Abstract
BackgroundIncretin therapies appear to provide cardioprotection and improve cardiovascular outcomes in patients with diabetes, but the mechanism of this effect remains elusive. We have previously shown that glucagon-like peptide (GLP)-1 is a coronary vasodilator and we sought to investigate if this is an adenosine-mediated effect.MethodsWe recruited 41 patients having percutaneous coronary intervention (PCI) for stable angina and allocated them into four groups administering a specific study-related infusion following successful PCI: GLP-1 infusion (Group G) (n = 10); Placebo, normal saline infusion (Group P) (n = 11); GLP-1 + Theophylline infusion (Group GT) (n = 10); and Theophylline infusion (Group T) (n = 10). A pressure wire assessment of coronary distal pressure and flow velocity (thermodilution transit time—Tmn) at rest and hyperaemia was performed after PCI and repeated following the study infusion to derive basal and index of microvascular resistance (BMR and IMR).ResultsThere were no significant differences in the demographics of patients recruited to our study. Most of the patients were not diabetic. GLP-1 caused significant reduction of resting Tmn that was not attenuated by theophylline: mean delta Tmn (SD) group G − 0.23 s (0.27) versus group GT − 0.18 s (0.37), p = 0.65. Theophylline alone (group T) did not significantly alter resting flow velocity compared to group GT: delta Tmn in group T 0.04 s (0.15), p = 0.30. The resulting decrease in BMR observed in group G persisted in group GT: − 20.83 mmHg s (24.54 vs. − 21.20 mmHg s (30.41), p = 0.97. GLP-1 did not increase circulating adenosine levels in group GT more than group T: delta median adenosine − 2.0 ng/ml (− 117.1, 14.8) versus − 0.5 ng/ml (− 19.6, 9.4); p = 0.60.ConclusionThe vasodilatory effect of GLP-1 is not abolished by theophylline and GLP-1 does not increase adenosine levels, indicating an adenosine-independent mechanism of GLP-1 coronary vasodilatation.Trial registration: The local research ethics committee approved the study (National Research Ethics Service-NRES Committee, East of England): REC reference 14/EE/0018. The study was performed according to institutional guidelines, was registered on http://www.clinicaltrials.gov (unique identifier: NCT03502083) and the study conformed to the principles outlined in the Declaration of Helsinki.
Highlights
Incretin therapies appear to provide cardioprotection and improve cardiovascular outcomes in patients with diabetes, but the mechanism of this effect remains elusive
Exclusion criteria included any severe co-morbidity with expected life expectancy < 6 months; use of warfarin, nicorandil, glibenclamide, sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, exenatide, liraglutide, lixisenatide and insulin use; women of child-bearing age; breast-feeding women; myocardial infarction within the previous 3 months in a remote territory; heart failure with ejection fraction < 50%; deranged renal function with eGFR < 60 ml/min/1.73 m2 by Modification of Diet in Renal Disease (MDRD); deranged liver function with alanine transaminase (ALT) > 3 times upper limit of normal; active peptic ulcer disease confirmed on endoscopy; history of seizures; history of tachyarrhythmias; patients already taking oral theophylline; allergy to theophylline or caffeine
Statistical analysis On the basis of previous data, we calculated that 10-paired data sets would provide 80% power to detect a clinically significant difference (ΔBMR, 20 mmHg s; SD, 15 mmHg s) after administration of glucagonlike peptide (GLP)‐1
Summary
Incretin therapies appear to provide cardioprotection and improve cardiovascular outcomes in patients with diabetes, but the mechanism of this effect remains elusive. We have previously shown that glucagonlike peptide (GLP)-1 is a coronary vasodilator and we sought to investigate if this is an adenosine-mediated effect. Endothelium-dependent vasodilation and microvascular coronary flow are frequently abnormal in patients with diabetes [2] and both are partly responsible for the observed increased cardiac morbidity and mortality in patients with diabetes mellitus. GLP-1, as well as its analogues, such as semaglutide and liraglutide, improve long-term cardiovascular outcomes with reduction in myocardial infarction and cardiovascular death for patients with diabetes [3, 6, 8]. The underlying mechanism of these of target GLP-1 effects is not well understood [11], the GLP-1 receptor is expressed in heart tissue and in particular on vascular smooth muscle cells [12]
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