Older adults with type 2 diabetes face a difficult trade-off: they are among the most vulnerable to medication-related harms yet are often underrepresented in the clinical trials that guide treatment decisions. A new study led by Yuan Lu, ScD, helps address this gap by providing large-scale, real-world evidence about the safety of commonly used diabetes medications. The study was co-led by Marc Suchard, PhD, of the University of California, Los Angeles, who also served as the study’s corresponding author.
Published in Nature Communications, the study analyzed data from more than 1.8 million people aged 65 and older across the United States and Europe. The researchers compared four major classes of second-line antihyperglycemic medications—typically prescribed when first-line therapy such as metformin is not sufficient—across 18 safety outcomes.
“Evidence from clinical trials often does not fully capture older adults,” says Lu, assistant professor of medicine (cardiovascular medicine) at Yale School of Medicine. “At the same time, they are more likely to experience side effects due to frailty, multiple chronic conditions, and the use of several medications.”
Newer diabetes drugs show overall safety advantages
The study found a consistent pattern: newer classes of medications, including GLP-1 receptor agonists and SGLT2 inhibitors, were generally associated with lower risks of several important adverse outcomes compared to older drugs such as sulfonylureas and DPP-4 inhibitors.
Newer agents were linked to lower risks of hypoglycemia, hyperkalemia, and peripheral edema—complications that can be especially dangerous in older adults. However, the findings also highlight important trade-offs. For example, SGLT2 inhibitors were associated with a higher risk of diabetic ketoacidosis, while GLP-1 receptor agonists were more likely to cause gastrointestinal side effects such as nausea and vomiting.
Rather than identifying a single “best” medication, Lu emphasizes that the results support more informed, individualized decision-making. “Some patients may have a higher risk of hypoglycemia, while others may be more susceptible to diabetic ketoacidosis,” she says. “These risks need to be considered together as part of an individual patient profile.”
Real-world data at global scale
A key strength of the study is its scale and approach. The analysis drew on nine large databases and was conducted through the Observational Health Data Sciences and Informatics (OHDSI), an international research network that enables standardized analyses across diverse health care systems.
By using harmonized real-world data and consistent analytic methods, the researchers were able to evaluate a broad range of safety outcomes in routine clinical practice—offering insights that complement and extend findings from randomized trials.
Supporting safer prescribing for an aging population
As the population ages and the use of newer diabetes medications continues to grow, understanding their safety profiles in older adults is increasingly important. The findings reinforce current guideline recommendations that often favor newer agents, while also underscoring the need to tailor treatment decisions to each patient’s risks and preferences.
Like all observational studies, the analysis cannot fully rule out unmeasured differences between patients. Still, the large, multinational design gives a more complete picture of medication safety in a population often underrepresented in clinical research.
Looking ahead, Lu and her colleagues hope to expand this work to examine the comparative safety of individual medications and to evaluate the safety of newer GLP-1 receptor agonists across a wider range of outcomes, including among people with obesity. “By providing more evidence in populations that clinicians see every day, our goal is to support safer, more informed care,” she says.
Yale authors on the study include Arya Aminorroaya, MD, MPH; Lovedeep S. Dhingra, MBBS, MHS; Rohan Khera, MD, MS; Chungsoo Kim, PharmD, PhD; Harlan M. Krumholz, MD, SM; Aline F. Pedroso, PhD; Mitsuaki Sawano, MD, PhD; and Phyllis Thangaraj, MD, PhD.
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