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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.
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Bydureon 2 mg Once Weekly | Experimental | 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. |
|
| Humulin kwickpen | Active Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Bydureon | Drug | 2 mg Once Weekly |
|
|
| Measure | Description | 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 |
| 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) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Thomas Nyström | Karolinska Institutet | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Dept of clinical science and education Karolinska Institutet Södersjukhuset | Stockholm | Other | 11883 | Sweden |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25966620 | Result | 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. | |
| 23343509 |
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| ID | Term |
|---|---|
| D050197 | Atherosclerosis |
| D003920 | Diabetes Mellitus |
| ID | Term |
|---|---|
| D001161 | Arteriosclerosis |
| D001157 | Arterial Occlusive Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D000077270 | Exenatide |
| D061267 | Insulin Aspart |
| D008687 | Metformin |
| D001645 | Biguanides |
| ID | Term |
|---|---|
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D014688 | Venoms |
| D045424 | Complex Mixtures |
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| Humulin kwickpen | Drug | Humulin kwickpen 10U QD at bedtime |
|
|
| Metformin | Drug | Metformin 1g BID |
|
|
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 |
| 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. |
| 20452396 | Result | 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. |
| 22390929 | Result | 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. |
| 15353407 | Result | 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. |
| 23241323 | Result | 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. |
| 20630463 | Result | 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. |
| 38066597 | Derived | Santos-Pardo I, Witt N, Angeras O, Nystrom T. Effects of exenatide on coronary stent's endothelialization in subjects with type 2 diabetes: a randomized controlled trial. The Rebuild study. Cardiovasc Diabetol. 2023 Dec 8;22(1):337. doi: 10.1186/s12933-023-02071-4. |
| D044882 |
| Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
| D014118 |
| Toxins, Biological |
| D001685 | Biological Factors |
| D061266 | Insulin, Short-Acting |
| D061385 | Insulins |
| D010187 | Pancreatic Hormones |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |