A consensus statement for the clinical use of the renal sodium-glucose co-transporter-2 inhibitor dapagliflozin in patients with type 2 diabetes mellitus

Expert Review of Clinical Pharmacology

Volumn 10, Issue 7, 2017, Pages 763-772

  Avogaro, A ^a   Giaccari, A ^b   Fioretto, P ^a   Genovese, S ^c   Purrello, F ^d   Giorgino, F ^e   Del Prato, S ^f  

^a UNIVERSITY OF PADOVA   (Italy)

^b FONDAZIONE POLICLINICO UNIVERSITARIO A GEMELLI IRCCS   (Italy)

^c IRCCS MULTIMEDICA   (Italy)

^d Department Gian Filippo Ingrassia   (Italy)

^e UNIVERSITY OF BARI   (Italy)

^f UNIVERSITY OF PISA   (Italy)

Author keywords

cardiovascular disease; Dapagliflozin; diabetes type 2; diabetic complications; sodium glucose co transporter 2 inhibitor

Indexed keywords

DAPAGLIFLOZIN; GLUCOSE; HEMOGLOBIN A1C; SODIUM GLUCOSE COTRANSPORTER 2; URIC ACID; 2-(3-(4-ETHOXYBENZYL)-4-CHLOROPHENYL)-6-HYDROXYMETHYLTETRAHYDRO-2H-PYRAN-3,4,5-TRIOL; ANTIDIABETIC AGENT; BENZHYDRYL DERIVATIVE; GLUCOSE BLOOD LEVEL; GLUCOSIDE;

ANTIDIABETIC ACTIVITY; BALANITIS; BALANITIS CANDIDA; BLOOD PRESSURE; BODY WEIGHT; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CLINICAL PRACTICE; CONSENSUS; DELPHI STUDY; DIABETIC PATIENT; DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; DRUG TOLERABILITY; DRUG USE; FUNGAL GENITAL INFECTION; GENITAL TRACT INFECTION; GLUCOSE BLOOD LEVEL; GLYCEMIC CONTROL; HUMAN; INCIDENCE; META ANALYSIS (TOPIC); MULTICENTER STUDY (TOPIC); NON INSULIN DEPENDENT DIABETES MELLITUS; OUTCOME ASSESSMENT; PANEL STUDY; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SIDE EFFECT; SYSTEMATIC REVIEW (TOPIC); URIC ACID BLOOD LEVEL; URINARY TRACT INFECTION; VAGINA CANDIDIASIS; VAGINA MYCOSIS; VAGINITIS; VULNERABLE POPULATION; ANTAGONISTS AND INHIBITORS; CARDIOVASCULAR DISEASES; DIABETES MELLITUS, TYPE 2; DRUG EFFECTS; GLOMERULUS FILTRATION RATE; PATHOPHYSIOLOGY; RISK FACTOR;

BENZHYDRYL COMPOUNDS; BLOOD GLUCOSE; CARDIOVASCULAR DISEASES; CONSENSUS; DELPHI TECHNIQUE; DIABETES MELLITUS, TYPE 2; GLOMERULAR FILTRATION RATE; GLUCOSIDES; HUMANS; HYPOGLYCEMIC AGENTS; RISK FACTORS; SODIUM-GLUCOSE TRANSPORTER 2;

EID: 85021120165     PISSN: 17512433     EISSN: 17512441     Source Type: Journal    
DOI: 10.1080/17512433.2017.1322507     Document Type: Review

References (65)

1. Tahrani AA, Barnett AH, Bailey CJ., Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nat Rev Endocrinol. 2016;12(10):566–592.
2. Fioretto P, Zambon A, Rossato M, et al. Sglt2 inhibitors and the diabetic kidney. Diabetes Care. 2016;39(Suppl 2):S165–171.
3. Sherman RE, Anderson SA, Dal Pan GJ, et al. Real-world evidence–what is it and what can it tell us? N Engl J Med. 2016;375(23):2293–2297.
4. Hasson F, Keeney S, McKenna H., Research guidelines for the Delphi survey technique. J Adv Nurs. 2000;32(4):1008–1015.
5. Komoroski B, Vachharajani N, Boulton D, et al. Dapagliflozin, a novel sglt2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Ther. 2009;85(5):520–526.
6. Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124(2):509–514.• This study shows that dapagliflozin improves peripheral insulin sensitivity.
7. Merovci A, Mari A, Solis C, et al. Dapagliflozin lowers plasma glucose concentration and improves beta-cell function. J Clin Endocrinol Metab. 2015;100(5):1927–1932.
8. Sonesson C, Johansson PA, Johnsson E, et al. Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories:a meta-analysis. Cardiovasc Diabetol. 2016;15:37.
9. Bonner C, Kerr-Conte J, Gmyr V, et al. Inhibition of the glucose transporter sglt2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015;21(5):512–517.•• This study highlights the mechanisms underlying the ability of SGLT2-I to increase glucagon secretion.
10. Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise:a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010;33(10):2217–2224.
11. Ferrannini E, Berk A, Hantel S, et al. Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin:an active-controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2 diabetes. Diabetes Care. 2013;36(12):4015–4021.
12. Barnett AH, Mithal A, Manassie J, et al.; investigators E-RRt. 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(5):369–384.
13. Bailey CJ, Gross JL, Pieters A, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin:a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375(9733):2223–2233.
14. Bailey CJ, Gross JL, Hennicken D, et al. Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin:a randomized, double-blind, placebo-controlled 102-week trial. BMC Med. 2013;11:43.
15. Nauck MA, Del Prato S, Duran-Garcia S, et al. 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;16(11):1111–1120.
16. Strojek K, Yoon KH, Hruba V, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride:a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2011;13(10):928–938.
17. Rosenstock J, Vico M, Wei L, et al. 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;35(7):1473–1478.
18. Jabbour SA, Hardy E, Sugg J, et al. 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):740–750.
19. Nauck MA, Del Prato S, Meier JJ, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin:a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care. 2011;34(9):2015–2022.
20. Henry RR, Murray AV, Marmolejo MH, et al. Dapagliflozin, metformin xr, or both:initial pharmacotherapy for type 2 diabetes, a randomised controlled trial. Int J Clin Pract. 2012;66(5):446–456.
21. Kaku K, Inoue S, Matsuoka O, et al. Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in japanese patients with inadequate glycaemic control:a phase ii multicentre, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2013;15(5):432–440.
22. Ji L, Ma J, Li H, et al. Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes mellitus:a randomized, blinded, prospective phase iii study. Clin Ther. 2014;36(1):84–100 e109.
23. List JF, Woo V, Morales E, et al. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009;32(4):650–657.
24. Strojek K, Yoon KH, Hruba V, et al. Dapagliflozin added to glimepiride in patients with type 2 diabetes mellitus sustains glycemic control and weight loss over 48 weeks:a randomized, double-blind, parallel-group, placebo-controlled trial. Diabetes Ther. 2014;5(1):267–283.
25. Del Prato S, Nauck M, Duran-Garcia S, et al. Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in patients with type 2 diabetes:4-year data. Diabetes Obes Metab. 2015;17(6):581–590.
26. Matthaei S, Bowering K, Rohwedder K, et al.; Study G. Durability and tolerability of dapagliflozin over 52 weeks as add-on to metformin and sulphonylurea in type 2 diabetes. Diabetes Obes Metab. 2015;17(11):1075–1084.
27. Leiter LA, Cefalu WT, De Bruin TW, et al. Long-term maintenance of efficacy of dapagliflozin in patients with type 2 diabetes mellitus and cardiovascular disease. Diabetes Obes Metab. 2016;18(8):766–774.
28. Frias JP, Guja C, Hardy E, et al. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (duration-8):a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016;4(12):1004–1016.
29. Wilding JP, Woo V, Rohwedder K, et al.; Dapagliflozin 006 Study G. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin:efficacy and safety over 2 years. Diabetes Obes Metab. 2014;16(2):124–136.
30. Wilding JP, Woo V, Soler NG, et al.; Dapagliflozin 006 Study G. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin:a randomized trial. Ann Intern Med. 2012;156(6):405–415.
31. Weber MA, Mansfield TA, Alessi F, et al. Effects of dapagliflozin on blood pressure in hypertensive diabetic patients on renin-angiotensin system blockade. Blood Press. 2016;25(2):93–103.
32. Sjostrom CD, Johansson P, Ptaszynska A, et al. Dapagliflozin lowers blood pressure in hypertensive and non-hypertensive patients with type 2 diabetes. Diab Vasc Dis Res. 2015;12(5):352–358.
33. Sjostrom CD, Hashemi M, Sugg J, et al. Dapagliflozin-induced weight loss affects 24-week glycated haemoglobin and blood pressure levels. Diabetes Obes Metab. 2015;17(8):809–812.
34. Weber MA, Mansfield TA, Cain VA, et al. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy:a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol. 2016;4(3):211–220.• This study assesses the antihypertensive effect of dapagliflozin on blood pressure and compares its efficacy to traditional antihypertensive drugs.
35. Yavin Y, Mansfield TA, Ptaszynska A, et al. Effect of the sglt2 inhibitor dapagliflozin on potassium levels in patients with type 2 diabetes mellitus:a pooled analysis. Diabetes Ther. 2016;7(1):125–137.
36. Johnsson K, Johnsson E, Mansfield TA, et al. Osmotic diuresis with sglt2 inhibition:analysis of events related to volume reduction in dapagliflozin clinical trials. Postgrad Med. 2016;128(4):346–355.
37. Lundkvist P, Sjostrom CD, Amini S, et al. Dapagliflozin once-daily and exenatide once-weekly dual therapy:a 24-week randomized, placebo-controlled, phase ii study examining effects on body weight and prediabetes in obese adults without diabetes. Diabetes Obes Metab. 2017 Mar 27. doi:10.1111/dom.12954. [Epub ahead of print]
38. Bolinder J, Ljunggren O, Kullberg J, 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):1020–1031.• This study shows that dapagliflozin reduces also visceral fat.
39. Ferrannini G, Hach T, Crowe S, et al. Energy balance after sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38(9):1730–1735.•• This study demonstrates that treatment with SGLT2-I evokes a compensatory increase in caloric intake.
40. Rizzi M, Trevisan R. Genitourinary infections in diabetic patients in the new era of diabetes therapy with sodium-glucose cotransporter-2 inhibitors. Nutr Metab Cardiovasc Dis. 2016;26(11):963–970.
41. Johnsson KM, Ptaszynska A, Schmitz B, et al. Urinary tract infections in patients with diabetes treated with dapagliflozin. J Diabetes Complications. 2013;27(5):473–478.
42. Johnsson KM, Ptaszynska A, Schmitz B, et al. Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin. J Diabetes Complications. 2013;27(5):479–484.
43. Geerlings S, Fonseca V, Castro-Diaz D, et al. Genital and urinary tract infections in diabetes:impact of pharmacologically-induced glucosuria. Diabetes Res Clin Pract. 2014;103(3):373–381.
44. Hirji I, Andersson SW, Guo Z, et al. Incidence of genital infection among patients with type 2 diabetes in the uk general practice research database. J Diabetes Complications. 2012;26(6):501–505.
45. Tang HL, Li DD, Zhang JJ, et al. Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (sglt2) inhibitors on fracture risk among type 2 diabetes patients:a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2016;18(12):1199–1206.
46. Fioretto P, Stefansson BV, Johnsson E, et al. Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment. Diabetologia. 2016;59(9):2036–2039.
47. Gilbert RE. Sodium-glucose linked transporter-2 inhibitors:potential for renoprotection beyond blood glucose lowering? Kidney Int. 2014;86(4):693–700.
48. Wanner C, Inzucchi SE, Lachin JM,. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323–334.•• This study shows that SGLT2-I has the ability to preserve renal function.
49. Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129(5):587–597.•• This study demonstrates that SGLT2-I restores tubuloglomerular feedback.
50. Heerspink HJ, Perkins BA, Fitchett DH, et al. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus:cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016;134(10):752–772.
51. De Nicola L, Gabbai FB, Liberti ME, et al. Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy:targeting the renal tubule in diabetes. Am J Kidney Dis. 2014;64(1):16–24.
52. Komala MG, Panchapakesan U, Pollock C, et al. Sodium glucose cotransporter 2 and the diabetic kidney. Curr Opin Nephrol Hypertens. 2013;22(1):113–119.
53. Peters AL, Buschur EO, Buse JB, et al. Euglycemic diabetic ketoacidosis:a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38(9):1687–1693.
54. Leiter LA, Cefalu WT, De Bruin TW, et al. Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease:a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. J Am Geriatr Soc. 2014;62(7):1252–1262.
55. Cefalu WT, Leiter LA, De Bruin TW, et al. Dapagliflozin’s effects on glycemia and cardiovascular risk factors in high-risk patients with type 2 diabetes:a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. Diabetes Care. 2015;38(7):1218–1227.
56. Franco OH, Massaro JM, Civil J, et al. Trajectories of entering the metabolic syndrome:the framingham heart study. Circulation. 2009;120(20):1943–1950.
57. Abdul-Ghani M, Del Prato S, Chilton R, et al. Sglt2 inhibitors and cardiovascular risk:lessons learned from the EMPA-REG outcome study. Diabetes Care. 2016;39(5):717–725.
58. Ptaszynska A, Hardy E, Johnsson E, et al. Effects of dapagliflozin on cardiovascular risk factors. Postgrad Med. 2013;125(3):181–189.
59. Musso G, Gambino R, Cassader M, et al. A novel approach to control hyperglycemia in type 2 diabetes:sodium glucose co-transport (sglt) inhibitors:systematic review and meta-analysis of randomized trials. Ann Med. 2012;44(4):375–393.
60. Heerspink HJ, Johnsson E, Gause-Nilsson I, et al. Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers. Diabetes Obes Metab. 2016;18(6):590–597.
61. Tang H, Fang Z, Wang T, et al. Meta-analysis of effects of sodium-glucose cotransporter 2 inhibitors on cardiovascular outcomes and all-cause mortality among patients with type 2 diabetes mellitus. Am J Cardiol. 2016;118(11):1774–1780.
62. Dziuba J, Alperin P, Racketa J, et al. Modeling effects of sglt-2 inhibitor dapagliflozin treatment versus standard diabetes therapy on cardiovascular and microvascular outcomes. Diabetes Obes Metab. 2014;16(7):628–635.
63. Neal B, Perkovic V, De Zeeuw D, et al. Rationale, design, and baseline characteristics of the canagliflozin cardiovascular assessment study (CANVAS)–a randomized placebo-controlled trial. Am Heart J. 2013;166(2):217–223 e211.
64. Zinman B, Lachin JM, Inzucchi SE. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2016;374(11):1094.•• This study shows that empagliflozin, an SGLT2-I, reduced mortality by almost 40% in patients with type 2 diabetes.
65. American Diabetes A. 8. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2017;40(Suppl 1):S64–S74.