Background: Multiple published quantitative systematic reviews have reported on adverse events associated with the use of sodium glucose co-transporter 2 (SGLT-2) inhibitors in patients with type 2 diabetes mellitus. Aims: To summarize and appraise the quality of evidence from quantitative systematic reviews assessing adverse events of SGLT-2 inhibitors. Methods: We searched PubMed, EMBASE and the Cochrane Library for quantitative systematic reviews assessing SGLT-2 inhibitor safety. Two reviewers extracted data and assessed methodological quality using the Assessment of Multiple Systematic Reviews 2 (AMSTAR 2) tool. Main outcomes included pooled and single study point estimaates (in the absence of pooled estimates) with corresponding 95% confidence intervals (CIs) of SGLT-2 inhibitors versus placebo or active comparators for genitourinary infections, volume depletion, acute kidney injury, bone fractures, diabetic ketoacidosis, lower limb amputations, cancers, and other notable adverse events. Results: Out of 1289 citations screened, 47 reviews assessed SGLT-2 inhibitor safety, of which 35 were of low quality. Canagliflozin, dapagliflozin and empagliflozin were consistently associated with an increased risk of genital tract infections versus placebo (point estimates ranged from 2.5 to 9.8) and other antihyperglycemic agents (point estimates ranged from 2.7 to 12.0). Canagliflozin and dapagliflozin were associated with an increased risk of diabetic ketoacidosis. Canagliflozin was the only agent associated with an increased amputation risk; however, this was driven by results from a single trial program. Dapagliflozin was the only agent that exhibited a statistically significant increased risk of urinary tract infections. Empagliflozin was associated with a statistically significant increased risk of bladder cancer; however, this finding was susceptible to detection bias. None of the agents were associated with a statistically significant increased risk of acute kidney injury, or bone fractures compared to placebo or mixed (active or placebo) comparators. Upper 95% CI limits do not rule out clinically meaningful outcomes. Conclusion: The majority of quantitative systematic reviews reporting on adverse events of SGLT-2 inhibitors were of low methodological quality. Despite almost 50 quantitative systematic reviews published on the safety of SGLT-2 inhibitors, clinicians are still left uncertain of the risks of important adverse effects. Plain Language Summary SGLT-2 iInhibitor side effects: overview of reviews Many published systematic reviews have reported on side effects associated with the use of sodium glucose co-transporter 2 (SGLT-2) inhibitors in patients with type 2 diabetes. We aimed to summarize and appraise the quality of evidence from quantitative systematic reviews assessing side effects of SGLT-2 inhibitors. Using the Assessment of Multiple Systematic Reviews 2 (AMSTAR 2) tool, two authors extracted data and assessed the methods of included reviews. Main outcomes included reported pooled and single study point estimates for several SGLT-2 inhibitor side effects such as genital infections, bone fractures, lower limb amputations, increased blood acidity, among others. Of the reviews included in our study, 35 of the 47 reviews assessed were of low quality. Canagliflozin and dapagliflozin were associated with an increased risk of blood acidity in a 2020 review. Canagliflozin was the only agent associated with an increased amputation risk; however, this was driven by results from a single trial program. Dapagliflozin was the only agent that exhibited a significantly increased risk of urinary tract infections. Empagliflozin was associated with an increased risk of bladder cancer; however, this finding was susceptible to bias. None of the agents were associated with an increased risk of kidney injury or bone fractures.

Aims To summarize reported cancer events associated with SGLT‐2 inhibitors used in patients with type 2 diabetes mellitus, as well as assess the quality of included reviews. Materials and methods In May 2019, we searched PubMed, Embase and the Cochrane Library for quantitative systematic reviews assessing the safety of SGLT‐2 inhibitors. Data were abstracted using a standardized form, and methodological quality was assessed using the AMSTAR 2 tool. Main outcome measures included total cancer events and specific cancers such as breast cancer, bladder cancer, gastrointestinal cancer, prostate cancer, respiratory cancer, renal cancer and skin cancer. Pooled treatment effects from included reviews were summarized for SGLT‐2 inhibitors as a class and for individual SGLT‐2 inhibitors commonly used worldwide (canagliflozin, dapagliflozin and empagliflozin). Results We screened 1248 unique citations, of which eight quantitative systematic reviews meta‐analysed results from studies reporting the association between an SGLT‐2 inhibitor and any cancer. Only one review was rated as high quality according to AMSTAR 2 assessment. In total, data from 170 cancer‐related point estimates (PE) were reported. As a class, SGLT‐2 inhibitors were not associated with an increased risk of any cancer event versus placebo and active comparators. Most point estimates (7/143) were nonsignificant for individual cancers except for two associations. Empagliflozin was associated with an increased risk of bladder cancer versus placebo and active comparators in two reviews, while canagliflozin appeared protective for gastrointestinal cancer versus placebo and active comparators in one review. Conclusions It appears that SGLT‐2 inhibitors are not associated with an increased risk of total cancer or specific cancers in patients with type 2 diabetes. However, higher quality evidence is needed to derive confident conclusions.

Medical students are faced with many unprecedented challenges, one of which is the large amount of material they are required to learn and retain. While effective learning strategies have been thoroughly researched, stress levels amongst medical students remain very high due to perceived failure to retain material, suggesting that novel methods of implementing such existing strategies are required. Aside from stress levels, additional challenges in medical education include the incorporation of inconsistent testing methods and the challenge of accommodating different learning styles and preferences. A more evidence-based approach that aims to cover many learning styles at once may be desirable. The aim of this commentary is to present some of the current learning and teaching strategies utilized within medical education across the world and to promote a novel supplementary approach to medical education involving a variable ratio incentive-based system of active recall and spaced repetition. This system aims to reward small achievements throughout the semester and complements formal structured examinations in order to motivate students. While this model has yet to be tested, we hope to motivate medical faculty to pilot a program with these evidence-based strategies in mind.

Medical students are faced with many unprecedented challenges, one of which is the large amount of material they are required to learn and retain. While effective learning strategies have been thoroughly researched, stress levels amongst medical students remain very high due to perceived failure to retain material, suggesting that novel methods of implementing such existing strategies are required. Aside from stress levels, additional challenges in medical education include the incorporation of inconsistent testing methods and the challenge of accommodating different learning styles and preferences. A more evidence-based approach that aims to cover many learning styles at once may be desirable. The aim of this commentary is to present some of the current learning and teaching strategies utilized within medical education across the world and to promote a novel supplementary approach to medical education involving a variable ratio incentive-based system of active recall and spaced repetition. This system aims to reward small achievements throughout the semester and complements formal structured examinations in order to motivate students. While this model has yet to be tested, we hope to motivate medical faculty to pilot a program with these evidence-based strategies in mind.

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