Skip to main content
main-content
Top

02-27-2018 | SGLT2 inhibitors | Article

SGLT-2 inhibitors and the risk of infections: a systematic review and meta-analysis of randomized controlled trials

Journal: Acta Diabetologica

Authors: Robert Puckrin, Marie-Philippe Saltiel, Pauline Reynier, Laurent Azoulay, Oriana H. Y. Yu, Kristian B. Filion

Publisher: Springer Milan

share
SHARE

Abstract

Aims

There is concern about the infection-related safety profile of sodium–glucose co-transporter 2 (SGLT-2) inhibitors. We aimed to determine the effect of SGLT-2 inhibitors on genitourinary and other infections via systematic review and meta-analysis of randomized controlled trials (RCTs).

Methods

We conducted a systematic search of Medline, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov to identify double-blinded RCTs enrolling ≥ 50 patients with type 2 diabetes which compared an SGLT-2 inhibitor to placebo or active comparator. Two independent reviewers extracted data and appraised study quality. Data were pooled using random-effects models.

Results

Eighty-six RCTs enrolling 50,880 patients were included. SGLT-2 inhibitors increased the risk of genital infections compared to placebo (relative risk [RR] 3.37, 95% CI 2.89–3.93, I2 0%) and active comparator (RR 3.89, 95% CI 3.14–4.82, I2 0.3%). The risk of urinary tract infection (UTI) was not increased with SGLT-2 inhibitors compared to placebo (RR 1.03, 95% CI 0.96–1.11, I2 0%) or active comparator (RR 1.08, 95% CI 0.93–1.25, I2 22%). In drug-specific analyses, only dapagliflozin 10 mg daily was associated with a significantly increased risk of UTI compared to placebo (RR 1.33, 95% CI 1.10–1.61, I2 0%). SGLT-2 inhibitors were associated with a reduced risk of gastroenteritis (RR 0.38, 95% CI 0.20–0.72, I2 0%) but did not affect the risk of respiratory tract infections.

Conclusions/interpretation

SGLT-2 inhibitors are associated with an increased risk of genital tract infections. Although there is no association overall between SGLT-2 inhibitors and UTI, higher doses of dapagliflozin are associated with an increased risk.
Literature
1.
Monami M, Nardini C, Mannucci E (2014) Efficacy and safety of sodium glucose co-transport 2 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 16(5):457–466 CrossRefPubMed
2.
Clar C, Gill J, Court R et al (2012) Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open 2(5):e001007 CrossRefPubMedPubMedCentral
3.
Musso G, Gambino R, Cassader M et al (2012) 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 44(4):375–393 CrossRefPubMed
4.
Vasilakou D, Karagiannis T, Athanasiadou E et al (2013) Sodium–glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 159(4):262–274 CrossRefPubMed
5.
Berhan A, Barker A (2013) Sodium glucose co-transport 2 inhibitors in the treatment of type 2 diabetes mellitus: a meta-analysis of randomized double-blind controlled trials. BMC Endocr Disord 13:58 CrossRefPubMedPubMedCentral
6.
Liu X, Zhang N, Chen R et al (2015) Efficacy and safety of sodium–glucose cotransporter 2 inhibitors in type 2 diabetes: a meta-analysis of randomized controlled trials for 1 to 2 years. J Diabetes Complicat 29(8):1295–1303 CrossRefPubMed
7.
Johnsson K, Ptaszynska A, Schmitz B et al (2013) Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin. J Diabetes Complicat 27(5):479–484 CrossRefPubMed
8.
Food and Drug Administration (2015) 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. http://​www.​fda.​gov/​Drugs/​DrugSafety/​ucm475463.​htm. Accessed 12 Jan 2016
9.
Food and Drug Administration (2016) FDA drug safety communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). http://​www.​fda.​gov/​Drugs/​DrugSafety/​ucm505860.​htm. Accessed 6 Aug 2016
10.
Yu S, Fu A, Qiu Y et al (2014) Disease burden of urinary tract infections among type 2 diabetes mellitus patients in the U.S. J Diabetes Complicat 28(5):621–626 CrossRefPubMed
11.
Mnif M, Kamoun N, Kacem F et al (2013) Complicated urinary tract infections associated with diabetes mellitus: pathogenesis, diagnosis and management. Indian J Endocrinol Metab 17(3):442–445 CrossRefPubMedPubMedCentral
12.
Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62:1006–1012 CrossRefPubMed
13.
Health Information Research Unit (2004) Hedges. http://​hiru.​mcmaster.​ca/​hiru/​HIRU_​Hedges_​home.​aspx. Accessed 15 Mar 2015
14.
Higgins J, Green S (2008) Cochrane handbook for systematic reviews of interventions, version 5.0.0. The Cochrane collaboration. www.​cochrane-handbook.​org. Accessed 18 Aug 2016
15.
Lundh A, Sismondo S, Lexchin J et al (2012) Industry sponsorship and research outcome. Cochrane Database Syst Rev 12:MR000033 PubMed
16.
Tahara A, Takasu T, Yokono M et al (2016) Characterization and comparison of sodium–glucose cotransporter 2 inhibitors in pharmacokinetics, pharmacodynamics, and pharmacologic effects. J Pharmacol Sci 130(3):159–169 CrossRefPubMed
17.
Geerlings S, Fonseca V, Castro-Diaz D et al (2014) Genital and urinary tract infections in diabetes: impact of pharmacologically-induced glucosuria. Diabetes Res Clin Pract 10(3):373–381 CrossRef
18.
Rosenstock J, Ferrannini E (2015) Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 38(9):1638–1642 CrossRefPubMed
19.
Food and Drug Administration (2016) FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes. https://​www.​fda.​gov/​newsevents/​newsroom/​pressannouncemen​ts/​ucm531517.​htm. Accessed 17 Jun 2017
20.
Zinman B, Wanner C, Lachin J et al (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373(22):2117–2128 CrossRefPubMed
21.
Monami M, Dicembrini I, Mannucci E (2017) Effects of SGLT-2 inhibitors on mortality and cardiovascular events: a comprehensive meta-analysis of randomized controlled trials. Acta Diabetol 54(1):19–36 CrossRefPubMed
22.
Zaccardi F, Webb D, Htike Z et al (2016) Efficacy and safety of sodium–glucose cotransporter 2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab 18(8):783–794 CrossRefPubMed
23.
Wu J, Foote C, Blomster J et al (2016) 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. Lancet Diabetes Endocrinol 4(5):411–419 CrossRefPubMed
24.
Shyangdan D, Uthman O, Waugh N (2016) SGLT-2 receptor inhibitors for treating patients with type 2 diabetes mellitus: a systematic review and network meta-analysis. BMJ Open 6(2):e009417 CrossRefPubMedPubMedCentral
25.
Li D, Wang T, Shen S et al (2017) Urinary tract and genital infections in patients with type 2 diabetes treated with sodium–glucose co-transporter 2 inhibitors: a meta-analysis of randomized controlled trials. Diabetes Obes Metab 19(3):348–355 CrossRefPubMed
26.
Saad M, Mahmoud A, Elgendy I et al (2017) Cardiovascular outcomes with sodium–glucose cotransporter-2 inhibitors in patients with type II diabetes mellitus: a meta-analysis of placebo-controlled randomized trials. Int J Cardiol 228:352–358 CrossRefPubMed
27.
Storgaard H, Gluud L, Bennett C et al (2016) Benefits and harms of sodium–glucose co-transporter 2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis. PLoS ONE 11(11):e0166125 CrossRefPubMedPubMedCentral
28.
Tang H, Fang Z, Wang T et al (2016) 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 118(11):1774–1780 CrossRefPubMed
29.
Sutton A, Cooper N, Lambert P et al (2002) Meta-analysis of rare and adverse event data. Expert Rev Pharmacoecon Outcomes Res 2(4):367–379 CrossRefPubMed
30.
Walker E, Hernandez A, Kattan M (2008) Meta-analysis: its strengths and limitations. Cleve Clin J Med 75(6):431–439 CrossRefPubMed

New additions to the Adis Journal Club

A selection of topical peer-reviewed articles from the Adis journals, curated by the editors.

GLP-1 receptor agonists

Browse the latest news, clinical trial updates, and expert commentary.