Skip to main content
Log in

Cardiovascular risk reduction throughout GLP-1 receptor agonist and SGLT2 inhibitor modulation of epicardial fat

  • Review
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Epicardial adipose tissue is a novel cardiovascular risk factor. It plays a role in the progression of coronary artery disease, heart failure and atrial fibrillation. Given its rapid metabolism, clinical measurability, and modifiability, epicardial fat works well as therapeutic target of drugs modulating the adipose tissue. Epicardial fat responds to glucagon-like peptide 1 receptor agonists (GLP1A) and sodium glucose co-transporter 2 inhibitors (SGLT2i). GLP-1A and SGLT2i provide weight loss and cardiovascular protective effects beyond diabetes control, as recently demonstrated. The potential of modulating the epicardial fat morphology and genetic profile with targeted pharmacological agents can open new avenues in the pharmacotherapy of diabetes and obesity, with particular focus on cardiovascular risk reduction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Iacobellis G (2015) Local and systemic effects of the multifaceted epicardial adipose tissue depot. Nat Rev Endocrinol 11:363–371

    CAS  PubMed  Google Scholar 

  2. Iacobellis G, Corradi D, Sharma AM (2005) Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart. Nat Clin Pract Cardiovasc Med 2:536–543

    PubMed  Google Scholar 

  3. Iacobellis G, Bianco AC (2011) Epicardial adipose tissue: emerging physiological, pathophysiological and clinical features. Trends Endocrinol Metab 22:450–457

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Sacks HS, Fain JN, Holman B, Cheema P, Chary A, Parks F (2009) Uncoupling Protein-1 and related mRNAs in human epicardial and other adipose tissues: epicardial fat functioning as brown fat. J Clin Endocrinol Metab 94:3611–3615

    CAS  PubMed  Google Scholar 

  5. Sacks HS, Fain JN, Bahouth SW, Ojha S, Frontini A, Budge H et al (2013) Human epicardial fat exhibits beige features. J Clin Endocrinol Metab 98:E1448–E1455

    CAS  PubMed  Google Scholar 

  6. McAninch EA, Fonseca TL, Poggioli R, Panos AL, Salerno TA, Deng Y, Li Y, Bianco AC, Iacobellis G (2015) Epicardial adipose tissue has a unique transcriptome modified in severe coronary artery disease. Obesity (Silver Spring) 23:1267–1278

    CAS  PubMed Central  Google Scholar 

  7. Mazurek T, Zhang L, Zalewski A, Mannion JD, Diehl JT, Arafat H et al (2003) Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 108:2460–2466

    PubMed  Google Scholar 

  8. Dutour A, Achard V, Sell H, Naour N, Collart F, Gaborit B et al (2010) Secretory type II phospholipase A2 is produced and secreted by epicardial adipose tissue and overexpressed in patients with CAD. J Clin Endocrinol Metab 95:963–967

    CAS  PubMed  Google Scholar 

  9. Karastergiou K, Evans I, Ogston N, Miheisi N, Nair D, Kaski JC et al (2010) Epicardial adipokines in obesity and coronary artery disease induce atherogenic changes in monocytes and endothelial cells. Arterioscler Thromb Vasc Biol 30:1340–1346

    CAS  PubMed  Google Scholar 

  10. Hirata Y, Tabata M, Kurobe H, Motoki T, Akaike M, Nishio C et al (2011) Coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue. J Am Coll Cardiol 58:248–255

    CAS  PubMed  Google Scholar 

  11. Iozzo P (2011) Myocardial, perivascular, and epicardial fat. Diabetes Care 34(Suppl 2):S371–S379

    CAS  PubMed  PubMed Central  Google Scholar 

  12. de Vos AM, Prokop M, Roos CJ, Meijs MF, van der Schouw YT, Rutten A (2008) Peri-coronary epicardial adipose tissue is related to cardiovascular risk factors and coronary artery calcification in post-menopausal women. Eur Heart J 29:777–783

    PubMed  Google Scholar 

  13. Mahabadi AA, Lehmann N, Kälsch H, Robens T, Bauer M, Dykun I et al (2014) Association of epicardial adipose tissue with progression of coronary artery calcification is more pronounced in the early phase of atherosclerosis: results from the Heinz Nixdorf recall study. JACC Cardiovasc Imaging 7:909–916

    PubMed  Google Scholar 

  14. Alexopoulos N, McLean DS, Janik M, Arepalli CD, Stillman AE, Raggi P (2010) Epicardial adipose tissue and coronary artery plaque characteristics. Atherosclerosis 210:150–154

    CAS  PubMed  Google Scholar 

  15. Iacobellis G, Lonn E, Lamy A, Singh N, Sharma AM (2011) Epicardial fat thickness and CAD correlate independently of obesity. Int J Cardiol 146:452–454

    PubMed  Google Scholar 

  16. Camarena V, Sant D, Mohseni M, Salerno T, Zaleski ML, Wang G, Iacobellis G (2017) Novel atherogenic pathways from the differential transcriptome analysis of diabetic epicardial adipose tissue. Nutr Metab Cardiovasc Dis 27:739–750

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Goldberger JJ, Arora R, Green D, Greenland P, Lee DC, Lloyd-Jones DM et al (2015) Evaluating the atrial myopathy underlying atrial fibrillation: identifying the arrhythmogenic and thrombogenic substrate. Circulation 132:278–291

    PubMed  PubMed Central  Google Scholar 

  18. Wong CX, Ganesan AN, Selvanayagam JB (2017) Epicardial fat and atrial fibrillation: current evidence, potential mechanisms, clinical implications, and future directions. Eur Heart J 38:1294–1302

    CAS  PubMed  Google Scholar 

  19. Gaborit B, Venteclef N, Ancel P, Pelloux V, Gariboldi V, Leprince P et al (2015) Human epicardial adipose tissue has a specific transcriptomic signature depending on its anatomical peri-atrial, peri-ventricular, or peri-coronary location. Cardiovasc Res 108:62–73

    CAS  PubMed  Google Scholar 

  20. Nagashima K, Okumura Y, Watanabe I, Nakai T, Ohkubo K, Kofune T et al (2011) Association between epicardial adipose tissue volumes on 3-dimensional reconstructed CT images and recurrence of atrial fibrillation after catheter ablation. Circulation 75:2559–2565

    CAS  Google Scholar 

  21. Packer M (2018) Epicardial adipose tissue may mediate deleterious effects of obesity and inflammation on the myocardium. J Am Coll Cardiol 71(20):2360–2372

    CAS  PubMed  Google Scholar 

  22. Wernstedt Asterholm I, Tao C, Morley TS, Wang QA, Delgado-Lopez F, Wang ZV, Scherer PE (2014) Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab 20(1):103–118

    CAS  PubMed  Google Scholar 

  23. van Woerden G, Gorter TM, Westenbrink BD, Willems TP, van Veldhuisen DJ, Rienstra M (2018) Epicardial fat in heart failure patients with mid-range and preserved ejection fraction. Eur J Heart Fail 20:1559–1566

    PubMed  Google Scholar 

  24. Kim SA, Kim MN, Shim WJ, Park SM (2017) Epicardial adipose tissue is related to cardiac function in elderly women, but not in men. Nutr Metab Cardiovasc Dis 27:41–47

    PubMed  Google Scholar 

  25. Iacobellis G, Willens HJ (2009) Echocardiographic Epicardial Fat: A Review of Research and Clinical Applications. J Am Soc Echocardiogr 22:1311–1319

    PubMed  Google Scholar 

  26. Iacobellis G, Assael F, Ribaudo MC, Zappaterreno A, Alessi G, Di Mario U, Leonetti F (2003) Epicardial fat from echocardiography: a new method for visceral adipose tissue prediction. Obes Res 11:304–310

    PubMed  Google Scholar 

  27. Iacobellis G, Mahabadi AA (2019) Is epicardial fat attenuation a novel marker of coronary inflammation? Atherosclerosis 284:212–213

    CAS  PubMed  Google Scholar 

  28. Epicardial Fat Inflammation in Severe COVID-19. Iacobellis G, Secchi F, Capitanio G, Basilico S, Schiaffino S, Boveri S, Sardanelli F, Corsi Romanelli MM, Malavazos AE (2020) Obesity (Silver Spring) 28:2260–226

  29. Malavazos AE, Goldberger JJ (2020) Iacobellis G Does epicardial fat contribute to COVID-19 myocardial inflammation? Eur Heart J 41(24):233

    Google Scholar 

  30. Kobylecka M, Mączewska J, Fronczewska-Wieniawska K, Mazurek T, Płazińska MT, Królicki L (2012) Myocardial viability assessment in 18FDG PET/CT study (18FDG PET myocardial viability assessment). Nucl Med Rev Cent East Eur 15(1):52–60

    PubMed  Google Scholar 

  31. Iacobellis G, Ribaudo MC, Assael F, Vecci E, Tiberti C, Zappaterreno A et al (2003) Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk. J Clin Endocrinol Metab 388:5163–5168

    Google Scholar 

  32. Malavazos AE, Di Leo G, Secchi F, Lupo EN, Dogliotti G, Coman C et al (2010) Relation of Echocardiographic Epicardial Fat Thickness and Myocardial Fat. Am J Cardiol 105:1831–1835

    PubMed  Google Scholar 

  33. Bertoccini L, Baroni MG (2021) GLP-1 receptor agonists and SGLT2 inhibitors for the treatment of Type 2 Diabetes: new insights and opportunities for cardiovascular protection. Adv Exp Med Biol 1307:193–212

    CAS  PubMed  Google Scholar 

  34. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, LEADER Steering Committee; LEADER Trial Investigators et al (2016) Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 375:311–322

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, SUSTAIN-6 Investigators et al (2016) Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 375:1834–2184

    CAS  PubMed  Google Scholar 

  36. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, REWIND Investigators et al (2019) Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 394:121–130

    CAS  PubMed  Google Scholar 

  37. Kadouh H, Chedid V, Halawi H, Burton DD, Clark MM, Khemani D, Vella A, Acosta A, Camilleri M (2020) GLP-1 analog modulates appetite, taste preference, gut hormones, and regional body fat stores in adults with obesity. J Clin Endocrinol Metab 105(5):1552–1563

    Google Scholar 

  38. Feng WH, Bi Y, Li P, Yin TT, Gao CX, Shen SM, Gao LJ, Yang DH, Zhu DL (2019) Effects of liraglutide, metformin and gliclazide on body composition in patients with both type 2 diabetes and non-alcoholic fatty liver disease: a randomized trial. J Diabetes Investig 10(2):399–407

    CAS  PubMed  Google Scholar 

  39. Dozio E, Vianello E, Malavazos AE, Tacchini L, Schmitz G, Iacobellis G, Corsi Romanelli MM (2019) Epicardial adipose tissue GLP-1 receptor is associated with genes involved in fatty acid oxidation and white-to-brown fat differentiation: a target to modulate cardiovascular risk? Int J Cardiol 1(292):218–224

    Google Scholar 

  40. Iacobellis G, Mohseni M, Bianco S, Banga PK (2017) Liraglutide causes large and rapid Epicardial Fat reduction. Obesity 25:311–316

    CAS  PubMed  Google Scholar 

  41. Morano S, Romagnoli E, Filardi T, Nieddu L, Mandosi E, Fallarino M et al (2015) Short-term effects of glucagon-like peptide 1 (GLP-1) receptor agonists on fat distribution in patients with type 2 diabetes mellitus: an ultrasonography study. Acta Diabetol 52:727–732

    CAS  PubMed  Google Scholar 

  42. Li Y, Liu X, Li G et al (2020) Effect of liraglutide on epicardial adipose tissue thickness with echocardiography in patients with obese type 2 diabetes mellitus. Int J Diabetes Dev Ctries 40:500–506

    CAS  Google Scholar 

  43. Dutour A, Abdesselam I, Ancel P, Kober F, Mrad G, Darmon P et al (2016) Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: a prospective randomized clinical trial using magnetic resonance imaging and spectroscopy. Diabetes Obes Metab 18:882–891

    CAS  PubMed  Google Scholar 

  44. Iacobellis G, Villasante Fricke AC (2020) Effects of semaglutide versus dulaglutide on epicardial fat thickness in subjects with Type 2 diabetes and obesity. J Endocr Soc. 4(4):bvz042

    PubMed  PubMed Central  Google Scholar 

  45. Iacobellis G, Camarena V, Sant DW, Wang G (2017) Human epicardial fat expresses glucagon-like peptide 1 and 2 receptors genes. Horm Metab Res 49:625–630

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Pyke C, Knudsen LB (2013) The glucagon-like peptide-1 receptor-or not? Endocrinology 154:4–8

    CAS  PubMed  Google Scholar 

  47. Yang J, Ren J, Song J, Liu F, Wu C, Wang X et al (2013) Glucagon-like peptide 1 regulates adipogenesis in 3T3-L1 preadipocytes. Int J Mol Med 31:1429–1435

    CAS  PubMed  Google Scholar 

  48. Beiroa D, Imbernon M, Gallego R, Senra A, Herranz D, Villarroya F et al (2014) GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 63:3346–3358

    CAS  PubMed  Google Scholar 

  49. Vendrell J, El Bekay R, Peral B, García-Fuentes E, Megia A, Macias-Gonzalez M et al (2011) Study of the potential association of adipose tissue GLP-1 receptor with obesity and insulin resistance. Endocrinology 152:4072–4079

    CAS  PubMed  Google Scholar 

  50. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, EMPA-REG OUTCOME Investigators et al (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373:2117–2128

    CAS  PubMed  Google Scholar 

  51. Mahaffey KW, Neal B, Perkovic V, de Zeeuw D, Fulcher G, Erondu N, CANVAS Program Collaborative Group et al (2018) Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation 137:323–334

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, DECLARE–TIMI 58 Investigators et al (2019) Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 380:347–357

    CAS  PubMed  Google Scholar 

  53. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, DAPA-HF Trial Committees and Investigators et al (2019) Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med 381(21):1995–2008. https://doi.org/10.1056/NEJMoa1911303

    Article  CAS  PubMed  Google Scholar 

  54. Hallow KM, Helmlinger G, Greasley PJ, McMurray JJV, Boulton DW (2018) Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metab 20(3):479–487

    CAS  PubMed  Google Scholar 

  55. Ferrannini E, Mark M, Mayoux E (2016) CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care 39:1108–1114

    PubMed  Google Scholar 

  56. Lopaschuk GD, Ussher JR, Folmes CDL, Jaswal JS, Stanley WC (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90:207–258

    CAS  PubMed  Google Scholar 

  57. Neubauer S (2007) The failing heart—an engine out of fuel. N Engl J Med 356:1140

    PubMed  Google Scholar 

  58. Verma S, Rawat S, Ho KL et al (2018) Empagliflozin increases cardiac energy production in diabetes novel translational insights into the heart failure benefits of SGLT2 inhibitors. J Am Coll Cardiol Basic Trans Sci 3:575–587

    Google Scholar 

  59. Dick SA, Epelman S (2016) Chronic heart failure and inflammation: what do we really know? Circ Res 119:159–176

    CAS  PubMed  Google Scholar 

  60. Mehta JL, Pothineni NV (2016) Inflammation in heart failure: the holy grail? Hypertension 68:27–29

    CAS  PubMed  Google Scholar 

  61. Lymperopoulos A, Borges JI, Cora N, Sizova A (2021) Sympatholytic mechanisms for the beneficial cardiovascular effects of SGLT2 inhibitors: a research hypothesis for Dapagliflozin’s effects in the adrenal gland. Int J Mol Sci 22:7684

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Kimura I, Inoue D, Maeda T et al (2011) Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci USA 108:8030–8035

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Guedes EP, Hohl A, de Melo TG, Lauand F (2013) Dapagliflozin: farmacology, efficacy and safety in type 2 diabetes treatment. Diabetol Metab Syndr 5:25

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Bolinder J, Ljunggren Ö, Kullberg J, Johansson L, Wilding J, Langkilde AM, Sugg J, Parikh S (2012) Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab 97:1020–1031

    CAS  PubMed  Google Scholar 

  65. Iacobellis G, Gra-Menendez S (2020) Effects of dapagliflozin on epicardial fat thickness in patients with Type 2 diabetes and obesity. Obesity (Silver Spring) 28:1068–1074

    CAS  Google Scholar 

  66. Sato T, Aizawa Y, Yuasa S, Kishi S, Fuse K, Fujita S et al (2018) The effect of dapagliflozin treatment on epicardial adipose tissue volume. Cardiovasc Diabetol 17:6

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Díaz-Rodríguez E, Agra RM, Fernández ÁL, Adrio B, García-Caballero T, González-Juanatey JR, Eiras S (2018) Effects of dapagliflozin on human epicardial adipose tissue: modulation of insulin resistance, inflammatory chemokine production, and differentiation ability. Cardiovasc Res 114:336–346

    PubMed  Google Scholar 

  68. Yagi S, Hirata Y, Ise T, Kusunose K, Yamada H, Fukuda D et al (2017) Canagliflozin reduces epicardial fat in patients with type 2 diabetes mellitus. Diabetol Metab Syndr 9:78

    PubMed  PubMed Central  Google Scholar 

  69. Fukuda T, Bouchi R, Terashima M, Sasahara Y, Asakawa M, Takeuchi T et al (2017) Ipragliflozin reduces epicardial fat accumulation in non-obese Type 2 diabetic patients with visceral obesity: a pilot study. Diabetes Ther 8:851–861

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Bouchi R, Terashima M, Sasahara Y, Asakawa M, Fukuda T, Takeuchi T et al (2017) Luseogliflozin reduces epicardial fat accumulation in patients with type 2 diabetes: a pilot study. Cardiovasc Diabetol 16:32

    PubMed  PubMed Central  Google Scholar 

  71. Requena-Ibanez JA, Santos-Gallego CG, Rodriguez-Cordero A, Vargas-Delgado AP et al (2021) Mechanistic insights of empagliflozin in non-diabetic patients with HFrEF. J Am Coll Cardiol HF 9:578–589

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to G. Iacobellis.

Ethics declarations

Conflict of interest

Marco G. Baroni is Assistant Editor and member of the Editorial Board of the Journal of Endocrinological Investigation. Gianluca Iacobellis declares no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

No informed consent.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Iacobellis, G., Baroni, M.G. Cardiovascular risk reduction throughout GLP-1 receptor agonist and SGLT2 inhibitor modulation of epicardial fat. J Endocrinol Invest 45, 489–495 (2022). https://doi.org/10.1007/s40618-021-01687-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-021-01687-1

Keywords

Navigation