Short-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of heart failure (HF)-related hospitalization in patients with type 2 diabetes mellitus (T2DM), new research suggests. The results could better guide physicians in prescribing NSAIDs, says the research team, who attribute the findings to a possible worsening of subclinical structural HF or a transient impact on the renal system, causing fluid build-up. “NSAID use has been associated with an increased risk of HF,” said the authors of the paper, which was published Monday online and in the April 18 issue of the Journal of the American College of Cardiology. “Proposed mechanisms include induction of arrhythmias and heart fibrosis, vasoconstriction and subclinical inflammation, blood pressure elevation, and adverse effects on the renal system affecting fluid balances.” Further findings by mostly Denmark-based team point to a heightened risk of HF-related hospitalization in patients with advanced age, elevated HbA1c levels and new users of NSAIDs. Study methodology The researchers used nationwide Danish registries to identify the 331,189 patients deemed suitable for this case crossover study. These patients (44.2% female, median age of 62 years [interquartile ratio: 52-71 years]) had been diagnosed with T2DM from 1998 to 2021. Also included in the selection criteria were patients without previous HF, rheumatic disease or use of NSAIDs 120 days before diagnosis. Primary exposure was defined as a claimed prescription of either celecoxib, diclofenac, ibuprofen or naproxen, as these are NSAIDs used primarily in Denmark. To illustrate the magnitude of NSAID use among patients with T2DM, the team noted those patients claiming a minimum of one, two, three or four prescriptions within 1 year from beginning of follow-up. For the case-crossover analyses, patients were exposed if an NSAID prescription was claimed within 28 days before first-time HF hospitalization. Exposure windows of 14 and 42 days were also explored. Initial analyses included all exposure windows graded by NSAID type. For subgroup, supplementary, and sensitivity analyses, the 28-day exposure windows were used with all NSAIDs combined as exposure. For the outcome, the research team included the primary and secondary diagnoses of first-time HF linked to overnight hospitalization. Subgroup specification To identify stronger susceptibilities to NSAIDs, the team also prespecified five subgroups that were defined at the start of the reference period 84 days before the date of first-time HF hospitalization. These subgroups included one containing three age groups (18 to 64, 65 to 79, and ≥80 years of age), and another that grouped the concomitant use of renin-angiotensin-system inhibitors (RASis), and diuretics. The remaining subgroups looked at the previous use of NSAIDs, estimated glomerular filtration rate (eGFR), and T2DM status. Results revealed that 23,308 patients were hospitalized with HF during follow-up, and 16% of patients claimed at least one NSAID prescription within 1 year. Short-term use of NSAIDs was associated with increased risk of HF hospitalization (odds ratio [OR]: 1.43; 95% confidence interval [CI]: 1.27-1.63). This was most notable in subgroups with age ≥80 years (OR: 1.78; 95% CI: 1.39-2.28), elevated hemoglobin (Hb) A1c levels treated with 0 to 1 antidiabetic drug (OR: 1.68; 95% CI: 1.00-2.88), and without previous use of NSAIDs (OR: 2.71; 95% CI: 1.78-4.23) Individual clinical assessments needed “This study both shows that magnitude of NSAID use is not negligible among patients with T2DM and that even short-term use of NSAIDs was associated with an elevated risk of first time HF hospitalization,” said the team, led by Anders Holt, MD, from Copenhagen University Hospital–Herlev and Gentofte, in Hellerup, Denmark, and the University of Auckland in New Zealand. “The association was not found in all subgroups, such as patients below 65 years of age and patients with well-regulated HbA1c levels, underlining the necessity of individual clinical assessment.” In an accompanying editorial, Hassan Khan, MD, PhD, from Norton Heart Specialists, Norton Healthcare in Louisville, Kentucky, and Setor K. Kunutsor, MD, PhD, from the Leicester General Hospital, Leicester, England, described the study’s findings as “timely and relevant.” The authors commented that given the relationship between NSAID use and increased HF risk, the findings were not unexpected as T2DM is a major risk factor for HF. “It is advised that patients should be treated only for the shortest duration of time and with the lowest dose necessary to provide relief,” the editorial said. “Evidence suggests that naproxen may be the NSAID of choice in patients with high cardiovascular risk.” Over 30 million Americans use NSAIDs on a daily basis, according to one study. Their use ranges from treatment of fever and pain as well as inflammation caused by conditions such as rheumatoid arthritis and gout. Sources: Holt A, Strange JE, Nouhravesh N, et al. Heart Failure Following Anti-Inflammatory Medications in Patients With Type 2 Diabetes Mellitus. J Am Coll Cardiol. 2023;81:1459–1470. Khan H, Kunutsor SK., Nonsteroidal Anti-Inflammatory Drugs and Type 2 Diabetes: A Recipe for Heart Failure? J Am Coll Cardiol. 2023;81:1471–1473. Image Credit: Joel bubble ben – stock.adobe.com