Effect of Liraglutide on the Metabolic Profile in Patients With Type 2 Diabetes and Cardiovascular Disease (Lirabolic)

In an unbiased metabolomics approach with subsequent pathway analyses, the current study seeks to examine the effect of Liraglutide treatment on the metabolic signature in treated patients as well as the effect of Liraglutide on various echocardiographic parameters of cardiac function and rhythm profile, thus paving the way for future research to explain the effects of Liraglutide on cardiovascular mortality and overall mortality in treated patients.

Study Overview

• Status: Withdrawn
• Conditions: Cardiovascular Diseases; Type 2 Diabetes
• Intervention / Treatment: Drug: Liraglutide Pen Injector [Victoza]; Drug: Placebo

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Aachen, Germany, 52074
    • Department of Internal Medicine I, University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Type 2 diabetes
2. Serum levels of HbA1c ≥ 7,0%
3. Age ≥ 18 years
4. Patients with existing cardiovascular disease: coronary heart disease, cerebrovascular disease, peripheral vascular disease, chronic kidney disease of stage III or chronic heart failure of NYHA II or III)
5. Written informed consent prior to study participation

Exclusion Criteria:

1. Type 1 diabetes
2. Treatment with GLP-1 receptor agonists or DPP-4 inhibitors within the last 4 weeks
3. Patients with familiar or personal history of multiple endocrine neoplasia-type 2 or medullary C-cell cancer
4. Renal impairment (eGFR < 30 mL/min)
5. Occurrence of acute vascular events within 6 weeks before screening and randomization
6. Known or suspected hypersensitivity to Liraglutide
7. Pregnant females as determined by positive (serum or urine) hCG test at Screening or prior to dosing. Participants of child-bearing age should use adequate contraception as defined in the study protocol.
8. Lactating females
9. The subject has a history of any other illness, which, in the opinion of the Investigator, might pose an unacceptable risk by administering study medication.
10. The subject received an investigational drug within 30 days prior to inclusion into this study.
11. The subject has any current or past medical condition and/or required medication to treat a condition that could affect the evaluation of the study.
12. The subject is unwilling or unable to follow the procedures outlined in the protocol.
13. The subject is mentally or legally incapacitated.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Liraglutide; Increasing dose of Liraglutide: 0.6 mg/d for the first week, 1.2 mg/d for the second week aiming for a maximum of 1.8 mg/d beginning with the third week (or highest tolerated dose).Subcutaneous injection once daily via pre-filled pen.	Drug: Liraglutide Pen Injector [Victoza]; Increasing dose of Liraglutide: 0.6 mg/d for the first week, 1.2 mg/d for the second week aiming for a maximum of 1.8 mg/d beginning with the third week (or highest tolerated dose).Subcutaneous injection once daily via pre-filled pen
PLACEBO_COMPARATOR: Placebo; Matching Placebo once daily, subcutaneous injection via pre-filled pen.	Drug: Placebo; Matching Placebo once daily, subcutaneous injection via pre-filled pen.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in the metabolomics profile (fold changes) between Liraglutide treatment group and placebo group after 1 and 3 months	Changes in the metabolomics profile (fold changes) between Liraglutide treatment group and placebo group after 1 and 3 months measured by a platform including 2 separate reverse phase (RP)/UPLC-MS/MS with positive ion mode electrospray ionization (ESI), (RP)/UPLC-MS/MS with negative ESI, and (HILIC)/UPLC-MS/MS with negative ESI.	3 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in left ventricular diastolic function	change in left ventricular diastolic function between baseline and after 12 weeks as determined by 2D and 3D parameter global Strain Rate E by echocardiography	3 month
change in left ventricular diastolic function	change in left ventricular diastolic function between baseline and after 12 weeks as determined by standardized parameter E/é and left atrial (LA) volume by echocardiography	3 month
change in left ventricular systolic function	change in left ventricular systolic function by ejection fraction (EF) by echocardiography	3 month
Changes in systolic and diastolic blood pressure (mmHg)	Changes in systolic and diastolic blood pressure (mmHg) between Liraglutide treatment group and placebo group after 1 and 3 months.	3 month
body weight		3 month
Changes in NT-proBNP serum levels (pg/ml)	Changes in NT-proBNP serum levels (pg/ml) between Liraglutide treatment group versus placebo group after 1 and 3 months.	3 month
Differences of the serum lipid profile between Liraglutide treatment group and placebo group	Differences of the serum lipid profile including serum levels of triglycerides (mg/dl), total cholesterol (mg/dl), low-density lipoprotein cholesterol (mg/dl) and high-density lipoprotein cholesterol (mg/dl)between Liraglutide treatment group and placebo group after 1 and 3 months	3 month
changes of serum levels of glucose, HbA1c, glucagon, insulin, C-Peptide, β-Hydroxybutyrate between Liraglutide treatment group and placebo group	Changes in serum levels of glucose (mg/dl), HbA1c (%), glucagon (pg/ml), insulin (ng/ml), C-Peptide (ng/ml), β-Hydroxybutyrate (mmol/l) between Liraglutide treatment group and placebo group after 1 and 3 months	3 month
Heart rate variability	Differences in heart rate variability measured by 24 hour ECG between Liraglutide treatment group and placebo group after 3 month including the following parameters: mean heart rate (bpm), maximum/minimum heart rate (bpm) and long-term variation of RR intervals (defined as standard deviation over 24 hours of per-minute means of RR intervals).	3 month
Resting energy expenditure	Resting energy expenditure measured by indirect calorimetry [CardioCoach CO2]	3 month
Respiratory Exchange Ratio	Respiratory Exchange Ratio measured by indirect calorimetry [CardioCoach CO2]	3 month
Differences in gut microbiome composition measured by 16S rRNA targeted gene sequencing of feces between Liraglutide treatment group and placebo group	Differences in gut microbiome composition measured by 16S rRNA targeted gene sequencing of feces between Liraglutide treatment group and placebo group after 1 and 3 month including the following parameters: alpha diversity (reported as Shannon diversity index) and differences in bacterial composition at different taxonomic levels including genus, family and class of bacteria (reported as relative abundance).	3 month
Albumin excretion	Albumin excretion by 24 h urine collection	3 month
changes in inflammasome analyses	Differences in serum levels of inflammatory cytokines including C-reactive protein (mg/ml), Interleukin 6 (pg/ml), Interleukin 1 beta (pg/ml) and tumor necrosis factor alpha (pg/ml) between Liraglutide treatment group and placebo group after 1 and 3 month	3 month
Differences in circulation inflammatory cell composition by flow cytometry analyses (FACS) between Liraglutide treatment group and placebo group	Differences in circulation inflammatory cell composition by flow cytometry analyses (FACS) between Liraglutide treatment group and placebo group after 1 and 3 month including the following parameters: Numbers of T-cells including T-cell subsets and monocytes including monocyte subsets. Numbers will be reported as percentage of parent, i.e. total pool of CD45+ immune cells).	3 month

Collaborators and Investigators

• Sponsor: RWTH Aachen University
• Collaborators: Novo Nordisk A/S

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): November 1, 2020
• Primary Completion (ANTICIPATED): August 1, 2022
• Study Completion (ANTICIPATED): November 1, 2022

Study Registration Dates

• First Submitted: July 18, 2019
• First Submitted That Met QC Criteria: August 12, 2019
• First Posted (ACTUAL): August 15, 2019

Study Record Updates

• Last Update Posted (ACTUAL): March 10, 2021
• Last Update Submitted That Met QC Criteria: March 9, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Liraglutide; Type 2 Diabetes; Myocardial Infarction; Metabolic Profile; High Cardiovascular Risk
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Liraglutide
• Other Study ID Numbers: 17-162

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No