Short-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with an increased risk of hospitalization for heart failure among patients with type 2 diabetes (T2D), according to a Danish registry study.
Among more than 300,000 patients with T2D, short-term use of NSAIDs was associated with a 43% relative increase in the risk of experiencing heart failure for the first time hospitalized in the subsequent 28 days (OR 1.43, 95% CI 1.27-1.63), according to It was reported by Anders Holt, MD, of Copenhagen-Herlev and Gentofte University Hospital in Hellerup, Denmark, and colleagues.
The highest-risk subgroups were patients aged 80 and over (OR 1.78, 95% CI 1.39–2.28), those who were poorly managed as evidenced by elevated HbA1c levels and only one drug OR 1.68, 95% confidence interval 1.00 -2.88), and new NSAID users without previous prescriptions (OR 2.71, 95% CI 1.78-4.23).
The authors concluded, “It is advisable to assess individual risk if NSAIDs are prescribed to patients with T2D.” Journal of the American College of Cardiology.
NSAIDs have previously been linked to heart failure risk, doubling the risk of hospitalization for heart failure in one study in a post-myocardial infarction population.
While the findings in T2D may not be surprising, they are concerning, given the widespread use of NSAIDs, according to an accompanying editorial by Hasan Khan, MD, PhD, of Norton Healthcare in Louisville, Kentucky, and Setor K. Kunutsor, MD, Ph.D. from the University of Leicester, England.
The editors noted that many of the position statements already caution against short- and long-term use of NSAIDs in patients at risk for cardiovascular disease, with the suggestion that use be of shorter duration at the lowest dose that provides relief.
Escalating this into a guideline recommendation would be “premature,” Khan and Konutsur wrote, based on a single observational study. More robust evidence from clinical trials is needed to replicate these findings and investigate the relationship between type and dose of NSAIDs with HF. [heart failure] risk. However, it should be recognized that short- or long-term use of NSAIDs may be harmful to cardiovascular health.”
NSAIDs have cardiotoxic effects on fluid retention and blood pressure, but in this study, the 5-year risk of death after first hospitalization for heart failure was similar for both NSAID-exposed and unexposed patients,” indicating Indicating that HF is associated with the use of NSAIDs could be more than a temporary fluid overload,” Holt and team wrote.
Subgroup analysis showed increased risk with poorly managed HbA1c but not among patients with normal HbA1c levels, regardless of the intensity of antidiabetic treatment, which the researchers said “suggests that the combined effects of hyperglycemia and exposure to NSAIDs may lead to endothelial dysfunction, leading to HF,” or “unmasking” subclinical heart failure induced by T2D.
However, the trend towards stronger associations in subgroups with suspected renal function implied that both mechanisms [fluid overload and endothelial dysfunction] It may play an important role.”
The study used Danish nationwide registries to identify all 331,189 adults (mean age 62, 44.2% women) who were diagnosed with T2D or started taking antidiabetic medication from 1998 to 2021, and who did not have Previous heart failure, rheumatic disease, or NSAID prescriptions within 120 days of diagnosis. Patients with type 1 diabetes and women under the age of 40 who were taking metformin only (who may present as polycystic ovary syndrome rather than T2D) were excluded.
While the primary associations examined were between NSAIDs and hospitalization for first-time heart failure using a cross-case design with exposure windows of 28 days, the results were similar for windows of 14 and 42 days.
The study classified exposure as filled prescriptions for celecoxib, diclofenac, ibuprofen, or naproxen — the main NSAIDs used in Denmark. The associations were similar for diclofenac and ibuprofen, but the results were nonsignificant for celecoxib and naproxen, likely due to fewer packaged prescriptions.
Of the 16% of patients who filled at least one NSAID prescription, ibuprofen was most commonly prescribed (12.2%), followed by diclofenac (3.3%), while naproxen and celecoxib prescriptions were filled in less than 1% of patients.
The editors noted that the few events that occurred after celecoxib and naproxen were prescribed limited the study’s ability to reliably explore a class effect.
“This is clinically important since various NSAIDs reversibly inhibit cyclooxygenase (COX) in both its isoforms, COX-1 and COX-2; however, COX selectivity and associated cardiovascular risks differ,” notes Khan. and Konutsur. “Evidence suggests that naproxen, a non-selective NSAID, is associated with the lowest risk of cardiovascular events, while diclofenac is associated with the highest cardiovascular risk among non-selective NSAIDs.”
Other limitations included the possibility of temporal and residual divergence and selection bias, as well as the fact that researchers were only able to capture short-term effects of transient exposure. In addition, an observational study cannot establish a causal relationship.
The study was funded by independent external grants from the Ib Mogens Kristiansens Almene Fond, the Health Foundation, MA Carpenter Sophos Jacobsen and his wife Astrid Jacobsen Fond, Marie, MB Richters Fond, and Dagmar Marshall Fond. Holt disclosed the same funding sources.
The editors did not disclose any relevant industry ties.
Journal of the American College of Cardiology
Source reference: Holt A, et al “Heart failure after administration of anti-inflammatory drugs in patients with type 2 diabetes” J Am Coll Cardiol 2023; DOI: 10.1016/j.jacc.2023.02.027.
Journal of the American College of Cardiology
Reference source: Khan H, Konsur SK “Non-steroidal anti-inflammatory drugs and type 2 diabetes: Is it a prescription for heart failure?” J Am Cool Cardiol 2023; DOI: 10.1016/j.jacc.2023.02.026.