Patients with type 2 diabetes who use short-term use of non-steroidal anti-inflammatory drugs (NSAIDs) have a greater risk of being hospitalised for heart failure, particularly older patients with poorly controlled diabetes, according to a Danish registry study.
Among more than 300 000 patients with T2D, short-term use of NSAIDs was linked to a relative 43% increased risk of a first-time heart failure hospitalisation in the subsequent 28 days (OR 1.43, 95% CI 1.27-1.63), reported Dr Anders Holt of Copenhagen University Hospital-Herlev Gentofte in Hellerup, Denmark, and colleagues.
The most at-risk subgroups were patients 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 anti-diabetic 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 wrote in the Journal of the American College of Cardiology.
NSAIDs have previously been linked to heart failure risk, doubling the risk of hospitalisations 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 Dr Hassan Khan of Norton Healthcare in Kentucky, and Dr Setor Kunutsor, 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 realised 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 five-year mortality risk after first-time heart failure hospitalisation was comparable for both NSAID-exposed and –non-exposed 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 hyperglycaemia 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.
How they did it
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 hospitalisation 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, possibly 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.
Study details
Heart Failure Following Anti-Inflammatory Medications in Patients With Type 2 Diabetes Mellitus
Anders Holt, Jarl E. Strange, Nina Nouhravesh, Sebastian Kinnberg Nielsen, Mariam Elmegaard Malik, Anne-Marie Schjerning, Lars Køber, Christian Torp-Pedersen, Gunnar Gislason,
Published in the Journal of the American College of Cardiology on 8 April 2023
Abstract
Background
Fluid retention and endothelial dysfunction have been related to use of nonsteroidal anti-inflammatory drugs (NSAIDs), and type 2 diabetes mellitus (T2DM) has been linked to both a decline in kidney function and subclinical cardiomyopathy.
Objectives
The authors hypothesised that short-term use of NSAIDs could lead to subsequent development of incident heart failure (HF) in patients with T2DM.
Methods
Using nationwide Danish registers, we identified patients diagnosed with T2DM during 1998 to 2021 and included patients without previous HF, rheumatic disease, or use of NSAIDs 120 days before diagnosis. Associations between NSAIDs and first-time HF hospitalisation were investigated using a case-crossover design with 28-day exposure windows, and ORs with 95% CIs were reported.
Results
Included were 331,189 patients with T2DM: 44.2% female, median age of 62 years (IQR: 52-71 years); 23,308 patients were hospitalized with HF during follow-up, and 16% of patients claimed at least 1 NSAID prescription within 1 year. Short-term use of NSAIDs was associated with increased risk of HF hospitalization (OR: 1.43; 95% CI: 1.27-1.63), most notably 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).
Conclusions
NSAIDs were widely used and were associated with an increased risk of first-time HF hospitalisation in patients with T2DM. Patients with advanced age, elevated HbA1c levels, and new users of NSAID seemed more susceptible. These findings could guide physicians prescribing NSAIDs.
See more from MedicalBrief archives:
Heart failure twice as likely for diabetics after taking ibuprofen – Danish study
Heart failure risk with diabetes medication
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