Efficacy and safety of dapagliflozin combined with hypoglycemic drugs for diabetes mellitus: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

YANG Yang ¹ , WEI Pengxiang ² , ZHANG Cun ² , ZHANG Nan ² , DUAN Yinyin ² ,  WEI Qunli ³

1. The Affiliated Changzhou Children's Hospital of Nantong University, Changzhou, 213003, P.R.China;
2. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221000, P.R.China;
3. Department of Clinical Pharmacology, Xuzhou Medical University, Xuzhou, 221000, P.R.China;

Corresponding author：

WEI Qunli, Email: weiqunli@126.com

Keywords：

Dapagliflozin; Diabetes; Efficacy; Safety; Meta-analysis; Systematic review; Randomized controlled trial

DOI：

10.7507/1672-2531.201904040

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Objectives To systematically review the efficacy and safety of dapagliflozin combined with hypoglycemic drugs in the treatment of diabetes patients.Methods PubMed, The Cochrane Library, EMbase, WanFang Data, VIP, CNKI and CBM databases were electronically searched to collect randomized controlled trials (RCTs) on the efficacy and safety of dapagliflozin combined with hypoglycemic drugs in the treatment of diabetes patients from inception to December, 2018. Two reviewers independently screened literature, extracted data, and assessed the risk of bias of included studies. Then, meta-analysis was performed using RevMan 5.3 software and Stata 14.0 software.Results A total of 16 RCTs involving 5 388 patients were included. The results of meta-analysis showed that, compared with control group, intervention group provided more reduction in HbAlc (MD=−0.55, 95%CI −0.63 to −0.48, P<0.000 01) and body weight (MD=−2.17, 95%CI −2.46 to −1.88, P<0.000 01). There were no significant differences in hypoglycaemia (RR=1.05, 95%CI 0.93 to 1.18, P=0.44) and hypotension (RR=1.63, 95%CI 0.73 to 3.65, P=0.23). The incidence of urinary tract infection (RR=1.29, 95%CI 1.03 to 1.61, P=0.02) and genital infection (RR=3.89, 95%CI 2.86 to 5.29, P< 0.000 01) in intervention groups were higher than those in the control groups.Conclusions Current evidence shows that dapagliflozin as an add-on drug to conventional antidiabetic drugs can more effectively reduce glycated hemoglobin and body weight in diabetic patients and does not increase the incidence of hypoglycemia and hypotension, however, with an increased risk for development of urinary tract infection and genital infections. Due to limited quality and quantity of the included studies, more high-quality studies are required to verify above conclusions.

Citation： YANG Yang, WEI Pengxiang, ZHANG Cun, ZHANG Nan, DUAN Yinyin, WEI Qunli. Efficacy and safety of dapagliflozin combined with hypoglycemic drugs for diabetes mellitus: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2019, 19(12): 1436-1445. doi: 10.7507/1672-2531.201904040 Copy

1.	Kolterman OG, Kim DD, Shen L, et al. Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am J Health Syst Pharm, 2005, 62(2): 173-181.
2.	Maya L, Villarreal FJ. Diagnostic approaches for diabetic cardiomyopathy and myocardial fibrosis. J Mol Cell Cardiol, 2010, 48(3): 524-529.
3.	Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med, 2008, 358(24): 2545-2559.
4.	Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract, 2010, 87(1): 4-14.
5.	Ripsin CM, Kang H, Urban RJ. Management of blood glucose in type 2 diabetes mellitus. Am Fam Physician, 2009, 79(1): 29-36.
6.	Prentki M, Nolan CJ. Islet beta cell failure in type 2 diabetes. J Clin Invest, 2006, 116(7): 1802-1812.
7.	Clar C, Gill JA, Court R, et al. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open, 2012, 2(5): e001007.
8.	Liebl A, Mata M, Eschwège E, et al. Evaluation of risk factors for development of complications in type II diabetes in Europe. Diabetologia, 2002, 45(7): S23-S28.
9.	Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA, 2004, 291(3): 335-342.
10.	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.
11.	万惠新, 沈竞康. 2型糖尿病治疗靶点钠-葡萄糖共转运蛋白2抑制剂研究进展. 药学学报, 2012, (6): 716-724.
12.	Chao EC, Henry RR. SGLT2 inhibition - a novel strategy for diabetes treatment (Reprinted from Nature Reviews Drug Discovery, vol 9, pg 551-559, 2010). Nat Rev Drug Discov, 2010: 29-37.
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.	Bolinder J, Ljunggren Ö, 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.
16.	Bolinder J, Ljunggren Ö, Johansson L, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab, 2014, 16(2): 159-169.
17.	Ljunggren Ö, Bolinder J, Johansson L, et al. Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin. Diabetes Obes Metab, 2012, 14(11): 990-999.
18.	Yang W, Han P, Min KW, et al. Efficacy and safety of dapagliflozin in Asian patients with type 2 diabetes after metformin failure: a randomized controlled trial. J Diabetes, 2016, 8(6): 796-808.
19.	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.
20.	Wilding JP, Norwood P, T'joen C, et al. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care, 2009, 32(9): 1656-1662.
21.	Wilding JP, Woo V, Soler NG, et al. 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.
22.	Wilding JP, Woo V, Rohwedder K, et al. 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.
23.	Yang W, Ma J, Li Y, et al. Dapagliflozin as add-on therapy in Asian patients with type 2 diabetes inadequately controlled on insulin with or without oral antihyperglycemic drugs: a randomized controlled trial. J Diabetes, 2018, 10(7): 589-599.
24.	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.
25.	Strojek K, Yoon K-H, 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-co-ntrolled trial. Diabetes Ther, 2014, 5(1): 267-283.
26.	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.
27.	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.
28.	Dandona P, Mathieu C, Phillip M, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol, 2017, 5(11): 864-876.
29.	Freemantle N, Holmes J, Hockey A, et al. How strong is the association between abdominal obesity and the incidence of type 2 diabetes? Int J Clin Pract, 2008, 62(9): 1391-1396.
30.	Gastaldelli A, Cusi K, Pettiti M, et al. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology, 2007, 133(2): 496-506.
31.	Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol, 2008, 28(4): 629-636.
32.	De Koning L, Merchant AT, Pogue J, et al. Waist circumference and waist-to-hip ratio as predictors of cardiovascular events: meta-regression analysis of prospective studies. Eur Heart J, 2007, 28(7): 850-856.
33.	Bays HE. Adiposopathy is "sick fat" a cardiovascular disease? J Am Coll Cardiol, 2011, 57(25): 2461-2473.
34.	Hermansen K, Mortensen LS. Bodyweight changes associated with antihyperglycaemic agents in type 2 diabetes mellitus. Drug Saf, 2007, 30(12): 1127-1142.
35.	Wilding JP, Hardy K. Glucagon-like peptide-1 analogues for type 2 diabetes. BMJ, 2011, 342: d410.
36.	Geerlings SE, Stolk RP, Camps MJ, et al. Risk factors for symptomatic urinary tract infection in women with diabetes. Diabetes Care, 2000, 23(12): 1737-1741.

1. Kolterman OG, Kim DD, Shen L, et al. Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am J Health Syst Pharm, 2005, 62(2): 173-181.
2. Maya L, Villarreal FJ. Diagnostic approaches for diabetic cardiomyopathy and myocardial fibrosis. J Mol Cell Cardiol, 2010, 48(3): 524-529.
3. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med, 2008, 358(24): 2545-2559.
4. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract, 2010, 87(1): 4-14.
5. Ripsin CM, Kang H, Urban RJ. Management of blood glucose in type 2 diabetes mellitus. Am Fam Physician, 2009, 79(1): 29-36.
6. Prentki M, Nolan CJ. Islet beta cell failure in type 2 diabetes. J Clin Invest, 2006, 116(7): 1802-1812.
7. Clar C, Gill JA, Court R, et al. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open, 2012, 2(5): e001007.
8. Liebl A, Mata M, Eschwège E, et al. Evaluation of risk factors for development of complications in type II diabetes in Europe. Diabetologia, 2002, 45(7): S23-S28.
9. Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA, 2004, 291(3): 335-342.
10. 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.
11. 万惠新, 沈竞康. 2型糖尿病治疗靶点钠-葡萄糖共转运蛋白2抑制剂研究进展. 药学学报, 2012, (6): 716-724.
12. Chao EC, Henry RR. SGLT2 inhibition - a novel strategy for diabetes treatment (Reprinted from Nature Reviews Drug Discovery, vol 9, pg 551-559, 2010). Nat Rev Drug Discov, 2010: 29-37.
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. Bolinder J, Ljunggren Ö, 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.
16. Bolinder J, Ljunggren Ö, Johansson L, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab, 2014, 16(2): 159-169.
17. Ljunggren Ö, Bolinder J, Johansson L, et al. Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin. Diabetes Obes Metab, 2012, 14(11): 990-999.
18. Yang W, Han P, Min KW, et al. Efficacy and safety of dapagliflozin in Asian patients with type 2 diabetes after metformin failure: a randomized controlled trial. J Diabetes, 2016, 8(6): 796-808.
19. 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.
20. Wilding JP, Norwood P, T'joen C, et al. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care, 2009, 32(9): 1656-1662.
21. Wilding JP, Woo V, Soler NG, et al. 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.
22. Wilding JP, Woo V, Rohwedder K, et al. 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.
23. Yang W, Ma J, Li Y, et al. Dapagliflozin as add-on therapy in Asian patients with type 2 diabetes inadequately controlled on insulin with or without oral antihyperglycemic drugs: a randomized controlled trial. J Diabetes, 2018, 10(7): 589-599.
24. 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.
25. Strojek K, Yoon K-H, 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-co-ntrolled trial. Diabetes Ther, 2014, 5(1): 267-283.
26. 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.
27. 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.
28. Dandona P, Mathieu C, Phillip M, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol, 2017, 5(11): 864-876.
29. Freemantle N, Holmes J, Hockey A, et al. How strong is the association between abdominal obesity and the incidence of type 2 diabetes? Int J Clin Pract, 2008, 62(9): 1391-1396.
30. Gastaldelli A, Cusi K, Pettiti M, et al. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology, 2007, 133(2): 496-506.
31. Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol, 2008, 28(4): 629-636.
32. De Koning L, Merchant AT, Pogue J, et al. Waist circumference and waist-to-hip ratio as predictors of cardiovascular events: meta-regression analysis of prospective studies. Eur Heart J, 2007, 28(7): 850-856.
33. Bays HE. Adiposopathy is "sick fat" a cardiovascular disease? J Am Coll Cardiol, 2011, 57(25): 2461-2473.
34. Hermansen K, Mortensen LS. Bodyweight changes associated with antihyperglycaemic agents in type 2 diabetes mellitus. Drug Saf, 2007, 30(12): 1127-1142.
35. Wilding JP, Hardy K. Glucagon-like peptide-1 analogues for type 2 diabetes. BMJ, 2011, 342: d410.
36. Geerlings SE, Stolk RP, Camps MJ, et al. Risk factors for symptomatic urinary tract infection in women with diabetes. Diabetes Care, 2000, 23(12): 1737-1741.

Chinese Journal of Evidence-Based Medicine

Efficacy and safety of dapagliflozin combined with hypoglycemic drugs for diabetes mellitus: a meta-analysis

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