Diabetes Metab J.  2019 Oct;43(5):711-717. 10.4093/dmj.2018.0208.

Effects of Dapagliflozin on Endothelial Function, Renal Injury Markers, and Glycemic Control in Drug-Naïve Patients with Type 2 Diabetes Mellitus

• Kong SH
• Koo BK
• Moon MK

• KMID: 2460963
• DOI: http://doi.org/10.4093/dmj.2018.0208

Abstract

BACKGROUND
The study aimed to evaluate the effects of dapagliflozin and metformin on vascular endothelial function and renal injury markers.
METHODS
This prospective, randomized, open-label, crossover study included drug-naïve patients with type 2 diabetes mellitus, who were randomized to receive 8 weeks of initial treatment using metformin or dapagliflozin and crossed over for another 8 weeks of treatment after a 1-week washout period. Systemic endothelial function was evaluated via the reactive hyperemic index (RHI).
RESULTS
The 22 participants included 10 males (45.5%) and had a median age of 58 years. The RHI values were not significantly changed during both 8-week treatment periods and there was no significant difference between the treatments. Relative to the metformin group, 8 weeks of dapagliflozin treatment produced significantly higher median N-acetyl-beta-D-glucosaminidase levels (10.0 ng/mL [interquartile range (IQR), 6.8 to 12.1 ng/mL] vs. 5.6 ng/mL [IQR, 3.8 to 8.0 ng/mL], P=0.013). Only the dapagliflozin group exhibited improved homeostatic model assessment of insulin resistance and body weight, while serum ketone and β-hydroxybutyrate levels increased.
CONCLUSION
Dapagliflozin treatment did not affect systemic endothelial function or renal injury markers except N-acetyl-beta-D-glucosaminidase.

Keyword

Diabetes mellitus; Disease management; Metformin

MeSH Terms

Acetylglucosaminidase
Body Weight
Cross-Over Studies
Diabetes Mellitus
Diabetes Mellitus, Type 2*
Disease Management
Humans
Insulin Resistance
Male
Metformin
Prospective Studies
Acetylglucosaminidase
Metformin

Reference

1. Luscher TF, Barton M. Biology of the endothelium. Clin Cardiol. 1997; 20:II-3-10.

2. Kinlay S, Libby P, Ganz P. Endothelial function and coronary artery disease. Curr Opin Lipidol. 2001; 12:383–389. PMID: 11507322.

3. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004; 109:III27–III32. PMID: 15198963.

4. Oelze M, Kroller-Schon S, Welschof P, Jansen T, Hausding M, Mikhed Y, Stamm P, Mader M, Zinbius E, Agdauletova S, Gottschlich A, Steven S, Schulz E, Bottari SP, Mayoux E, Munzel T, Daiber A. The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity. PLoS One. 2014; 9:e112394. PMID: 25402275.

5. Salim HM, Fukuda D, Yagi S, Soeki T, Shimabukuro M, Sata M. Glycemic control with ipragliflozin, a novel selective SGLT2 inhibitor, ameliorated endothelial dysfunction in streptozotocin-induced diabetic mouse. Front Cardiovasc Med. 2016; 3:43. PMID: 27833913.

6. Steven S, Oelze M, Hanf A, Kroller-Schon S, Kashani F, Roohani S, Welschof P, Kopp M, Godtel-Armbrust U, Xia N, Li H, Schulz E, Lackner KJ, Wojnowski L, Bottari SP, Wenzel P, Mayoux E, Munzel T, Daiber A. The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats. Redox Biol. 2017; 13:370–385. PMID: 28667906.

7. Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, Broedl UC. EMPA-REG RENAL trial investigators. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014; 2:369–384. PMID: 24795251.

8. Fioretto P, Zambon A, Rossato M, Busetto L, Vettor R. SGLT2 inhibitors and the diabetic kidney. Diabetes Care. 2016; 39(Suppl 2):S165–S171. PMID: 27440829.

9. Cherney DZ, Perkins BA, Soleymanlou N, Xiao F, Zimpelmann J, Woerle HJ, Johansen OE, Broedl UC, von Eynatten M, Burns KD. Sodium glucose cotransport-2 inhibition and intrarenal RAS activity in people with type 1 diabetes. Kidney Int. 2014; 86:1057–1058. PMID: 25360497.

10. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE. EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373:2117–2128. PMID: 26378978.

11. Anderson TJ, Elstein E, Haber H, Charbonneau F. Comparative study of ACE-inhibition, angiotensin II antagonism, and calcium channel blockade on flow-mediated vasodilation in patients with coronary disease (BANFF study). J Am Coll Cardiol. 2000; 35:60–66. PMID: 10636260.

12. Cheetham C, Collis J, O'Driscoll G, Stanton K, Taylor R, Green D. Losartan, an angiotensin type 1 receptor antagonist, improves endothelial function in non-insulin-dependent diabetes. J Am Coll Cardiol. 2000; 36:1461–1466. PMID: 11079643.

13. Deshmukh SH, Patel SR, Pinassi E, Mindrescu C, Hermance EV, Infantino MN, Coppola JT, Staniloae CS. Ranolazine improves endothelial function in patients with stable coronary artery disease. Coron Artery Dis. 2009; 20:343–347. PMID: 19444092.

14. Liangos O, Perianayagam MC, Vaidya VS, Han WK, Wald R, Tighiouart H, MacKinnon RW, Li L, Balakrishnan VS, Pereira BJ, Bonventre JV, Jaber BL. Urinary N-acetyl-beta-(D)-glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure. J Am Soc Nephrol. 2007; 18:904–912. PMID: 17267747.

15. Patel DN, Kalia K. Efficacy of urinary N-acetyl-β-D-glucosaminidase to evaluate early renal tubular damage as a consequence of type 2 diabetes mellitus: a cross-sectional study. Int J Diabetes Dev Ctries. 2015; 35(Suppl 3):449–457.

16. Hussey EK, Dobbins RL, Stoltz RR, Stockman NL, O'Connor-Semmes RL, Kapur A, Murray SC, Layko D, Nunez DJ. Multiple-dose pharmacokinetics and pharmacodynamics of sergliflozin etabonate, a novel inhibitor of glucose reabsorption, in healthy overweight and obese subjects: a randomized double-blind study. J Clin Pharmacol. 2010; 50:636–646. PMID: 20200268.

17. Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol. 2004; 44:2137–2141. PMID: 15582310.

18. Kuvin JT, Patel AR, Sliney KA, Pandian NG, Sheffy J, Schnall RP, Karas RH, Udelson JE. Assessment of peripheral vascular endothelial function with finger arterial pulse wave amplitude. Am Heart J. 2003; 146:168–174. PMID: 12851627.