Dapagliflozin induced metabolic health markers dynamics in patients with type 2 diabetes mellitus

• Sayyyna P. Gogoleva
• Alexander S. Ametov
• Alla A. Shabalina
• Ksenia V. Antonova

Abstract

Sodium-glucose cotransporter type 2 inhibitors (iSGLT2) have demonstrated significant cardio- and renoprotective effects that cannot be explained only by the hypoglycemic effect of these drugs in a number of studies. Thus, it is important to study the effect of this class of drugs on fat metabolism, primarily due to the fact that 85% of patients with type 2 diabetes mellitus (T2DM) are obese.

Aim. To evaluate the effect of dapagliflozin on fat metabolism in patients with T2DM.

Material and methods. We examined 60 people with DM2 and obesity. As a hypoglycemic treatment patients received metformin. Dapagliflozin was added to metformin at a dose of 10 mg. The study lasted for 6 months. Along with the traditional indicators of carbohydrate (fasting plasma glucose, glycated hemoglobin) and lipid metabolism [total cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL), triglycerides, lipoprotein (a), small, LDL, atherogenic index, we studied markers of fat metabolism: anthropometric data, bioimpedance body composition analysis, levels of adiponectin, leptin, interleukin‑6, and irisin.

Results. Along with a decrease in body weight, waist circumference and fat mass, a significant increase in the levels of adiponectin (p=0.04) and irisin (p=0.05), as well as a tendency to decrease of the leptin level was documented.

Conclusion. In response to hypoglycemic drug dapagliflozin addition significant positive effects on fat metabolism were obtained. A decrease in body weight and adipose tissue mass correlated with a decrease in leptin levels. Simultaneously an increase in the level of adiponectin and irisin was documented.

Keywords:adiponectin; leptin; irisin; interleukin 6; dapagliflozin; metabolic health

References

1. IDF Diabetes Atlas. 10th ed. Brussels, Belgium: International Diabetes Federation, 2021. URL: https://diabetesatlas.org/

2. World Health Organization Diabetes Fact Sheets, 2022. URL: https://www.who.int/news-room/fact-sheets/detail/diabetes

3. Blonde L., Stenlöf K., Fung A., Xie J., Canovatchel W., Meininger G. Effects of canagliflozin on body weight and body composition in patients with type 2 diabetes over 104 weeks. Postgrad Med. 2016; 128 (4): 371–80. DOI: https://doi.org/10.1080/00325481.2016.1169894

4. Zelniker T.A., Wiviott S.D., Raz I., Im K., Goodrich E.L., Bonaca M.P., et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019; 393 (10 166): 31–9. DOI: https://doi.org/10.1016/S-0140-6736(18)32590-X

5. Wiviott S.D., Raz I., Bonaca M.P., Mosenzon O., Kato E.T., Cahn A., et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019; 380 (4): 347–57. DOI: https://doi.org/10.1056/NEJMoa1812389

6. Wilding J., Bailey C., Rigney U., Blak B. Glycated hemoglobin, body weight and blood pressure in type 2 diabetes patients initiating dapagliflozin treatment in primary care: a retrospective study. Diabetes Ther. 2016; 7: 695–711. DOI: https://doi.org/10.1007/s13300-016-0193-8

7. Zinman B., Wanner C., Lachin J.M., Fitchett D., Bluhmki E., Hantel S., et al.; on behalf of the EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373: 2117–28. DOI: https://doi.org/10.1056/NEJMoa1504720

8. Mikhail N. Place of sodium-glucose co-transporter type 2 inhibitors for treatment of type 2 diabetes. World J Diabetes. 2014; 5 (6): 854–9. PMID: 25512787 DOI: https://doi.org/10.4239/wjd.v5.i6.854

9. Report CMaMW. Prevalence of overweight and obesity among adults with diagnosed diabetes – United States, 1988–1994 and 1999–2002. MMWR Morb Mortal Wkly Rep. 2004; 53 (45): 1066–8. URL: https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5345a2.htm

10. Harvard Medical School. Healthy Eating Plate dishes out sound diet advice: more specific than MyPlate, it pinpoints the healthiest food choices. Harv Heart Lett. 2011; 22 (4): 6. URL: https://www.health.harvard.edu/heart-health/healthy-eating-plate-dishes-out-sound-diet-advice

11. Stefan N., Stumvoll M. Adiponectin--its role in metabolism and beyond. Horm Metab Res. 2002; 34 (9): 469–74. DOI: https://doi.org/10.2302/kjm.60.1

12. Kobayashi M., Deguchi Y., Nozaki Y., et al. Contribution of PGC-1a to obesity- and caloric restriction-related physiological changes in white adipose tissue. Int J Mol Sci. 2021; 22 (11): 6025. DOI: https://doi.org/10.3390/ijms22116025

13. Bao J.F., She Q.Y., Hu P.P., Jia N., Li A. Irisin, a fascinating field in our times. Trends Endocrinol Metab. 2022; 33 (9): 601–13. DOI: https://doi.org/10.1016/j.tem.2022.06.003

14. Ciaraldi T.P., Ryan A.J., Mudaliar S.R., Henry R.R. Altered myokine secretion is an intrinsic property of skeletal muscle in type 2 diabetes. PLoS One. 2016; 11 (7): e0158209. DOI: https://doi.org/10.1371/journal.pone.0158209

15. Schmidt F.M., Weschenfelder J., Sander C., et al. Inflammatory cytokines in general and central obesity and modulating effects of physical activity. PLoS One. 2015; 10 (3): e0121971. DOI: https://doi.org/10.1371/journal.pone.0121971

16. Tsalamandris S., Antonopoulos A.S., Oikonomou E., et al. The role of inflammation in diabetes: current concepts and future perspectives. Eur Cardiol. 2019; 14 (1): 50–9. DOI: https://doi.org/10.15420/ecr.2018.33.1

17. Rus H.G., Vlaicu R., Niculescu F. Interleukin-6 and interleukin-8 protein and gene expression in human arterial atherosclerotic wall. Atherosclerosis. 1996; 127 (2): 263–71. DOI: https://doi.org/10.1016/S-0021-9150(96)05968-0

18. Eltoft A., Arntzen K.A., Wilsgaard T., Mathiesen E.B., Johnsen S.H. Interleukin-6 is an independent predictor of progressive atherosclerosis in the carotid artery: the Tromso Study. Atherosclerosis. 2018; 271: 1–8. DOI: https://doi.org/10.1016/j.atherosclerosis.2018.02.005

19. Mohammed Saeed W., Nasser Binjawhar D. Association of serum leptin and adiponectin concentrations with type 2 diabetes biomarkers and complications among Saudi women. Diabetes Metab Syndr Obes. 2023; 16: 2129–40. DOI: https://doi.org/10.2147/DMSO.S405476

20. Zaccardi F., Webb D.R., Htike Z.Z., Youssef D., Khunti K., Davies M.J. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: Systematic review and network meta-analysis. Diabetes Obes Metab. 2016; 18 (8): 783–94. DOI: https://doi.org/10.1111/dom.12670

21. Scheerer M.F., Rist R., Proske O., Meng A., Kostev K. Changes in HbA1c, body weight, and systolic blood pressure in type 2 diabetes patients initiating dapagliflozin therapy: a primary care database study. Diabetes Metab Syndr Obes. 2016; 9: 337–45. DOI: https://doi.org/10.2147/DMSO.S-116243

22. Bolinder J., Ljunggren Ö., Kullberg J., Johansson L., Wilding J., Langkilde A.M., et al. 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. 2012; 97 (3): 1020–31. DOI: https://doi.org/10.1210/jc.2011-2260

23. Blonde L., Stenlöf K., Fung A., Xie J., Canovatchel W., Meininger G. Effects of canagliflozin on body weight and body composition in patients with type 2 diabetes over 104 weeks. Postgrad Med. 2016; 128 (4): 371–80. DOI: https://doi.org/10.1080/00325481.2016.1169894

24. Bolinder J., Ljunggren Ö., Kullberg J., Johansson L., Wilding J., Langkilde A.M., et al. 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. 2012; 97 (3): 1020–31. DOI: https://doi.org/10.1210/jc.2011-2260

25. Tobita H., Sato S., Miyake T., Ishihara S., Kinoshita Y. Effects of dapagliflozin on body composition and liver tests in patients with nonalcoholic steatohepatitis associated with type 2 diabetes mellitus: a prospective, open-label, uncontrolled study. Curr Ther Res Clin Exp. 2017; 87: 13–9. DOI: https://doi.org/10.1016/j.curtheres.2017.07.002

26. Yamakage H., Tanaka M., Inoue T., Odori S., Kusakabe T., Satoh-Asahara N. Effects of dapagliflozin on the serum levels of fibroblast growth factor 21 and myokines and muscle mass in Japanese patients with type 2 diabetes: a randomized, controlled trial. J Diabetes Investig. 2020; 11 (3): 653–61. DOI: https://doi.org/10.1111/jdi.13179

27. Merovci S.-H.C., Daniele G., Eldor R., Fiorentino T.V., Tripathy D., et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014; 124 (2): 509–14. DOI: https://doi.org/10.1172/JCI70704

28. Obata K.N., Kubota T., Iwamoto M., Sato H., Sakurai Y., Takamoto I., et al. Tofogliflozin improves insulin resistance in skeletal muscle and accelerates lipolysis in adipose tissue in male mice. Endocrinology. 2016; 157 (3): 1029–42. DOI: https://doi.org/10.1210/en.2015-1588

29. Sugiyama S., Jinnouchi H., Kurinami N., Hieshima K., Yoshida A., Jinnouchi K., et al. Dapagliflozin reduces fat mass without affecting muscle mass in type 2 diabetes. J Atheroscler Thromb. 2018; 25 (6): 467–76. DOI: https://doi.org/10.5551/jat.40873

30. Bell D.S., Patil H.R., O’Keefe J.H. Divergent effects of various diabetes drugs on cardiovascular prognosis. Rev Cardiovasc Med. 2013; 14 (2-4): e107-22. DOI: https://doi.org/10.3909/ricm0671

31. Zaccardi F., Webb D.R., Htike Z.Z., Youssef D., Khunti K., Davies M.J. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: Systematic review and network meta-analysis. Diabetes Obes Metab. 2016; 18 (8): 783–94. DOI: https://doi.org/10.1111/dom.12670

All articles in our journal are distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0 license)