Sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors and cancer: A meta‐analysis of randomized controlled trials

Abstract

Aim: The aim of this meta-analysis of randomized trials was to assess the effects of SGLT-2i on the overall incidence of malignancies and on different types of cancer, summerizing the results of trials with a duration of at least 1 year. This was done in light of the effect of SGLT-2 inhibitors (SGLT-2is) that has been highlighted by some studies, showing an increased incidence of bladder cancer, particularly with use of empagliflozin.Materials and methods: A Medline and Embase search for "Canaglifozin", "Dapaglifozin", "Empaglifozin", "Ertuglifozin", "Ipraglifozin", Tofoglifozin" or "Luseoglifozin" was performed, identifying randomized trials with a duration of more than 52 weeks up to 1 December 2018 that compared SGLT-2is with placebo or active comparators. The outcomes considered were all types of cancer and several site-specific cancers (ie, breast, pulmonary, gastrointestinal, hepatic, pancreatic, skin, prostate and bladder). Mantel-Haenszel odds ratios with 95% Confidence Intervals (MH-OR, 95% CI) were calculated for all outcomes.Results: A total of 27 trials fulfilled the inclusion criteria. Retrieved trials had enrolled 27 744 and 20 441 patients in SGLT-2 inhibitor and comparator groups, respectively.No difference was observed in the incidence of all malignancies between patients allocated to ). The incidence of bladder cancer, and of any other type of cancer, was not significantly increased by treatment with any SGLT-2i.Conclusions: Available data from randomized trials do not suggest a detrimental effect of SGLT-2is on the incidence of malignancies in general, or in bladder cancer in particular. K E Y W O R D Smalignancies, meta-analysis, SGLT-2 inhibitors, type 2 diabetes

SGLT2 Inhibitors and Bladder Cancer: Analysis of Cases Reported in the European Pharmacovigilance Database

“…In a meta‐analysis of clinical trials, SGLT2is were associated with an increased risk of bladder cancer 7 . Although this was not confirmed in the most recently published meta‐analysis, it has to be considered that high‐risk patients for bladder cancer (those with a history of previous bladder cancer, radiation to lower abdomen or pelvis or unexplained hematuria) were excluded 8 . Although our results of reporting disproportionality cannot be compared with the results of the meta‐analyses, we can suggest the possible association of SGLT2is with bladder cancer.…”

“…Later, a meta‐analysis of clinical trials suggested that the administration of an SGLT2i, especially empagliflozin, was associated with a higher risk of bladder cancer compared to placebo or other glucose‐lowering treatments 7 . Nevertheless, a more recent meta‐analysis including only studies with >52 week follow‐up concluded that available data from randomized trials do not suggest a detrimental effect of SGLT2is on the incidence of malignancies in general, or in bladder cancer in particular 8 . However, as this trial excluded patients at high risk for bladder cancer, the potential association between SGLT2is and bladder cancer remains unclear.…”

More recent, better designed studies have weakened links between antidiabetes medications and cancer risk

“…Inhibition of the SGLT2 transporter leads to increased urinary excretion of glucose, resulting in a decline in plasma glucose concentrations. A recent meta‐analysis of 27 RCTs concluded that current evidence does not indicate an association of SGLT2 inhibitors with an increased risk of bladder or any other cancer . Further, a meta‐analysis of seven studies on dapagliflozin found no association with cancer risk .…”

Type 2 diabetes and cancer: problems and suggestions for best patient management

“…The newest class of oral diabetes drugs, the sodium glucose transporter-2 inhibitors (SGLT2-I) (empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin), reduces plasma glucose by inhibiting renal glucose reabsorption and increasing urinary glucose excretion. These drugs are not only not linked to an increased risk of malignancies [59,60], but preclinical studies also indicated, mainly for canagliflozin, an interesting anti-proliferative effect on liver cancer cells [61][62][63][64][65]. SGLT2-I are potentially useful to treat diabetes in cancer patients, although the increased risk of genitourinary infections, volume depletion, and euglycaemic diabetic ketoacidosis should be carefully considered.…”