The association of sodium‐glucose cotransporter 2 inhibitors with cancer: An overview of quantitative systematic reviews

Pelletier, Ryan; Ng, Kelvin; Alkabbani, Wajd; Labib, Youssef; Mourad, Nicolas; Gamble, John‐Michael

doi:10.1002/edm2.145

Cited by 27 publications

(22 citation statements)

References 21 publications

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“…This meta-analysis showed neither a significant association between SGLT-2i and the overall risk of malignancy in T2D patients nor with medication duration, consistent with the results of previous analysis ( 11 , 93 , 94 ). In different types of SGLT-2i analyses, we found that ertugliflozin significantly increased overall malignancy incidence, had no statistically significant difference compared to other hypoglycemic drugs or placebo alone, and had no great risk of a specific malignant tumor.…”

Section: Discussionsupporting

confidence: 88%

SGLT-2i and Risk of Malignancy in Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials

Shi

et al. 2021

Front. Public Health

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Background: Currently, the association between sodium-glucose cotransporter 2 inhibitor (SGLT-2i) and malignancy risk has yet to be fully elucidated. This meta-analysis aimed to determine the relationship between SGLT-2i and malignancy risk in type 2 diabetes (T2D) patients.Methods: We searched PubMed, ScienceDirect, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science to identify randomized controlled trials (RCTs) published up to August 2020 related to T2D patients treated with SGLT-2i vs. placebo or other hypoglycemic agents. The meta-analysis's primary outcome was malignancies' incidence, and the results were evaluated using risk ratio (RR) and 95% confidence interval (CI).Results: We reviewed 76 articles (77 RCTs), comprising 45,162 and 43,811 patients in SGLT-2i and control groups, respectively. Compared with the control group, SGLT-2i had no significant association with augmented overall malignancy risk in T2D patients (RR = 1.05, 95% CI = 0.97–1.14, P = 0.20), but ertugliflozin may upsurge the risk (RR = 1.80, 95% CI = 1.02–3.17, P = 0.04). Compared with active hypoglycemic agents, dapagliflozin may increase (RR = 2.71, 95% CI = 1.46–6.43, P = 0.02) and empagliflozin may decrease (RR = 0.67, 95% CI = 0.45–0.98, P = 0.04) the malignancy risk. Compared with placebo, empagliflozin may exhibit risk increase (RR = 1.25, 95% CI = 1.05–1.49, P = 0.01), primarily in digestive system (RR = 1.48, 95% CI = 0.99–2.21, P = 0.05).Conclusions: Our results proposed that in diverse comparisons, ertugliflozin and dapagliflozin seemed to increase the malignancy risk in T2D patients. Empagliflozin may cause malignancy risk reduction compared with active hypoglycemic agents but increase overall risk primarily in the digestive system compared with placebo. In short, the relationship between SGLT-2i and malignancy in T2D patients remains unclear.

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Section: Discussionsupporting

confidence: 88%

SGLT-2i and Risk of Malignancy in Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials

Shi

et al. 2021

Front. Public Health

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“…These results are in line with that of the present study, which also demonstrated the superiority of dapagliflozin and ertugliflozin in relation to cancer risk. Such findings are further emphasized by that of Pelletier et al, which also failed to display an increased cancer risk with SGLT2I users, regardless of cancer type (28). However, the obscurity in the findings concerning SGLT2I primarily resides in the fact that the malignancy risk varies depending on the SGLT2I and cancer subtypes.…”

Section: Discussionmentioning

confidence: 88%

Sodium-glucose cotransporter 2 inhibitors versus dipeptidyl peptidase 4 inhibitors on new-onset overall cancer in type 2 diabetes mellitus: a population-based study

Chung

Lakhani

Chou

et al. 2022

Preprint

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Background: There is much uncertainty regarding the comparative risks of cancer for T2DM patients on SGLT2I versus DPP4I. Methods: This population-based cohort study patients included T2DM patients who were administered with either SGLT2I or DPP4I between January 1st, 2015, to December 31st, 2020 in Hong Kong. Results: Amongst 60112 T2DM patients (mean baseline age: 62.1+/-12.4 years, male: 56.36%), 18167 patients were SGLT2I users and 41945 patients were DPP4I users. Multivariate cox regression analysis revealed that SGLT2I usage was associated with a decreased risk of all-cause mortality (HR:0.92; 95%CI:0.84-0.99; P=0.04), cancer-related mortality (HR:0.58; 95%CI:0.42-0.80; P≤0.001) and a 30% risk reduction of new-onset overall cancer (HR:0.70; 95%CI:0.59-0.84; P≤0.001). Dapagliflozin and ertugliflozin both demonstrated superiority in relation to new-onset cancer development, with the former demonstrating a lowered risk of breast cancer (HR:0.48; 95%CI:0.27-0.83; P=0.001). Conclusion: SGLT2I was associated with lower risk of all-cause mortality, cancer-related mortality and new-onset overall cancer compared to DPP4I.

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“…The protocol for this study is registered with the PROSPERO international prospective register of systematic reviews (PROSPERO 2019: CRD42019135863). 14…”

Section: Methodsmentioning

confidence: 99%

Adverse events associated with sodium glucose co-transporter 2 inhibitors: an overview of quantitative systematic reviews

Pelletier

Alkabbani

et al. 2021

Therapeutic Advances in Drug Safety

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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.

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The association of sodium‐glucose cotransporter 2 inhibitors with cancer: An overview of quantitative systematic reviews

Cited by 27 publications

References 21 publications

SGLT-2i and Risk of Malignancy in Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials

SGLT-2i and Risk of Malignancy in Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials

Sodium-glucose cotransporter 2 inhibitors versus dipeptidyl peptidase 4 inhibitors on new-onset overall cancer in type 2 diabetes mellitus: a population-based study

Adverse events associated with sodium glucose co-transporter 2 inhibitors: an overview of quantitative systematic reviews

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