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Sulfonylureas No More!

Cheapest treatment associated with increased risks of cardiovascular events and death.

After the cardiovascular issues with rosiglitazone, cardiovascular safety trials had to be conducted for all new anti-hyperglycemic agents. However, approval for older medications was based simply on evidence of a reduction in glucose parameters; cardiovascular safety was not a concern back then.

But, data from the UKPDS trial shows that metformin reduces CV events, so, it was never in doubt. The ORIGIN trial has shown no increased harm with early initiation of insulin. However, some questions linger regarding the cardiovascular safety profile of sulfonylureas. Data exist on the weight gain and risk of hypoglycemia associated with sulfonylureas, but the associated cardiovascular events have not been well-quantified. Sulfonylureas are used commonly across the world and are very effective in lowering HbA1C, but often the effect wears off, as shown in the ADOPT study.

Recent randomized trials have compared the newer antidiabetic agents to treatments involving sulfonylureas, drugs associated with increased cardiovascular risks and mortality in some observational studies with conflicting results. They reviewed the methodology of these observational studies by searching MEDLINE from inception to December 2015 for all studies of the association between sulfonylureas and cardiovascular events or mortality.

Each study was appraised with respect to the comparator, the outcome, and study design–related sources of bias. A meta-regression analysis was used to evaluate heterogeneity. A total of 19 studies were identified, of which six had no major design-related biases. Sulfonylureas were associated with an increased risk of cardiovascular events and mortality in five of these studies (relative risks 1.16–1.55). Overall, the 19 studies resulted in 36 relative risks as some studies assessed multiple outcomes or comparators. Of the 36 analyses, metformin was the comparator in 27 (75%) and death was the outcome in 24 (67%). The relative risk was higher by 13% when the comparator was metformin, by 20% when death was the outcome, and by 7% when the studies had design-related biases.

The lowest predicted relative risk was for studies with no major bias, comparator other than metformin, and cardiovascular outcome (1.06 [95% CI 0.92–1.23]), whereas the highest was for studies with bias, metformin comparator, and mortality outcome.

In summary, sulfonylureas were associated with an increased risk of cardiovascular events and mortality in the majority of studies with no major design-related biases. Among studies with important biases, the association varied significantly with respect to the comparator, the outcome, and the type of bias. With the introduction of new antidiabetic drugs, the use of appropriate design and analytical tools will provide their more accurate cardiovascular safety assessment in the real-world setting.

So this study reviewed over 19 trials looking at sulfonylureas, specifically studying cardiovascular events and mortality. The problem with some studies is that they don’t take into account the duration of diabetes et cetera; so, they may end up comparing sicker patients with those who aren’t as sick. This group looked at potential biases such as exposure misclassification, time-lag bias, and selection bias, and, of the 19 studies, 6 did not have any of these biases. Of those 6 studies, 5 showed that sulfonylureas were associated with an increased risk of cardiovascular events and mortality, with relative risks ranging from 1.16 to 1.55.

It is not possible to tease out what the cause of the increase in events is based on this type of analysis. Is it hypoglycemia? Is it a direct drug effect? However, regardless of the mechanism, the consistent finding of increased cardiovascular risk may have an impact on selection of agents for our patients. Newer agents have been shown not to increase events, and recently some have even shown reduction in events. So, perhaps our algorithm of selecting medications for our patients may have to change to focus on the cardiovascular effects first and then the glycemic benefits because, in the end, our goal is preventing cardiovascular events from happening in our patients with diabetes.

Practice Pearls:

  • Sulfonylureas are associated with increased risks of cardiovascular events and death.
  • Sulfonylureas also associated with hypoglycemia events.
  • Data exist on the weight gain and risk of hypoglycemia associated with sulfonylureas.

UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837-853.

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)07019-6/fulltext

The ORIGIN Trial Investigators. Basal Insulin and Cardiovascular and Other Outcomes in Dysglycemia. N Engl J Med. 2012;367(4):319-328. http://www.nejm.org/doi/full/10.1056/NEJMoa1203858

Sulfonylureas and the Risks of Cardiovascular Events and Death: A Methodological Meta-Regression Analysis of the Observational Studies. http://care.diabetesjournals.org/content/40/5/706

Sulfonylureas and the Risks of Cardiovascular Events and Death: A Methodological Meta-Regression Analysis of the Observational Studies. Diabetes Care. 2017 May;40(5):706-714. doi: 10.2337/dc16-1943. https://www.ncbi.nlm.nih.gov/pubmed/28428321