Type 2 diabetes (T2D) is a chronic metabolic disorder. People who are diagnosed with T2D have high levels of sugar in their blood. This happens either when the cells of the body become resistant to insulin (insulin resistance) or there is a relative lack of insulin released by the pancreas. Long-term complications of T2D include heart disease, strokes, blindness, kidney failure, and amputations. T2D is also considered a strong risk factor for some kinds of cancer, e.g., bladder cancer.
A healthy lifestyle, including diet and regular exercise, is a good choice to control blood sugar levels, which will delay or prevent complications. However, many people also need insulin therapy or diabetes medicines such as metformin, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, or GLP-1 receptor agonists. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the newest oral diabetes drugs, have been on the market since 2013. SGLT2 is a cotransporter that helps the body reabsorb glucose through the kidney. Therefore, inhibiting SGLT2 can lower blood sugar by facilitating the excretion of sugar in the urine. Recently, four SGLT2 inhibitors have been approved by the US Food and Drug Association (FDA): dapagliflozin (Forxiga), canagliflozin (Invokana), empagliflozin (Jardiance), and ertugliflozin (Steglatro).
However, along with their beneficial effect of managing T2D, some diabetes medicines may influence the risk of cancer. Metformin, for instance, the first line choice of management of T2D, has been reported to have the potential to decrease the risk of cancer. However, pioglitazone, belonging to the thiazolidinediones, was found to be positively associated with bladder cancer. In 2011, a potential increase in the risk of bladder and breast cancers associated with dapagliflozin was observed in the regulatory reporting submitted to US FDA.
However, the cancer risk associated with SGLT2 inhibitors has not yet been well explored. Profs. Jiali Han and Yiqing Song from the Department of Epidemiology of the Richard M. Fairbanks School of Public Health at Indiana University are leading a project focused on the pharmacoepidemiology of cancer. They recently investigated the potential effect of SGLT2 inhibitors on cancer risk in patients with T2D by meta-analysis of 46 independent randomized controlled trials involving 580 cancer cases among 34,569 T2D patients.
They found no significant increase in the risk of overall cancer among the T2D patients taking SGLT2 inhibitors. Furthermore, to clarify any difference among the risk of specific cancers, their findings indicated an elevated risk of bladder cancer among those using SGLT2 inhibitors, especially empagliflozin. However, the exact underlying mechanisms remain unknown. It is interesting that canagliflozin was found to be inversely associated with risk of gastrointestinal cancers.
This might be due to the fact that canagliflozin inhibits not only SGLT2 but also SGLT1, which is overexpressed in many cancers. However, according to Dr. Song, “Considering the relatively short term of randomized trials included in our study, currently available evidence about the potential association between SGLT2 inhibitors and risk of cancer is suggestive .”
Given the several benefits of SGLT2 inhibitors in patients with T2D, their use will rapidly increase. Thus, it is critical to clarify the association between SGLT2 inhibitors and risk of cancer. According to Dr. Han, “Although further long-term studies are warranted to confirm our findings, our studies will help physicians make better decisions to avoid the cancer risk among those taking SGLT2 inhibitors “.
These findings are described in the article SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials in the journal Diabetologia. This work was led by Huilin Tang from Indiana University.