Benefits and Harms of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis

Objective Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are a novel drug class for the treatment of diabetes. We aimed at describing the maximal benefits and risks associated with SGLT2-i for patients with type 2 diabetes. Design Systematic review and meta-analysis. Data Sources and Study Selection We included double-blinded, randomised controlled trials (RCTs) evaluating SGLT2-i administered in the highest approved therapeutic doses (canagliflozin 300 mg/day, dapagliflozin 10 mg/day, and empagliflozin 25 mg/day) for ≥12 weeks. Comparison groups could receive placebo or oral antidiabetic drugs (OAD) including metformin, sulphonylureas (SU), or dipeptidyl peptidase 4 inhibitors (DPP-4-i). Trials were identified through electronic databases and extensive manual searches. Primary outcomes were glycated haemoglobin A1c (HbA1c) levels, serious adverse events, death, severe hypoglycaemia, ketoacidosis and CVD. Secondary outcomes were fasting plasma glucose, body weight, blood pressure, heart rate, lipids, liver function tests, creatinine and adverse events including infections. The quality of the evidence was assessed using GRADE. Results Meta-analysis of 34 RCTs with 9,154 patients showed that SGLT2-i reduced HbA1c compared with placebo (mean difference -0.69%, 95% confidence interval -0.75 to -0.62%). We downgraded the evidence to ‘low quality’ due to variability and evidence of publication bias (P = 0.015). Canagliflozin was associated with the largest reduction in HbA1c (-0.85%, -0.99% to -0.71%). There were no differences between SGLT2-i and placebo for serious adverse events. SGLT2-i increased the risk of urinary and genital tract infections and increased serum creatinine, and exerted beneficial effects on bodyweight, blood pressure, lipids and alanine aminotransferase (moderate to low quality evidence). Analysis of 12 RCTs found a beneficial effect of SGLT2-i on HbA1c compared with OAD (-0.20%, -0.28 to -0.13%; moderate quality evidence). Conclusion This review includes a large number of patients with type 2 diabetes and found that SGLT2-i reduces HbA1c with a notable increased risk in non-serious adverse events. The analyses may overestimate the intervention benefit due bias.


Introduction page 4-5
Full PICO statement of inclusion criteria in Methods, 'Trial eligibility and selection' page 6

Protocol and registration
5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
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.
Methods 'trial eligibility and selection' "Published, English language RCTs, conducted in adult patients (at least 18 years of age) and lasted for at least 12 weeks to permit assessment the effect of SGLT2-i on HbA1c.The intervention comparisons comprised SGLT2-i (dapagliflozin, canagliflozin and empagliflozin) versus placebo, or other oral antidiabetic drugs (OAD) at doses that are currently recommended by FDA and/or EMA as a maximum daily dose i.e. canagliflozin 300 mg; dapagliflozin 10 mg; empagliflozin 25 mg.Co-interventions with other antidiabetic agents were allowed if administered to the intervention and control groups).
We excluded studies which involved participants with impaired kidney function, as reduced glomerular filtration rate reduces the glucosuria and thereby the glucose-lowering effect of the SGLT2-i."We obtained additional data on e.g.heart rate, ALT and lipids from the study investigators, the manufacturers and the YODA-project

Data items
List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.
All variables, for all included studies provided in the S1 For continuous outcomes, we estimated the mean differences (MDs) between groups.We present dichotomous outcomes data as risk ratios (RRs).Page 8

Synthesis of results
Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I 2 ) for each meta-analysis.

Methods 'Data synthesis'
We undertook meta-analyses (intention-to-treat analyses including all patients randomized were performed where possible) in RevMan using the Mantel-Haenszel test with a random effects model, unless stated otherwise, and present these with 95% confidence intervals (CI) and standard deviations.For continuous outcomes, we estimated the mean differences (MDs) between groups.We present dichotomous outcomes data as risk ratios (RRs).In all cases, if the calculated effect size was statistically significant (P value < 0.05), we state whether the result favored the intervention group or the control condition.For effect sizes of MD, values greater than 0.70 have been treated as large; values between 0.40 and 0.70 as moderate; and values less than 0.40 but greater than 0.10 as small.Differences between subgroups were reported using tests for subgroup differences expressed as P values.I 2 values were was used as a measure of heterogeneity and are reported they exceeded 30%.Risk of bias across studies Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).
The bias risk assessment followed the using the Cochrane Collaboration's risk of bias assessment tool .In each domain, studies were given a rating of low, unclear or high risk.We used the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) system to describe the quality of the evidence and the strength of recommendation, 'high' to Additional analyses Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, metaregression), if done, indicating which were prespecified.
We conducted subgroup analysis on the basis of SGLT2-i type (canagliflozin, dapagliflozin, empagliflozin), and on the basis of OAD type (metformin, SU, DPP4-i).
Page 8

Study selection
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.
"We identified 1050 records in total through our electronic database searches up to October 2013.An update search in October 2015 found 37 potential new studies; 25 were discarded as they did not meet the inclusion criteria.Thus we have included 42 studies (59 of reports of studies) (Fig. 1) in this review comprising 24,500 randomized participants in total (please see S1 Appendix.docx).The studies compared different doses of SGLT2-i versus placebo or another other oral-antidiabetic drug.Four studies were multi-arm, comparing SGLT2-i versus placebo and versus OAD" Page 9 and PRISMA flowchart figure 1 Study characteristics For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

Synthesis of results
Present results of each meta-analysis done, including confidence intervals and measures of consistency.
Results, page 11-14 Figure 2   See subgroup analyses, presented with primary and secondary outcome findings.

Summary of evidence
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).
Discussion, page 15 conclusions page 19 "The highest approved doses of canagliflozin, dapagliflozin and empagliflozin compared with placebo, were effective in reducing HbA1c in patients with type 2 diabetes.In spite of the large number of RCTs with a low risk of bias in several domains, we downgraded the evidence to low quality.Based on our assessment of publication bias and other smalls study effects, we found evidence of bias and therefore a risk that the analyses overestimate the intervention benefit.In the included RCTs, SGLT2-i had no discernible beneficial or harmful effects on serious adverse events including mortality, cancer, ketoacidosis, severe hypoglycaemia, bladder cancer, breast cancer or other cancer types.SGLT2-i also had no effect on CVD events, but SGLT2-i were associated a beneficial effect on CVD-associated risk factors including body weight, blood pressure and lipids (although elevations in LDL lipids may be a concern).As expected, SGLT2-i increased the risk of non-serious adverse events, including serum creatinine levels, UTI and GTI.Additional meta-analyses showed similar effects, when comparing SGLT2-i versus other OAD, but the analyses with active comparators included a smaller number of trials and patients.We also identified important potential limitations, which mainly included a high degree of inconsistency.The inconsistency is likely to reflect clinical heterogeneity in terms of the interventions, populations and follow-up times.Furthermore, selective reporting of outcomes (e.g.CVD, cancer etc.) may also bias the estimates.Therefore, it is possible that the true effect differs somewhat from the estimated effects".
Limitations 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).
Discussion page 16 "However, none of the trials compared the individual SGLT2-is and the results, therefore, remain exploratory.Thus, the lack of head-to-head comparisons between the SGLT2-i means that we cannot exclude the possibility that the difference between SGLT2i reflect patient inclusion criteria rather than a true difference between intervention effects."

Conclusions
Provide a general interpretation of the results in the context of other evidence, and implications for future research.
Discussion page 18 Future research: discussion "Future RCTs would ideally be long-lasting and large-scale comparing SGLT2-i with placebo or existing therapies.Such RCTs should additionally include reporting of serious adverse events such as CVD risk, renal safety, ketoacidosis and severe hypoglycaemia with adequate follow-up (over one year), to establish the long-term consequences of SGLT2-i therapy."Page 17-18

Funding
Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.
Declarations of interest "Funding: The research did not receive specific grant from any funding agency in the public, commercial or not-for-profit sectors.No sponsor was involved in study design, and no sponsor had authority in collection, management, analysis and interpretation of data."

Table 1 ,
and in S1 table.