Sulfonylureas are antidiabetic drugs that have been used for more than 50 years in the treatment of type 2 diabetes. While sulfonylureas can effectively reduce elevated blood sugar levels found in patients with type 2 diabetes, they have also been linked to adverse events, such as hypoglycemia. This is important given that severe forms of hypoglycemia are known to increase the risk of cardiovascular disease and death.
To better characterize the safety profile of sulfonylureas, we initiated a research project that aimed to assess the risk of severe hypoglycemia and other serious adverse events associated with their use. In our first study, we used data from the United Kingdom Clinical Practice Research Datalink for 14,012 patients with type 2 diabetes who started treatment with sulfonylureas between 1998 and 2012 matched to 14,012 patients with type 2 diabetes who started treatment with metformin in the same period. Metformin is the drug usually recommended as first-line treatment according to most guidelines, including those recommended by the American Diabetes Association. We found that compared with metformin, sulfonylureas were associated with a more than 4-fold elevated risk of severe hypoglycemia.
In a subsequent study also using data from the United Kingdom Clinical Practice Research Datalink, we considered 77,138 patients with type 2 diabetes who started treatment with metformin between 1998 and 2013. Patients who subsequently added or switched to a sulfonylurea were identified and matched to a similar patient who continued metformin alone. We found that compared with continuing metformin alone, adding or switching to sulfonylureas was associated with a more than 7-fold elevated risk of severe hypoglycemia.
In the same study, we also assessed the cardiovascular safety of sulfonylureas. Compared with continuing metformin alone, adding or switching to sulfonylureas was associated with a 26% elevated risk of myocardial infarction and a 28% elevated risk of death. There was also a trend towards elevated risks of ischemic stroke and cardiovascular death with sulfonylurea use. Importantly, compared with adding sulfonylureas to metformin treatment, switching to sulfonylureas from metformin treatment was associated with a greater risk of myocardial infarction and death, but no differences were found with respect to ischemic stroke, cardiovascular death, or severe hypoglycemia.
Overall, our results argue against the use of sulfonylureas as first-line treatment when metformin is not tolerated or contraindicated. They also suggest that using sulfonylureas as second-line treatment could increase the risk of serious adverse events, especially when sulfonylureas are prescribed without metformin.
Patients with type 2 diabetes should try to use metformin for as long as possible. Moreover, those in need of treatment escalation that are also at increased cardiovascular risk could discuss with their treating physicians about other second-line treatments instead of sulfonylureas.
Further observational studies are needed to replicate our findings. Moreover, future research should aim to assess the longer-term risks of sulfonylureas as second-line treatments given the relatively short follow-up of our study. Finally, there is a need for studies comparing sulfonylureas with newer antidiabetic agents such as glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors.
These findings are described in the article entitled Sulfonylureas as Initial Treatment for Type 2 Diabetes and the Risk of Severe Hypoglycemia, recently published in the American Journal of Medicine. This work was conducted by Oriana Yu, Laurent Azoulay, Hui Yin, Kristian B. Filion, and Samy Suissa from the Jewish General Hospital, Montreal. These findings are also described in the article entitled Sulfonylureas as second line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycaemic events: population based cohort study, recently published in the journal BMJ. This work was conducted by Antonios Douros, Sophie Dell’Aniello, Oriana Hoi Yun Yu, Kristian B Filion, Laurent Azoulay, and Samy Suissa from the Jewish General Hospital, Montreal.