Endocrine

, Volume 51, Issue 3, pp 448–455 | Cite as

Effect of sitagliptin on epicardial fat thickness in subjects with type 2 diabetes and obesity: a pilot study

  • Marcos M. Lima-Martínez
  • Mariela Paoli
  • Marianela Rodney
  • Nathalie Balladares
  • Miguel Contreras
  • Luis D’Marco
  • Gianluca Iacobellis
Original Article

Abstract

The aim of the study was to assess the effect of sitagliptin addition on the epicardial adipose tissue (EAT) thickness in subjects with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. This was a 24-week interventional pilot study in 26 consecutive type 2 diabetic patients, 14 females and 12 males average age of 43.8 ± 9.0 years, with Hemoglobin A1c (HbA1c) ≥7 % on metformin monotherapy. Subjects who met the inclusion criteria were added on sitagliptin and started on sitagliptin/metformin combination at the dosage of 50 mg/1000 mg twice daily. EAT and visceral and total body fat were measured, respectively, with echocardiography and bioelectrical impedance analysis at baseline and after 24 weeks of sitagliptin/metformin treatment in each subject. HbA1c and plasma lipids were also measured. EAT decreased significantly from 9.98 ± 2.63 to 8.10 ± 2.11 mm, p = 0.001, accounting for a percentage of reduction (∆ %) of −15 % after 24 weeks of sitagliptin addition, whereas total body fat percentage, visceral fat, and body mass index (BMI), decreased by 8, 12, and 7 %, respectively (p = 0.001 for all). After 6 month, EAT ∆ % was significantly correlated with ∆ % of visceral fat (r = 0.456; p = 0.01), whereas no correlation with either BMI ∆ % (r = 0.292; p = 0.147) or HbA1c ∆ % was found. The addition of Sitagliptin produced a significant and rapid reduction of EAT, marker of organ-specific visceral fat, in overweight/obese individuals with type 2 diabetes inadequately controlled on metformin monotherapy. EAT as measured with ultrasound can serve as no invasive and accurate marker of visceral fat changes during pharmaceutical interventions targeting the fat.

Keywords

Epicardial adipose tissue Epicardial fat Sitagliptin Diet Exercise 

Notes

Acknowledgments

The authors thank Ana Pensa and José Ledezma for their support, and Prof. Carlos Mota for his valuable comments to the manuscript.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts to disclose.

References

  1. 1.
    G. Iacobellis, A.M. Sharma, Epicardial adipose tissue as new cardio-metabolic risk marker and potential therapeutic target in the metabolic syndrome. Curr. Pharm. Des. 13, 2180–2184 (2007)CrossRefPubMedGoogle Scholar
  2. 2.
    A. Gastaldelli, G. Basta, Ectopic fat and cardiovascular disease: what is the link? Nutr. Metab. Cardiovasc. Dis. 20, 481–490 (2010)CrossRefPubMedGoogle Scholar
  3. 3.
    G. Iacobellis, D. Corradi, A.M. Sharma, Epicardial adipose tissue: anatomical, biomolecular and clinical relation to the heart. Nat. Clin. Pract. Cardiovasc. Med. 2, 536–543 (2005)CrossRefPubMedGoogle Scholar
  4. 4.
    G. Iacobellis, Epicardial adipose tissue in endocrine and metabolic diseases. Endocrine 46, 8–15 (2014)CrossRefPubMedGoogle Scholar
  5. 5.
    M.M. Lima-Martínez, C. Blandenier, G. Iacobellis, Epicardial adipose tissue: more than a simple fat deposit? Endocrinol. Nutr. 60, 320–328 (2013)CrossRefPubMedGoogle Scholar
  6. 6.
    G. Iacobellis, Local and systemic effects of the multifaceted epicardial adipose tissue depot. Nat. Rev. Endocrinol. 11, 363–371 (2015)CrossRefPubMedGoogle Scholar
  7. 7.
    G. Iacobellis, H.J. Willens, Echocardiographic epicardial fat: a review of research and clinical applications. J. Am. Soc. Echocardiogr. 22, 1311–1319 (2009)CrossRefPubMedGoogle Scholar
  8. 8.
    A.E. Malavazos, G. Di Leo, F. Secchi, E.N. Lupo, G. Dogliotti, C. Coman, L. Morricone, M.M. Corsi, F. Sardanelli, G. Iacobellis, Relation of echocardiographic epicardial fat thickness and myocardial fat. Am. J. Cardiol. 105, 1831–1835 (2010)CrossRefPubMedGoogle Scholar
  9. 9.
    G. Iacobellis, M.C. Ribaudo, F. Assael, E. Vecci, C. Tiberti, A. Zappaterreno, U. Di Mario, F. Leonetti, Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk. J. Clin. Endocrinol. Metab. 88, 5163–5168 (2003)CrossRefPubMedGoogle Scholar
  10. 10.
    M.M. Lima-Martínez, G. López-Mendez, R. Odreman, J.H. Donis, M. Paoli, Epicardial adipose tissue thickness and its association with adiponectin in metabolic syndrome patients from Mérida, Venezuela. Arq. Bras. Endocrinol. Metab. 58, 352–361 (2014)CrossRefGoogle Scholar
  11. 11.
    S.D. Pierdomenico, A.M. Pierdomenico, F. Cuccurullo, G. Iacobellis, Meta-analysis of the relation of echocardiographic epicardial adipose tissue thickness and the metabolic syndrome. Am. J. Cardiol. 111, 73–78 (2013)CrossRefPubMedGoogle Scholar
  12. 12.
    G. Iacobellis, E. Lonn, A. Lamy, N. Singh, A.M. Sharma, Epicardial fat thickness and coronary artery disease correlate independently of obesity. Int. J. Cardiol. 146, 452–454 (2011)CrossRefPubMedGoogle Scholar
  13. 13.
    Y. Xu, X. Cheng, K. Hong, C. Huang, L. Wan, How to interpret epicardial adipose tissue as a cause of coronary artery disease: a meta-analysis. Coron. Artery Dis. 23, 227–233 (2012)CrossRefPubMedGoogle Scholar
  14. 14.
    H.S. Sacks, J.N. Fain, P. Cheema, S.W. Bahouth, E. Garrett, R.Y. Wolf, D. Wolford, J. Samaha, Inflammatory genes in epicardial fat contiguous with coronary atherosclerosis in the metabolic syndrome and type 2 diabetes: changes associated with pioglitazone. Diabetes Care 34, 730–733 (2011)PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    J.T. Jonker, H.J. Lamb, R.W. van der Meer, L.J. Rijzewijk, L.J. Menting, M. Diamant, J.J. Bax, A. de Roos, J.A. Romijn, J.W. Smit, Pioglitazone compared with metformin increases pericardial fat volume in patients with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 95, 456–460 (2010)CrossRefPubMedGoogle Scholar
  16. 16.
    J.H. Park, Y.S. Park, Y.J. Kim, I.S. Lee, J.H. Kim, J.H. Lee, S.W. Choi, J.O. Jeong, I.W. Seong, Effects of statins on the epicardial fat thickness in patients with coronary artery stenosis underwent percutaneous coronary intervention: comparison of atorvastatin with simvastatin/ezetimibe. J. Cardiovasc. Ultrasound. 18, 121–126 (2010)PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    G. Iacobellis, N. Singh, S. Wharton, A.M. Sharma, Substantial changes in epicardial fat thickness after weight loss in severely obese subjects. Obesity 16, 1693–1697 (2008)CrossRefPubMedGoogle Scholar
  18. 18.
    H.J. Willens, P. Byers, J.A. Chirinos, E. Labrador, J.M. Hare, E. de Marchena, Effects of weight loss after bariatric surgery on epicardial fat measured using echocardiography. Am. J. Cardiol. 99, 1242–1245 (2007)CrossRefPubMedGoogle Scholar
  19. 19.
    A.J. Scheen, Cardiovascular effects of dipeptidyl peptidase-4 inhibitors: from risk factors to clinical outcomes. Postgrad. Med. 125, 7–20 (2013)CrossRefPubMedGoogle Scholar
  20. 20.
    A. Mikada, T. Narita, H. Yokoyama, R. Yamashita, Y. Horikawa, K. Tsukiyama, Y. Yamada, Effects of miglitol, sitagliptin, and initial combination therapy with both on plasma incretin responses to a mixed meal and visceral fat in over-weight Japanese patients with type 2 diabetes. “The MASTER randomized, controlled trial”. Diabetes Res. Clin. Pract. 106, 538–547 (2014)CrossRefPubMedGoogle Scholar
  21. 21.
    R. Scott, T. Loeys, M.J. Davies, S.S. Engel, Sitagliptin Study 801 Group, Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes. Obes. Metab. 10, 959–969 (2008)CrossRefGoogle Scholar
  22. 22.
    American Diabetes Association, Classification and diagnosis of diabetes. Diabetes Care 38(Suppl), S8–S16 (2015)CrossRefGoogle Scholar
  23. 23.
    American Diabetes Association, Foundations of care: education, nutrition, physical activity, smoking cessation, psychosocial care, and immunization. Diabetes Care 38(Suppl), S20–S30 (2015)CrossRefGoogle Scholar
  24. 24.
    D.R. Matthews, J.P. Hosker, A.S. Rudenski, B.A. Naylor, D.F. Treacher, R.C. Turner, Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412–419 (1985)CrossRefPubMedGoogle Scholar
  25. 25.
    G. Iacobellis, F. Assael, M.C. Ribaudo, A. Zappaterreno, G. Alessi, U. Di Mario, F. Leonetti, Epicardial fat from echocardiography: a new method for visceral adipose tissue prediction. Obes. Res. 11, 304–310 (2003)CrossRefPubMedGoogle Scholar
  26. 26.
    T.B. Nguyen-Duy, M.Z. Nichaman, T.S. Church, S.N. Blair, R. Ross, Visceral fat and liver fat are independent predictors of metabolic risk factors in men. Am. J. Physiol. Endocrinol. Metab. 284, E1065–E1071 (2003)CrossRefPubMedGoogle Scholar
  27. 27.
    M.M. Lima-Martínez, M. Paoli, J.H. Donis, R. Odreman, C. Torres, G. Iacobellis, Cut-off point of epicardial adipose tissue thickness for predicting metabolic syndrome in Venezuelan population. Endocrinol. Nutr. 60, 570–576 (2013)CrossRefPubMedGoogle Scholar
  28. 28.
    G. Iacobellis, G. Barbaro, H.C. Gerstein, Relationship of epicardial fat thickness and fasting glucose. Int. J. Cardiol. 128, 424–426 (2008)CrossRefPubMedGoogle Scholar
  29. 29.
    G. Iacobellis, F. Leonetti, Epicardial adipose tissue and insulin resistance in obese subjects. J. Clin. Endocrinol. Metab. 90, 6300–6302 (2005)CrossRefPubMedGoogle Scholar
  30. 30.
    G. Iacobellis, S. Diaz, A. Mendez, R. Goldberg, Increased epicardial fat and plasma leptin in type 1 diabetes independently of obesity. Nutr. Metab. Cardiovasc. Dis. 24, 725–729 (2014)CrossRefPubMedGoogle Scholar
  31. 31.
    S.W. Rabkin, H. Campbell, Comparison of reducing epicardial fat by exercise, diet or bariatric surgery weight loss strategies: a systematic review and meta-analysis. Obes. Rev. 16, 406–415 (2015)CrossRefPubMedGoogle Scholar
  32. 32.
    Y. Yilmaz, O. Yonal, O. Deyneli, C.A. Celikel, C. Kalayci, D.G. Duman, Effects of sitagliptin in diabetic patients with nonalcoholic steatohepatitis. Acta Gastroenterol. Belg. 75, 240–244 (2012)PubMedGoogle Scholar
  33. 33.
    M. Itou, T. Kawaguchi, E. Taniguchi, T. Oriishi, M. Sata, Dipeptidyl peptidase IV inhibitor improves insulin resistance and steatosis in a refractory nonalcoholic fatty liver disease patient: a case report. Case Rep. Gastroenterol. 6, 538–544 (2012)PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    G. Iacobellis, G. Barbarini, C. Letizia, G. Barbaro, Epícardial fat thickness and nonalcoholic fatty liver disease in obese subjects. Obesity (Silver Spring) 22, 332–336 (2014)CrossRefGoogle Scholar
  35. 35.
    J. Vendrell, R. El Bekay, B. Peral, E. García-Fuentes, A. Megia, M. Macias-Gonzalez, J. Fernández-Real, Y. Jimenez-Gomez, X. Escoté, G. Pachón, R. Simó, D.M. Selva, M.M. Malagón, F.J. Tinahones, Study of the potential association of adipose tissue GLP-1 receptor with obesity and insulin resistance. Endocrinology 152, 4072–4079 (2011)CrossRefPubMedGoogle Scholar
  36. 36.
    S. Morano, E. Romagnoli, T. Filardi, L. Nieddu, E. Mandosi, M. Fallarino, I. Turinese, M.P. Dagostino, A. Lenzi, V. Carnevale, Short-term effects of glucagon-like peptide 1 (GLP-1) receptor agonist on fat distribution in patients with type 2 diabetes mellitus: an ultrasonography study. Acta Diabetol. 52, 727–732 (2015)CrossRefPubMedGoogle Scholar
  37. 37.
    A.R. Baker, A.L. Harte, N. Howell, D.C. Pritlove, A.M. Ranasinghe, N.F. da Silva, E.M. Youssef, K. Khunti, M.J. Davies, R.S. Bonser, S. Kumar, D. Pagano, P.G. McTernan, Epicardial adipose tissue as a source of nuclear factor-kappaB and c-Jun N-terminal kinase mediated inflammation in patients with coronary artery disease. J. Clin. Endocrinol. Metab. 94, 261–267 (2009)CrossRefPubMedGoogle Scholar
  38. 38.
    Z. Shah, T. Kampfrath, J.A. Deiuliis, J. Zhong, C. Pineda, Z. Ying, X. Xu, B. Lu, S. Moffatt-Bruce, R. Durairaj, Q. Sun, G. Mihai, A. Maiseyeu, S. Rajagopalan, Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation 124, 2338–2349 (2011)PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    A. Aroor, S. McKarns, R. Nistala, V. DeMarco, M. Gardner, M. Garcia-Touza, A. Whaley-Connell, J.R. Sowers, DPP-4 inhibitors as therapeutic modulators of immune cell function and associated cardiovascular and renal insulin resistance in obesity and diabetes. Cardiorenal. Med. 3, 48–56 (2013)PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    M.M. Lima-Martínez, E. Guerra-Alcalá, M. Contreras, J. Nastasi, J.A. Noble, C. Polychronakos, One year remission of type 1 diabetes mellitus in a patient treated with sitagliptin. Endocrinol. Diabetes Metab. Case Rep. 2014, 140072 (2014)PubMedCentralPubMedGoogle Scholar
  41. 41.
    M.M. Lima-Martínez, E. Campo, J. Salazar, M. Paoli, I. Maldonado, C. Acosta, M. Rodney, M. Contreras, J.O. Cabrera-Rego, G. Iacobellis, Epicardial fat thickness as cardiovascular risk factor and therapeutic target in patients with rheumatoid arthritis treated with biological and nonbiological therapies. Arthritis 2014, 782850 (2014)PubMedCentralCrossRefPubMedGoogle Scholar
  42. 42.
    D. Lamers, S. Famulla, N. Wronkowitz, S. Hartwig, S. Lehr, D.M. Ouwens, K. Eckardt, J.M. Kaufman, M. Ryden, S. Müller, F.G. Hanisch, J. Ruige, P. Arner, H. Sell, J. Eckel, Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes 60, 1917–1925 (2011)PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    A.D. Dobrian, Q. Ma, J.W. Lindsay, K.A. Leone, K. Ma, J. Coben, E.V. Galkina, J.L. Nadler, Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice. Am. J. Physiol. Endocrinol. Metab. 300, E410–E421 (2011)PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.
    R. Verovská, Z. Lacnák, D. Haluziková, P. Fábin, P. Hájek, L. Horák, M. Haluzík, S. Svacina, M. Matoulek, Comparison of various methods of body fat analysis in overweight and obese women. Vnitr. Lek. 55, 455–461 (2009)PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Marcos M. Lima-Martínez
    • 1
    • 2
  • Mariela Paoli
    • 3
  • Marianela Rodney
    • 4
  • Nathalie Balladares
    • 1
    • 2
  • Miguel Contreras
    • 5
  • Luis D’Marco
    • 6
  • Gianluca Iacobellis
    • 7
  1. 1.Departamento de Ciencias FisiológicasUniversidad de OrienteCiudad BolívarVenezuela
  2. 2.Anexo A Centro Médico OrinocoUnidad de Endocrinología, Diabetes, Metabolismo y NutriciónCiudad BolívarVenezuela
  3. 3.Instituto Autónomo Hospital Universitario de los AndesUnidad de EndocrinologíaMéridaVenezuela
  4. 4.Servicio de CardiologíaHospital Universitario Ruíz y PáezCiudad BolívarVenezuela
  5. 5.Centro Médico El ValleNueva EspartaVenezuela
  6. 6.Clínica Puerto OrdazUnidad Avanzada de Investigación y Diagnóstico Ecográfico y Renal (UNIRENAL)Ciudad GuayanaVenezuela
  7. 7.Division of Endocrinology, Department of MedicineUniversity of Miami Miller School of MedicineMiamiUSA

Personalised recommendations