Effects on Re-endothelialisation With Bydureon Treatment in Type 2 Diabetes Subjects (Rebuild)

Effects on Re-endothelialisation With Bydureon Treatment Add on to Insulin Versus Insulin Alone, Both in Combination With Metformin in Type 2 Diabetic Subjects

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.

Study Overview

• Status: Completed
• Conditions: Diabetes; Atherosclerosis; Restenosis
• Intervention / Treatment: Drug: Bydureon; Drug: Humulin kwickpen; Drug: Metformin

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

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 4

Contacts and Locations

Study Locations

• Sweden
  • Other
    • Stockholm, Other, Sweden, 11883
      • Dept of clinical science and education Karolinska Institutet Södersjukhuset

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bydureon 2 mg Once Weekly; Patients randomised to Bydureon will be treated with Metformin 1g BID, and only receive 10U of Humulin kwickpen QD at bedtime, with no more up-titration of insulin during the study.	Drug: Bydureon; 2 mg Once Weekly; Other Names: Exenatide; Drug: Humulin kwickpen; Humulin kwickpen 10U QD at bedtime; Other Names: Insulin Aspart; Drug: Metformin; Metformin 1g BID; Other Names: Biguanide
Active Comparator: Humulin kwickpen; Patients randomised to the comparator group will be treated with Meformin 1g BID and Humulin kwickpen to reach a fP-glucose level of 6 mmol/l. For that reason patients will be instructed to increase the bedtime Insulin dose of 2-4U every third day until this goal is reached.	Drug: Humulin kwickpen; Humulin kwickpen 10U QD at bedtime; Other Names: Insulin Aspart; Drug: Metformin; Metformin 1g BID; Other Names: Biguanide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The degree of non-covered stent struts by Bydureon add on to Insulin over that of Insulin as analyzed by optical coherence tomography (OCT).	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fractional Flow Reserve (FFR)	FFR is a unitless index calculated as the ratio between distal coronary and aortic pressure during maximum hyperemia.	12 weeks
Coronary Flow velocity Reserve (CRF)	CFR is a unitless index calculated as the ratio between the the mean transit time recorded at maximum hyperemia and at baseline using the thermodilution.	12 weeks
Index of Microcirculatory Resistance (IMR)	IMR is a unitless index calculated by dividing the mean distal coronary pressure by the inverse of the mean transit time recorded using the thermodilution technique during maximum hyperemia	12 weeks
Fractional flow reserve positive re-stenosis		12 weeks
Target lesion failure	Need of unplanned PCI in the treated stenosis or significant re-stenosis in the follow-up	12 weeks
Acute coronary syndrome (ACS) and/or repeat revascularization		12 weeks
Late lumen loss/neointima thickness measured with OCT		12 weeks
Change in minimal lumen area by OCT		12 weeks
Left ventricular systolic and diastolic function assessed by echocardiography		12 weeks
Recovery from endothelial damage, measured by high resolution ultrasound, after PCI	Non-invasive ultrasound over the radialis artery after the PCI procedure using Standard 6-7F guiding catheters.	12 weeks
Plasma markers of endothelial activation i.e., E-Selectin, VCAM-1, ICAM-1, nitrotyrosine levels		12 weeks
Plasma markers of inflammation i.e., CRP, IL-1β, IL-6 and IL-8.		12 weeks
Plasma markers of matrix remodeling enzymes i.e., MMP-2 and MMP9		12 weeks
Circulating endothelial progenitor cells		12 weeks
Gene expression (Affymetrix) e.g., transcription factors of sirtuins (SIRT) and nitric oxide synthase (NOS)		12 weeks

Collaborators and Investigators

• Sponsor: Karolinska Institutet
• Investigators: Principal Investigator: Thomas Nyström, Karolinska Institutet

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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. Erratum In: Am J Physiol Heart Circ Physiol. 2018 Dec 1;315(6):H1861.
• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2015
• Primary Completion (Actual): August 1, 2022
• Study Completion (Actual): October 1, 2022

Study Registration Dates

• First Submitted: November 22, 2015
• First Submitted That Met QC Criteria: December 1, 2015
• First Posted (Estimate): December 3, 2015

Study Record Updates

• Last Update Posted (Actual): April 20, 2023
• Last Update Submitted That Met QC Criteria: April 19, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Optical Coherence Tomography; Cardiac Function; Exenatide; Glucagon-like peptide-1; Endothelialization
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Obesity Agents; Incretins; Insulin Aspart; Metformin; Exenatide; Biguanides
• Other Study ID Numbers: BY2015

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO