Sodium glucose co-transport 2 inhibitors in the treatment of type 2 diabetes mellitus: a meta-analysis of randomized double-blind controlled trials

BMC Endocrine Disorders

Alex Barker¹  Asres Berhan² 

[1] Veteran Affairs Medical Center, Iron Mountain, Michigan, USA;Hawassa University College of Medicine and Health Sciences, P. O. Box: 1560, Hawassa, Ethiopia

关键词: Type 2 diabetes;    SGLT2 inhibitors;    Meta-analysis;    Ipragliflozin;    Empagliflozin;    Dapagliflozin;    Canagliflozin;   

Others  :  1085441
DOI  :  10.1186/1472-6823-13-58

 received in 2013-08-24, accepted in 2013-12-13,  发布年份 2013

【 摘 要 】

Background

The discovery of sodium-glucose co-transporter 2 (SGLT2) inhibitors, with a novel mechanism independent of insulin secretion or sensitization, bring about a new therapeutic approach to the management of type 2 diabetes mellitus. The aim of this meta-analysis was to evaluate the safety and efficacy of SGLT2 inhibitors at different doses in randomized double blind clinical trials.

Methods

This meta-analysis was conducted by including randomized double-blind controlled trials of SGLT2 inhibitors in patients with type 2 diabetes irrespective of their antidiabetic drug exposure history but with an inadequate glycemic control. All the effect sizes were computed using the random effects model. Standardized mean differences (SMDs) and odds ratios (OR) were computed for continuous and dichotomous variables, respectively. Additional analyses like sensitivity analysis, subgroup analysis and meta-regression were also performed.

Results

The pooled analyses demonstrated a significant reduction in mean changes in Hemoglobin A1c (HbA1c) (SMD = −0.78%, 95% CI, -0.87 to −0.69), fasting plasma glucose (FPG) (SMD = −0.70 mg/dl, 95% CI, -0.79 to −0.61), body weight (overall SMD = −0.59 kg, 95% CI, -0.65 to −0.52) and blood pressure from baseline with SGLT2 inhibitors based therapy. Consistently a significant number of patients treated with SGLT2 inhibitors achieved HbA1c < 7% (OR = 2.09, 95% CI, 1.77 to 2.46). SGLT2 inhibitors based therapy was associated with adverse events like genital and urinary tract infections.

Conclusion

All studied doses of SGLT2 inhibitors, either as monotherapy or in combination with other antidiabetic agents, consistently improved glycemic control in patients with type 2 diabetes. However, a small percentage of patients suffer from genital and urinary tract infections.

【 授权许可】

   
2013 Berhan and Barker; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Stratton IM, Adler AI, Neil HAW, Matthews DR, Manley SE, Cull CA, et al.: Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000, 321:405-412.
• [2]Rossetti L, Giaccari A, DeFronzo RA: Glucose toxicity. Diabetes Care 1990, 13(6):610-630.
• [3]Centers for Disease Control and Prevention: Diabetes: successes and opportunities for population-based prevention and control: at a glance 2011. Avalilable from: URL: http://www.cdc.gov/chronicdisease/resources/publications/aag/pdf/2011/Diabetes-AAG-2011-508.pdf webcite. (Accessed May 20, 2013)
• [4]Bate KL, Jerums G: Preventing complications of diabetes. MJA 2003, 179:498-503.
• [5]Khaw K, Wareham N, Bingham S, Luben R, Welch A, Day N: Association of hemoglobin a 1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med 2004, 141:413-420.
• [6]Shichiri M, Kishikawa H, Ohkubo Y, Wake N: Long-term results of the Kumamoto study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 2000, 23(2):B21-B29.
• [7]Ray KK, Seshasai SRK, Wijesuriya S, Sivakumaran R, Nethercott S, Preiss D, et al.: Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009, 373:1765-1772.
• [8]Kurukulasuriya LR, Sowers JR: Therapies for type 2 diabetes: lowering HbA1c and associated cardiovascular risk factors. Cardiovasc Diabetol 2010, 9(1):45. BioMed Central Full Text
• [9]Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al.: Glycemic durability of rosiglitazone, metformin, or Glyburide monotherapy. N Engl J Med 2006, 355:2427-2443.
• [10]Turner RC, Holman RR, Cull CA, Stratton IM, Matthews DR, Frighi V, et al.: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998, 352(9131):837-853.
• [11]Kanai Y, Lee W, You G, Brown D, Hediger MA: The human kidney Low affinity Na+/glucose cotransporter SGLT2: delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest 1994, 93:397-404.
• [12]Abdul-Ghani MA, Norton L, DeFronzo RA: Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev 2011, 32(4):515-531.
• [13]Musso G, Gambino R, Cassader M, Pagano G: 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, 44:375-393.
• [14]Clar C, Gill JA, Court R, Waugh N: Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open 2012, 2(5):e001007.
• [15]Kaku K, Inoue S, Matsuoka O, Kiyosue A, Azuma H, Hayashi N, 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.
• [16]Stenlöf K, Cefalu WT, Kim K, Alba M, Usiskin K, Tong C, et al.: Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 2013, 15(4):372-382.
• [17]Conversion of units of glucose plasmatic level Available from: URL: http://en.mte.cz/conversion.php?mmol=10&mg=&count_it=1 webcite
• [18]Wilding JP, Norwood P, T’Joen C, Bastien A, List JF, et al.: A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers. Diabetes Care 2009, 32(2):1656-1662.
• [19]Bailey CJ, Iqbal N, T’joen C, List JF: Dapagliflozin monotherapy in drug-naïve patients with diabetes: a randomized-controlled trial of low-dose range. Diabetes Obes Metab 2012, 14(1):951-959.
• [20]Ferrannini EL, Ramos SJ, Salsali A, Tang W, List J: 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(2):2217-2224.
• [21]Henry RR, Murray AV, Marmolejo MH, Hennicken D, Ptaszynska A, List JF: Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomised controlled trial. Int J Clin Pract 2012, 66(5):446-456.
• [22]Strojek K, Yoon KH, Hruba V, Elze M, Langkilde AM, Parikh S: 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.
• [23]Bailey CJ, Gross JL, Pieters A, Bastien A, List JF: 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(2):2223.
• [24]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 Endocr Metab 2012, 97(3):1020-1031.
• [25]Rosenstock J, Vico M, Wei LI, Salsali A, List JF: Effects of dapagliflozin, an SGLT2 inhibitor, on HbA1c, body weight, and hypoglycemia risk in patients with Type2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care 2012, 35(2):1473-1478.
• [26]Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, 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(3):405-415.
• [27]List JF, Woo V, Morales E, Tang W, Fiedorek FT: Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 2009, 32:650-657.
• [28]Rosenstock J, Aggarwal N, Polidori D, Zhao Y, Arbit D, Usiskin K, et al.: Dose- ranging effects of canagliflozin, a sodium-glucose Cotransporter2 inhibitor, as add-on to metformin in subjects with Type2 diabetes. Diabetes Care 2012, 35(1):1232-1238.
• [29]Yale JF, Bakris G, Cariou B, Yue D, David-Neto E, Xi L, et al.: Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 2013, 15(5):463-473.
• [30]Wilding JPH, Ferrannini E, Fonseca V, Wilpshaar W, Dhanjal P, Houzer A: Efficacy and safety of ipragliflozin in patients with type 2 diabetes inadequately controlled on metformin: a dose-finding study. Diabetes Obes Metab 2013, 15(1):403-409.
• [31]Fonseca VA, Ferrannini E, Wilding JP, Wilpshaar W, Dhanjal P, Ball G, et al.: Active- and placebo-controlled dose-finding study to assess the efficacy, safety, and tolerability of multiple doses of ipragliflozin in patients with type 2 diabetes mellitus. J Diabetes Complicat 2012, 27(3):268-273.
• [32]Ferrannini E, Seman L, Seewaldt-Becker E, Hantel S, Pinnetti S, Woerle HJ: A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes. Diabetes Obes Metab 2013., (1) doi:10.1111/dom.12081 5
• [33]Saudek CD, Kalyani RR, Derr RL: Assessment of glycemia in diabetes mellitus: hemoglobin A1 c. JAPI 2005, 53:299-305.
• [34]Wang W, Lee ET, Howard BV, Fabsitz RR, Devereux RB, Welty TK: Fasting plasma glucose and hemoglobin A1c in identifying and predicting diabetes: the strong heart study. Diabetes Care 2011, 34(2):363-368.
• [35]Bailey CJ, Gross JL, Hennicken D, Iqbal N, Mansfield TA, List JF: 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. Available from: URL: http://www.biomedcentral.com/1741-7015/11/43 webcite BioMed Central Full Text
• [36]Daousi C, Casson IF, Gill GV, MacFarlane IA, Wilding JP, Pinkney JH: Prevalence of obesity in type 2 diabetes in secondary care: association with cardiovascular risk factors. Postgrad Med J 2006, 82(966):280-284.
• [37]Katakura M, Naka M, Kondo T, Nishii N, Komatsu M, Sato Y, et al.: Prospective analysis of mortality, morbidity, and risk factors in elderly diabetic subjects. Diabetes Care 2003, 26:638-644.
• [38]Neter JE, Stam BE, Kok FJ, Grobbee DE, Geleijnse JM: Influence of weight reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension 2003, 42:878-884.
• [39]Dattilo AM, Etherton K: Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr 1992, 56:320-328.
• [40]Misra M: SGLT2 inhibitors: a promising new therapeutic option for treatment of type 2 diabetes mellitus. JPP 2013, 65:317-327.
• [41]Nyirjesy P, Zhao Y, Ways K, Usiskin K: Evaluation of vulvovaginal symptoms and Candida colonization in women with type 2 diabetes mellitus treated with canagliflozin, a sodium glucose co-transporter 2 inhibitor. Curr Med Res Opin 2012, 28(7):1173-1178.
• [42]FDAAdvisory Committee Meeting. FDA briefing document. NDA 202293. (Dapagliflozin tablets 5 mg and 10 mg. Sponsor: Bristol Myers Squibb) Available from: http://www.fda.gov/downloads/AdvisoryCommittees/ webcite
• [43]Walker E, Hernandez AV, Kattan MW: Meta-analysis: its strengths and limitations. Clev Clin J Med 2008, 75(6):431-439.