Frequent Hypoglycemic Episodes Raise Cardiac Event Risk

Andrew D. Bowser

June 25, 2020

Frequent hypoglycemic episodes were linked to a raised incidence of cardiovascular events in adults with type 2 diabetes in a recent retrospective study, suggesting certain hypoglycemia-associated diabetes drugs should be avoided, an investigator said.

Patients who had more than five hypoglycemic episodes per year had a 61% greater risk of cardiovascular (CV) events, compared with patients with less frequent episodes, according to results of the study.

Although there were fewer strokes among younger patients, the overall increase in cardiovascular event risk held up regardless of age group, according to investigator Aman Rajpal, MD, of Louis Stokes Veterans Affairs Medical Center and Case Western Reserve University, both in Cleveland.

On the basis of these and earlier studies tying hypoglycemia to CV risk, health care providers need to "pay close attention" to low blood sugar and personalize glycemic control targets for each patient based on risk of hypoglycemia, Dr. Rajpal said in a presentation of the study at the virtual annual scientific sessions of the American Diabetes Association.

"Also, this suggests that avoidance of drugs associated with increased risk of hypoglycemia – namely insulin, sulfonylureas, or others – is essential to avoid and minimize the risk of cardiovascular events in this patient population with type 2 diabetes," said Dr. Rajpal. "Let us remember part of our Hippocratic oath: 'Above all, do no harm.' "

Tailoring Treatment to Mitigate Risk

Mark Schutta, MD, medical director of Penn Rodebaugh Diabetes Center in Philadelphia, said that results of this study suggest a need to carefully select medical therapy for each individual patient with diabetes in order to mitigate CV risk.

"It's really about tailoring their drugs to their personal situation," Dr. Schutta said in an interview.

Although newer diabetes drug classes are associated with low to no risk of hypoglycemia, Dr. Schutta said that there is still a place for drugs such as sulfonylureas in certain situations.

Among sulfonylureas, glyburide comes with a much higher incidence of hypoglycemia, compared with glipizide and glimepiride, according to Dr. Schutta. "I think there's a role for both drugs, but you have to be very careful, and you have to get the data from your patients."

Hypoglycemia Frequency and Outcomes

Speculation that hypoglycemia could be linked to adverse CV outcomes was sparked years ago by trials such as ADVANCE. Severe hypoglycemia in that study was associated with a 168% increased risk of death from a CV cause (N Engl J Med. 2010 Oct 7;363:1410-8).

At the time, ADVANCE investigators said they were unable to find evidence that multiple severe hypoglycemia episodes conferred a greater risk of CV events versus a single hypoglycemia episode, though they added that few patients had recurrent events.

"In other words, the association between the number of hypoglycemia events, and adverse CV outcomes is still unclear," said Dr. Rajpal in his virtual ADA presentation.

Potential Elevated Risks With More Than Five Episodes

To evaluate the association between frequent hypoglycemic episodes (i.e., more than five per year, compared with one to five episodes) and CV events, Dr. Rajpal and colleagues evaluated outcomes data for 4.9 million adults with type 2 diabetes found in a large commercial database including information on patients in 27 U.S. health care networks.

Database records indicated that about 182,000 patients, or nearly 4%, had episodes of hyperglycemia, which Dr. Rajpal said was presumed to mean a plasma glucose level of less than 70 mg/dL.

Characteristics of the patients with more than five hypoglycemic episodes were similar to those with one to five episodes, although they were more likely to be 65 years or older, and were "slightly more likely" to be on insulin, which could possibly precipitate more hypoglycemic episodes in that group, Dr. Rajpal said.

Key Findings

In the main analysis, Dr. Rajpal said, risk of CV events was significantly increased in those with more than five hypoglycemic episodes, compared with those with one to five episodes, with an odds ratio of 1.61 (95% confidence interval, 1.56-1.66). The incidence of cardiovascular events was 33.1% in those with more than five episodes and 23.5% in those with one to five episodes, according to the data presented.

Risks were also significantly increased specifically for cardiac arrhythmias, cerebrovascular accidents, and MI, Dr. Rajpal said, with ORs of 1.65 (95% CI, 1.9-1.71), 1.38 (95% CI, 1.22-1.56), and 1.43 (95% CI, 1.36-1.50), respectively.

Because individuals in the group with more than five hypoglycemic episodes were more likely to be elderly, Dr. Rajpal said that he and coinvestigators decided to perform an age-specific stratified analysis.

Although cerebral vascular incidence was low in younger patients, risk of CV events overall was nevertheless significantly elevated for those aged 65 years or older, 45-64 years, and 18-44 years, with ORs of 1.69 (95% CI, 1.61-1.7), 1.58 (95% CI, 1.48-1.69), and 1.62 (95% CI, 1.33-1.97).

"The results were still valid in stratified analysis based on different age groups," Dr. Rajpal said.

Dr. Rajpal and coauthors reported that he had no conflicts of interest related to the research.

SOURCE: Rajpal A et al. ADA 2020, Abstract 161-OR.

This article originally appeared on


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.