Sulfonylureas are oral antidiabetic drugs that have been used in the treatment of type 2 diabetes for more than 50 years. While they can effectively reduce elevated blood sugar levels, sulfonylureas have also been linked to cardiovascular and hypoglycemic adverse events. However, the randomized controlled trials evaluating sulfonylureas were underpowered to assess cardiovascular complications of diabetes or severe hypoglycemia. Thus, and given the persistently high utilization of sulfonylureas as second- but also as first-line treatments in type 2 diabetes, we initiated a large research program of observational studies to assess these potential associations. For all studies, we used the Clinical Practice Research Datalink, a large primary care database from the United Kingdom (UK), linked to inpatient data from the Hospital Episode Statistics database and mortality data from the Office for National Statistics database.
Our initial studies focused on the cardiovascular and hypoglycemic safety of sulfonylureas in the setting of first-line treatment. First, we compared sulfonylureas with metformin, which is the first-line treatment of choice in most guidelines including the ones by the National Institute for Health and Care Excellence in the UK (https://www.ncbi.nlm.nih.gov/pubmed/29032229). Second, we compared different sulfonylurea groups with each other after classifying them based on important pharmacologic properties (https://www.ncbi.nlm.nih.gov/pubmed/28864502).
In our recent study, we assessed the cardiovascular and hypoglycemic safety of sulfonylureas as second-line treatments (https://www.ericas.org/reviews/view/62). We considered 77,138 patients with type 2 diabetes who started treatment with metformin between 1998 and 2013. Using the newly-developed prevalent new-user design, we matched patients who subsequently added or switched to a sulfonylurea to similar patients who continued metformin alone. We observed that 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 all-cause mortality. There was also a trend towards elevated risks of ischemic stroke and cardiovascular death. Finally, adding or switching to sulfonylureas was associated with a more than 7-fold elevated risk of severe hypoglycemia. Importantly, compared with adding sulfonylureas to metformin treatment, switching to sulfonylureas from metformin treatment was associated with a greater risk of myocardial infarction and all-cause mortality, while no differences were found regarding ischemic stroke, cardiovascular death, or severe hypoglycemia.
Overall, our results argue against the use of sulfonylureas as monotherapy when metformin is not tolerated or contraindicated. They are also in line with current guidelines on the treatment of type 2 diabetes that recommend the continuation of metformin when introducing sulfonylureas. Finally, our results highlight the importance of large observational studies in the assessment of adverse events that randomized controlled trials are not designed or underpowered to assess.
Dr Antonio Douros, McGill University, Quebec, Canada