Effectiveness of Dapagliflozin for Weight Loss

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

Effectiveness of the Treatment With Dapagliflozin and Metformin Compared to Metformin Monotherapy for Weight Loss on Diabetic and Prediabetic Patients With Obesity Class III

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03968224
• Other study ID #: R-2016-785-094
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: July 7, 2018
• Est. completion date: July 1, 2021

Study information

• Verified date: August 2020
• Source: Centro Medico Nacional Siglo XXI IMSS
• Contact: Aldo Ferreira-Hermosillo, MSc
• Phone: +52156276900
• Email: aldo.nagisa[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Mexico has one of the highest prevalence of obesity, reported on 32.4 percent of people over 20 years old, with a prevalence of obesity class III of 1.8 percent on males and 4.1 percent on females.

According to previous data in our Obesity Clinic the mean age of these patients is 41 years, 46 percent have pre-diabetes or type 2 diabetes mellitus (T2D); 66 percent has hypertension and 33 percent has dyslipidemia. The management of alterations in the glucose metabolism in this unit is made by dietary treatment and with the use of metformin at doses of 1,700 mg/day and/or basal insulin.

Dapagliflozin is a selective SGLT2 inhibitor than has shown a sustained effect on the reduction of glycated hemoglobin at 0.4 to 0.8 percent (initial 7.8 to 8.0 percent). Additionally, due to the induction of glycosuria up to 20 to 85 g/day, it has been calculated that its use induces a caloric deficit at 80 to 340 kcal/day. This has been tested in patients with T2D in which induces a weight loss of 2 to 3 kg and in combination with metformin even a weight loss up to 5.07 kg (-6.21 to 3.93 kg) without regain (at least for 2 years). Furthermore, dapagliflozin decrease systolic blood pressure, increases HDL cholesterol concentrations and decreases triglyceride concentration. The drug product action is independent of the insulin production at pancreas, consequently, it exists a possibility of using the drug product on patients with prediabetes or even on other types of diabetes. Regarding the adverse effects related to its use, it has been described an increase in the risk of genitourinary infections with a low risk for inducing hypoglycemia.

A previous study that included 182 patients with T2D inadequately controlled with metformin assessed the effect of dapagliflozin 10 mg in total weight loss after 24 weeks compared to placebo. It was found a decrease in weight of 2.08 kg (2.8 to 1.31 kg), decrease in waist circumference of 1.52 cm (2.74 to 0.31), decrease in total fat mass assessed with densitometry of 1.48 kg (2.22 to 0.74), decrease of visceral fat mass of 258.4 cm^3 (448.1 to 68.6) and subcutaneous fat of 184.9 cm^3 (359.7 to 10.1). Most of these studies on weight and metabolic control have been performed in patients with obesity class II or I. The aim of this study is to assess if dapagliflozin in combination with metformin is at least 10 percent more effective for weight reduction in comparison with metformin in patients with prediabetes or T2D and obesity grade III.

Description:

Methods:

A convenience sampling will be done for patients diagnosed with diabetes or prediabetes according to the American Diabetes Association (ADA) criteria, who assist to the Obesity Clinic and meet the selection criteria. Data from patients that during the study protocol are called to undergo bariatric surgery procedure will be used until the time of surgery (intention-to-treat analysis). The prevalence of comorbidities at baseline and the type and dose of drugs used for treatment will be recorded. Patients will be randomized by a random numbers system generated with a computational software and will be assigned to a group: metformin (1,700 mg/day) or metformin (1,700 mg/day) and dapagliflozin 10 mg. All patients will receive dietary treatment and follow-up during the study by the Nutrition Service. Once assigned to the corresponding group, patients will receive an identification code that will be retained throughout the study. One of the researchers not directly involved in patient care, will assign tablets needed for daily intake for a month and then the number of tablets required for 3 months in a sealed envelope. A run-in period will be used to assess tolerance to treatments. This period will be for a month. At this time patients may notice an increase of uresis and will be instructed to increase fluid intake. Anthropometric and biochemical variables will be recorded baseline and at 1, 3, 6 and 12 months. The determination of glucagon, ghrelin, adiponectin, resistin, interleukin 6 (IL-6) and interleukin 10 (IL-10) will be held on initial appointment and before surgery (depending on the response of each patient). For the determination of these cytokines and peptides, an ELISA kit (Enzyme Linked Immunosorbent Assay) will be used. Adherence to treatment will be evaluated and will consist in consumption of 90 percent of pills granted. The patient will be required to return the drug blister. The registration of adverse events will take place from the start of treatment and throughout the study. Each event will be evaluated by researchers and classified according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 list. CTCAE considers that an adverse event grade 4 or 5 indicates discontinuation of treatment; grade 3 must be submitted to review by the medical team, and grades 1 or 2 require registration and intervention but not discontinuation of treatment. Adverse events will be recorded in the report sheet. An intention-to-treat analysis will be used if patients require treatment with insulin or sulfonylureas (grade 3 adverse event). They will provide information until the time of its inception. Patients who do not achieve weight loss at one year follow-up, will be discarded to their primary care hospital for continue with dietary recommendations.

Sample Size:

A convenience sample will be performed of patients with obesity class III and prediabetes or diabetes according ADA criteria at Obesity Clinic who meet selection criteria. The sample size was calculated using a mean difference formula with data from Zhang et al. who evaluated weight loss in patients using metformin/dapagliflozin and compared with placebo. Sample size required is 90 patients: 45 patients in metformin group and 45 patients in dapagliflozin/metformin group. Considering a loss of 20 percent of population during study, the final sample size required is 108 patients: 54 patients in metformin and 54 patients in dapagliflozin group.

Statistical analysis Quantitative variables will be presented as means and standard deviation or median with interquartile ranges according to data distribution. Qualitative variables will be presented as frequencies or percentages. For assessing data distribution, a Shapiro-Wilk test will be performed. Association between quantitative variables will be assessed through Repeated measures ANOVA and qualitative variables with McNemar test. Statistical significance will be evaluated with p < 0.05. Statistical analysis will be performed using statistical packages: Statistical Package for the Social Sciences (SPSS) version 17.0.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 90
• Est. completion date: July 1, 2021
• Est. primary completion date: July 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• BMI greater than or equal to 40 kg/m^2

• Diagnosis of diabetes or prediabetes according to the criteria of the ADA

• Patients who sign informed consent letter

Exclusion Criteria:

• Use of insulin or sulfonylureas

• Chronic renal failure with glomerular filtration rate <60 ml/min/1.73 m^2

• Use of loop diuretics with no possibility to suspend

• Active genitourinary tract infections determined by symptomatology or urinalysis

• Use of drugs for weight control

• Patients with untreated or uncontrolled hypothyroidism

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Glucose Intolerance
• Obesity
• Obesity, Morbid
• PreDiabetes
• Prediabetic State
• Weight Loss

Intervention

Drug:
• Dapagliflozin/Metformin
Two tablets of Metformin 850 mg every 12 hours will be provided in combination with Dapagliflozin 10 mg per day. Each participant will receive diet and exercise intervention according to their BMI and current physical condition.
• Metformin
Two tablets of Metformin 850 mg every 12 hours will be provided. Each participant will receive diet and exercise intervention according to their BMI and current physical condition.

Locations

Country	Name	City	State
Mexico	Hospital de Especialidades Centro Médico Nacional Siglo XXI	Mexico City

Sponsors (1)

Lead Sponsor	Collaborator
Centro Medico Nacional Siglo XXI IMSS

Country where clinical trial is conducted

Mexico, 

References & Publications (88)

American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019 Jan;42(Suppl 1):S13-S28. doi: 10.2337/dc19-S002. Review. — View Citation

American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019 Jan;42(Suppl 1):S90-S102. doi: 10.2337/dc19-S009. Review. — View Citation

Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Murad MH, Pagotto U, Ryan DH, Still CD; Endocrine Society. Pharmacological management of obesity: an endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015 Feb;100(2):342-62. doi: 10.1210/jc.2014-3415. Epub 2015 Jan 15. Erratum in: J Clin Endocrinol Metab. 2015 May;100(5):2135-6. — View Citation

Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens. 2014 Apr;8(4):262-75.e9. doi: 10.1016/j.jash.2014.01.007. Epub 2014 Jan 26. Review. — View Citation

Barquera S, Campos-Nonato I, Hernández-Barrera L, Pedroza A, Rivera-Dommarco JA. [Prevalence of obesity in Mexican adults 2000-2012]. Salud Publica Mex. 2013;55 Suppl 2:S151-60. Spanish. — View Citation

Barrera-Cruz A, Avila-Jiménez L, Cano-Pérez E, Molina-Ayala MA, Parrilla-Ortiz JI, Ramos-Hernández RI, Sosa-Caballero A, Sosa-Ruiz Mdel R, Gutiérrez-Aguilar J. [Practice clinical guideline. Prevention, diagnosis and treatment of overweight and obesity]. Rev Med Inst Mex Seguro Soc. 2013 May-Jun;51(3):344-57. Review. Spanish. — View Citation

Barrera-Cruz A, Rodríguez-González A, Molina-Ayala MA. [The current state of obesity in Mexico]. Rev Med Inst Mex Seguro Soc. 2013 May-Jun;51(3):292-9. Spanish. — View Citation

Blüher M, Fasshauer M, Tönjes A, Kratzsch J, Schön MR, Paschke R. Association of interleukin-6, C-reactive protein, interleukin-10 and adiponectin plasma concentrations with measures of obesity, insulin sensitivity and glucose metabolism. Exp Clin Endocrinol Diabetes. 2005 Oct;113(9):534-7. — View Citation

Bolinder J, Ljunggren Ö, Kullberg J, Johansson L, Wilding J, Langkilde AM, Sugg J, Parikh S. 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 Mar;97(3):1020-31. doi: 10.1210/jc.2011-2260. Epub 2012 Jan 11. — View Citation

Bonner C, Kerr-Conte J, Gmyr V, Queniat G, Moerman E, Thévenet J, Beaucamps C, Delalleau N, Popescu I, Malaisse WJ, Sener A, Deprez B, Abderrahmani A, Staels B, Pattou F. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015 May;21(5):512-7. doi: 10.1038/nm.3828. Epub 2015 Apr 20. — View Citation

Briasoulis A, Al Dhaybi O, Bakris GL. SGLT2 Inhibitors and Mechanisms of Hypertension. Curr Cardiol Rep. 2018 Jan 19;20(1):1. doi: 10.1007/s11886-018-0943-5. Review. — View Citation

Calapkulu M, Cander S, Gul OO, Ersoy C. Anthropometric outcomes in type 2 diabetic patients with new dapagliflozin treatment; actual clinical experience data of six months retrospective glycemic control from single center. Diabetes Metab Syndr. 2019 Jan - Feb;13(1):284-288. doi: 10.1016/j.dsx.2018.09.005. Epub 2018 Sep 8. — View Citation

Dandona P, Mathieu C, Phillip M, Hansen L, Tschöpe D, Thorén F, Xu J, Langkilde AM; DEPICT-1 Investigators. Efficacy and Safety of Dapagliflozin in Patients With Inadequately Controlled Type 1 Diabetes: The DEPICT-1 52-Week Study. Diabetes Care. 2018 Dec;41(12):2552-2559. doi: 10.2337/dc18-1087. Epub 2018 Oct 23. — View Citation

DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med. 1995 Aug 31;333(9):541-9. — View Citation

Devenny JJ, Godonis HE, Harvey SJ, Rooney S, Cullen MJ, Pelleymounter MA. Weight loss induced by chronic dapagliflozin treatment is attenuated by compensatory hyperphagia in diet-induced obese (DIO) rats. Obesity (Silver Spring). 2012 Aug;20(8):1645-52. doi: 10.1038/oby.2012.59. Epub 2012 Mar 8. — View Citation

Erondu N, Desai M, Ways K, Meininger G. Diabetic Ketoacidosis and Related Events in the Canagliflozin Type 2 Diabetes Clinical Program. Diabetes Care. 2015 Sep;38(9):1680-6. doi: 10.2337/dc15-1251. Epub 2015 Jul 22. — View Citation

Færch K, Amadid H, Nielsen LB, Ried-Larsen M, Karstoft K, Persson F, Jørgensen ME. Protocol for a randomised controlled trial of the effect of dapagliflozin, metformin and exercise on glycaemic variability, body composition and cardiovascular risk in prediabetes (the PRE-D Trial). BMJ Open. 2017 Jun 6;7(5):e013802. doi: 10.1136/bmjopen-2016-013802. — View Citation

Fernandez-Real JM, Vayreda M, Richart C, Gutierrez C, Broch M, Vendrell J, Ricart W. Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J Clin Endocrinol Metab. 2001 Mar;86(3):1154-9. — View Citation

Fernández-Sánchez A, Madrigal-Santillán E, Bautista M, Esquivel-Soto J, Morales-González A, Esquivel-Chirino C, Durante-Montiel I, Sánchez-Rivera G, Valadez-Vega C, Morales-González JA. Inflammation, oxidative stress, and obesity. Int J Mol Sci. 2011;12(5):3117-32. doi: 10.3390/ijms12053117. Epub 2011 May 13. Review. — View Citation

Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, Broedl UC, Woerle HJ. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014 Feb;124(2):499-508. doi: 10.1172/JCI72227. Epub 2014 Jan 27. Erratum in: J Clin Invest. 2014 Apr 1;124(4):1868. — View Citation

Fioretto P, Giaccari A, Sesti G. Efficacy and safety of dapagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in diabetes mellitus. Cardiovasc Diabetol. 2015 Oct 17;14:142. doi: 10.1186/s12933-015-0297-x. Review. — View Citation

Furtado RHM, Bonaca MP, Raz I, Zelniker TA, Mosenzon O, Cahn A, Kuder J, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Nicolau JC, Gause-Nilsson IAM, Fredriksson M, Langkilde AM, Sabatine MS, Wiviott SD. Dapagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Previous Myocardial Infarction. Circulation. 2019 May 28;139(22):2516-2527. doi: 10.1161/CIRCULATIONAHA.119.039996. Epub 2019 Mar 18. — View Citation

Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, Dagogo-Jack S, DeFronzo RA, Einhorn D, Fonseca VA, Garber JR, Garvey WT, Grunberger G, Handelsman Y, Hirsch IB, Jellinger PS, McGill JB, Mechanick JI, Rosenblit PD, Umpierrez GE. CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM - 2019 EXECUTIVE SUMMARY. Endocr Pract. 2019 Jan;25(1):69-100. doi: 10.4158/CS-2018-0535. Erratum in: Endocr Pract. 2019 Feb;25(2):204. — View Citation

García de la Torre N, Rubio MA, Bordiú E, Cabrerizo L, Aparicio E, Hernández C, Sánchez-Pernaute A, Díez-Valladares L, Torres AJ, Puente M, Charro AL. Effects of weight loss after bariatric surgery for morbid obesity on vascular endothelial growth factor-A, adipocytokines, and insulin. J Clin Endocrinol Metab. 2008 Nov;93(11):4276-81. doi: 10.1210/jc.2007-1370. Epub 2008 Aug 19. — View Citation

Goktas Z, Moustaid-Moussa N, Shen CL, Boylan M, Mo H, Wang S. Effects of bariatric surgery on adipokine-induced inflammation and insulin resistance. Front Endocrinol (Lausanne). 2013 Jun 10;4:69. doi: 10.3389/fendo.2013.00069. eCollection 2013. — View Citation

Goodarzi MO, Bryer-Ash M. Metformin revisited: re-evaluation of its properties and role in the pharmacopoeia of modern antidiabetic agents. Diabetes Obes Metab. 2005 Nov;7(6):654-65. Review. — View Citation

Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011;29:415-45. doi: 10.1146/annurev-immunol-031210-101322. Review. — View Citation

Hajer GR, van Haeften TW, Visseren FL. Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J. 2008 Dec;29(24):2959-71. doi: 10.1093/eurheartj/ehn387. Epub 2008 Sep 5. Review. — View Citation

Handelsman Y, Henry RR, Bloomgarden ZT, Dagogo-Jack S, DeFronzo RA, Einhorn D, Ferrannini E, Fonseca VA, Garber AJ, Grunberger G, LeRoith D, Umpierrez GE, Weir MR. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON THE ASSOCIATION OF SGLT-2 INHIBITORS AND DIABETIC KETOACIDOSIS. Endocr Pract. 2016 Jun;22(6):753-62. doi: 10.4158/EP161292.PS. Epub 2016 Jun 1. — View Citation

Hattersley AT, Thorens B. Type 2 Diabetes, SGLT2 Inhibitors, and Glucose Secretion. N Engl J Med. 2015 Sep 3;373(10):974-6. doi: 10.1056/NEJMcibr1506573. — View Citation

Hermann LS, Karlsson JE, Sjöstrand A. Prospective comparative study in NIDDM patients of metformin and glibenclamide with special reference to lipid profiles. Eur J Clin Pharmacol. 1991;41(3):263-5. — View Citation

Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993 Jan 1;259(5091):87-91. — View Citation

Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi SE, Schumann WC, Petersen KF, Landau BR, Shulman GI. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000 Dec;49(12):2063-9. — View Citation

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 Jun;50(6):636-46. doi: 10.1177/0091270009352185. Epub 2010 Mar 3. — View Citation

Idris I, Donnelly R. Sodium-glucose co-transporter-2 inhibitors: an emerging new class of oral antidiabetic drug. Diabetes Obes Metab. 2009 Feb;11(2):79-88. doi: 10.1111/j.1463-1326.2008.00982.x. Review. — View Citation

Jabbour SA, Hardy E, Sugg J, Parikh S; Study 10 Group. Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Diabetes Care. 2014;37(3):740-50. doi: 10.2337/dc13-0467. Epub 2013 Oct 21. — View Citation

Jayawardene D, Ward GM, O'Neal DN, Theverkalam G, MacIsaac AI, MacIsaac RJ. New treatments for type 2 diabetes: cardiovascular protection beyond glucose lowering? Heart Lung Circ. 2014 Nov;23(11):997-1008. doi: 10.1016/j.hlc.2014.05.007. Epub 2014 Jun 10. Review. — View Citation

Kalupahana NS, Moustaid-Moussa N, Claycombe KJ. Immunity as a link between obesity and insulin resistance. Mol Aspects Med. 2012 Feb;33(1):26-34. doi: 10.1016/j.mam.2011.10.011. Epub 2011 Oct 21. Review. — View Citation

Kanety H, Feinstein R, Papa MZ, Hemi R, Karasik A. Tumor necrosis factor alpha-induced phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1. J Biol Chem. 1995 Oct 6;270(40):23780-4. — View Citation

Kelly MS, Lewis J, Huntsberry AM, Dea L, Portillo I. Efficacy and renal outcomes of SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease. Postgrad Med. 2019 Jan;131(1):31-42. doi: 10.1080/00325481.2019.1549459. Epub 2018 Nov 30. Review. — View Citation

Komoroski B, Vachharajani N, Feng Y, Li L, Kornhauser D, Pfister M. Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus. Clin Pharmacol Ther. 2009 May;85(5):513-9. doi: 10.1038/clpt.2008.250. Epub 2009 Jan 7. Erratum in: Clin Pharmacol Ther. 2009 May;85(5):558. — View Citation

Leick L, Lindegaard B, Stensvold D, Plomgaard P, Saltin B, Pilegaard H. Adipose tissue interleukin-18 mRNA and plasma interleukin-18: effect of obesity and exercise. Obesity (Silver Spring). 2007 Feb;15(2):356-63. — View Citation

Liakos A, Karagiannis T, Bekiari E, Boura P, Tsapas A. Update on long-term efficacy and safety of dapagliflozin in patients with type 2 diabetes mellitus. Ther Adv Endocrinol Metab. 2015 Apr;6(2):61-7. doi: 10.1177/2042018814560735. Review. — View Citation

List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009 Apr;32(4):650-7. doi: 10.2337/dc08-1863. Epub 2008 Dec 29. — View Citation

Luzi L, Barrett EJ, Groop LC, Ferrannini E, DeFronzo RA. Metabolic effects of low-dose insulin therapy on glucose metabolism in diabetic ketoacidosis. Diabetes. 1988 Nov;37(11):1470-7. — View Citation

Mason EE, Doherty C, Maher JW, Scott DH, Rodriguez EM, Blommers TJ. Super obesity and gastric reduction procedures. Gastroenterol Clin North Am. 1987 Sep;16(3):495-502. — View Citation

Meng W, Ellsworth BA, Nirschl AA, McCann PJ, Patel M, Girotra RN, Wu G, Sher PM, Morrison EP, Biller SA, Zahler R, Deshpande PP, Pullockaran A, Hagan DL, Morgan N, Taylor JR, Obermeier MT, Humphreys WG, Khanna A, Discenza L, Robertson JG, Wang A, Han S, Wetterau JR, Janovitz EB, Flint OP, Whaley JM, Washburn WN. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem. 2008 Mar 13;51(5):1145-9. doi: 10.1021/jm701272q. Epub 2008 Feb 9. — View Citation

Mogul HR, Peterson SJ, Weinstein BI, Zhang S, Southren AL. Metformin and carbohydrate-modified diet: a novel obesity treatment protocol: preliminary findings from a case series of nondiabetic women with midlife weight gain and hyperinsulinemia. Heart Dis. 2001 Sep-Oct;3(5):285-92. — View Citation

Monami M, Nreu B, Zannoni S, Lualdi C, Mannucci E. Effects of SGLT-2 inhibitors on diabetic ketoacidosis: A meta-analysis of randomised controlled trials. Diabetes Res Clin Pract. 2017 Aug;130:53-60. doi: 10.1016/j.diabres.2017.04.017. Epub 2017 May 18. — View Citation

Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683-765. Review. — View Citation

Nauck MA, Del Prato S, Durán-García S, Rohwedder K, Langkilde AM, Sugg J, Parikh SJ. Durability of glycaemic efficacy over 2 years with dapagliflozin versus glipizide as add-on therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin. Diabetes Obes Metab. 2014 Nov;16(11):1111-20. doi: 10.1111/dom.12327. Epub 2014 Jul 10. — View Citation

Nguyen NT, Ho HS, Palmer LS, Wolfe BM. Laparoscopic Roux-en-Y gastric bypass for super/super obesity. Obes Surg. 1999 Aug;9(4):403-6. — View Citation

Nogués Solán X, Sorli Redó ML, Villar García J. [Tools to measure treatment adherence]. An Med Interna. 2007 Mar;24(3):138-41. Spanish. — View Citation

Nowak A, Czkwianianc E. A contemporary approach to body mass regulation mechanisms. Prz Gastroenterol. 2016;11(2):73-7. doi: 10.5114/pg.2016.60043. Epub 2016 May 19. Review. — View Citation

Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser. 2000;894:i-xii, 1-253. — View Citation

Okamoto A, Yokokawa H, Sanada H, Naito T. Changes in Levels of Biomarkers Associated with Adipocyte Function and Insulin and Glucagon Kinetics During Treatment with Dapagliflozin Among Obese Type 2 Diabetes Mellitus Patients. Drugs R D. 2016 Sep;16(3):255-261. — View Citation

Oku A, Ueta K, Arakawa K, Ishihara T, Nawano M, Kuronuma Y, Matsumoto M, Saito A, Tsujihara K, Anai M, Asano T, Kanai Y, Endou H. T-1095, an inhibitor of renal Na+-glucose cotransporters, may provide a novel approach to treating diabetes. Diabetes. 1999 Sep;48(9):1794-800. — View Citation

Orme M, Fenici P, Lomon ID, Wygant G, Townsend R, Roudaut M. A systematic review and mixed-treatment comparison of dapagliflozin with existing anti-diabetes treatments for those with type 2 diabetes mellitus inadequately controlled by sulfonylurea monotherapy. Diabetol Metab Syndr. 2014 Jun 11;6:73. doi: 10.1186/1758-5996-6-73. eCollection 2014. Review. — View Citation

Panee J. Monocyte Chemoattractant Protein 1 (MCP-1) in obesity and diabetes. Cytokine. 2012 Oct;60(1):1-12. doi: 10.1016/j.cyto.2012.06.018. Epub 2012 Jul 4. Review. — View Citation

Patel PS, Buras ED, Balasubramanyam A. The role of the immune system in obesity and insulin resistance. J Obes. 2013;2013:616193. doi: 10.1155/2013/616193. Epub 2013 Mar 21. Review. — View Citation

Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB. Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care. 2015 Sep;38(9):1687-93. doi: 10.2337/dc15-0843. Epub 2015 Jun 15. — View Citation

Pryor R, Cabreiro F. Repurposing metformin: an old drug with new tricks in its binding pockets. Biochem J. 2015 Nov 1;471(3):307-22. doi: 10.1042/BJ20150497. Review. — View Citation

Queipo-Ortuño MI, Escoté X, Ceperuelo-Mallafré V, Garrido-Sanchez L, Miranda M, Clemente-Postigo M, Pérez-Pérez R, Peral B, Cardona F, Fernández-Real JM, Tinahones FJ, Vendrell J. FABP4 dynamics in obesity: discrepancies in adipose tissue and liver expression regarding circulating plasma levels. PLoS One. 2012;7(11):e48605. doi: 10.1371/journal.pone.0048605. Epub 2012 Nov 5. — View Citation

Rizzello M, De Angelis F, Campanile FC, Silecchia G. Effect of gastrointestinal surgical manipulation on metabolic syndrome: a focus on metabolic surgery. Gastroenterol Res Pract. 2012;2012:670418. doi: 10.1155/2012/670418. Epub 2012 Oct 22. — View Citation

Romero-Martínez M, Shamah-Levy T, Cuevas-Nasu L, Gómez-Humarán IM, Gaona-Pineda EB, Gómez-Acosta LM, Rivera-Dommarco JÁ, Hernández-Ávila M. [Methodological design of the National Health and Nutrition Survey 2016]. Salud Publica Mex. 2017 May-Jun;59(3):299-305. doi: 10.21149/8593. Spanish. — View Citation

Rosenstock J, Ferrannini E. Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, and Preventable Safety Concern With SGLT2 Inhibitors. Diabetes Care. 2015 Sep;38(9):1638-42. doi: 10.2337/dc15-1380. — View Citation

Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care. 2012 Jul;35(7):1473-8. doi: 10.2337/dc11-1693. Epub 2012 Mar 23. — View Citation

Santo MA, Riccioppo D, Pajecki D, Cleva Rd, Kawamoto F, Cecconello I. Preoperative weight loss in super-obese patients: study of the rate of weight loss and its effects on surgical morbidity. Clinics (Sao Paulo). 2014;69(12):828-34. doi: 10.6061/clinics/2014(12)07. — View Citation

Saponaro C, Pattou F, Bonner C. SGLT2 inhibition and glucagon secretion in humans. Diabetes Metab. 2018 Nov;44(5):383-385. doi: 10.1016/j.diabet.2018.06.005. Epub 2018 Jun 30. Review. — View Citation

Scheen AJ. An update on the safety of SGLT2 inhibitors. Expert Opin Drug Saf. 2019 Apr;18(4):295-311. doi: 10.1080/14740338.2019.1602116. Epub 2019 Apr 16. Review. — View Citation

Schork A, Saynisch J, Vosseler A, Jaghutriz BA, Heyne N, Peter A, Häring HU, Stefan N, Fritsche A, Artunc F. Effect of SGLT2 inhibitors on body composition, fluid status and renin-angiotensin-aldosterone system in type 2 diabetes: a prospective study using bioimpedance spectroscopy. Cardiovasc Diabetol. 2019 Apr 5;18(1):46. doi: 10.1186/s12933-019-0852-y. — View Citation

Senn JJ, Klover PJ, Nowak IA, Mooney RA. Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes. 2002 Dec;51(12):3391-9. — View Citation

Shepherd PR, Kahn BB. Glucose transporters and insulin action--implications for insulin resistance and diabetes mellitus. N Engl J Med. 1999 Jul 22;341(4):248-57. Review. — View Citation

Steinberg GR. Inflammation in obesity is the common link between defects in fatty acid metabolism and insulin resistance. Cell Cycle. 2007 Apr 15;6(8):888-94. Epub 2007 Apr 11. Review. — View Citation

Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes. Nature. 2001 Jan 18;409(6818):307-12. — View Citation

Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1995 Aug 31;333(9):550-4. — View Citation

Tilg H, Moschen AR. Role of adiponectin and PBEF/visfatin as regulators of inflammation: involvement in obesity-associated diseases. Clin Sci (Lond). 2008 Feb;114(4):275-88. doi: 10.1042/CS20070196. Review. — View Citation

Ueta K, Ishihara T, Matsumoto Y, Oku A, Nawano M, Fujita T, Saito A, Arakawa K. Long-term treatment with the Na+-glucose cotransporter inhibitor T-1095 causes sustained improvement in hyperglycemia and prevents diabetic neuropathy in Goto-Kakizaki Rats. Life Sci. 2005 Apr 22;76(23):2655-68. — View Citation

Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, Sarigianni M, Matthews DR, Tsapas A. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013 Aug 20;159(4):262-74. doi: 10.7326/0003-4819-159-4-201308200-00007. Review. — View Citation

Vidal-Puig A, O'Rahilly S. Resistin: a new link between obesity and insulin resistance? Clin Endocrinol (Oxf). 2001 Oct;55(4):437-8. Review. — View Citation

Wang Z, Nakayama T. Inflammation, a link between obesity and cardiovascular disease. Mediators Inflamm. 2010;2010:535918. doi: 10.1155/2010/535918. Epub 2010 Aug 5. — View Citation

Warne JP. Tumour necrosis factor alpha: a key regulator of adipose tissue mass. J Endocrinol. 2003 Jun;177(3):351-5. Review. — View Citation

Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003 Dec;112(12):1796-808. — View Citation

Wilding J, Bailey C, Rigney U, Blak B, Beekman W, Emmas C. Glycated Hemoglobin, Body Weight and Blood Pressure in Type 2 Diabetes Patients Initiating Dapagliflozin Treatment in Primary Care: A Retrospective Study. Diabetes Ther. 2016 Dec;7(4):695-711. Epub 2016 Sep 1. — View Citation

Wolf G. Serum retinol-binding protein: a link between obesity, insulin resistance, and type 2 diabetes. Nutr Rev. 2007 May;65(5):251-6. Review. — View Citation

Wood IS, Trayhurn P. Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins. Br J Nutr. 2003 Jan;89(1):3-9. Review. — View Citation

Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA. 2014 Jan 1;311(1):74-86. doi: 10.1001/jama.2013.281361. Review. — View Citation

Zhang Q, Dou J, Lu J. Combinational therapy with metformin and sodium-glucose cotransporter inhibitors in management of type 2 diabetes: systematic review and meta-analyses. Diabetes Res Clin Pract. 2014 Sep;105(3):313-21. doi: 10.1016/j.diabres.2014.06.006. Epub 2014 Jun 22. Review. — View Citation

* Note: There are 88 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in Cytokines Level	Change in interleukin-6, interleukin-10, adiponectin, and resistin, comparing initial versus final levels	12 months
Primary	Change in Weight	Change of 10 percent of initial weight	12 months
Secondary	Change in Blood Pressure	Change of 10 percent of initial blood pressure (systolic and diastolic)	12 months
Secondary	Change in Waist Circumference	Change of 10 percent of initial waist circumference	12 months
Secondary	Change in Triglycerides level	Change of 10 percent of initial triglycerides levels	12 months