A phase 4, monocenter, 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

Phase 4

Completed

• Conditions: Type 2 Diabetes Mellitus; 10012653; 10029149

• Registration Number: NL-OMON42165
• Lead Sponsor: Diabetes Centrum / Interne Geneeskunde

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Last Update Posted: 23 April 2024

Recruitment & Eligibility

• Status: Completed
• Sex: Not specified
• Target Recruitment: 82

Inclusion Criteria

Main study:
•Type 2 diabetes mellitus
•Caucasian
•Both genders (females must be post-menopausal; no menses >1 year)
•Age: 35 - 75 years
•BMI: >25 kg/m2
•HbA1c: 6.5 - 10% DCCT (48 - 86 mmol/mol International Federation of Clinical Chemistry)
•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 (FPG) <10 mmol/L or the use of >50 units of basal insulin glargine
•Hypertension should be under control, i.e. <140/90 mmHg, and treated with a RAAS-interfering agent (ACE-I or ARB) 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;Substudy:
Male and female patients with type 1 diabetes (as a homogenous model of DKD) with:
• Normal eGFR (MDRD >=60 mL/min/1.73m2) and normoalbuminuria (spot urine: ACR 3-30 mg/mmol)
• Normal eGFR (MDRD >=60 mL/min/1.73m2) and microalbuminuria (spot urine: ACR 3-30 mg/mmol)
• Normal eGFR (MDRD >=60 mL/min/1.73m2) and macroalbuminuria (spot urine: ACR >30 mg/mmol)
• Reduced eGFR (MDRD <45 mL/min/1.73m2) and macroalbuminuria (spot urine: ACR >30 mg/mmol) ;We will include 6 type 1 diabetes patients per group. ;For control groups, we will collect spot-urine sample from:
• Healthy age- and BMI-matched subjects (negative control; normal eGFR and normoalbuminuria)
• Patients with biopsy-proven DKD (positive control; any type of diabetes, eGFR or albuminuria)
• Patients with IgA nephropathy and albuminuria (to assess specificity for DKD)
We will include 6 subjects/patients per group.

Exclusion Criteria

Main study:
•Current/chronic use of the following medication: TZD, SU derivative, GLP-1RA, DPP-4I, glucocorticoids, immune suppressants, antimicrobial agents, chemotherapeutics antipsychotics, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). 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 (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
•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:
oAcute coronary syndrome
oChronic heart failure (New York Heart Association grade II-IV)
oStroke 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 (AST)/alanine aminotransferase (ALT)) 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 (i.e. GLP-1RA, inulin, metacresol (component lixisenatide and insulin glulisine), PAH, latex (component of PAH vial stopper))
•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;Sub study:
See inclusioncriteria

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Main study:<br /><br>Renal hemodynamics, measured as:<br /><br>• Glomerular filtration rate (measured by the inulin-clearance technique)<br /><br>• Effective renal plasma flow (measured by the para-aminohippuric acid<br /><br>clearance technique)<br /><br><br /><br>Sub study:<br /><br>To explore the sensitivity and clinical usefulness of podocyte-derived urinary<br /><br>MPs in human DKD. </p><br>