The Effect of Liraglutide on the Treatment of Coronary Artery Disease and Type 2 Diabetes

NCT01595789 | Completed Phase 4 DMC

• 2 other identifiers: BBHAH-20114302011-005405-78
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to investigate the effect of combined glucagon-like-peptide-1 (GLP-1) analogue and metformin therapy on glucose metabolic and cardiovascular endpoints compared to metformin monotherapy in patients with coronary artery disease (CAD) and newly diagnosed type 2 diabetes (T2D). It is hypothesized that GLP-1 analogue added to backbone therapy of metformin in CAD patients with T2D will improve beta-cell function, left ventricular ejection fraction (LVEF), heart rate variability and lower 24h blood pressure among other selected endpoints. The present study on CAD patients with newly diagnosed T2D will address these selected endpoints during an investigator initiated, randomized, double blind, crossover, placebo-controlled 12 + 12 weeks intervention study with a 2 week wash-out period.

Conditions

Coronary Artery Disease; Diabetes Mellitus, Type 2

Keywords

Coronary Artery Disease; Diabetes Mellitus; Left ventricular ejection fraction; Beta-cell function

Outcome Measures

Primary Outcomes (2)

• Beta-cell function

  Beta-cell function (disposition index) as measured during an intravenous glucose tolerance test (By Bergman Minimal Model)

  after 12 weeks of intervention

• LVEF

  Changes in LVEF assessed by dobutamine stress echocardiography

  after 12 weeks of intervention

Secondary Outcomes (10)

• Glucagon, incretin, glucose, NEFA, insulin and C-peptide response during meal test

  Baseline (week 0), week 12, week 14, week 26

• Insulin sensitivity (Si), acute insulin and C-peptide response to intravenous glucose (AIRg, ACRg), glucose clearance (Kg), glucose effectiveness (Sg) and hepatic extraction of insulin (HEXi)

  Baseline (week 0), week 12, week 14, week 26

• CRP, TNF-alfa and IL-6 in plasma and gene expression of IL6 and TNF-alfa in subcutaneous fat

  Baseline (week 0), week 12, week 14, week 26

• Non esterified fatty acids (NEFA)

  Baseline (week 0), week 12, week 14, week 26

• Heart rate variability (HRV)

  Baseline (week 0), week 12, week 14, week 26

Study Arms (2)

Placebo + metformin

PLACEBO COMPARATOR

Drug: Placebo

Liraglutide + metformin

ACTIVE COMPARATOR

Drug: Liraglutide

Interventions

Liraglutide DRUG

Liraglutide injection pen is administered by the participant once daily by subcutaneous injection. It is given independent of meals. The starting dose is 0.6 mg. After 2 weeks the dose will be increased to 1.2 mg. The dose will be further increased after 4 weeks to 1.8 mg. After a total of 12 weeks of treatment, a wash-out period of 2 weeks follows. Subsequently, the participant will be crossed over to a second period of 12 weeks of treatment with placebo.

Also known as: Brand name: Victoza, Active substance: liraglutide, EMA Product number: EMEA/H/C/001026, ATC Code: A10BX07

Liraglutide + metformin

Placebo DRUG

Volume-matched placebo injection pen is administered by the participant once daily by subcutaneous injection. It is given independent of meals. The starting dose is 0.6 mg volume-matched placebo. After 2 weeks the dose will be increased to 1.2 mg. The dose will be further increased after 4 weeks to 1.8 mg. After a total of 12 weeks of treatment, a wash-out period of 2 weeks follows. Subsequently, the participant will be crossed over to a second period of 12 weeks of treatment with liraglutide.

Placebo + metformin

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Stable CAD documented by one of the following:
• Previous MI (a minimum of 6 weeks after an acute MI)
• Previous coronary revascularization
• CAD confirmed by an abnormal coronary angiography (CAG) or CT-angiography showing stenosis \> 50% of any major coronary arteries.
• Body mass index (BMI) \>/= 25,0 kg/m2
• Age \>/= 18 years and \</= 85 years
• Type 2 diabetes diagnosed by one of the following criteria:
• HbA1c \>/= 6.5%
• HbA1c \< 6.5 % and fasting plasma glucose \>/= 7.0 mmol/l (confirmed)
• HbA1c \< 6.5 % and a 2 h plasma glucose value during OGTT \>/= 11.1 mmol/l

You may not qualify if:

• Type 1 diabetes mellitus defined as C-peptide \< 450 pM
• Previously diagnosed diabetes mellitus for more than 24 months prior to the screening procedure for this trial, except from gestational diabetes
• Use of more than 2 types of oral antidiabetic medication and/or use of parenteral antidiabetic medication in the period of 3 months prior to the screening visit. It is accepted that the patient continues his usual antidiabetic medication after the screening visit but antidiabetic medication must be discontinued 2 weeks prior to the baseline visit.
• Significant heart disease (NYHA \> 2; Ejection Fraction \< 40% and unstable angina pectoris) and known severe valve disease
• Documented atrial fibrillation or atrial flutter within 6 weeks previous to the screening. Paroxysmal atrial fibrillation is accepted if sinus rhythm is achieved at the screening.
• Uncontrolled arterial hypertension (\> 180/100 mmHg) at the time of screening
• Liver (transaminases greater than x 2 the upper normal level) or renal diseases (eGFR \< 60 ml/min)
• Amylase greater than x 3 the upper reference value
• Any chronic medical condition to unduly increase risk for the potential enrollee as judged by study investigators
• Dysregulated myxedema or hyperthyroid condition defined by a value of TSH \< 0,1 and \> 10,0 milli U/L
• Anemia (\< 85% of lower normal limit), leucopenia (\< 85% of lower normal limit), or thrombocytopenia (\< 85% of lower normal limit)
• Pregnancy or failure to comply with contraception planning within two years, or breastfeeding
• Abuse of alcohol or drugs, or any other co-existing condition that would make patients unsuitable to participate in the study, as judged by the investigators
• Use of immunosuppressive therapy in the preceding 12 months
• Chronic pancreatitis or previous acute pancreatitis

Sponsors & Collaborators

• Haugaard, Steen Bendix, M.D., DMSc: lead

Study Sites (1)

Copenhagen University Hospital, Bispebjerg

Copenhagen, Bispebjerg, 2400, Denmark

Location

Related Publications (6)

• Kumarathurai P, Sajadieh A, Anholm C, Kristiansen OP, Haugaard SB, Nielsen OW. Effects of liraglutide on diastolic function parameters in patients with type 2 diabetes and coronary artery disease: a randomized crossover study. Cardiovasc Diabetol. 2021 Jan 7;20(1):12. doi: 10.1186/s12933-020-01205-2.

  PMID: 33413428 DERIVED

• Anholm C, Kumarathurai P, Jurs A, Pedersen LR, Nielsen OW, Kristiansen OP, Fenger M, Holst JJ, Madsbad S, Sajadieh A, Haugaard SB. Liraglutide improves the beta-cell function without increasing insulin secretion during a mixed meal in patients, who exhibit well-controlled type 2 diabetes and coronary artery disease. Diabetol Metab Syndr. 2019 May 31;11:42. doi: 10.1186/s13098-019-0438-6. eCollection 2019.

  PMID: 31164926 DERIVED

• Kumarathurai P, Anholm C, Fabricius-Bjerre A, Nielsen OW, Kristiansen O, Madsbad S, Haugaard SB, Sajadieh A. Effects of the glucagon-like peptide-1 receptor agonist liraglutide on 24-h ambulatory blood pressure in patients with type 2 diabetes and stable coronary artery disease: a randomized, double-blind, placebo-controlled, crossover study. J Hypertens. 2017 May;35(5):1070-1078. doi: 10.1097/HJH.0000000000001275.

  PMID: 28129251 DERIVED

• Kumarathurai P, Anholm C, Larsen BS, Olsen RH, Madsbad S, Kristiansen O, Nielsen OW, Haugaard SB, Sajadieh A. Effects of Liraglutide on Heart Rate and Heart Rate Variability: A Randomized, Double-Blind, Placebo-Controlled Crossover Study. Diabetes Care. 2017 Jan;40(1):117-124. doi: 10.2337/dc16-1580. Epub 2016 Oct 19.

  PMID: 27797930 DERIVED

• Kumarathurai P, Anholm C, Nielsen OW, Kristiansen OP, Molvig J, Madsbad S, Haugaard SB, Sajadieh A. Effects of the glucagon-like peptide-1 receptor agonist liraglutide on systolic function in patients with coronary artery disease and type 2 diabetes: a randomized double-blind placebo-controlled crossover study. Cardiovasc Diabetol. 2016 Jul 26;15(1):105. doi: 10.1186/s12933-016-0425-2.

  PMID: 27455835 DERIVED

• Anholm C, Kumarathurai P, Klit MS, Kristiansen OP, Nielsen OW, Ladelund S, Madsbad S, Sajadieh A, Haugaard SB; AddHope2 Trial Study Group. Adding liraglutide to the backbone therapy of biguanide in patients with coronary artery disease and newly diagnosed type-2 diabetes (the AddHope2 study): a randomised controlled study protocol. BMJ Open. 2014 Jul 16;4(7):e005942. doi: 10.1136/bmjopen-2014-005942.

  PMID: 25031198 DERIVED

MeSH Terms

Conditions

Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetes Mellitus

Interventions

Liraglutide

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Glucagon-Like Peptide 1; Glucagon-Like Peptides; Proglucagon; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Steen B Haugaard, M.D., DMSc

  Amager Hospital

  STUDY DIRECTOR

• Ahmad Sajadieh, M.D., DMSc

  University Hospital Bispebjerg and Frederiksberg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDIV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 8, 2012
• First Posted: May 10, 2012
• Study Start: May 1, 2012
• Primary Completion: October 1, 2014
• Study Completion: July 1, 2015
• Last Updated: March 7, 2017

Record last verified: 2017-03

Locations

DK (1)