A review of 46 clinical trials involving more than 34,000 patients and published online in the journal Diabetologia showed no increased risk of developing most forms of cancer for individuals taking sodium-glucose cotransporter 2 (SGLT2) inhibitors. The article is the first meta-analysis looking at the risk associated with SGLT2 and cancer using multiple resources including all available randomized clinical trials, multiple subgroup analyses, as well as meta-regression and sensitivity analyses.
Researchers from the Indiana University Melvin and Bren Simon Cancer Center and the Richard M. Fairbanks School of Public Health at IU conducted the analysis.
"It is important to note that the evidence from our meta-analysis of available randomized clinical trial data is suggestive of, but not conclusive for, the potential impact by SGLT2 inhibitor use on cancer risk,” said co-author Yiqing Song, MD, ScD, professor of epidemiology at the Fairbanks School of Public Health and a researcher at the IU Simon Cancer Center. “Given rapidly increasing use of SGLT2 inhibitors, it is our hope that long-term safety of its use be carefully monitored in future clinical trials and real-world settings."
SGLT2 inhibitors are a class of prescription oral medications approved by the FDA in 2013 to be used in combination with diet and exercise to lower blood sugar in adults with type 2 diabetes. SGLT2 is a protein found in the kidney that helps the body reabsorb glucose. SGLT2 inhibitors specifically block that process, resulting in increased renal glucose excretion and decreased levels of blood glucose.
A growing body of evidence suggests that people with Type 2 diabetes are at elevated risk for cancer. Obesity is a known risk factor for developing both cancer and diabetes. Although all the mechanisms at play for this elevated risk are unknown, physicians do know that several glucose-lowering drugs have the potential to affect cancer risk, according to the study’s co-author Jiali Han, PhD, professor and chair of the Department of Epidemiology at the Fairbanks School of Public Health and the Rachel Cecile Efroymson Professor of Cancer Research at the IU Simon Cancer Center.
“Metformin therapy has been shown to decrease the risk of cancer while other drugs may increase the risk of specific cancers,” Dr. Han said. “For instance, in 2011 a federal report raised concerns about the risk of bladder and breast cancer associated with dapagliflozin, but a later analysis of 21 clinical trials suggested it was more likely the increased incidence was due to under-diagnosis prior to patients being randomized to the trial.”
Dapagliflozin (Forxiga) is one of three SGLT2 inhibitors recently approved for use by the FDA and reviewed in the literature for this study. The others are canagliflozin (Invokana) and empagliflozin (Jardiance).
“In addition to lower glucose levels, SGLT2 inhibitors may offer other benefits, such as weight loss and lowering blood pressure,” Dr. Han said. “More and more patients will use SGLT2 inhibitors, with more than 12 million U.S. prescriptions to date just for canagliflozin.”
The researchers screened for the risk of all forms of cancer and then looked at the risk of specific cancers such as skin, breast, respiratory, gastrointestinal, bladder, prostate and renal.
Diabetes and obesity are known risk factors for bladder cancer but the exact mechanisms involving SGLT2 inhibitors and the increased risk for that cancer, as well as urinary tract infections, are unknown. The meta-analysis did not detect an increased risk associated with use of SGLT2 inhibitors for breast cancer or other cancers, but the authors caution that an increased risk cannot be ruled out without more randomized clinical trials.
“Our study provides the latest evidence about the association between use of SGLT2 inhibitors and risk of cancer and will help physicians and patients to better understand the risk when choosing these drugs. However, due to the relatively short term of randomized trials, our study also requires further long-term studies,” Dr. Han said.
The IU Health - IU School of Medicine Strategic Research Initiative and the IU Simon Cancer Center supported this research. Also contributing to the paper was Huilin Tang, MSc, research associate in the Fairbanks School of Public Health's Department of Epidemiology.