The Cardiovascular Effect of GLP-1 Agonist, SGLT2 Inhibitor and Their Combination

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

The Effect of GLP-1 Agonist, SGLT2 Inhibitor and Their Combination on Endothelial Function, Arterial Stiffness and Left Ventricular Deformation in Patients With Type 2 Diabetes With High Cardiovascular Risk

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03878706
• Other study ID #: 2790/03-11-2017
• Status: Recruiting
• Start date: November 3, 2017
• Est. completion date: June 30, 2027

Study information

• Verified date: March 2024
• Source: University of Athens
• Contact: Ignatios Ikonomidis, Prof.
• Phone: 00306944805732
• Email: ignoik[@]gmail.com
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

A. Four groups of patients with type 2 diabetes mellitus with high or very high cardiovascular risk will be studied before and at 6 and 12 months of treatment: - 60 patients treated with a combination of GLP1 analogue and SGLT2 inhibitor ± metformin - 60 patients treated with GLP-1 agonist as a second step after metformin - 60 patients treated with SGLT2 inhibitor as a second step after metformin - 60 patients treated with a combination of insulin and other antidiabetic agents (metformin - DPP4 inhibitors) Individuals will be equal distributed as far as age, gender and body mass index concerned. In addition, patients suffered from kidney disease and retinopathy are excluded.

Description:

Disordered glucose tolerance in patients with type 2 diabetes mellitus is multifactorial and includes dysfunction not only of β-cells of the pancreas, liver and muscles, but also of the adipose tissue, gastrointestinal tract, kidney, α-cells of the pancreas and the brain. Therefore, it is likely that the use of drugs that act on multiple aspects of the pathophysiology of diabetes will have beneficial effects on glycemic control and outcome of patients.In addition to the many possible causes of glucose deregulation, people with type 2 diabetes have comorbidities such as hypertension, hyperlipidemia and obesity resulting in increased cardiovascular risk. Optimal treatment of hyperglycaemia and cardiovascular risk factors is necessary to reduce adverse events. Although the initial approach is the modification of dietary factors (physical activity, diet, smoking cessation), the progressive nature of type 2 diabetes ultimately leads to the use of multiple therapies. Guidelines for the treatment of patients with type 2 diabetes with high HbA1c are initial double-combined therapy or triple combination if glycemic control is not achieved after 3 months. Although insulin is usually included in such combinations, additional treatment options are required for patients with high HbA1c who also need to lose weight and avoid hypoglycaemia. It is likely that the outcome of patients could be improved by using drugs targeting different aspects of the disease (glycemia, body weight, blood pressure, lipids). Over the last decade, two classes of antidiabetic drugs have been added to weight loss, improved cardiovascular risk factors and a low risk of hypoglycemia: glucagon-like peptide-1 agonists (GLP-1, glucagon like peptide-1) and inhibitors of the sodium glucose subtype 2 (SGLT2, sodium-glucose co-transporters). Recent studies have shown that these two drugs have cardioprotective effects possibly through different mechanisms of action, while their complementary mechanical, pharmacological and clinical effects make their combination (in addition to metformin) potentially beneficial in type 2 diabetes patients. Specifically, SGLT2 inhibitors manifest their cardioprotective activity by improving hemodynamic parameters, while GLP-1 agonists through antiatherogen / anti-inflammatory mechanisms. The increased arterial stiffness with the associated increase in the range of reflected pressure waves, determines not only the augmentation of systolic pressure but also the rate of increase which depends on age. Increased levels of pulse pressure (indirect atherosclerotic index) and pulse wave velocity (PWV), a reliable measure of arterial stiffness, predict future cardiovascular events. Endothelial dysfunction is associated with the presence of atherosclerosis and is also considered as an indicator of the early changes preceding it. The role of impaired endothelial function of large arteries seems to be significant in the pathogenesis of cardiovascular disease. Endothelial glycocalyx is a glycoprotein layer that covers the surface of endothelial cells and regulates arterial wall permeability and the interaction of endothelial cells with circulating blood cells. Inflammatory or atherogenic stimuli, such as hyperglycemia, lead to glucocalyx disorder and increased vascular sensitivity to further atherogenic stimuli. The two-dimensional speckle tracking ultrasound allows accurate estimation of left ventricular distortion, which is disordered in diabetics in relation to healthy subjects. Hypothesis of the proposed study: Endothelial function, arterial stiffness and left ventricular deformation are improved in patients with type 2 diabetes with high cardiovascular risk treated with GLP-1 agonist and SGLT2 inhibitor compared to either one or both combination of insulin and other antidiabetic tablets. Aim of the study: The aim of this study is to investigate the effect of GLP-1 agonist, SGLT2 inhibitor and their combination on endothelial function, arterial stiffness, central hemodynamic characteristics and left ventricular deformation in patients with type 2 diabetes with high or very high cardiovascular risk and compared with the combination of insulin and other antidiabetic tablets. Materials and methods : A. Four groups of patients with type 2 diabetes mellitus with high or very high cardiovascular risk will be studied before and at 6 and 12 months of treatment: - 60 patients treated with a combination of GLP1 analogue and SGLT2 inhibitor ± metformin - 60 patients treated with GLP-1 agonist as a second step after metformin - 60 patients treated with SGLT2 inhibitor as a second step after metformin - 60 patients treated with a combination of insulin and other antidiabetic agents (metformin - DPP4 inhibitors) Individuals will be equal distributed as far as age, gender and body mass index concerned. In addition, patients suffered from kidney disease and retinopathy are excluded. B. All patients will be submitted to an echocardiographic study in order to estimate the total left ventricular and atrial myocardial global longitudinal strain (GLS) as well as the twisting-untwisting of the left ventricle using speckle tracking imaging. In addition, pulse wave velocity (PWV, measured in m/s), pulse wave augmentation index [AIx %, which is calculated by the formula (P2-P1)/PP x 100, where P1 stands for peak systolic pressure, P2 stands for second peak systolic pressure due to wave reflection and PP stands for Pulse Pressure ], central systolic blood pressure (SBPao, measured in mm Hg) and central pulse pressure (PPao, measured ) with Arteriograph, Mobilograph and Complior, and perfused boundary region (PBR) of sublingual vessels (5-25 μm in size) using a high-resolution camera with Sideview Darkfield Imaging technique (Microscan, Glucockeck). PBR consists the cell-free space which is formed from the separation of red blood cells from plasma at the surface of the endothelial glycocalyx. Increased PBR is considered to be an accurate indicator of the reduction of endothelial glycocalyx thickness due to plasma penetration into the glycocalyx. Μalondialdehyde (MDA), protein carbonyls (PC) as oxidative stress markers, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, thrombomodulin, nitrites and nitrates, N-terminal pro B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, blood glucose, glycosylated hemoglobin HbA1c and a full lipidemic profile will be measured before and at 6 months and at 12 months of treatment. The examination will be carried out at the Laboratory of Preventive Cardiology of the 2nd Department of Cardiology of the University of Athens at "Attikon" Hospital. Τhe investigators will also compare the participants with history of coronary artery disease with those without hisotry of coronary artery disease. C. For the statistical analysis of the results, the significance of each intervention will be measured by t-test and the 4 groups will be compared by ANOVA (post-hoc comparisons with Bonferroni correction). Non-parametric tests will be used for non-Gaussian distributions. Forty individuals should be included in each group in order the results being statistically significant. In a previous study, myocardial global longitudinal strain of the left ventricle showed normal distribution with standard deviation 10. A true difference in mean left ventricular myocardial distortion between the intervention group (GLP-1 agonist compined with SGLT2 inhibitor) and a control one (combination of insulin and other antidiabetic tablets) which is calculated of -6.344% or 6.344% will be calculated with probability 0.8. The probability of a type I error if the null hypothesis is that the mean difference between the two groups is equal, is equivalent to 0.05. Significance/future prospects: This study is expected to open the horizons of better understanding the cardiovascular benefits of GLP-1 agonist, SGLT2 inhibitor and their combination in patients with type 2 diabetes mellitus. Moreover, the contribution of the investigator's results, in a clinical-level could be the use of new drug therapies that reduce both microvascular complications by reducing glycemia and macrovascular complications (myocardial infarction, stroke, cardiovascular mortality) as the first treatment line in patients with type 2 diabetes with high or very high cardiovascular risk.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 240
• Est. completion date: June 30, 2027
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 45 Years to 80 Years

Eligibility

Inclusion Criteria:

• Subject has type 2 diabetes mellitus
• Subject has high or very high cardiovascular risk

Exclusion Criteria:

• Subject has type 1 diabetes mellitus
• Subject has kidney disease
• Subject has retinopathy

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2

Locations

Country	Name	City	State
Greece	"Attikon" University General Hospital	Athens	Attiki

Sponsors (1)

Lead Sponsor	Collaborator
University of Athens

Country where clinical trial is conducted

Greece, 

References & Publications (23)

American Diabetes Association. 7. Approaches to Glycemic Treatment. Diabetes Care. 2016 Jan;39 Suppl 1:S52-9. doi: 10.2337/dc16-S010. No abstract available. — View Citation

Avolio AP, Deng FQ, Li WQ, Luo YF, Huang ZD, Xing LF, O'Rourke MF. Effects of aging on arterial distensibility in populations with high and low prevalence of hypertension: comparison between urban and rural communities in China. Circulation. 1985 Feb;71(2 — View Citation

Chae CU, Pfeffer MA, Glynn RJ, Mitchell GF, Taylor JO, Hennekens CH. Increased pulse pressure and risk of heart failure in the elderly. JAMA. 1999 Feb 17;281(7):634-9. doi: 10.1001/jama.281.7.634. — View Citation

Domanski M, Norman J, Wolz M, Mitchell G, Pfeffer M. Cardiovascular risk assessment using pulse pressure in the first national health and nutrition examination survey (NHANES I). Hypertension. 2001 Oct;38(4):793-7. doi: 10.1161/hy1001.092966. — View Citation

Ferrannini G, Hach T, Crowe S, Sanghvi A, Hall KD, Ferrannini E. Energy Balance After Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care. 2015 Sep;38(9):1730-5. doi: 10.2337/dc15-0355. Epub 2015 Jul 15. — View Citation

Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is pulse pressure useful in predicting risk for coronary heart Disease? The Framingham heart study. Circulation. 1999 Jul 27;100(4):354-60. doi: 10.1161/01.cir.100.4.354. — View Citation

Frias JP, Guja C, Hardy E, Ahmed A, Dong F, Ohman P, Jabbour SA. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): — View Citation

Handelsman Y, Bloomgarden ZT, Grunberger G, Umpierrez G, Zimmerman RS, Bailey TS, Blonde L, Bray GA, Cohen AJ, Dagogo-Jack S, Davidson JA, Einhorn D, Ganda OP, Garber AJ, Garvey WT, Henry RR, Hirsch IB, Horton ES, Hurley DL, Jellinger PS, Jovanovic L, Leb — View Citation

Ikonomidis I, Lekakis J, Papadopoulos C, Triantafyllidi H, Paraskevaidis I, Georgoula G, Tzortzis S, Revela I, Kremastinos DT. Incremental value of pulse wave velocity in the determination of coronary microcirculatory dysfunction in never-treated patients — View Citation

Ikonomidis I, Makavos G, Papadavid E, Varoudi M, Andreadou I, Gravanis K, Theodoropoulos K, Pavlidis G, Triantafyllidi H, Parissis J, Paraskevaidis I, Rigopoulos D, Lekakis J. Similarities in coronary function and myocardial deformation between psoriasis — View Citation

Ikonomidis I, Pavlidis G, Lambadiari V, Kousathana F, Varoudi M, Spanoudi F, Maratou E, Parissis J, Triantafyllidi H, Dimitriadis G, Lekakis J. Early detection of left ventricular dysfunction in first-degree relatives of diabetic patients by myocardial de — View Citation

Ikonomidis I, Tzortzis S, Tsantes A, Ntai K, Triantafyllidi H, Trivilou P, Katsimaglis G, Dima K, Parissis J, Lekakis J. The interplay between renin-angiotensin system activation, abnormal myocardial deformation and neurohumoral activation in hypertensive — View Citation

Jabbour SA, Hardy E, Sugg J, Parikh S; Study 10 Group. Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Diabetes Care. 2014;37(3):740-50. doi — View Citation

Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, Ducimetiere P, Benetos A. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension. 2001 May;37(5):1236-41. doi: 10.1161/0 — View Citation

Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and Cardiovas — View Citation

Meaume S, Benetos A, Henry OF, Rudnichi A, Safar ME. Aortic pulse wave velocity predicts cardiovascular mortality in subjects >70 years of age. Arterioscler Thromb Vasc Biol. 2001 Dec;21(12):2046-50. doi: 10.1161/hq1201.100226. — View Citation

Nauck MA, Kemmeries G, Holst JJ, Meier JJ. Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans. Diabetes. 2011 May;60(5):1561-5. doi: 10.2337/db10-0474. Epub 2011 Mar 23. — View Citation

Shaefer CF Jr, Kushner P, Aguilar R. User's guide to mechanism of action and clinical use of GLP-1 receptor agonists. Postgrad Med. 2015;127(8):818-26. doi: 10.1080/00325481.2015.1090295. Epub 2015 Sep 15. — View Citation

Tzortzis S, Ikonomidis I, Lekakis J, Papadopoulos C, Triantafyllidi H, Parissis J, Trivilou P, Paraskevaidis I, Anastasiou-Nana M, Kremastinos DT. Incremental predictive value of carotid intima-media thickness to arterial stiffness for impaired coronary f — View Citation

Vaitkevicius PV, Fleg JL, Engel JH, O'Connor FC, Wright JG, Lakatta LE, Yin FC, Lakatta EG. Effects of age and aerobic capacity on arterial stiffness in healthy adults. Circulation. 1993 Oct;88(4 Pt 1):1456-62. doi: 10.1161/01.cir.88.4.1456. — View Citation

van Bloemendaal L, Ten Kulve JS, la Fleur SE, Ijzerman RG, Diamant M. Effects of glucagon-like peptide 1 on appetite and body weight: focus on the CNS. J Endocrinol. 2014 Mar 7;221(1):T1-16. doi: 10.1530/JOE-13-0414. Print 2014 Apr. — View Citation

Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B; EMPA-REG OUTCOME Investigators. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):323 — View Citation

Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2 — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Comparison of Global Longitudinal Strain (GLS) difference among treatment groups.	Comparison of Global Longitudinal Strain (GLS) difference among treatment groups, measured by echocardiographic study	12 months
Secondary	Comparison of arterial stiffness markers difference among treatment groups.	Comparison of pulse wave velocity difference among treatment groups	12 months
Secondary	Comparison of wave reflection markers difference among treatment groups	Comparison of central augmentation index (Aix%) difference among treatment groups	12 months
Secondary	Comparison of central aortic blood pressure differences among treatment groups	Comparison of both central systolic and diastolic aortic blood pressure differences among treatment groups	12 months
Secondary	Comparison of endothelial glycocalyx thickness difference among treatment groups	Comparison of Perfused Boundary Region (PBR) difference of sublingual vessels among treatment groups	12 months
Secondary	Comparison of oxidative stress and endothelial function biomarkers differences among treatment groups	Comparison of malondialdehyde, protein carbonyls vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, thrombomodulin, nitrites and nitrates plasma levels differences among treatment groups	12 months
Secondary	Comparison of cardiac biomarkers differences among treatment groups.	Comparison of N-terminal pro B-type natriuretic peptide (NT-proBNP) and growth differentiation factor (GDF)-15 levels differences among treatment groups	12 months
Secondary	Comparison of left ventricular myocardial function difference between coronary artery disease patients and non-coronary artery disease patients in each study group.	Comparison of Global Longitudinal Strain (GLS) difference between coronary artery disease patients and non-coronary artery disease patients in each study group.	12 months
Secondary	Comparison of arterial stiffness difference between coronary artery disease patients and non-coronary artery disease patients in each study group.	Comparison of pulse wave velocity difference between coronary artery disease patients and non-coronary artery disease patients in each study group.	12 months
Secondary	Comparison of endothelial glycocalyx thickness difference between coronary artery disease patients and non-coronary artery disease patients in each study group.	Comparison of Perfused Boundary Region (PBR) difference between coronary artery disease patients and non-coronary artery disease patients in each study group.	12 months
Secondary	Comparison of oxidative stress and endothelial function biomarkers differences between coronary artery disease patients and non-coronary artery disease patients in each study group.	Comparison of malondialdehyde, protein carbonyls, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, thrombomodulin, nitrites and nitrates plasma levels difference between coronary artery disease patients and non-coronary artery disease patients in each study group.	12 months
Secondary	Comparison of cardiac biomarkers differences between coronary artery disease patients and non-coronary artery disease patients in each study group.	Comparison of N-terminal pro B-type natriuretic peptide (NT-proBNP) and growth differentiation factor (GDF)-15 levels difference between coronary artery disease patients and non-coronary artery disease patients in each study group.	12 months
Secondary	Comparison of liver steatosis level between treatment groups	Comparison of Fibrosis-4 (FIB-4) Index for Liver Fibrosis and Non Alcoholic Fatty Liver Disease Score between treatment groups	12 months