Effect of LIXIsenatide on the Renal System (ELIXIRS)

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Diabetic Kidney Disease; Diabetic Nephropathy; Diabetes Mellitus; Glucagon-Like Peptide 1	Drug: Lixisenatide; Drug: Insulin glulisine	Phase 4

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	40 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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
Study Start Date :	September 2014
Actual Primary Completion Date :	April 2016
Actual Study Completion Date :	April 2016

Arms and Interventions

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

Outcome Measures

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Primary Outcome Measures :

1. 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) [ Time Frame: 8 weeks ]
   ml/min

Secondary Outcome Measures :

1. Renal damage, measured by urine biomarkers [ Time Frame: 8 weeks ]
   enzyme immuno assay
2. Renal tubular function [ Time Frame: 8 weeks ]
   e.g. percentage (%)
3. Blood Pressure [ Time Frame: 8 weeks ]
   mmHg

Other Outcome Measures:

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

Eligibility Criteria

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Ages Eligible for Study:	35 Years to 75 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Locations

Netherlands
VU Universtiy Medical Center
Amsterdam, Netherlands, 1081 HV

Sponsors and Collaborators

VU University Medical Center

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Responsible Party:	M.H.H. Kramer, MD PhD, VU University Medical Center
ClinicalTrials.gov Identifier:	NCT02276196 History of Changes
Other Study ID Numbers:	DC2014ELIX001
First Posted:	October 28, 2014
Last Update Posted:	April 29, 2016
Last Verified:	February 2016

Additional relevant MeSH terms:

Diabetes Mellitus; Kidney Diseases; Diabetic Nephropathies; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Urologic Diseases; Diabetes Complications; Insulin, Globin Zinc	Lixisenatide; Insulin glulisine; Insulin; Glucagon-Like Peptide 1; Hypoglycemic Agents; Physiological Effects of Drugs; Incretins; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists