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ORIGINAL ARTICLE
Year : 2022  |  Volume : 25  |  Issue : 7  |  Page : 1094-1101

Comparison of the effects of exenatide and insulin glargine on right and left ventricular myocardial deformation as shown by 2D-speckle-tracking echocardiograms


1 Department of Endocrinology and Metabolism, Sanliurfa Mehmet Akif İnan Education and Research Hospital, Health Sciences University, Esentepe Sanliurfa, Turkey
2 Department of Cardiology, Kocaeli University School of Medicine, Turkey
3 Department of Oncology, Kocaeli University School of Medicine, Turkey
4 Department of Endocrinology and Metabolism, Anadolu Medical Center, Turkey
5 Department of Endocrinology and Metabolism, Kocaeli University School of Medicine, Turkey
6 Department of Endocrinology and Metabolism, Gebze Medical Park Hospital, Turkey

Date of Submission26-Jun-2021
Date of Acceptance08-Jun-2022
Date of Web Publication20-Jul-2022

Correspondence Address:
Dr. O Z Akyay
Sanliurfa Mehmet Akif İnan Education and Research Hospital, Health Sciences University, Esentepe Sanliurfa - 41380
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_1640_21

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   Abstract 


Background: Exenatide is a glucagon-like peptide-1 (GLP-1) analogs. The effects of GLP-1 analogs on myocardial function are controversial. Aims: The purpose of this study is to compare the effects of exenatide and insulin glargine on subclinical right and left ventricular dysfunction. Methods and Material: In this study, 27 patients with type 2 diabetes were randomized into exenatide and insulin glargine treatment groups. The patients were monitored for six months by conventional echocardiography (ECHO) and 2D-speckle-tracking echocardiography (2D-STE) to evaluate right and left ventricular functions. Results: ECHO parameters did not change significantly pre- and post-treatment, except for the tricuspid annular plane systolic excursion (TAPSE) values. Post-treatment TAPSE values significantly increased in both groups compared to pre-treatment values. In the insulin group, values for 2D-STE parameters of the left ventricular global longitudinal strain (LVGLS) based on apical long-axis (ALA) images increased significantly (p: 0.047) compared to pre-treatment values; however, apical 4-chamber (A4C), apical 2-chamber (A2C), LVGLS, and right ventricular global longitudinal strain (RVGLS) values did not change. In the exenatide group, LVGLS based on A4C values improved (p: 0.048), while ALA, A2C, and LVGLS values did not change. Moreover, the RVGLS values improved significantly after exenatide treatment (p: 0.002). Based on 2D-STE parameters the two treatments did not differ statistically in either pre- or post-treatment periods. Conclusions: Glp-1 treatment can improve left ventricular regional and right ventricular global subclinical dysfunction. Therefore, early GLP-1 treatment may be recommended in diabetic patients with a high risk of cardiac dysfunction.

Keywords: 2D-speckle-tracking echocardiography, exenatide, insulin glargine, type 2 diabetes, ventricular dysfunction


How to cite this article:
Akyay O Z, Sahin T, Cakmak Y, Tarkun I, Selek A, Canturk Z, Cetinarslan B, Karakaya D. Comparison of the effects of exenatide and insulin glargine on right and left ventricular myocardial deformation as shown by 2D-speckle-tracking echocardiograms. Niger J Clin Pract 2022;25:1094-101

How to cite this URL:
Akyay O Z, Sahin T, Cakmak Y, Tarkun I, Selek A, Canturk Z, Cetinarslan B, Karakaya D. Comparison of the effects of exenatide and insulin glargine on right and left ventricular myocardial deformation as shown by 2D-speckle-tracking echocardiograms. Niger J Clin Pract [serial online] 2022 [cited 2022 Aug 14];25:1094-101. Available from: https://www.njcponline.com/text.asp?2022/25/7/1094/351453




   Introduction Top


Diabetes mellitus (DM) may contribute to the development of heart failure (HF) despite the absence of ischemic and heart valve diseases in patients with preserved left ventricular (LV) function. Such a condition is known as diabetic cardiomyopathy[1] and it can be caused by other conditions, such as insulin resistance and cardiac autonomic neuropathy.[2] Moreover, various drugs[3],[4] have been associated with cardiac dysfunction, while other drugs[5],[6] are associated with a lower risk of cardiac dysfunction. In a diabetic heart, fatty acid oxidation increases, while glucose intake decreases, causing a decrease in cardiac efficiency because more oxygen is required to form adenosine triphosphate (ATP).[7]

Glucagon-like peptide-1 (GLP-1) is an incretin-based therapeutic that increases myocardial glucose uptake.[8] The beneficial effects of GLP-1 treatment on systolic heart function have been demonstrated in several small studies[9],[10]; however, recent investigations have not supported these previous findings.[11],[12] Furthermore, studies on the effect of GLP-1 treatment on patients with type 2 diabetes mellitus (T2DM) and subclinical myocardial dysfunction are scarce.[13],[14]

Most studies focus on the early stages of ventricular dysfunction, because it is commonly assumed that the condition can be reversed more readily during this period. The current clinical guidelines emphasize the importance of early diagnosis and treatment for persons at risk.[15] However, there is no consensus on the best procedure for detecting subclinical ventricular dysfunction, and the present techniques are both too complex and difficult or not sensitive enough (conventional and Doppler echocardiography). 2D-speckle-tracking echocardiography (2D-STE) is a recently developed, non-invasive technique for the evaluation of myocardial systolic and diastolic functions.[16],[17],[18] Unlike conventional methods, 2D-STE is not limited by inter/intra-observer variability, angle dependence, or noise interference.[19]

Recent studies suggest that LV longitudinal myocardial systolic dysfunction is the first marker of preclinical diabetic cardiomyopathy in patients with preserved left ventrıcular ejection fraction (LVEF).[20],[21]

The aim of the present study was to compare the effects of exenatide and insulin glargine for the treatment of left and right ventricular subclinical dysfunction.


   Methods and Materials Top


The present study was carried out between the 2016 and 2018 at Kocaeli University school of Medicine. Volunteers were recruited from patients referred to the endocrinology outpatient unit of our medical school. (The study protocol was approved by the Ethical Committee of the Kocaeli University at 2017).

The following inclusion criteria was used to select patients: Patients were type 2 diabetic; ages ≥35 and ≤70 years; HbA1c levels >7% and <10%, on regular metformin at 2 × 1 g/day alone or on metformin + sulfonylurea for at least two months; stable on cardioprotective drugs (e.g., anti-hypertensive drugs, statin, fibrate) in the last three months; and with LV ejection fraction >55%.

The following were the exclusion criteria: Patients who had previously received insulin or incretin-based therapy; who were previously ischemic or had valvular heart disease and/or HF; had acute or chronic renal failure; had acute or chronic hepatic failure; had uncontrolled hypertension (HT); had acute or chronic pancreatic disease; had thyroid dysfunction, anemia, chronic obstructive pulmonary disease, arrhythmia disorders and heart conduction disturbances, implanted cardiac pacemaker, acute myocarditis, cardiotoxic drug use, global and/or regional wall motion abnormality in ECHO; with angina or anginal equivalent symptoms; ischemic changes in the electrocardiography, and were current drug or alcohol abusers.

After selection, 18 and 14 patients were randomized to the exenatide and insulin glargine treatments, respectively. Patients were randomized according to their Turkish goverment's ID numbers. Patients with an even ID number were randomized to the insulin glargine arm and patients with an odd ID number were randomized to the exenatide arm.

One patient in the exenatide arm was excluded from the study due to nausea and vomiting. In the insulin glargine group, four patients (two patients who rejected injection therapy and two patients who were lost to follow-up) were excluded from the study. Thus, the study was completed with 27 patients.

Both study groups were maintained on metformin at 2 g/day. The exenatide group took exenatide 5 μg 2 × 1 subcutaneous s.c. 45 min before meals for one month, followed by an increased dosage of to 2 × 10 μg which was maintained for the remainder of the six months. Patients in insulin group were started on insulin glargine at 0.2 U/kg, which was titrated according to the fasting blood glucose level. All patients were assessed at 0, 1, 3, and 6 months through anthropometric measurements and routine biochemistry. Conventional echocardiography (ECHO) and 2D-STE were performed only at the baseline and sixth month visits.

A maximal exercise test was administered to six patients who displayed suspicious symptoms consisting of exercise dyspnea and sweating, which were subsequently proven to be due to non-ischemic heart disease.

Biochemical analysis

Peripheral blood specimens were collected between 08.00 and 09.00 am after at least 8 hours of fasting. Biochemical analyzes of levels of fasting plasma glucose (FPG), triglycerides, LDL-cholesterol, and total cholesterol were performed using Roche Diagnostics commercial kits in the Cobas 8000 Core Unit (Roche Diagnostics, USA) autoanalyzer. Serum HbA1c levels were measured by high-performance liquid chromatography in an ADAMS A1c HA-8180V (Arkray Factory, Japan) autoanalyzer.

Body weight assessment

Body weight was measured by the bioimpedance analysis technique using a Tanita BC-418 body composition analyzer device.

Conventional Doppler echocardiography

Conventional ECHO and 2D-STE were performed by a senior cardiologist who was blinded to patient information. Echocardiograms were obtained using a GE Vivid 7 ultrasound system. The biplane LVEF was estimated from apical 2- and 4-chamber images using Simpson's method.[22] The right ventricle (RV) dimensions and TAPSE were measured from apical 4-chamber images.

2D-speckle-tracking echocardiography

STE was estimated using a commercially available speckle-tracking system and an ECHOPAC (v. 6.3; GE Vingmed, Horten, Norway) workstation. The displacement of myocardial speckles in each spot was analyzed and tracked frame to frame. Longitudinal strain was evaluated using automated functional imaging (AFI). The peak systolic longitudinal strain for each segment was displayed based on a 17-segment model for each plane, and the results of all 3 planes were combined into a single bull's eye summary. The LVGLS was automatically calculated as an averaged value of the peak longitudinal strain in all 3 image planes (apical 2- and 4-chamber and long-axis views). RVGLS was measured in the apical 4-chamber by the AFI method. The right ventricular free wall was evaluated as lateral wall during 4-chamber imaging.

Intra-observer variability

The intra-observer variability among members of our cardiology unit was as follows: r = 0.98 for two dimensional and M-mode echocardiographic measurements; r: 0.97 for Doppler measurements; and r: 0.98 for speckle-tracking echocardiographic measurements, where r is the intra-observer variability.

Statistical assessment

The IBM SPSS for Windows version 21.0 program (SPSS, Chicago, IL, USA) was used for statistical analyzes. Kolmogorov–Smirnov tests were used to determine the normality of data distributions. Normally distributed data are expressed as means ± standard deviations, and non-normally distributed data are expressed as medians (interquartile range). Categorical variables were compared by the Chi-square test. Categorical variables between independent groups were compared using the T-test statistic. The T-test statistic was also used to compare dependent measurements such as pre- and post-treatment measurements. The Mann–Whitney U test was used for the pairwise comparison of groups for data that were non-normally distributed. The Wilcoxon signed rank test was used to compare pre- and post-treatment results with abnormal distributions. P values < 0.05 were regarded as statistically significant.


   Results Top


The demographic and anthropometric data for both groups are summarized in [Table 1]. Insulin and exenatide groups were similar in terms of age, gender, age of diabetes, weight, and body mass index (BMI). [Table 1] shows that compared with their pre-treatment measurements, body weight, BMI, and waist circumference measurements of the exenatide group were significantly lower post-treatment. Pre- and post-treatment levels of FPG c-peptide, serum triglyceride, LDL-cholesterol, and HDL-cholesterol in both groups were similar. HbA1c levels significantly decreased after exenatide and insulin glargine treatment, but there was no statistically significant difference between the groups [Table 2].
Table 1: Demographic data and pre- and post-treatment anthropometric measurements of groups of patients

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Table 2: Pre- and post-treatment biochemical values of the groups of patients

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Conventional Doppler echocardiography

Echocardiographic data of the groups before and after six months of treatment are shown in [Table 3]. LVEF values were normal and >55% in both groups. Pre- and post-treatment values for conventional ECHO parameters (LVEF, left atrial diameter [LAD], right ventricular diameter [RVD], E/E', and TAPSE) were similar in both groups (P > 0.05). LVEF, LAD, RVD, and E/E´ values did not change significantly after both treatments. Insulin and exenatide treatments increased TAPSE values significantly compared to pre-treatment values (p: 0.005, p: 0.001, respectively [Table 3].
Table 3: Pre- and post-treatment values from conventional echocardiography on the groups of patients

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2D-Speckle-tracking echocardiography

The LVGLS and RVGLS values of our study population were −16.9 ± 3.02 and −16.5 ± 4.6, respectively. Despite little changes in LVEF values, the LVGLS and RVGLS values of our patients were lower compared to the previously suggested normal reference values (−19.7% and −21.5%, respectively).[23],[24] The left ventricular longitudinal strain in the insulin group based on the ALA images increased significantly (p: 0.047) but apical 4-chamber, apical 2-chamber, LVGLS, and RVGLS values did not change after insulin treatment (p: 0.508, p: 0.683, p: 0.262 and p: 0.169, respectively).

The exenatide treatment significantly improved the LVGLS based on the apical 4-chamber images (p: 0.048) but ALA, apical 2-chamber and LVGLS values did not improve significantly after exenatide treatment (p: 0.362, p: 0.433, p: 0.233). However, RVGLS improved significantly after six months of exenatide treatment (p: 0.002). The two groups did not differ statistically in terms of 2D-STE parameters in pre- and post-treatment periods. [Table 4]
Table 4: Pre- and post-treatment values of 2D-speckle-tracking echocardiography on the groups of patients

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   Discussion Top


Diabetic cardiomyopathy results from the combination of increased fatty acid oxidation and decreased glucose intake. It is an initially clinically silent condition that causes decreased cardiac efficiency. Our study shows that exenatide treatment may improve LV regional and right ventricular global subclinical dysfunctions; and treatment with insulin glargine may also improve LV regional subclinical dysfunction.

In our study, GLS was evaluated by 2D-STE, which allows the angle-independent evaluation of systolic function. GLS is also a sensitive marker that can be used for the early diagnosis of myocardial dysfunction.[25] To the best of our knowledge, the present study is the first to compare the effects of exenatide and insulin glargine on subclinical LV dysfunction; it is also the first study to examine the effect of exenatide on RVGLS.

Despite little changes in LVEF values, our patients initially had LVGLS (−16.9 ± 3.02) and RVGLS (−16.5 ± 4.6) values that were lower than previously suggested normal reference values (−19.7% and −21.5%, respectively).[23],[24] This indicates the likely presence of a subclinical systolic dysfunction in our diabetic patients. The effects of GLP-1 analogs on myocardial function are controversial. Various theories have been proposed to explain the favorable effects of GLP-1 on the myocardium, and the most commonly accepted one involves heart metabolism.[26] Patients with T2DM have myocardial insulin resistance,[27] and studies have shown that GLP-1 analogs improve insulin resistance and inflammation.[28],[29] GLP-1 analogs are thought to improve insulin resistance by increasing the levels of the glucose transporters GLUT-2 and GLUT-4, especially in cardiomyocytes.[30],[31]

Several small studies have shown that GLP-1 treatment is beneficial to systolic heart function,[9],[10] although other studies have not supported this finding.[11],[12] Moreover, there are few studies on the effects of GLP-1 treatment on subclinical HF in patients with T2DM.[13],[14]

In a study similar to ours, Lambadiari et al.[32] compared the results of six months of liraglutide and metformin treatments on newly diagnosed patients with T2DM and without ischemic heart disease, and found that liraglutide improves LV myocardial strain. In another study, three months of exenatide treatment on uncomplicated patients with T2DM resulted in improved cardiac function and decreased arterial stiffness.[33]

In contrast to our findings, a study found that 18 weeks of liraglutide or glimeprid treatment in patients with T2DM and subclinical HF did not improve diastolic and systolic longitudinal functional reserve indexes. We did not evaluate these two parameters, which are early markers of subclinical HF.[34] In a recent study, liraglutide treatment of patients with T2DM did not improve cardiac systolic functions as assessed by dobutamine stress echocardiography.[35] Chen et al.[36] showed that neither insulin glargine nor exenatide treatments (for 26 weeks) in patients with T2DM and LV dysfunction resulted in positive effects on cardiac function, perfusion, and oxidative metabolism. The results of these studies differ from that of our study.

Although the results of the abovementioned studies conflict with ours, there has been no major clinical study showing that GLP-1 analogs have any adverse effect on cardiovascular function.[6],[37],[38] A meta-analysis showed that GLP-1 analogs reduce the levels of cardiovascular events, cardiovascular mortality, and all-cause mortality, although there are differences between groups of patients.[39]

RV function is an important parameter in cardiac disease[40]; however, much of the previous research on diabetes-related changes in myocardial dysfunction has ignored the role of the RV. Also, the effects of anti-diabetic drugs on right ventricular function have not been investigated. Animal studies show that GLP-1s improve pulmonary HT and right ventricular hypertrophy.[41],[42],[43] Similarly, GLP-1s improve right ventricular function and are usually associated with vascular and parenchymal healing of the diabetic lung. The recovery that we observed may be due to this effect, or it may be due to the effect of weight loss on right heart function.

To the best of our knowledge, the effect of GLP-1 on right ventricular function in humans has not been previously studied. Here compared to pre-treatment levels, the RVGLS of patients with T2DM with subclinical right ventricular dysfunction improved significantly after six months of exenatide treatment, while RVGLS did not improve after insulin therapy. However, the RVGLS levels of the two groups did not differ after the treatments.

TAPSE, defined as the total movement of the tricuspid annulus from its highest position to its deepest position during ventricular systole, is an indicator of global systolic function in RV.[44] In a study, we observed a decrease in TAPSE in patients with diabetes and without LV dysfunction.[45] The literature is silent regarding the effect of GLP-1 or insulin therapy on TAPSE levels. In our study, we observed significant improvements in TAPSE after both exenatide and insulin glargine treatments (p: 0.001, p: 0.005, respectively).

We found no significant change in the ejection fraction of conventional ECHO parameters after both treatments. In contrast to the results of other studies,[34],[35],[36] we observed no increase in EF levels after GLP-1 treatment. Nevertheless, there are also studies showing a significant increase in EF after GLP-1 treatment.[46],[47]

Both groups had similar HbA1c values before and after treatment; thus, the improvement in strain parameters (especially in RVGLS) may be due to the effect of the exenatide molecule rather than the improvement in blood glucose. In addition, considering that the improvement we observed in the myocardium started regionally and then spread globally, we suggest that exenatide-induced regional improvement in the left ventricle can turn into global recovery as the treatment time increases.

The present study has some limitations. First and most importantly, our study relied on a small number of patients. Second, the patient follow-up period was relatively short. Third, none of the patients underwent coronary angiography or exercise testing to exclude undiagnosed coronary artery disease. Lastly, specific diastolic function in 2D-STE parameters was not included in our research protocol, although diastolic dysfunction often occurs in patients with T2DM.

Our study suggests that exenatide treatment may improve LV regional and right ventricular global subclinical dysfunctions; and treatment with insulin glargine may also improve LV regional subclinical dysfunction.


   Conclusions Top


GLP-1 treatment can improve left ventricular regional and right ventricular global subclinical dysfunction

Therefore, early GLP-1 treatment may be recommended in patients with diabetes and a high risk of cardiac dysfunction. There is a need for human studies examining the effects of incretin-based therapies on overt right ventricular dysfunction. The effect of incretins on right ventricular dysfunction has been either previously underestimated or overlooked in the literature.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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