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Paradigm Shift in Second-Line Diabetes Treatment

An ongoing question among diabetes specialists, whether second-line medications (ADMs) are associated with cardiovascular events in patients with type 2 diabetes, has been clarified. Two drugs commonly prescribed to treat type 2 diabetes carry a high risk of cardiovascular events such as heart attack, stroke, heart failure or amputation, according to a study. Understanding cardiovascular outcomes of initiating second-line antidiabetic medications (ADMs) may help inform treatment decisions after metformin alone is not sufficient or not tolerated.

“People should know if the medications they’re taking to treat their diabetes could lead to serious cardiovascular harm,” said lead author Dr. Matthew O’Brien, assistant professor of general internal medicine and geriatrics at Northwestern University Feinberg School of Medicine. “This calls for a paradigm shift in the treatment of type 2 diabetes.”

The two drugs —sulfonylureas and basal insulin—are commonly prescribed to patients after they have taken metformin but need a second-line medication because metformin alone didn’t work or wasn’t tolerated. This is the first study to compare how each of the six major second-line drugs impact cardiovascular outcomes in type 2 diabetes patients taking a second diabetes medication. 

More than half of patients nationwide (60 percent) who need a second-line drug are prescribed one of these two drugs, the study found. Yet, patients who take one of these two drugs are more likely— 36 percent more for sulfonylureas and twice as likely for basal insulin—to experience cardiovascular harm than those taking a newer class of diabetes drugs known as DPP-4 inhibitors, the authors report. The primary outcome was time to first cardiovascular event after starting the second-line ADM. This composite outcome was based on hospitalization for the following cardiovascular conditions: congestive heart failure, stroke, ischemic heart disease, or peripheral artery disease.

“According to our findings, we only have to prescribe basal insulin to 37 people over two years to observe one cardiovascular event, such as a heart attack, stroke, heart failure or amputation,” O’Brien said. “For sulfonylureas, that number was 103 people. But when you apply these numbers to 30 million Americans with diabetes, this has staggering implications for how we may be harming many patients.” 

Physicians should consider prescribing newer classes of antidiabetic medications, such as GLP-1 agonists (e.g. liraglutide), SGLT-2 inhibitors (e.g. empagliflozin)or DPP-4 inhibitors (e.g. sitagliptin), more routinely after metformin, rather than sulfonylureas or basal insulin, the study authors suggest. These drugs, however, are more expensive than the sulfonylureas, which is the main reason they are not as commonly prescribed. 

This was an observational study using data from 132,737 patients with Type 2 diabetes who were starting second-line treatment. The scientists were, therefore, able to use real-world evidence that complements findings from previous randomized trials which studied only one active drug compared to placebo.  

Among insured adult patients with type 2 diabetes initiating second-line ADM therapy, the short-term cardiovascular outcomes of GLP-1 receptor agonists, SGLT-2 inhibitors, and DPP-4 inhibitors were similar. Higher cardiovascular risk was associated with use of sulfonylureas or basal insulin compared with newer ADM classes. Clinicians may want to consider prescribing GLP-1 receptor agonists, SGLT-2 inhibitors, or DPP-4 inhibitors more routinely after metformin rather than sulfonylureas or basal insulin.

  • O’Brien, MJ, Karam, S, Wallia, A. Association of Second-line Antidiabetic Medications With Cardiovascular Events Among Insured Adults With Type 2 Diabetes. JAMA Network Open. 2018;1(8):e186125. doi:10.1001/jamanetworkopen.2018.6125 (R
  • Campbell PT, Newton CC, Patel AV, Jacobs EJ, Gapstur SM. Diabetes and cause-specific mortality in a prospective cohort of one million US adults. Diabetes Care. 2012;35(9):1835-1844. doi:10.2337/dc12-0002 2. American Diabetes Association. 
  • Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2018. Diabetes Care. 2018;41(suppl 1):S73-S85. doi:10.2337/dc18-S008 
  • Nesti L, Natali A. Metformin effects on the heart and the cardiovascular system: a review of experimental and clinical data. Nutr Metab Cardiovasc Dis. 2017;27(8):657-669. doi:10.1016/j.numecd.2017.04.009

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