Comparative safety of different recommended doses of sodium–glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus: a systematic review and network meta-analysis of randomized clinical trials

Objective The safety results of different recommended doses of sodium-glucose cotransporter 2 inhibitors (SGLT-2i) for patients with type 2 diabetes mellitus (T2DM) remain uncertain. This study aims to comprehensively estimate and rank the relative safety outcomes with different doses of SGLT-2i for T2DM. Methods PubMed, Embase, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Chinese National Knowledge Infrastructure, WanFang database, and SinoMed database were searched from the inception to 31 May 2023. We included double-blind randomized controlled trials (RCTs) comparing SGLT-2i with placebo or another antihyperglycemic as oral monotherapy in the adults with a diagnosis of T2DM. Results Twenty-five RCTs with 12,990 patients randomly assigned to 10 pharmacological interventions and placebo were included. Regarding genital infections (GI), all SGLT-2i, except for ertugliflozin and ipragliflozin, were associated with a higher risk of GI compared to placebo. Empagliflozin 10mg/d (88.2%, odds ratio [OR] 7.90, 95% credible interval [CrI] 3.39 to 22.08) may be the riskiest, followed by empagliflozin 25mg/d (83.4%, OR 7.22, 95%CrI 3.11 to 20.04)) and canagliflozin 300mg/d (70.8%, OR 5.33, 95%CrI 2.25 to 13.83) based on probability rankings. Additionally, dapagliflozin 10mg/d ranked highest for urinary tract infections (UTI, OR 2.11, 95%CrI 1.20 to 3.79, 87.2%), renal impairment (80.7%), and nasopharyngitis (81.6%) when compared to placebo and other treatments. No increased risk of harm was observed with different doses of SGLT-2i regarding hypoglycemia, acute kidney injury, diabetic ketoacidosis, or fracture. Further subgroup analysis by gender revealed no significantly increased risk of UTI. Dapagliflozin 10mg/d (91.9%) and canagliflozin 300mg/d (88.8%) ranked first in the female and male subgroups, respectively, according to the probability rankings for GI. Conclusion Current evidence indicated that SGLT-2i did not significantly increase the risk of harm when comparing different doses, except for dapagliflozin 10mg/d, which showed an increased risk of UTI and may be associated with a higher risk of renal impairment and nasopharyngitis. Additionally, compared with placebo and metformin, the risk of GI was notably elevated for empagliflozin 10mg/d, canagliflozin 300mg/d, and dapagliflozin 10mg/d. However, it is important to note that further well-designed RCTs with larger sample sizes are necessary to verify and optimize the current body of evidence. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023396023.


Rationale
3 Describe the rationale for the review in the context of what is already known, including mention of why a network meta-analysis has been conducted.

3
Objectives 4 Provide an explicit statement of questions being addressed, with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

Protocol and registration 5
Indicate whether a review protocol exists and if and where it can be accessed (e.g., Web address); and, if available, provide registration information, including registration number. 2 Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.Clearly describe eligible treatments included in the treatment network, and note whether any have been clustered or merged into the same node (with justification).
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
Table S2 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

Data items 11
List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

Geometry of the network S1
Describe methods used to explore the geometry of the treatment network under study and potential biases related to it.This should include how the evidence base has been graphically summarized for presentation, and what characteristics were compiled and used to describe the evidence base to readers.

Risk of bias within individual studies 12
Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

Summary measures 13
State the principal summary measures (e.g., risk ratio, difference in means).Also describe the use of additional summary measures assessed, such as treatment rankings and surface under the cumulative ranking curve (SUCRA) values, as well as modified approaches used to present summary findings from meta-analyses.

Planned methods of analysis 14
Describe the methods of handling data and combining results of studies for each network meta-analysis.This should include, but not be limited to: • Handling of multi-arm trials; • Selection of variance structure; • Selection of prior distributions in Bayesian analyses; and • Assessment of model fit.

S2
Describe the statistical methods used to evaluate the agreement of direct and indirect evidence in the treatment network(s) studied.Describe efforts taken to address its presence when found.

Risk of bias across studies 15
Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

5
Additional analyses 16 Describe methods of additional analyses if done, indicating which were pre-specified.This may include, but not be limited to, the following: • Sensitivity or subgroup analyses; • Meta-regression analyses; • Alternative formulations of the treatment network; and • Use of alternative prior distributions for Bayesian analyses (if applicable).

Study selection 17
Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

5
Presentation of network structure

S3
Provide a network graph of the included studies to enable visualization of the geometry of the treatment network.

S4
Provide a brief overview of characteristics of the treatment network.This may include commentary on the abundance of trials and randomized patients for the different interventions and pairwise comparisons in the network, gaps of evidence in the treatment network, and potential biases reflected by the network structure.

Study characteristics 18
For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.S3 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: 1) simple summary data for each intervention group, and 2) effect estimates and confidence intervals.Modified approaches may be needed to deal with information from larger networks.

6-9
Synthesis of results 21 Present results of each meta-analysis done, including confidence/credible intervals.In larger networks, authors may focus on comparisons versus a particular comparator (e.g.placebo or standard care), with full findings presented in an appendix.League tables and forest plots may be considered to summarize pairwise comparisons.If additional summary measures were explored (such as treatment rankings), these should also be presented.

S5
Describe results from investigations of inconsistency.This may include such information as measures of model fit to compare consistency and inconsistency models, P values from statistical tests, or summary of inconsistency estimates from different parts of the treatment network.S7 Risk of bias across studies 22 Present results of any assessment of risk of bias across studies for the evidence base being studied.Figure S2 Results of additional analyses 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression analyses, alternative network geometries studied, alternative choice of prior distributions for Bayesian analyses, and so forth).

Summary of evidence 24
Summarize the main findings, including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy-makers).

9-12
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review level (e.g., incomplete retrieval of identified research, reporting bias).Comment on the validity of the assumptions, such as transitivity and consistency.Comment on any concerns regarding network geometry (e.g., avoidance of certain comparisons).

11
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.
12 FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.This should also include information regarding whether funding has been received from manufacturers of treatments in the network and/or whether some of the authors are content experts with professional conflicts of interest that could affect use of treatments in the network.
12 PICOS = population, intervention, comparators, outcomes, study design.* Text in italics indicates wording specific to reporting of network meta-analyses that has been added to guidance from the PRISMA statement.((((((((((((((((((((Diabetes   Effect sizes represent summary odds ratio and 95% credible intervals."-" indicate the effect size with very width credible interval owing to the small sample sizes, which were not shown.OR>1 indicate that the treatment specified in the column got more risk effect than that specified in the row, which values with significant differences are in bold.Effect sizes represent summary odds ratio and 95% credible intervals.OR>1 indicate that the treatment specified in the column got more risk effect than that specified in the row, which values with significant differences are in bold.Effect sizes represent summary odds ratio and 95% credible intervals."-" indicate the effect size with very width credible interval owing to the small sample sizes, which were not shown.OR>1 indicate that the treatment specified in the column got more risk effect than that specified in the row, which values with significant differences are in bold.Effect sizes represent summary odds ratio and 95% credible intervals.OR>1 indicate that the treatment specified in the column got more risk effect than that specified in the row.Effect sizes represent summary odds ratio and 95% credible intervals.OR>1 indicate that the treatment specified in the column got more risk effect than that specified in the row, which values with significant differences are in bold.

FigureFigure S2
Figure S1 Summary risk of bias of the included studies.(A) Risk of bias graph.(B) Risk of bias summary

Table 1 Risk
of bias within studies 19Present data on risk of bias of each study and, if available, any outcome level assessment.Table

Table S2 Literature search strategy PubMed
1 (

Table S4 Results of traditional pairwise meta-analysis of different safety outcomes
Abbreviation: OR: odds ratio; Cl: confidence interval; NA: not applicable; NR: not reported; AEs: adverse events

Table S7C Node-splitting analysis of the hypoglycemia outcome
P-values < 0.05 are in bold, indicating a significant inconsistency between the direct effect and indirect effects.

Table S8 Meta-regression on risk of adverse outcomes with duration of trial. Outcome Genital infections Unitary tract infections
Abbreviation: Coef., coefficient; Std.Err., standard error.* Intervention arms and control arms across all included trials.