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Common Diabetes Drugs Linked to Higher Risk of Heart Attack and Stroke

Jan 5, 2019

Author: Steve Freed, R.PH., CDE

Even though most diabetes drugs can help in managing blood sugar levels, they can also be detrimental to the heart.

“To date, no studies have directly compared the cardiovascular effects of all contemporary [glucose-lowering drug] options among patients starting second-line therapy…By examining cardiovascular outcomes among patients initiating second-line [glucose-lowering drugs] in the real world, this study aimed to complement findings from individual drug trials and further inform [glucose-lowering drug] choices for the broad population of patients currently receiving these medications,” the investigators say.


Researchers from Northwestern University Feinberg School of Medicine recently conducted a study, published in JAMA Network Open, to determine the association between diabetes medication and cardiovascular events like heart attack, heart failure and stroke. To do so, they examined 132,737 patients with type 2 diabetes who were starting second-line treatments. After starting metformin, the patients needed the second-line medications because they were still not at goal. It is not uncommon for patients with type 2 diabetes to be on two to five diabetes drugs.

The current study included 132,737 adults with type 2 diabetes enrolled in commercial or Medicare Advantage health insurance plans during 2011-2015. All had initiated a second-line glucose-lowering drug, mostly along with metformin. The data were analyzed from January 2017 to October 2018.  Overall, 5.5% had a history of cardiovascular events before starting treatment with the index second-line agent. Of the prescription fills for those agents, 47.6% were sulfonylureas, 21.8% DPP-4 inhibitors, 12.2% basal insulin, 8.6% GLP-1 agonists, 5.6% TZDs, and 4.3% SGLT2 inhibitors. The investigators established the DPP-4 inhibitor users as the comparison group because data have shown that class to have a neutral effect on cardiovascular outcomes. The primary outcome was time to first cardiovascular event after starting the second-line agent, with events defined as hospitalization for congestive heart failure, stroke, ischemic heart disease, or peripheral artery disease. There were 3,480 such events during 169,384 person-years of follow-up.

Among more than 130,000 insured adults with type 2 diabetes who required a second glucose-lowering agent after metformin, use of insulin or sulfonylureas was associated with consistent cardiovascular harm compared with dipeptidyl peptidase 4 (DPP-4) inhibitors, which have been shown to have a neutral cardiovascular effect. On the other hand, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and thiazolidinediones (TZDs) were not associated with cardiovascular harm compared with DPP-4 inhibitors, but they also didn’t produce the significant cardiovascular benefit that has been demonstrated in randomized clinical outcome trials of these agents in patients with type 2 diabetes and established cardiovascular disease.

After analyzing the results, they found that 60 percent of patients who need a second-line drug are prescribed either sulfonylureas and basal insulin. They also discovered those who take one of these two drugs are more likely to experience a cardiovascular event, compared to those taking a newer class of diabetes drugs. In fact, those on sulfonylureas were 36 percent more likely to have a heart attack, heart failure or stroke, and those on basal insulin were twice as likely.

“According to the 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,” coauthor Matthew O’Brien said in a statement. “For sulfonylureas, that number was a bit higher: 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.”

The authors suggest that doctors prescribe newer classes of diabetes medications, such as GLP-1 agonists, SGLT-2 inhibitors, or DPP-4 inhibitors. Although these drugs are more expensive, the scientists believe they can help lower the risk of heart damage.

Among the newer agents, use of a GLP-1 agonist was associated with a significantly lower adjusted risk of composite cardiovascular events compared with DPP-4 inhibitor use (hazard ratio, 0.78; 95% CI, 0.63 – 0.96). However, that benefit lost significance in several sensitivity analyses. The CV event rates after starting treatment with either SGLT2 inhibitors or TZDs weren’t significantly different from those of DPP-4 inhibitors (HR, 0.81 and HR, 0.92, respectively).

“This should force providers to think about cardiovascular effects of these drugs early in the course of diabetes treatment,” O’Brien said, “and shift prescribing patterns to newer drugs that have more favorable cardiovascular profiles.”

The study showed that patients who take a sulfonylurea or basal insulin are thirty-six percent more likely and twice as likely to experience cardiovascular harm.

In conclusion, the researchers say their new findings, “raise concerns about the cardiovascular safety of sulfonylureas and basal insulin” compared with newer glucose-lowering drugs and suggest that short-term cardiovascular outcomes of newer glucose-lowering drug classes may be similar among patients starting second-line treatment.

“Therefore, clinicians may consider prescribing GLP-1 agonists, DPP-4 inhibitors, or SGLT2 inhibitors more routinely after metformin rather than sulfonylureas or basal insulin.”

Practice Pearls:

  • Sulfonylureas and basal insulin are thirty-six percent more likely and twice as likely to experience cardiovascular harm.
  • Consider prescribing GLP-1 agonists, DPP-4 inhibitors, or SGLT2 inhibitors more routinely after metformin.
  • The findings raise concerns about the cardiovascular safety of sulfonylureas and basal insulin.


Primary Source:  JAMA Network Open;  O’Brien MJ, et al “Association of second-line antidiabetic medications with cardiovascular events among insured adults with type 2 diabetes” JAMA Network Open 2018; DOI: 10.1001/jamanetworkopen.2018.6125.

Secondary Source:  JAMA Network Open:  Callahan A, Shah NH “A second opinion from observational data on second-line diabetes drugs” JAMA Network Open 2018; DOI: 10.1001/jamanetworkopen.2018.6119.