Effect of LIXIsenatide on the Renal System (ELIXIRS)

A Phase 4, Mono-center, Randomized, Open Label, Comparator-controlled, Parallel-group, Mechanistic Intervention Trial to Assess the Effect of 8-week Treatment With the Glucagon-like Peptide-1 Receptor Agonist Lixisenatide Versus Insulin Glulisine on Renal Physiology and Biomarkers in Insulin Glargine-treated Patients With Type 2 Diabetes Mellitus

Based on preclinical and small-sized studies in non-diabetic individuals, incretin-based therapies, i.e. glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, may hold promise in preventing the onset and progression of diabetic kidney disease. However, the potential renoprotective effects of these agents, that are believed to be effectuated "beyond glucose control", have not been sufficiently detailed in human diabetes.

Therefore, the present study aims to explore the mechanistic and clinical effects of GLP-1 receptor agonists on renal physiology and biomarkers in patients with type 2 diabetes.

Forty patients with insulin-treated type 2 diabetes will undergo an eight week intervention with lixisenatide or insulin glulisine in order to assess changes in the outcome parameters.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus; Diabetic Nephropathy; Diabetic Kidney Disease; Glucagon-Like Peptide 1
• Intervention / Treatment: Drug: Lixisenatide; Drug: Insulin glulisine

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VU Universtiy 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:

• Patients with type 2 diabetes (HbA1c: 6.5-10.0% or 48-86 mmol/mol)
• Stable treatment with basal insulin glargine (dose ±20%) and metformin or basal insulin glargine (dose ±20%) alone for at least 3 months
• Fasting plasma glucose <10 mmol/L or the use of >50 units of basal insulin glargine
• Females must be post-menopausal
• Caucasian
• Age: 35 - 75 years
• Body Mass Index: >25 kg/m2
• Hypertension should be under control, i.e. <140/90 mmHg, and treated with an angiotensin-converting enzyme inhibitor or angiotensin-II-receptor blocker for at least 3 months.
• Albuminuria should be treated with an angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin-II-receptor blocker (ARB) for at least 3 months.

Exclusion Criteria:

• Current/chronic use of the following medication: thiazolidinediones, sulfonylurea derivatives, GLP-1 receptor agonists, dipeptidyl peptidase (DPP)-4 inhibitors, glucocorticoids, immune suppressants, antimicrobial agents, chemotherapeutics, antipsychotics, tricyclic antidepressants and monoamine oxidase inhibitors. Subjects on diuretics, will only be excluded when these drugs cannot be stopped for the duration of the study.
• Chronic use of non-steroidal anti-inflammatory drugs 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
• Hypoglycemia unawareness based on investigator judgment
• History of severe hypoglycemia that required emergency hospital treatment within 3 months prior to screening
• Estimated GFR <60 mL/min/1.73m2 (determined by the Modification of Diet in Renal Disease (MDRD) study equation)
• Pregnancy
• Current urinary tract infection and active nephritis
• Recent (<6 months) history of cardiovascular disease, including: acute coronary syndrome, chronic heart failure (New York Heart Association grade II-IV), stroke or transient ischemic neurologic disorder
• Complaints compatible with or established gastroparesis, neurogenic bladder and/or incomplete bladder emptying (as determined by ultrasonic bladder scan)
• Active liver disease or a 3-fold elevation of liver enzymes (aspartate aminotransferase/alanine aminotransferase) at screening
• History of or actual pancreatic disease
• History of or actual malignancy (except basal cell carcinoma)
• History of or actual severe mental disease
• Substance abuse (alcohol: defined as >4 units/day)
• Allergy to any of the agents used in the study
• 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
• Inability to understand the study protocol or give informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lixisenatide; Lixisenatide will be administered subcutaneously, once daily for 8 weeks	Drug: Lixisenatide; GLP-1 receptor agonist; Other Names: Lyxumia
Active Comparator: Insulin glulisine; Insulin glulisine will be administered subcutaneously, once daily for 8 weeks	Drug: Insulin glulisine; Insulin analogue; Other Names: Apidra

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes from baseline following 8-week treatment with a glucagon-like peptide(GLP)-1 receptor agonist versus insulin glulisine on renal hemodynamics, measured as glomerular filtration rate (GFR) / effective renal plasma flow (ERPF)	ml/min	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Renal damage, measured by urine biomarkers	enzyme immuno assay	8 weeks
Renal tubular function	e.g. percentage (%)	8 weeks
Blood Pressure	mmHg	8 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body anthropometrics: body weight, height, body mass index, waist circumference	kilogram, meters, centimeters	8 weeks
Body fat content	e.g. percentage (%)	8 weeks
Glycemic variables	e.g. mmol/l, mmol/mol	8 weeks
Lipid spectrum	e.g. mmol/l	8 weeks
Inflammatory markers	e.g. nmol/l	8 weeks
Systemic hemodynamic variables	e.g. ml/min	8 weeks
Heart rate	beat per minute	8 weeks
Microvascular function	e.g. count	8 weeks
Arterial stiffness	e.g. augmentation index	8 weeks

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc

Publications and helpful links

General Publications

• Tonneijck L, Muskiet MHA, Smits MM, Hoekstra T, Kramer MHH, Danser AHJ, Diamant M, Joles JA, van Raalte DH. Postprandial renal haemodynamic effect of lixisenatide vs once-daily insulin-glulisine in patients with type 2 diabetes on insulin-glargine: An 8-week, randomised, open-label trial. Diabetes Obes Metab. 2017 Dec;19(12):1669-1680. doi: 10.1111/dom.12985. Epub 2017 Jul 25.

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Actual): April 1, 2016
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: October 16, 2014
• First Submitted That Met QC Criteria: October 27, 2014
• First Posted (Estimate): October 28, 2014

Study Record Updates

• Last Update Posted (Estimate): April 29, 2016
• Last Update Submitted That Met QC Criteria: April 28, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Urologic Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Kidney Diseases; Diabetic Nephropathies; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin glulisine; Lixisenatide
• Other Study ID Numbers: DC2014ELIX001