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Series of studies clarifies effectiveness and safety of newer medications for type 2 diabetes
The Canadian Network for Observational Drug Effect Studies (CNODES) has published a series of important papers about sodium glucose co-transporter 2 (SGLT-2) inhibitors, a class of drugs that has been used for second- or third-line treatment of type 2 diabetes in Canada since 2014. One looked at their effectiveness in preventing cardiovascular events. The others addressed potential safety concerns, including diabetic ketoacidosis (DKA), below-knee amputation, and serious urinary tract infection (UTI). “SGLT-2 inhibitors are a relatively new therapy for type 2 diabetes,” explains Dr. Kristian Filion, a Senior Investigator at the Lady Davis Institute (LDI) and Associate Professor of Medicine and of Epidemiology and Biostatistics at McGill University, who contributed to all four studies. “They performed well in clinical trials, but their real-world safety and effectiveness, based on the experiences of hundreds of thousands of people, have yet to be confirmed. It’s always essential to ascertain the effects of drugs beyond the controlled setting of a clinical trial.”

SGLT-2 inhibitors interrupt glucose re-absorption in the kidneys. They were compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, which block the enzyme DPP-4 to increase levels of gastrointestinal hormones called incretins, thus helping to lower blood glucose levels. The studies employed databases from seven Canadian provinces and the United Kingdom, providing access to the anonymized health care records of more than 400,000 patients between 2013 and 2018.

With respect to cardiovascular events, previous observational studies have indicated that SGLT-2 inhibitors reduce the risk of cardiovascular events as compared to other anti-diabetic drugs. Indeed, this research, published in BMJ, concluded that their use was associated with a decreased risk of serious cardiovascular events. “These drugs became popular, in particular, after demonstrating that they reduce the risk for myocardial infarction, heart failure, renal failure, cardiovascular mortality, and potentially all-cause mortality in patients with type 2 diabetes in randomized controlled trials,” points out Dr. Filion, “so this represents important confirmation of their benefits in everyday clinical practice.”

The researchers found that, compared with DPP-4 inhibitors, SGLT-2 inhibitors were associated with an almost 3-fold increased risk for DKA, a rare but potentially life-threatening complication of diabetes. This finding was published in the Annals of Internal Medicine. Both Health Canada and the Food and Drug Administration (FDA) in the United States have issued warnings about this adverse drug reaction. The results suggest that the risk of this adverse effect could be higher among patients with less advanced disease. However, further studies are needed to corroborate this finding. “This risk should be interpreted in the context of the cardiovascular and renal benefits of SGLT-2 inhibitors,” points out Dr. Antonios Douros of the LDI, who was the lead author of this study. “Patients should be aware of the initial symptoms of this adverse effect, and, if they occur, should stop taking the drug and seek medical attention immediately.” With respect to below-knee amputation, reports have been “inconsistent,” according to Dr. Oriana Yu of the LDI, the first author of the paper published in Diabetes Care. Earlier observational studies suggested an association between SGLT-2 inhibitors and below-knee amputation, thus demanding further study in a real-world setting. During a mean exposed follow-up time of 11 months, the amputation rate among SGLT-2 inhibitor users was 1.3 per 1,000 patients per year and 1.5 per 1,000 patients per year among DPP4 inhibitor users, thus the difference was negligible. “While these findings provide some reassurance,” Dr. Yu wrote, “studies with longer duration of follow-up are needed to assess potential long-term effects.” Following up on warnings from the FDA of an increased risk of serious UTI in patients with type 2 diabetes treated with SGLT-2 inhibitors, the study published in Diabetes, Obesity and Metabolism found no such association.

“However,” the authors caution, “considering all available evidence, SGLT-2 inhibitors may not be safer than DPP-4 inhibitors.” The request to conduct these studies came to CNODES from Quebec’s Institut national d’excellence en santé et en services sociaux (INESSS), which manages the province’s drug plan and is evaluating therapies for diabetes because of the high prevalence of the disease and corresponding high treatment costs. SGLT-2 inhibitors available in Canada that were incorporated in these studies are sold under the following trade names: canagliflozin (Invokana®), dapagliflozin (Forxiga®), and empagliflozin (Jardiance®). This series of studies on SGLT-2 inhibitors was led by Dr. Pierre Ernst, Senior Investigator at the LDI and Professor of Medicine at McGill University. “The CNODES initiative, supported by the Canadian Institutes of Health Research and Health Canada, has been instrumental in accomplishing this broad research on the effects of drugs used to treat diabetes,” said Dr. Samy Suissa, Principal Investigator of CNODES, Director of the Centre for Clinical Epidemiology at the LDI, and Distinguished James McGill Professor in the Departments of Epidemiology and Biostatistics, and of Medicine at McGill University. “By combining Canada’s best minds in drug safety research and our access to big data, CNODES continues to contribute to improving the health of Canadians.”

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