Certain Painkillers Linked to Heart Failure in Type 2 Diabetes

Short-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an increased risk for heart failure hospitalization among patients with type 2 diabetes (T2D), according to a Danish registry study.

Among over 300,000 patients with T2D, short-term use of NSAIDs was associated with a relative 43% increased risk of a first-time heart failure hospitalization in the subsequent 28 days (OR 1.43, 95% CI 1.27-1.63), reported Anders Holt, MD, of Copenhagen University Hospital-Herlev and Gentofte in Hellerup, Denmark, and colleagues.

The most at-risk subgroups were patients ages 80 and older (OR 1.78, 95% CI 1.39-2.28), those poorly managed as evidenced by elevated HbA1c levels and no or only one antidiabetic drug (OR 1.68, 95% CI 1.00-2.88), and new NSAID users without previous prescriptions (OR 2.71, 95% CI 1.78-4.23).

"Individual risk assessment is advised if prescribing NSAIDs for patients with T2D," the researchers concluded in the Journal of the American College of Cardiology.

NSAIDs have previously been linked to heart failure risk, doubling the risk of heart failure hospitalizations in one study in a post-myocardial infarction population.

Implications

While the findings in T2D might not be surprising, they are worrying, given the widespread use of NSAIDs, according to an accompanying editorial by Hassan Khan, MD, PhD, of Norton Healthcare in Louisville, Kentucky, and Setor K. Kunutsor, MD, PhD, of the University of Leicester in England.

Several position statements already caution against both short-term and long-term use of NSAIDs in patients at high cardiovascular risk, with the suggestion that use be of the shortest duration at the lowest dose that provides relief, the editorialists noted.

Escalating that to a guideline recommendation would be "premature" based on a single observational study, Khan and Kunutsor wrote. "Further robust clinical trial evidence is needed to replicate these results and investigate the relationship of the type and dose of NSAIDs with HF [heart failure] risk. However, it should be realized that short-term or long-term use of NSAIDs may be detrimental to cardiovascular health."

NSAIDs have potential cardiotoxic effects on fluid retention and blood pressure, but in this study, the 5-year mortality risk after first-time heart failure hospitalization was comparable for both NSAID-exposed and -nonexposed patients, "suggesting that HF associated with use of NSAIDs could be more than temporary fluid overload," Holt and team wrote.

Subgroup analysis turned up increased risk with poorly managed HbA1c but not among patients with normal HbA1c levels, independent of antidiabetic treatment intensity, which the researchers said "suggests that the combined effects of hyperglycemia and NSAID exposure may lead to endothelial dysfunction, resulting in HF," or "demasking" subclinical heart failure caused by T2D.

"However, the trend for stronger associations in subgroups with suspected compromised kidney function implies that both mechanisms [fluid overload and endothelial dysfunction] probably play important roles," they added.

Study Details

The study used nationwide Danish registers to identify all 331,189 adults (mean age 62, 44.2% women) diagnosed with T2D or started on antidiabetic medication from 1998 to 2021, who had no previous heart failure, rheumatic disease, or filled NSAID prescriptions 120 days before diagnosis. Type 1 diabetes patients and women under age 40 who were only taking metformin (who might represent polycystic ovary syndrome rather than T2D) were excluded.

While the primary associations examined were between NSAIDs and first-time heart failure hospitalization using a case-crossover design with 28-day exposure windows, results were similar with 14- and 42-day windows.

The study classified exposure as filled prescriptions for celecoxib, diclofenac, ibuprofen, or naproxen -- the main NSAIDs used in Denmark. Associations were similar for diclofenac and ibuprofen, but the results were insignificant for celecoxib and naproxen, likely due to too few prescriptions filled.

Of the 16% of patients who filled at least one NSAID prescription, ibuprofen was most common (12.2%), followed by diclofenac (3.3%), while naproxen and celecoxib prescriptions were each filled by less than 1% of patients.

The few events that occurred after celecoxib and naproxen prescription limited the study's ability to reliably explore for a class effect, the editorialists pointed out.

"This is clinically relevant given that the various NSAIDs reversibly inhibit the enzyme cyclooxygenase (COX) in both of its isoforms, COX-1 and COX-2; however, their COX selectivity and associated cardiovascular risk vary," Khan and Kunutsor noted. "Evidence suggests that naproxen, a nonselective NSAID, is associated with the lowest risk of cardiovascular events, whereas diclofenac is associated with the highest cardiovascular risk among nonselective NSAIDs."

Other limitations included the potential for time-varying and residual confounding and selection bias, as well as the fact that the researchers were only able to capture the short-term effects of transient exposures. In addition, the observational study could not establish a causal relationship.

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