Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: a systematic review and meta-analysis

Jiali Liu, Ling Li, Sheyu Li, Pengli Jia, Ke Deng, Wenwen Chen, Xin Sun, Jiali Liu, Ling Li, Sheyu Li, Pengli Jia, Ke Deng, Wenwen Chen, Xin Sun

Abstract

Previous trial evidence suggested potential risk of serious urinary tract infections (UTIs) and genital infections in type 2 diabetes patients using sodium glucose co-transporter-2 inhibitors (SGLT2) inhibitors. We conducted a systematic review and meta-analysis to assess the effects of SGLT2 inhibitors on UTIs and genital infections in patients with type 2 diabetes. In total, 77 RCTs involving 50,820 participants were eligible. The meta-analyses of randomized controlled trials (RCTs) showed no significant difference in UTIs between SGLT2 inhibitors versus control (2,526/29,086 vs. 1,278/14,940; risk ratio (RR) 1.05, 95% confidence interval (CI) 0.98 to 1.12; moderate quality evidence), but suggested increased risk of genital infections with SGLT2 inhibitors (1,521/24,017 vs. 216/12,552; RR 3.30, 95% CI 2.74 to 3.99; moderate quality evidence). Subgroup analyses by length of follow up (interaction p = 0.005), type of control (interaction p = 0.04) and individual SGLT2 inhibitors (interaction p = 0.03) also showed statistically significant differences in genital infections. The upcoming major trials may provide important additional insights on UTIs, and more efforts are needed to address comparative effects of each individual SGLT2 inhibitors on the infections.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Flow chart of study selection
Figure 2
Figure 2
UTIs in type 2 diabetes patients receiving SGLT2 inhibitors versus control in randomized controlled trials.
Figure 3
Figure 3
Events suggestive UTIs in type 2 diabetes patients receiving SGLT2 inhibitors versus control in randomized controlled trials.
Figure 4
Figure 4
Genital infections in type 2 diabetes patients receiving SGLT2 inhibitors versus control in randomized controlled trials.
Figure 5
Figure 5
Events suggestive genital infections in type 2 diabetes patients receiving SGLT2 inhibitors versus control in randomized controlled trials

References

    1. Hasan FM, Alsahli M, Gerich JE. SGLT2 inhibitors in the treatment of type 2 diabetes. Diabetes research and clinical practice. 2014;104:297–322. doi: 10.1016/j.diabres.2014.02.014.
    1. Dardi I, Kouvatsos T, Jabbour SA. SGLT2 inhibitors. Biochemical pharmacology. 2016;101:27–39. doi: 10.1016/j.bcp.2015.09.005.
    1. Zaccardi F, et al. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus: Systematic review and network meta-analysis. Diabetes, obesity & metabolism. 2016;18:783–794. doi: 10.1111/dom.12670.
    1. Vasilakou D, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Annals of internal medicine. 2013;159:262–274. doi: 10.7326/0003-4819-159-4-201308200-00007.
    1. U.S. Food and Drug Administration. FDA approves Farxiga to treat type 2 diabetes [FDA NEWS RELEASE]. , (Date of access: 10 November 2016) (2014).
    1. U.S. Food and Drug Administration. FDA approves Invokana to treat type 2 diabetes [FDA NEWS RELEASE]. , (Date of access: 10 November 2016) (2013).
    1. U.S. Food and Drug Administration. FDA approves Jardiance to treat type 2 diabetes [FDA News Release]. , (Date of access: 10 November 2016) (2014).
    1. European Medicines Agency. Forxiga (dapagliflozin): EPAR summary for the public. EMEA/H/C/002322. , (Date of access: 10 November 2016) (2012).
    1. European Medicines Agency. Invokana (canagliflozin): EPAR summary for the public. EMEA/H/C/002649. , (Date of access: 10 November 2016) (2013).
    1. European Medicines Agency. Jardiance (empagliflozin): EPAR summary for the public. EMEA/H/C/002677. , (Date of access: 10 November 2016) (2014).
    1. Markham A, Elkinson S. Luseogliflozin: first global approval. Drugs. 2014;74:945–950. doi: 10.1007/s40265-014-0230-8.
    1. Poole RM, Dungo RT. Ipragliflozin: first global approval. Drugs. 2014;74:611–617. doi: 10.1007/s40265-014-0204-x.
    1. Poole RM, Prossler JE. Tofogliflozin: first global approval. Drugs. 2014;74:939–944. doi: 10.1007/s40265-014-0229-1.
    1. Benfield T, Jensen JS, Nordestgaard BG. Influence of diabetes and hyperglycaemia on infectious disease hospitalisation and outcome. Diabetologia. 2007;50:549–554. doi: 10.1007/s00125-006-0570-3.
    1. Geerlings S, Fonseca V, Castro-Diaz D, List J, Parikh S. Genital and urinary tract infections in diabetes: impact of pharmacologically-induced glucosuria. Diabetes research and clinical practice. 2014;103:373–381. doi: 10.1016/j.diabres.2013.12.052.
    1. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. , (Date of access: 10 November 2016) (2015).
    1. Kawalec P, Mikrut A, Lopuch S. The safety of dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter 2 (SGLT-2) inhibitors added to metformin background therapy in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes/metabolism research and reviews. 2014;30:269–283. doi: 10.1002/dmrr.2494.
    1. Wu JH, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. The lancet. Diabetes & endocrinology. 2016;4:411–419. doi: 10.1016/S2213-8587(16)00052-8.
    1. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. International journal of surgery (London, England). 2010;8:336–341. doi: 10.1016/j.ijsu.2010.02.007.
    1. . Why should I register and submit results? , (Date of access: 10 November 2016) (2015).
    1. US Food and Drug Administration. Food and Drug Administration Amendments Act (FDAAA) of 2007. US Public Law 110-85 section 801. , (Date of access: 10 November 2016) (2007).
    1. Higgins JP, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ (Clinical research ed.). 2011;343:d5928–d5928. doi: 10.1136/bmj.d5928.
    1. Guyatt GH, Busse JW. Modification of Cochrane Tool to assess risk of bias in randomized trials. , (Date of access: 10 November 2016) (2013).
    1. Akl EA, et al. Specific instructions for estimating unclearly reported blinding status in randomized trials were reliable and valid. Journal of clinical epidemiology. 2012;65:262–267. doi: 10.1016/j.jclinepi.2011.04.015.
    1. Higgins, J. P. T. & Green, S. The Cochrane Collaboration network , (Date of access: 10 November 2016) (2011).
    1. Sun X, Briel M, Walter SD, Guyatt GH. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses. BMJ (Clinical research ed.). 2010;340:c117–c117. doi: 10.1136/bmj.c117.
    1. Guyatt G, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. Journal of clinical epidemiology. 2011;64:383–394. doi: 10.1016/j.jclinepi.2010.04.026.
    1. Zinman B, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. The New England journal of medicine. 2015;373:2117–2128. doi: 10.1056/NEJMoa1504720.
    1. Inagaki N, et al. Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, 12-week study. Diabetes, obesity & metabolism. 2013;15:1136–1145. doi: 10.1111/dom.12149.
    1. Seino Y, et al. Efficacy and safety of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, phase 3 study. Current medical research and opinion. 2014;30:1245–1255. doi: 10.1185/03007995.2014.912983.
    1. Liakos A, et al. Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysis. Diabetes, obesity & metabolism. 2014;16:984–993. doi: 10.1111/dom.12307.
    1. Neal, B. et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)–a randomized placebo-controlled trial. American heart journal. 166, 217–223.e211–223, doi:10.1016/j.ahj.2013.05.007 (2013).
    1. AstraZeneca, B-M Squibb, The TIMI Study Group, Hadassah Medical Organization, Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58). National Library of Medicine (US), 2000. , (Date of access: 10 November 2016) (2012).
    1. M Sharp & D Corp, Pfizer. Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease, The VERTIS CV Study (MK-8835-004). National Library of Medicine (US), 2000. , (Date of access: 10 November 2016) (2013).
    1. Berhan A, Barker A. 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. 2013;13:58. doi: 10.1186/1472-6823-13-58.
    1. Liu XY, Zhang N, Chen R, Zhao JG, Yu P. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes: a meta-analysis of randomized controlled trials for 1 to 2years. Journal of diabetes and its complications. 2015;29:1295–1303. doi: 10.1016/j.jdiacomp.2015.07.011.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera