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KSR Number: KSRA62436

SGLT2 inhibitors and risk of stroke in patients with type 2 diabetes: a systematic review and meta-analysis

Risk of Bias Assessment

Overall summary: Low risk of bias in the review

Bottom Line

Current evidence suggests that sodium-glucose cotransporter 2 (SGLT2) inhibitors do not increase the risk of stroke compared to placebo in patients with type 2 diabetes mellitus. Of note, black patients may have a lower risk of stroke after treatment with SGLT2 inhibitors compared to white or Asian patients. Robust methodology supports these findings. Future studies are needed to explore these ethnic/racial differences and additional sodium-glucose cotransporter 2 inhibitor classes.

Risk of Bias Assessment

Overall summary Low risk of bias in the review

Low

All domains were considered at low concern for risk of bias.

A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4? Probably yes
B. Was the relevance of identified studies to the review's research question appropriately considered? Probably yes
C. Did the reviewers avoid emphasizing results on the basis of their statistical significance? Probably yes
Risk of bias in the review Low

Details of Review

Number of studies 32
Number of participants 75,540
Last search date 19th September 2017
Review type Intervention
Objective To qualitatively and quantitatively assess the effects of different sodium-glucose cotransporter 2 inhibitors on stroke risk in patients with type 2 diabetes mellitus.
Population Subjects with type 2 diabetes mellitus, irrespective of gender, age, race or nationality.
Interventions Sodium-glucose cotransporter 2 inhibitors taken for at least six months
Comparator Not pre-specified (ultimately placebo or active comparator)
Outcome Stroke events
Study design Randomised controlled trials.

Duplicate reports, letters, case reports, editorials were excluded.

Results

Pooled analysis reported no difference in stroke risk for any type of sodium-glucose cotransporter 2 (SGLT2) inhibitor monotherapy or combination therapy compared with placebo (relative risk [RR] 1.00, 95% confidence interval [CI] 0.92 to 1.09; 32 studies, n=75,540 patients). Pooled analysis also reported no difference in stroke risk for specific SGLT2 inhibitors compared with placebo, including canagliflozin (RR 0.91, 95% CI 0.62 to 1.33; 7 studies, n=14,358 patients), dapagliflozin (RR 0.99, 95% CI 0.91 to 1.09; 12 studies, n=46,894 patients) or empagliflozin (RR 1.03, 95% CI 0.71 to 1.48; 13 studies, n=14,278 patients).

Similarly, pooled analysis reported no difference in stroke risk for any type of SGLT2 inhibitor monotherapy compared to placebo (RR 1.00, 95% CI 0.81 to 1.24; 24 studies, n=29,003 patients) or for specific types of SGLT2 inhibitors, including canagliflozin (RR 0.85, 95% CI 0.57 to 1.27; 5 studies, n=5,178 patients), dapagliflozin (RR 0.59, 95% CI 0.26 to 1.32; 10 studies, n=5,195 patients) and empagliflozin (RR 1.14, 95% CI 0.87 to 1.48; 9 studies, n=11,630 patients).

In terms of race, pooled subgroup analyses reported that black patients had a lower incidence of stroke following treatment with SGLT2 inhibitors compared to control therapy (RR 0.51, 95% CI 0.30 to 0.89; n=2000 patients); however, white (RR 1.00, 95% CI 0.61 to 1.63; n=2000 patients) or Asian patients (RR 0.97, 95% CI 0.58 to 1.61; n=2000 patients) were reported to have no difference in stroke risk.

Full Risk of Bias Assessment

The research objective was clearly stated and appropriate inclusion criteria were defined. No restrictions were reported based on study characteristics or sources of information.

1.1 Did the review adhere to pre-defined objectives and eligibility criteria? Probably yes
1.2 Were the eligibility criteria appropriate for the review question? Probably yes
1.3 Were eligibility criteria unambiguous? Probably yes
1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)? Probably yes
1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)? Probably yes
Concerns regarding specification of study eligibility criteria Low

PubMed, Embase, CENTRAL, Web of Science and Scopus were searched for relevant studies. The references in the selected trials and meta-analyses, ClinicalTrials.gov were manually searched and contacted authors for unpublished studies and additional information. The search strategy was reported in full and appeared broadly adequate, although it would have been improved by adding additional terms for stroke, such as cerebrovascular accident, apoplexy or CVA. There were no search restrictions imposed based on language. Two authors were involved in the study selection process. Any disagreements were resolved by discussion with a third investigator when necessary.

2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports? Probably yes
2.2 Were methods additional to database searching used to identify relevant reports? Probably yes
2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible? Probably yes
2.4 Were restrictions based on date, publication format, or language appropriate? Probably yes
2.5 Were efforts made to minimise error in selection of studies? Probably yes
Concerns regarding methods used to identify and/or select studies Low

Data extraction was performed by two authors independently and disagreements were resolved by discussion with a third investigator or by referencing the original report when necessary. Sufficient study characteristics appear to have been extracted to allow interpretation of results. Relevant study results appear to have been extracted. The methodological quality of included studies was assessed using the Cochrane risk of bias tool for randomised controlled trials. At least two authors were involved in the assessment of the risk of bias. Disagreements were resolved by discussion with a third investigator or by referencing the original report when necessary.

3.1 Were efforts made to minimise error in data collection? Yes
3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results? Probably yes
3.3 Were all relevant study results collected for use in the synthesis? Probably yes
3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria? Probably yes
3.5 Were efforts made to minimise error in risk of bias assessment? Probably yes
Concerns regarding methods used to collect data and appraise studies Low

The synthesis appeared to include all relevant studies. The method of analysis was explained and appeared appropriate. There was no evidence of significant heterogeneity among the studies. Publication bias was assessed using funnel plots and Begg's test and found to be low. The quality of individual studies was considered in the synthesis.

4.1 Did the synthesis include all studies that it should? Probably yes
4.2 Were all pre-defined analyses reported or departures explained? Probably yes
4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies? Probably yes
4.4 Was between-study variation minimal or addressed in the synthesis? Probably yes
4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses? Probably yes
4.6 Were biases in primary studies minimal or addressed in the synthesis? Yes
Concerns regarding synthesis and findings Low

Abstract

The effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on risk of stroke have not been conclusively established. Therefore, we conducted a meta-analysis to evaluate the effects of SGLT2 inhibitors on stroke risk in patients with type 2 diabetes mellitus (T2DM) by searching available randomized trials in PubMed, Embase, CENTRAL, Web of Science, Scopus and ClinicalTrials.gov databases. We identified 32 eligible trials involving 75540 participants. The incidence of stroke in groups receiving SGLT2 inhibitor monotherapy or combination therapy did not differ significantly from that in control groups, with a relative risk (RR) of 1.01 and 1.0, respectively. Three SGLT2 inhibitors were tested, with similar RR values (canagliflozin [RR, 0.91], dapagliflozin [RR, 0.99] and empagliflozin [RR, 1.03]). Subgroup analyses showed that RR values were not affected by gender, age, diabetes duration, BMI or HbA1C levels, but Black patients had a lower incidence of stroke than White or Asian patients. This meta-analysis indicated that SGLT2 inhibitor therapy did not increase stroke incidence, and no significant differences in stroke risk were observed among 3 SGLT2 inhibitors (class effect). However, the small racial disparity requires further study and confirmation.