistance	Continuous beat-to-beat hemodynamic monitor (NexFin®)	8 weeks
Other	Cardiac autonomic nervous system function	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	16 weeks
Other	Cardiac autonomic nervous system function	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	8 weeks
Other	Microvascular function	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	16 weeks
Other	Microvascular function	Measured by continuous beat-to-beat hemodynamic monitor (NexFin®)	8 weeks
Other	Arterial stiffness	Assessed by radial artery applanation tonometry (SphygmoCor®)	16 weeks
Other	Arterial stiffness	Assessed by radial artery applanation tonometry (SphygmoCor®)	8 weeks
Other	Insulin sensitivity (M-value)	Derived from the glucose infusion rate during the euglycemic clamp (M-value)	16 weeks
Other	Insulin sensitivity (M-value)	Derived from the glucose infusion rate during the euglycemic clamp (M-value)	8 weeks
Other	Insulin sensitivity (OGIS)	Meal tolerance test (OGIS)	16 weeks
Other	Insulin sensitivity (OGIS)	Meal tolerance test (OGIS)	8 weeks
Other	Insulin sensitivity (Matsuda index)	Meal tolerance test (Matsuda index)	16 weeks
Other	Insulin sensitivity (Matsuda index)	Meal tolerance test (Matsuda index)	8 weeks
Other	Beta-cell function (insulinogenic index)	Meal tolerance test (insulinogenic index)	16 weeks
Other	Beta-cell function (insulinogenic index)	Meal tolerance test (insulinogenic index)	8 weeks
Other	Beta-cell function (HOMA-B)	HOMA-B	16 weeks
Other	Beta-cell function (HOMA-B)	HOMA-B	8 weeks
Other	Beta-cell function (ratio of postprandial glucose and C-peptide)	Meal tolerance test (ratio of postprandial glucose and C-peptide)	16 weeks
Other	Beta-cell function (ratio of postprandial glucose and C-peptide)	Meal tolerance test (ratio of postprandial glucose and C-peptide)	8 weeks
Other	Lipid spectrum	(triglycerides (TG), total-cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C)	16 weeks
Other	Lipid spectrum	(triglycerides (TG), total-cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C)	8 weeks
Other	DPP-4	DPP-4 activity	16 weeks
Other	DPP-4	DPP-4 activity	8 weeks
Other	ACE	ACE activity	16 weeks
Other	ACE	ACE activity	8 weeks
Other	HbA1c (%)	HbA1c (%)	16 weeks
Other	HbA1c (%)	HbA1c (%)	8 weeks
Other	Fasting plasma glucose (mmol/L)	Fasting plasma glucose (mmol/L)	16 weeks
Other	Fasting plasma glucose (mmol/L)	Fasting plasma glucose (mmol/L)	8 weeks
Other	Postprandial plasma glucose (mmol/L)	Postprandial plasma glucose (mmol/L)	16 weeks
Other	Postprandial plasma glucose (mmol/L)	Postprandial plasma glucose (mmol/L)	8 weeks
Other	Free Fatty Acids (FFA) (mmol/L)	Free Fatty Acids (FFA) (mmol/L)	16 weeks
Other	Free Fatty Acids (FFA) (mmol/L)	Free Fatty Acids (FFA) (mmol/L)	8 weeks
Other	Insulin (mg/L)	Insulin (mg/L)	16 weeks
Other	Insulin (mg/L)	Insulin (mg/L)	8 weeks
Other	Glucagon (mg/L)	Glucagon (mg/L)	16 weeks
Other	Glucagon (mg/L)	Glucagon (mg/L)	8 weeks
Primary	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
Primary	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	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
Secondary	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
Secondary	Renal Damage	24-hour urinary albumin excretion, albumin/creatinine ratio (UCR)	16 weeks
Secondary	Renal Damage	24-hour urinary albumin excretion, albumin/creatinine ratio (UCR)	10 weeks
Secondary	Renal Damage	24-hour urinary albumin excretion, albumin/creatinine ratio (UCR)	8 weeks
Secondary	Renal Damage	24-hour urinary albumin excretion, albumin/creatinine ratio (UCR)	2 weeks
Secondary	Heart Rate (Dinamap®)	Measured using an automated oscillometric blood pressure device (Dinamap®)	16 weeks
Secondary	Heart Rate (Dinamap®)	Measured using an automated oscillometric blood pressure device (Dinamap®)	10 weeks
Secondary	Heart Rate (Dinamap®)	Measured using an automated oscillometric blood pressure device (Dinamap®)	8 weeks
Secondary	Heart Rate (Dinamap®)	Measured using an automated oscillometric blood pressure device (Dinamap®)	2 weeks
Secondary	Blood Pressure (Dinamap®)	Measured using an automated oscillometric blood pressure device (Dinamap®)	16 weeks
Secondary	Blood Pressure (Dinamap®)	Measured using an automated oscillometric blood pressure device (Dinamap®)	10 weeks
Secondary	Blood Pressure (Dinamap®)	Measured using an automated oscillometric blood pressure device (Dinamap®)	8 weeks
Secondary	Blood Pressure (Dinamap®)	Measured using an automated oscillometric blood pressure device (Dinamap®)	2 weeks