Endocrinol Metab.  2020 Jun;35(2):329-338. 10.3803/EnM.2020.35.2.329.

Glycemic Efficacy and Metabolic Consequences of an Empagliflozin Add-on versus Conventional Dose-Increasing Strategy in Patients with Type 2 Diabetes Inadequately Controlled by Metformin and Sulfonylurea

Affiliations
  • 1Divisions of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
  • 2Divisions of Nephrology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
  • 3CNR Institute of Clinical Physiology, Pisa, Italy

Abstract

Background
We assessed the glucose-lowering efficacy of adding empagliflozin versus dose escalating existing medications in patients with uncontrolled type 2 diabetes (T2D).
Methods
This was a 6-month retrospective case-control study in subjects with uncontrolled T2D (glycated hemoglobin [HbA1c] >7%) on conventional treatment. The study group started add-on therapy with empagliflozin (10 mg once a day) while the control group was up-titrated with existing medication, using either monotherapy or a combination of metformin, sulfonylurea, and a dipeptidyl peptidase-4 inhibitor. The primary endpoints included changes in HbA1c, fasting plasma glucose (FPG), and 2-hour postprandial glucose (PP2) levels. Secondary outcomes included changes in body composition, body mass index (BMI), and serum ketone bodies, and urinary excretion of sodium, potassium, chlorine, calcium, phosphorus, and glucose.
Results
After treatment, the reduction in HbA1c was significantly greater in the empagliflozin group than in controls (from 8.6%±1.6% to 7.6%±1.5% vs. 8.5%±1.1% to 8.1%±1.1%; P<0.01). Similar patterns were found in FPG and PP2 levels. Empagliflozin decreased systolic and diastolic blood pressure, triglycerides, and alanine and aspartate aminotransferase levels. Body weight, BMI, waist circumference, fat mass, and abdominal visceral fat area decreased significantly while lean body mass was maintained. Total ketones, β-hydroxybutyrate, and acetoacetate levels increased significantly after empagliflozin.
Conclusion
In addition to glucose lowering, an empagliflozin add-on regimen decreased blood pressure and body fat, and improved metabolic profiles significantly. Empagliflozin add-on is superior to dose escalation in patients with T2D who have inadequate glycemic control on standard medications.

Keyword

Sodium-glucose transporter 2 inhibitors; Ketones; Glycosuria

Figure

  • Fig. 1 Changes in glucose homeostasis parameters after 6 months of treatment. (A) Glycated hemoglobin (HbA1c), (B) fasting plasma glucose (FPG), (C) 2-hour postprandial glucose (PP2), and (D) homeostatic model assessment of insulin resistance (HOMA-IR). aP<0.05 between the two groups.

  • Fig. 2 Changes in blood pressure and body composition after 6 months of treatment. (A) Systolic blood pressure (SBP), (B) diastolic blood pressure (DBP), (C) weight, (D) body fat, (E) abdominal visceral fat area (VFA), and (F) muscle mass. aP<0.05 between the two groups at 3 or 6 months; bP<0.05 for difference between 0 and 6 months.

  • Fig. 3 Changes in ketone bodies, glucagon, and free fatty acid (FFA) levels after 6 months of treatment. (A) Total ketone, (B) β-OH butyric acid, (C) acetoacetate, (D) glucagon, and (E) FFA. aP<0.05 between the two groups.


Reference

1. Cahn A, Cefalu WT. Clinical considerations for use of initial combination therapy in type 2 diabetes. Diabetes Care. 2016; 39(Suppl 2):S137–45.
Article
2. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2019. Diabetes Care. 2019; 42:S90–102.
3. Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia. 2017; 60:215–25.
Article
4. Ridderstrale M, Rosenstock J, Andersen KR, Woerle HJ, Salsali A. EMPA-REG H2H-SU trial investigators. Empagliflozin compared with glimepiride in metformin-treated patients with type 2 diabetes: 208-week data from a masked randomized controlled trial. Diabetes Obes Metab. 2018; 20:2768–77.
Article
5. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985; 28:412–9.
6. Lee DH, Park KS, Ahn S, Ku EJ, Jung KY, Kim YJ, et al. Comparison of abdominal visceral adipose tissue area measured by computed tomography with that estimated by bioelectrical impedance analysis method in Korean subjects. Nutrients. 2015; 7:10513–24.
Article
7. Daniele G, Xiong J, Solis-Herrera C, Merovci A, Eldor R, Tripathy D, et al. Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes. Diabetes Care. 2016; 39:2036–41.
Article
8. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care. 2016; 39:1115–22.
Article
9. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care. 2016; 39:1108–14.
Article
10. Weber MA, Mansfield TA, Alessi F, Iqbal N, Parikh S, Ptaszynska A. Effects of dapagliflozin on blood pressure in hypertensive diabetic patients on renin-angiotensin system blockade. Blood Press. 2016; 25:93–103.
Article
11. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373:2117–28.
Article
12. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019; 380:347–57.
Article
13. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; 377:644–57.
Article
14. Muskiet MHA, van Bommel EJ, van Raalte DH. Antihypertensive effects of SGLT2 inhibitors in type 2 diabetes. Lancet Diabetes Endocrinol. 2016; 4:188–9.
Article
15. Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014; 129:587–97.
Article
16. Lim S, Eckel RH, Koh KK. Clinical implications of current cardiovascular outcome trials with sodium glucose cotransporter-2 (SGLT2) inhibitors. Atherosclerosis. 2018; 272:33–40.
Article
17. Lee SJ, Lee KH, Oh HG, Seo HJ, Jeong SJ, Kim CH. Effect of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase 4 inhibitors on cardiovascular function in patients with type 2 diabetes mellitus and coronary artery disease. J Obes Metab Syndr. 2019; 28:254–61.
Article
18. Sattar N, Fitchett D, Hantel S, George JT, Zinman B. Empagliflozin is associated with improvements in liver enzymes potentially consistent with reductions in liver fat: results from randomised trials including the EMPA-REG OUTCOME® trial. Diabetologia. 2018; 61:2155–63.
Article
19. Kuchay MS, Krishan S, Mishra SK, Farooqui KJ, Singh MK, Wasir JS, et al. Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E-LIFT Trial). Diabetes Care. 2018; 41:1801–8.
Article
20. Sumida Y, Yoneda M. Current and future pharmacological therapies for NAFLD/NASH. J Gastroenterol. 2018; 53:362–76.
Article
21. Lim S, Taskinen MR, Boren J. Crosstalk between nonalcoholic fatty liver disease and cardiometabolic syndrome. Obes Rev. 2019; 20:599–611.
Article
22. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019; 380:2295–306.
Article
23. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016; 375:323–34.
Article
24. Dekkers CCJ, Wheeler DC, Sjostrom CD, Stefansson BV, Cain V, Heerspink HJL. Effects of the sodium-glucose co-transporter 2 inhibitor dapagliflozin in patients with type 2 diabetes and stages 3b-4 chronic kidney disease. Nephrol Dial Transplant. 2018; 33:2005–11.
Article
25. Skrtic M, Yang GK, Perkins BA, Soleymanlou N, Lytvyn Y, von Eynatten M, et al. Characterisation of glomerular haemodynamic responses to SGLT2 inhibition in patients with type 1 diabetes and renal hyperfiltration. Diabetologia. 2014; 57:2599–602.
Article
26. Bolinder J, Ljunggren O, Kullberg J, Johansson L, Wilding J, Langkilde AM, 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; 97:1020–31.
Article
27. Cho HA, Jung YL, Lee YH, Lee YC, Lee JE, Lee SJ, et al. Efficacy of body weight reduction on the SGLT2 inhibitor in people with type 2 diabetes mellitus. J Obes Metab Syndr. 2017; 26:107–13.
Article
28. Lim S. Effects of sodium-glucose cotransporter inhibitors on cardiorenal and metabolic systems: latest perspectives from the outcome trials. Diabetes Obes Metab. 2019; 21(Suppl 2):5–8.
Article
29. Wanner C, Marx N. SGLT2 inhibitors: the future for treatment of type 2 diabetes mellitus and other chronic diseases. Diabetologia. 2018; 61:2134–9.
Article
30. Lupsa BC, Inzucchi SE. Use of SGLT2 inhibitors in type 2 diabetes: weighing the risks and benefits. Diabetologia. 2018; 61:2118–25.
Article
Full Text Links
  • ENM
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr