Comparing the effects of dipeptidyl-peptidase 4 Inhibitor and sulfonylurea on heart function in patients with type 2 diabetes mellitus

Posted on by admin

RESEARCH ARTICLE

Hippokratia 2024, 28(3): 115-119

Cheng PC1,2, Tu ST1
1Division of Endocrinology and Metabolism, Department of Internal Medicine, Changhua Christian Hospital, Changhua City
2School of Post Baccalaureate Medicine, National Chung Hsing University, Taichung City
Taiwan

Abstract

Background: Heart failure is a detrimental complication of type 2 diabetes mellitus (T2DM). Considering the different pharmacologic effects of dipeptidyl-peptidase 4 (DPP-4) inhibitors and sulfonylureas, the investigator hypothesized that these medications may exert distinct effects on heart function in diabetic individuals.

Methods: We conducted a cross-sectional study at a tertiary medical center in Taiwan, which enrolled adult patients with T2DM who were receiving either DPP-4 inhibitors or sulfonylureas. We excluded eligible candidates with preexisting heart failure. Participants underwent echocardiography and blood sampling at the Cardiology outpatient clinic.

Results: We enrolled in the study 252 participants classified according to their glucose-lowering medications. Clinical characteristics including age (67.8 vs 67.5 years, p =0.83), systolic blood pressure (130 vs 133 mm Hg, p =0.24), and glycated hemoglobin A1c (7.4 vs 7.7 %, p =0.1) were similar between treatment groups. According to ventricular ejection fraction measurements, enrolled patients receiving DPP-4 inhibitors were associated with more favorable heart function than recipients of sulfonylureas (58.4 vs 51.6 %, p =0.001).

Conclusion: Glucose-lowering medications have distinct effects on heart function. Participants receiving DPP-4 inhibitors were associated with better heart function than recipients of sulfonylureas. Therefore, glucose-lowering drugs should be selected based on their potential effects on heart function. HIPPOKRATIA 2024, 28 (3):115-119.

Keywords: Type 2 diabetes mellitus, heart function, dipeptidyl-peptidase 4 inhibitor, sulfonylurea, left ventricular ejection fraction

Corresponding author: Shih Te Tu, Division of Endocrinology and Metabolism, Department of Internal Medicine, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua, 500 Taiwan, tel: +88647238595, #3504, e-mail: 180459@cch.org.tw

Introduction

A substantial number of patients worldwide is influenced by Type 2 diabetes mellitus (T2DM), which is a prevailing metabolic disease1. Diabetes mellitus incurs a significant burden on healthcare systems and patients’ quality of life, leading to a myriad of complications that include diabetic eye, diabetic kidney, and cardiovascular diseases2. Heart disease is the highest causative for morbidity and mortality in T2DM individuals3, and chronic hyperglycemia is associated with functional vascular perturbations, myocardial oxidative stress, as well as pro-inflammatory cytokines that impair heart function4-6. Therefore, appropriate management of heart dysfunction is paramount to attenuate morbidity and mortality in diabetic patients7.

In the context of heart dysfunction, various risk factors have been proposed that contribute to impaired heart contractility in T2DM. Firstly, chronic hyperglycemia induces reactive oxygen species production by cellular metabolism that impairs the contractile function of the myocardium8. Secondly, a hyperglycemic milieu promotes insulin resistance and impairs myocardial cells’ capacity to uptake and utilize arterial glucose molecules9. Thirdly, longstanding diabetes mellitus increases circulating growth factors in the myocardium, resulting in fibrosis and excessive mesenchymal tissue growth10. Lastly, people with T2DM are predisposed to coronary heart disease that negatively impacts the blood supply of functional myocardial tissues11.

Importantly, clinical studies demonstrate that T2DM predisposes patients to cardiomyopathy even in the absence of established cardiovascular risk factors such as coronary heart disease12,13. Chronic hyperglycemia and abnormal cardiometabolic signaling likely contribute to diabetic cardiomyopathy, leading to subtle changes in left ventricular structure that, if left untreated, may progress to overt heart failure14. Therefore, diabetic individuals are at risk of heart failure even in the absence of concomitant atherosclerotic heart disease, and timely therapeutic intervention may attenuate the onset of overt heart dysfunction15.

There is currently insufficient knowledge concerning the potential influence of glucose-lowering drugs on heart function. Two commonly prescribed glucose-lowering drugs in T2DM, the dipeptidyl-peptidase 4 (DPP-4) inhibitor and sulfonylurea, harbor unique pharmacologic properties that may lead to distinct effects on heart function16. The DPP-4 inhibitors are well known for their weight neutrality and negligible side effects17. In contrast, sulfonylureas have been associated with modest fluid retention that can impose hemodynamic stress on at-risk myocardial tissues18. Moreover, in vitro studies demonstrated that the sulfonylureas activate drug-sensitive type 2 sulfonylurea receptors in the heart, leading to variable degrees of cardiac arrhythmias that may also disturb myocardial contractility19,20.

Considering a potential link between different pharmacologic properties of glucose-lowering medications, the investigators hypothesized that DPP-4 inhibitors and sulfonylureas may pose distinct effects on diabetic patients’ heart function. We investigated the association between DPP-4 inhibitor, sulfonylurea prescription, and heart function in T2DM individuals, as well as evaluated other plasma metabolites’ influence on heart function. 

Methods

Participant selection

We conducted a cross-sectional study at Changhua Christian Hospital, Taiwan’s tertiary medical center. We assessed for eligibility patients attending the Cardiology clinic based on the study’s inclusion criteria that comprised adults aged over 18 years, diagnosed with T2DM according to American Diabetes Association (ADA) criteria, receiving either DPP-4 inhibitor or sulfonylurea monotherapy for a minimum of six months at the time of the study recruitment, scheduled for transthoracic echocardiography by the attending cardiologists.

The ADA criteria we employed referred to fasting plasma glucose levels ≥126 mg/dL, serum glycosylated hemoglobin A1c (HbA1c) levels ≥6.5 %, two-hour postprandial plasma glucose levels ≥200 mg/dL following a 75-gram oral glucose tolerance test, or random plasma glucose levels ≥200 mg/dL with classic diabetes symptoms.

We excluded eligible candidates if they had i) preexisting heart failure diagnosis, ii) concomitant valvular heart disease, iii) chronic kidney disease, hemoglobin disorders, or thyroid dysfunction, iv) were receiving any second-line glucose-lowering drug, or v) were unable to comply with transthoracic echocardiography.

The study was approved by the Institutional Review Board of Changhua Christian Hospital (protocol No. Y_107_0198) and performed according to relevant national regulations regarding human-related research, institutional policies, and the tenets of the Helsinki Declaration. We obtained informed consent from all study participants for relevant procedures in the study’s protocol.

Laboratory evaluation

The study patients received glucose-lowering medications with either the DPP-4 inhibitor Linagliptin 5 milligrams or the sulfonylurea Glimepiride 2 milligrams once daily for at least six months before recruitment. They had blood tests for HbA1c following a 12-hour fast, low-density, and high-density lipoprotein cholesterol (LDL and HDL, respectively) and plasma triglycerides (TG) before the scheduled echocardiography. The central laboratory received the blood samples within one hour and utilized the UniCel DxC 800 Synchron Clinical Systems (Beckman Coulter Inc., Brea, CA, USA) to assay them. Using a commercial polyanion solution, they measured plasma LDL cholesterol by the timed endpoint method. Analytical precision was specified within 3.0, 1.7, and 7.5 ml/dL for LDL, HDL, and TG, respectively.

Echocardiographic assessment

Researchers from the authors’ institution21 have previously reported a protocol for measuring echocardiographic parameters. Transthoracic echocardiography was performed by the Cardiology clinic sonographers using the Aplio 300 CV Platinum system (Canon Medical Systems Corp., Ōtawara, Tochigi Prefecture, Japan), performing all measurements according to present sonographic guidelines22. Specifically, in the parasternal long-axis view, they measured the left atrial diameter, left ventricular end-systolic diameter, and end-diastolic diameter. In the apical four-chamber view, they measured the right ventricular diameter. To calculate the E/A ratio, they used E and A velocities from mitral valve inflow, and from the modified Quinones equation, they derived the left ventricular ejection fraction23.

Statistical analysis

To detect, with 80 % statistical power, a difference in heart function between treatment groups, power analysis calculated a total sample size of 200 participants divided into two groups according to the glucose-lowering drugs they used at study enrolment. For continuous variables, we compared the features between the groups using the Student’s independent t-test, and for categorical variables, Pearson’s χ2-test. We compared echocardiographic parameters using the Student’s independent t-test. Moreover, we used sensitivity analysis to investigate the relationship between glucose-lowering medications and left ventricular function. We performed all statistical analyses using the IBM SPSS Statistics for Windows, Version 22.0 (IIBM Corp., Armonk, NY, USA), with statistical significance set at a two-tailed p <0.05 value. 

Results

We screened 270 individuals for study eligibility and excluded 10 individuals due to preexisting heart failure, and eight patients harbored concomitant valvular heart disease. Figure 1 shows the enrollment process.

Figure 1: Flow diagram showing the enrollment protocol of this cross-sectional study that enrolled diabetic patients to investigate the association between glucose-lowering drugs and heart function.
DPP-4: dipeptidyl-peptidase 4.

Participants’ clinical characteristics

We enrolled 252 participants in the study, divided into two groups according to the glucose-lowering drugs they used at study enrolment. We found no significant differences between the two groups regarding their clinical features, including age (67.8 vs 67.5 years, p =0.83), female sex (43.5 % vs 33.6 %, p =0.1), systolic blood pressure (130 vs 133 mmHg, p =0.24), diabetes duration (6.6 vs 6.4 years, p =0.63), plasma TG level (159 vs 143 mg/dL, p =0.15), plasma HDL cholesterol level (39.2 vs 38.5 mg/dL, p =0.59), serum HbA1c (7.4 % vs. 7.7 %, p =0.1), and serum creatinine (0.75 vs 0.69 mg/dL, p =0.11) (Table 1). In contrast, recipients of DPP-4 inhibitors harbored lower body weight (69.7 vs 74.5 kg, p <0.001) and LDL cholesterol (89.7 vs 99.6 mg/dL, p =0.026) than patients receiving sulfonylureas.

Effect of glucose-lowering drugs on heart function

Patients receiving DPP-4 inhibitors compared to those receiving sulfonylureas were associated with better heart function measured by the left ventricular ejection fraction (58.4 % vs 51.6 %, p =0.001) (Table 2). The two groups did not differ significantly regarding left atrial diameter (43 vs 42.8 mm, p =0.95), right ventricular diameter (25.6 vs 26.0 mm, p =0.98), left ventricular end systolic diameter (31 vs 30.8 mm, p =0.88), left ventricular end diastolic diameter (49.1 vs 50 mm, p =0.57), and E/A ratio (0.92 vs 0.91, p =0.23). 

Sensitivity analysis of heart function and glucose-lowering drugs

In Figure 2, sensitivity analysis revealed an interaction between heart function (left ventricular ejection fraction) and the choice of glucose-lowering drugs with an area under the curve of 0.7.

Figure 2: Receiver operating characteristic curve demonstrating the interaction between the antidiabetic drug and the left ventricular ejection fraction.
ROC: receiver operating characteristic.

Discussion

The current study showed that recipients of DPP-4 inhibitors harbored better left ventricular function than patients receiving sulfonylureas. Moreover, sensitivity analysis demonstrated an association between left ventricular function and the type of glucose-lowering medication, being, to our knowledge, the first study to directly compare the effect of antidiabetic drugs on heart function in diabetic patients.

This relationship between different glucose-lowering drugs and heart function may be attributed to several physiologic mechanisms. First, sulfonylureas induce modest weight gain that negatively impacts the hemodynamic stability of the diabetic heart, a side effect absent in DPP-4 inhibitors24,25. Furthermore, investigators demonstrated that sulfonylureas induce reactive oxygen species in glucose-metabolizing tissues such as the heart, and the presence of arrhythmogenic sulfonylurea receptors in the myocardium has been described26,27. In comparison, DPP-4 inhibitors do not have specific receptors on the myocardium28, which may explain a more favorable effect on heart function.

The cardiometabolic profile of DPP-4 inhibitors has been extensively assessed. Overall, the effect of this class of glucose-lowering medications on heart function remains uncertain, as demonstrated by a recent meta-analysis29. Specifically, an increased incidence of hospitalization was associated with the DPP-inhibitors Alogliptin and Saxagliptin due to heart failure in clinical studies30,31. In contrast, a clinical trial demonstrated that Linagliptin had a neutral effect on left ventricular function32. Considering the varying substrate specificity of these glucose-lowering drugs33, different brands of DPP-4 inhibitors may exert distinct effects on diabetic patients’ heart function.

The association between glucose-lowering medications and heart function has clinical implications. Medications that can modify heart function, such as sulfonylureas, should be prescribed with care in diabetic patients at risk of heart failure. Moreover, recipients of longstanding sulfonylurea therapy may be at risk of heart dysfunction, and an appropriate survey may be warranted in such patients who experience signs of heart failure. Furthermore, daily sodium intake targeting medical nutrition therapy may benefit sulfonylurea users by reducing fluid retention and preserving heart contractility.

Our study reveals novel knowledge regarding the relationship between glucose-lowering drugs and left ventricular function. Experienced sonographers documented echocardiographic measurements and, subsequently, to lessen inter-operator variability, were verified by attending cardiologists. Blood samples were drawn for all participants’ tests at the same clinical laboratory to reduce the potential confounding effects of intraassay variations. Importantly, patients had received the study medications for at least six months before echocardiography, reducing the interference of other second-line glucose-lowering drugs on their heart function.

Nevertheless, the current study has limitations, too. Firstly, as the sonographic examination is operator-dependent, the accuracy of LVEF measurement decisively relies on the sonosonographer’s experience. Furthermore, dietary supplement intake such as omega-3 polyunsaturated fatty acids might affect left ventricular function34, which was unaccounted for in this study. The study is also limited by its cross-sectional design; therefore, longer prospective studies are required to confirm its findings.

Conclusion

There are differences concerning the effect of glucose-lowering medications on heart function in diabetic patients. Patients receiving DPP-4 inhibitors were associated with better left ventricular function than recipients of sulfonylureas. Therefore, the prescription of glucose-lowering drugs should consider any potential deleterious effect of these medications on heart function besides their therapeutic efficacy. 

Conflict of interest

Authors declare no conflicts of interest.

References

  1. Khan MAB, Hashim MJ, King JK, Govender RD, Mustafa H, Al Kaabi J. Epidemiology of Type 2 Diabetes – Global Burden of Disease and Forecasted Trends. J Epidemiol Glob Health. 2020; 10: 107-111.
  2. Ali MK, Pearson-Stuttard J, Selvin E, Gregg EW. Interpreting global trends in type 2 diabetes complications and mortality. Diabetologia. 2022; 65: 3-13.
  3. Viigimaa M, Sachinidis A, Toumpourleka M, Koutsampasopoulos K, Alliksoo S, Titma T. Macrovascular Complications of Type 2 Diabetes Mellitus. Curr Vasc Pharmacol. 2020; 18: 110-116.
  4. Singh A, Kukreti R, Saso L, Kukreti S. Mechanistic Insight into Oxidative Stress-Triggered Signaling Pathways and Type 2 Diabetes. Molecules. 2022; 27: 950.
  5. Halim M, Halim A. The effects of inflammation, aging and oxidative stress on the pathogenesis of diabetes mellitus (type 2 diabetes). Diabetes Metab Syndr. 2019; 13: 1165-1172.
  6. Robson R, Kundur AR, Singh I. Oxidative stress biomarkers in type 2 diabetes mellitus for assessment of cardiovascular disease risk. Diabetes Metab Syndr. 2018; 12: 455-462.
  7. Kenny HC, Abel ED. Heart Failure in Type 2 Diabetes Mellitus. Circ Res. 2019; 124: 121-141.
  8. Rovira-Llopis S, Bañuls C, Diaz-Morales N, Hernandez-Mijares A, Rocha M, Victor VM. Mitochondrial dynamics in type 2 diabetes: Pathophysiological implications. Redox Biol. 2017; 11: 637-645.
  9. Pinti MV, Fink GK, Hathaway QA, Durr AJ, Kunovac A, Hollander JM. Mitochondrial dysfunction in type 2 diabetes mellitus: an organ-based analysis. Am J Physiol Endocrinol Metab. 2019; 316: E268-E285.
  10. Dennis M, Howpage S, McGill M, Dutta S, Koay Y, Nguyen-Lal L, et al. Myocardial fibrosis in Type 2 Diabetes is associated with functional and metabolomic parameters. Int J Cardiol. 2022; 363: 179-184.
  11. Zarkasi KA, Abdul Murad NA, Ahmad N, Jamal R, Abdullah N. Coronary Heart Disease in Type 2 Diabetes Mellitus: Genetic Factors and Their Mechanisms, Gene-Gene, and Gene-Environment Interactions in the Asian Populations. Int J Environ Res Public Health. 2022; 19: 647.
  12. Dillmann WH. Diabetic Cardiomyopathy. Circ Res. 2019; 124: 1160-1162.
  13. Jia G, Hill MA, Sowers JR. Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity. Circ Res. 2018; 122: 624-638.
  14. Salvatore T, Pafundi PC, Galiero R, Albanese G, Di Martino A, Caturano A, et al. The Diabetic Cardiomyopathy: The Contributing Pathophysiological Mechanisms. Front Med (Lausanne). 2021; 8: 695792.
  15. Grubić Rotkvić P, Planinić Z, Liberati Pršo AM, Šikić J, Galić E, Rotkvić L. The Mystery of Diabetic Cardiomyopathy: From Early Concepts and Underlying Mechanisms to Novel Therapeutic Possibilities. Int J Mol Sci. 2021; 22: 5973.
  16. Kim KJ, Choi J, Lee J, Bae JH, An JH, Kim HY, et al. Dipeptidyl peptidase-4 inhibitor compared with sulfonylurea in combination with metformin: cardiovascular and renal outcomes in a propensity-matched cohort study. Cardiovasc Diabetol. 2019; 18: 28.
  17. Deacon CF. Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2020; 16: 642-653.
  18. Levey GS, Lasseter KC, Palmer RF. Sulfonylureas and the heart. Annu Rev Med. 1974; 25: 69-74.
  19. Emdin CA, Klarin D, Natarajan P; CARDIOGRAM Exome Consortium; Florez JC, Kathiresan S, et al. Genetic Variation at the Sulfonylurea Receptor, Type 2 Diabetes, and Coronary Heart Disease. Diabetes. 2017; 66: 2310-2315.
  20. Mahdi H, Jovanović A. SUR2A as a base for cardioprotective therapeutic strategies. Mol Biol Rep. 2022; 49: 6717-6723.
  21. Cheng PC, Hsu SR, Li JC, Chen CP, Chien SC, Tu ST, et al. Plasma Low-Density Lipoprotein Cholesterol Correlates With Heart Function in Individuals With Type 2 Diabetes Mellitus: A Cross-Sectional Study. Front Endocrinol (Lausanne). 2019; 10: 234.
  22. Echocardiographic Normal Ranges Meta-Analysis of the Left heart (EchoNoRMAL) Collaboration. A meta-analysis of echocardiographic measurements of the left heart for the development of normative reference ranges in a large international cohort: the EchoNoRMAL study. Eur Heart J Cardiovasc Imaging. 2014; 15: 341-348.
  23. Tortoledo FA, Fernandez GC, Quinones MA. An accurate and simplified method to calculate angiographic left ventricular ejection fraction. Cathet Cardiovasc Diagn. 1983; 9: 357-362.
  24. Apovian CM, Okemah J, O’Neil PM. Body Weight Considerations in the Management of Type 2 Diabetes. Adv Ther. 2019; 36: 44-58.
  25. Ahrén B. DPP-4 inhibitors. Best Pract Res Clin Endocrinol Metab. 2007; 21: 517-533.
  26. Sawada F, Inoguchi T, Tsubouchi H, Sasaki S, Fujii M, Maeda Y, et al. Differential effect of sulfonylureas on production of reactive oxygen species and apoptosis in cultured pancreatic beta-cell line, MIN6. Metabolism. 2008; 57: 1038-1045.
  27. Nichols CG, Singh GK, Grange DK. KATP channels and cardiovascular disease: suddenly a syndrome. Circ Res. 2013; 112: 1059-1072.
  28. Subrahmanyan NA, Koshy RM, Jacob K, Pappachan JM. Efficacy and Cardiovascular Safety of DPP-4 Inhibitors. Curr Drug Saf. 2021; 16: 154-164.
  29. Li L, Li S, Deng K, Liu J, Vandvik PO, Zhao P, et al. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies. BMJ. 2016; 352: i610.
  30. Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015; 385: 2067-2076.
  31. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013; 369: 1317-1326.
  32. McGuire DK, Alexander JH, Johansen OE, Perkovic V, Rosenstock J, Cooper ME, et al. Linagliptin Effects on Heart Failure and Related Outcomes in Individuals With Type 2 Diabetes Mellitus at High Cardiovascular and Renal Risk in CARMELINA. Circulation. 2019; 139: 351-361.
  33. Deacon CF. Physiology and Pharmacology of DPP-4 in Glucose Homeostasis and the Treatment of Type 2 Diabetes. Front Endocrinol (Lausanne). 2019; 10: 80. Erratum in: Front Endocrinol (Lausanne). 2019; 10: 275.
  34. Moertl D, Hammer A, Steiner S, Hutuleac R, Vonbank K, Berger R. Dose-dependent effects of omega-3-polyunsaturated fatty acids on systolic left ventricular function, endothelial function, and markers of inflammation in chronic heart failure of nonischemic origin: a double-blind, placebo-controlled, 3-arm study. Am Heart J. 2011; 161: 915.e1-915.e9.