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

Diabetes Clinical Trial

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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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02621489
• Other study ID #: BY2015
• Status: Completed
• Phase: Phase 4
• Start date: December 2015
• Est. completion date: October 2022

Study information

• Verified date: April 2023
• Source: Karolinska Institutet
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 38
• Est. completion date: October 2022
• Est. primary completion date: August 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Atherosclerosis
• Diabetes
• Restenosis

Intervention

Drug:
• Bydureon
2 mg Once Weekly
• Humulin kwickpen
Humulin kwickpen 10U QD at bedtime
• Metformin
Metformin 1g BID

Locations

Country	Name	City	State
Sweden	Dept of clinical science and education Karolinska Institutet Södersjukhuset	Stockholm	Other

Sponsors (1)

Lead Sponsor	Collaborator
Karolinska Institutet

Country where clinical trial is conducted

Sweden, 

References & Publications (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: poten — View 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 — View 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. — View 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) — View 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 M — View 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-segm — View 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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Fractional Flow Reserve (FFR)	FFR is a unitless index calculated as the ratio between distal coronary and aortic pressure during maximum hyperemia.	12 weeks
Secondary	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
Secondary	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
Secondary	Fractional flow reserve positive re-stenosis		12 weeks
Secondary	Target lesion failure	Need of unplanned PCI in the treated stenosis or significant re-stenosis in the follow-up	12 weeks
Secondary	Acute coronary syndrome (ACS) and/or repeat revascularization		12 weeks
Secondary	Late lumen loss/neointima thickness measured with OCT		12 weeks
Secondary	Change in minimal lumen area by OCT		12 weeks
Secondary	Left ventricular systolic and diastolic function assessed by echocardiography		12 weeks
Secondary	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
Secondary	Plasma markers of endothelial activation i.e., E-Selectin, VCAM-1, ICAM-1, nitrotyrosine levels		12 weeks
Secondary	Plasma markers of inflammation i.e., CRP, IL-1ß, IL-6 and IL-8.		12 weeks
Secondary	Plasma markers of matrix remodeling enzymes i.e., MMP-2 and MMP9		12 weeks
Secondary	Circulating endothelial progenitor cells		12 weeks
Secondary	Gene expression (Affymetrix) e.g., transcription factors of sirtuins (SIRT) and nitric oxide synthase (NOS)		12 weeks