Clinical trial NCT02621489: Effects on Re-endothelialisation With Bydureon Treatment in Type 2 Diabetes Subjects
Official title: Effects on Re-endothelialisation With Bydureon Treatment Add on to Insulin Versus Insulin Alone, Both in Combination With Metformin in Type 2 Diabetic Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Atherosclerosis
Diabetes
Restenosis
Keywords: Glucagon-like peptide-1
Endothelialization
Cardiac Function
Exenatide
Optical Coherence Tomography
Lead sponsor: Karolinska Institutet
Sponsor class: OTHER
First posted: 2015-12-03
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The aim of the study is to use Exenatide long-acting release (LAR) \[Bydureon\] to minimize vascular remodeling and neointima formation after Percutaneous Coronary Intervention (PCI) and to accelerate stent endothelialisation.

Detailed description: Exenatide LAR will be given as a once-weekly (s.c.) dose of Bydureon (2 mg) add on to Insulin in combination with Metformin. If patients are Insulin naïve (both groups) an initial dose of 10U (s.c.) at bedtime will be started, and further up-titrated to achieve a fP-glucose levels at 6 mmol/l. Standard care for post myocardial infarction will be given after PCI.

Primary objectives:

To test whether Bydureon, add on to Insulin Neutral Protamine Hagedorn (NPH) + Metformin, is superior vs. Insulin NPH + Metformin alone, in covered stent struts

Secondary objectives:

To test whether Bydureon, add on to Insulin NPH + Metformin, is superior vs. Insulin NPH + Metformin alone: in cardiac and endothelial functions

Eligibility criteria: Inclusion Criteria:

1. Patients eligible for PCI with application of DES, due to ACS.
2. Patients with known or newly diagnosed T2D (type 2 diabetes is diagnosed according to current WHO criteria or by the use of anti-diabetic drugs)
3. Male and female subjects 18-80 years.
4. HbA1c (accordingly to IFCC) 47 mmol/mol - 110 mmol/mol.
5. Signed informed consent form.

Exclusion Criteria:

1. Type 1 diabetes (autoantibody positive).
2. Any history of receiving GLP-1 analogues or dipeptidyl peptidase inhibitors within 6 months
3. Known severe heart failure, classified as NYHA 4.
4. Active myocarditis; malfunctioning artificial heart valve.
5. History of ventricular tachycardia within 3 months before study entry; second- or third-degree atrioventricular block.
6. Supine systolic blood pressure \<85 mm Hg or \>200 mm Hg at screening.
7. Primary renal impairment, creatinine clearance \< 45 ml/min if treated with metformin.
8. Uncorrected hypokalemia or hyperkalemia (potassium \<3.5 mmol/l or \>5.5 mmol/l).
9. Significant anemia (Hb \< 90 g/l)
10. Severe gastrointestinal disease, including gastroparesis. As judged by the Investigator.
11. Body mass index (BMI) \> 45 kg/m2.
12. Malignant neoplasm requiring chemotherapy, surgery, radiation or palliative therapy in the previous 5 years. Patients with intraepithelial squamous cell carcinoma of the skin treated with topical 5FU and subjects with basal cell skin cancer are allowed to enter the trial.
13. Females of child bearing potential who are pregnant, breast-feeding or intend to become pregnant.
14. Current drug and alcohol abuse.
15. History of acute or chronic pancreatitis
16. Subjects considered by the Investigator to be unsuitable for the study.

Primary outcomes:
measure: The degree of non-covered stent struts by Bydureon add on to Insulin over that of Insulin as analyzed by optical coherence tomography (OCT).
timeFrame: 12 weeks
Secondary outcomes:
measure: Fractional Flow Reserve (FFR)
timeFrame: 12 weeks
measure: Coronary Flow velocity Reserve (CRF)
timeFrame: 12 weeks
measure: Index of Microcirculatory Resistance (IMR)
timeFrame: 12 weeks
measure: Fractional flow reserve positive re-stenosis
timeFrame: 12 weeks
measure: Target lesion failure
timeFrame: 12 weeks
measure: Acute coronary syndrome (ACS) and/or repeat revascularization
timeFrame: 12 weeks
measure: Late lumen loss/neointima thickness measured with OCT
timeFrame: 12 weeks
measure: Change in minimal lumen area by OCT
timeFrame: 12 weeks
measure: Left ventricular systolic and diastolic function assessed by echocardiography
timeFrame: 12 weeks
measure: Recovery from endothelial damage, measured by high resolution ultrasound, after PCI
timeFrame: 12 weeks
measure: Plasma markers of endothelial activation i.e., E-Selectin, VCAM-1, ICAM-1, nitrotyrosine levels
timeFrame: 12 weeks
measure: Plasma markers of inflammation i.e., CRP, IL-1β, IL-6 and IL-8.
timeFrame: 12 weeks
measure: Plasma markers of matrix remodeling enzymes i.e., MMP-2 and MMP9
timeFrame: 12 weeks
measure: Circulating endothelial progenitor cells
timeFrame: 12 weeks
measure: Gene expression (Affymetrix) e.g., transcription factors of sirtuins (SIRT) and nitric oxide synthase (NOS)
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Stockholm
country: Sweden
facility: Dept of clinical science and education Karolinska Institutet Södersjukhuset
state: Other
Study officials:
affiliation: Karolinska Institutet
name: Thomas Nyström
role: PRINCIPAL_INVESTIGATOR
References:
citation: Eriksson L, Saxelin R, Rohl S, Roy J, Caidahl K, Nystrom T, Hedin U, Razuvaev A. Glucagon-Like Peptide-1 Receptor Activation Does not Affect Re-Endothelialization but Reduces Intimal Hyperplasia via Direct Effects on Smooth Muscle Cells in a Nondiabetic Model of Arterial Injury. J Vasc Res. 2015;52(1):41-52. doi: 10.1159/000381097. Epub 2015 May 7.
citation: Erdogdu O, Eriksson L, Xu H, Sjoholm A, Zhang Q, Nystrom T. Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways. J Mol Endocrinol. 2013 Mar 18;50(2):229-41. doi: 10.1530/JME-12-0166. Print 2013 Apr.
citation: Erdogdu O, Nathanson D, Sjoholm A, Nystrom T, Zhang Q. Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA- and PI3K/Akt-dependent pathways and requires GLP-1 receptor. Mol Cell Endocrinol. 2010 Aug 30;325(1-2):26-35. doi: 10.1016/j.mce.2010.04.022. Epub 2010 May 7.
citation: Erdogdu O, Eriksson L, Nystrom T, Sjoholm A, Zhang Q. Exendin-4 restores glucolipotoxicity-induced gene expression in human coronary artery endothelial cells. Biochem Biophys Res Commun. 2012 Mar 23;419(4):790-5. doi: 10.1016/j.bbrc.2012.02.106. Epub 2012 Feb 27.
citation: Nystrom T, Gutniak MK, Zhang Q, Zhang F, Holst JJ, Ahren B, Sjoholm A. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab. 2004 Dec;287(6):E1209-15. doi: 10.1152/ajpendo.00237.2004. Epub 2004 Sep 7.
citation: Dokken BB, Piermarini CV, Teachey MK, Gura MT, Dameff CJ, Heller BD, Krate J, Ashgar AM, Querin L, Mitchell JL, Hilwig RW, Kern KB. Glucagon-like peptide-1 preserves coronary microvascular endothelial function after cardiac arrest and resuscitation: potential antioxidant effects. Am J Physiol Heart Circ Physiol. 2013 Feb 15;304(4):H538-46. doi: 10.1152/ajpheart.00282.2012. Epub 2012 Dec 15.
citation: Guagliumi G, Sirbu V, Bezerra H, Biondi-Zoccai G, Fiocca L, Musumeci G, Matiashvili A, Lortkipanidze N, Tahara S, Valsecchi O, Costa M. Strut coverage and vessel wall response to zotarolimus-eluting and bare-metal stents implanted in patients with ST-segment elevation myocardial infarction: the OCTAMI (Optical Coherence Tomography in Acute Myocardial Infarction) Study. JACC Cardiovasc Interv. 2010 Jun;3(6):680-7. doi: 10.1016/j.jcin.2010.04.005.