C Myocardial stress perfusion and energetics improves in patients with type 2 diabetes after treatment with a Glucagon like peptide-1 receptor agonist (Liraglutide)- A randomised, single centre, open label, cross-over drug trial
Year: 2023
Type: conference-paper
Study designs: Randomized Controlled Trial, Clinical Trial
Abstract: Both the insulin secretion and insulin resistance in Type 2 diabetes (T2D) are amenable to pharmacological intervention. In a single center, open-label, randomized, cross-over design trial we sought to compare two distinct glycaemic control strategies of promoting insulin secretion using Glucagon-like peptide-1 receptor agonists (GLP-1RA) -liraglutide and targeting peripheral insulin resistance using a peroxisome proliferator activated receptor-gamma agonist (PPAR-γ)-pioglitazone to compare improvements in myocardial perfusion and energetics in patients with T2D. Four hundred and forty-seven participants were screened and the eligible patients were randomized in a 1:1 ratio to the study drugs for a 16-week treatment period followed by an 8-week washout and a further 16-week treatment period for the second drug. Participants underwent rest and dobutamine-stress 31phosphorus magnetic resonance spectroscopy followed by the cardiac magnetic resonance (CMR) scans – four scans in total. Liraglutide resulted in significant weight loss of 1.7kg and significant improvements in glycaemic control. The improvement in glycaemic control was significantly higher with liraglutide (p=0.03) and only liraglutide led to significant reductions in fasting blood glucose. Pioglitazone led to a significant increment in LV mass. Liraglutide therapy resulted in increased rest and dobutamine stress energetics, global stress myocardial blood flow and myocardial perfusion reserve (MPRI). With pioglitazone treatment, only an isolated improvement in the rest diastolic function was observed. In this study we showed for the first time that treatment with liraglutide results in significant improvements in myocardial perfusion and energetics. Pioglitazone results in significant increases in LV mass and an improvement in rest diastolic function. Main Text Introduction Type 2 diabetes is characterized by dysregulated insulin secretion and resistance to insulin action. People with T2D are two to three times more likely to die from cardiovascular causes than people with no history of diabetes even after controlling for other cardiovascular risk factors, making it the leading cause of morbidity and mortality in this population. Heart failure (HF) is a leading cardiovascular complication of diabetes(1, 2) with a 2.5-fold increased risk of developing HF in patients with T2D. While strict risk factor control was shown to significantly diminish the vascular complications of T2D with no excess risk of death, myocardial infarction, or stroke, as compared with the general population, the same benefit was not seen in heart failure hospitalisations(3). It is therefore imperative to identify effective strategies that prevent heart failure in T2D. Both the insulin secretion and insulin resistance are amenable to pharmacological intervention. Glucagon-like peptide-1 receptor activation promotes insulin secretion, causes weight loss and is an important pharmacological target in T2D with a proven cardiovascular safety profile and beneficial cardiovascular outcomes(4, 5). Pioglitazone is a widely used peroxisome proliferator activated receptor gamma agonist which targets peripheral insulin sensitivity. Meta-analyses of prior randomized trials studying the risk of cardiovascular events have demonstrated a significant reduction in the risk of all-cause mortality with pioglitazone use(6). In a single center, open-label, randomized, cross-over design trial we sought to compare the efficacies of two distinct glycemic control strategies of 1) targeting beta-cell dysfunction (liraglutide), 2) insulin resistance (pioglitazone) results in greater improvements in myocardial perfusion, energetics and function in T2D patients. Methods Eligible participants with T2D and no known prior cardiovascular disease were randomized in a 1:1 ratio to the study drugs for a 16-week treatment period followed by an 8-week washout and a further 16-week treatment period for the second drug (figure 1). At each visit, participants underwent full history, clinical examination, anthropometric measurements, blood tests, 12 lead ECG in addition to rest and dobutamine stress 31phosphorus magnetic resonance spectroscopy followed by the cardiac magnetic resonance (CMR) scans. The CMR protocol consisted of rest and dobutamine stress cine imaging, perfusion imaging (motion corrected, automated in-line perfusion mapping), velocity-encoded mitral in-flow imaging and late gadolinium enhanced imaging at 3T immediately before commencement and after completion of each treatment arm (four scans per participant). Intravenous dobutamine was delivered peripherally, at incremental doses (10 to 40 µg/kg/min as necessary to achieve 65% of the age-predicted maximal heart rate. Average infusion time was 18 mins. Homeostasis model of insulin resistance (HOMA-IR), calculated as fasting serum insulin (µU/L) × fasting plasma glucose (mmol l-1)/22.5 and Triglyceride index (ln [fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2] were calculated as validated surrogate markers of insulin resistance from fasting blood samples. Results A total of 447 patients were assessed for eligibility (figure 3). Out of these 400 were excluded (figure 3). Out of the remaining 47 participants, six participants either did not tolerate the scan or showed evidence of prior MI on the initial CMR. The remaining 41 participants were randomized to the pioglitazone-first arm (n=19) or the liraglutide-first arm (n=22). In the pioglitazone-first arm three participants discontinued therapy due to the side effect of weight gain and mild ankle swelling. These symptoms resolved promptly with the discontinuation of the medication. In the liraglutide-first arm, three participants discontinued therapy due to gastrointestinal symptoms of nausea and fullness and therefore discontinued the medication. A total of 19 participants were commenced on the pioglitazone-second arm and 16 participants were commenced on the liraglutide-second arm. In the pioglitazone-second arm, all the 19 participants completed 16-week treatment course whereas in liraglutide-second arm 13 participants completed the 16-week course of treatment (3 participants discontinued the treatment due to gastrointestinal side effects of nausea and fullness). Liraglutide therapy resulted in significant reductions in the body mass index, with average weight loss of 1.7kg and significant improvements in glycaemic control (table 1; figure 2). The improvement in glycaemic control was significantly higher with liraglutide compared to pioglitazone (p=0.03) and only liraglutide led to significant reductions in fasting blood glucose (figure 2). Pioglitazone led to a significant increment in LV mass, while no such effect was detected with liraglutide. Liraglutide therapy resulted in increased rest and dobutamine stress energetics, global stress myocardial blood flow and myocardial perfusion reserve (MPRI) (table 2; figure 3). With pioglitazone treatment, only an isolated improvement in the rest diastolic function was observed (table 2). Conclusions In this randomised cross-over study we showed for the first time that four months treatment with GLP-1RA (liraglutide) results in significant improvements in myocardial perfusion and energetics, while the insulin sensitiser pioglitazone shows no effect in modulation of these parameters. Pioglitazone results in significant increases in LV mass and an improvement in rest diastolic function References Kannel WB, McGee DL. Diabetes and cardiovascular disease: The framingham study. JAMA. 1979;241(19):2035-8. WHO. Fact sheet no 310; the top 10 causes of death, updated May 2014. World Health Organization, Geneva. Rawshani A, Rawshani A, Franzén S, Sattar N, Eliasson B, Svensson A-M, et al. Risk Factors, Mortality, and Cardiovascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine. 2018;379(7):633-44. DeFronzo RA. From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus. Diabetes. 2009;58(4):773-95. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine. 2016;375(4):311-22. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and Risk of Cardiovascular Events in Patients With Type 2 Diabetes MellitusA Meta-analysis of Randomized Trials. JAMA. 2007;298(10):1180-8. Statement of Contribution The first author – Amrit Chowdhary was involved in the ethics submission, recruited every participant, conducted the study visits, performed all the spectroscopy scans, supervised the dobutamine scans, analysed the scans, did the statistics and data interpretation, and wrote up the manuscript. ST, NJ, SA, SK, MG, HP helped with the study visits and review of the manuscript. PK, SP and JPG helped with data interpretation and reviewed the manuscript. EL designed the study, applied for ethics, helped with setting up recruitment pathways, statistics analysis, data interpretation and reviewed the manuscript.
Institution: University of Leeds
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4384567716