Can Nonsteroidal Anti-Inflammatory Drugs Lead to First-Time Heart Failure in Patients with Diabetes Mellitus Type-2: Is There a Link?

Dear Editor,

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed drugs; however, they can lead to potential adverse effects [1]. The detrimental association between NSAIDs (apart from aspirin) usage and the peril to cardiac health has been documented profoundly in the literature [2–7]. The possible mechanism behind this adverse relationship can be due to an imbalance in the levels of prostaglandin E2 and vasodilatory prostacyclin compared to those of vasoconstrictive thromboxane A2, established due to NSAID usage targeting the endothelium and eventually leading to thrombus formation [8, 9]. Unlike other NSAIDs, aspirin irreversibly inhibits COX-1, leading to a reduction in thromboxane A2 and clot formation, while not significantly impacting vasodilatory prostaglandins and at low doses, this provides a cardioprotective effect [2]. NSAIDs are further known to exacerbate heart failure (HF) through increased salt and water retention [10–12]. A study conducted by Page and Henry [13] evaluated the hospitalization risk of HF for patients on NSAIDs. A relative risk of 2.1 was found in patients taking NSAIDs compared to nonusers. According to this study, NSAIDs use might contribute to 19% of newly diagnosed congestive HF cases. A study by Mamdani et al. [14] compared the hospitalization risk for congestive HF for patients being managed with nonselective NSAIDs, coxibs, and controls. Patients taking rofecoxib showed the most significant risk (RR = 1.8, 95% confidence interval [CI] = 1.5–2.2). While those taking nonselective NSAIDs showed a relative risk of 1.4 (95% CI = 1.0–1.9). These studies demonstrate that NSAIDs can cause as well as exacerbate preexisting HF. However, there is very limited data available that can relate to patients with first-time cardiac failure prescribed NSAIDs having T2DM.

A study recently presented at the 2022 Congress of the European Society of Cardiology (ESC) revealed that short-term NSAID use could potentially augment the chance of first-time HF in patients having T2DM [15]. A greater than 40% increase in the likelihood of hospitalization for first-time HF in patients who took NSAIDs, including ibuprofen, the most widely used drug, was observed. According to the statement from ESC, lead investigator Anders Holt, MD, stated that almost 1 in 6 patients with T2DM in their study had usage of at least one NSAID for 1 year. Holt and a team of colleagues from institutions in Denmark and the United Kingdom designed this study as an observational one using data from Danish registers to find patients suffering with DM from 1998 to 2018. Investigators used a case-crossover method where the patients act as their own controls to mitigate confounding factors. A total of 331,189 patients with T2DM have no history of HF or rheumatologic conditions. The cohort had a mean age of 62 years, where 44% were females. Almost 16% reported using at least one NSAID, and 3% reported using three or more NSAID prescriptions. Although the case-crossover design of this study helps control potential confounders by using patients as their controls, comparing exposure during different periods. Still, these controls for time-invariant confounders, but time-varying confounders may still influence results. To address these, researchers may conduct subgroup analyses, use statistical methods like multivariable regression or propensity score analysis, and perform sensitivity analyses to test the findings’ robustness. Patient percentages (%) that individual were prescribed NSAIDs are shown in Table 1.

Table 1.

Patient percentages (%) prescribed with individual NSAIDs

NSAID	Prescribed patient percentage (%)
Ibuprofen	12.2
Diclofenac	3.3
Naproxen	0.9
Celecoxib	0.4

The follow-up period was a median of 5.85 years, and during this period, 23,308 patients had a first-time HF hospitalization. Results revealed a relationship between NSAIDs and the rise in hospitalization risk for first-time HF within 120 days (OR, 1.43 [95% CI, 1.27–1.63]). The aforementioned association was only seen for ibuprofen and diclofenac, while naproxen and celecoxib did not demonstrate such a link. That might have been due to the small sample size, as per the investigators. Results for the study are illustrated in Table 2. No association was observed in patients with an HbA1c of 6.5% or less. A significant association was observed for patients having an age >65 years and among those who were new NSAIDs users [16]. Differences in HF risk among NSAIDs like ibuprofen, diclofenac, naproxen, and celecoxib may result from their distinct COX enzyme affinities [17]. Nonselective NSAIDs could disrupt prostaglandin balance, while selective COX-2 inhibitors may increase thromboxane A2 levels. Naproxen, a preferential COX-1 inhibitor, shows a lower cardiovascular risk [17].

Table 2.

Association between different NSAIDs for the risk of hospitalization for first-time heart failure within 120 days

NSAID	Odds ratio (OR)	95% confidence interval (CI)
Ibuprofen	01.46	01.26–01.69
Diclofenac	01.48	01.10–02.00
Naproxen	_	_
Celecoxib	_	_

Moreover, while the evidence available is limited and based on a relatively small number of patients, it is difficult to conclusively determine the exact type of HF caused by NSAIDs in T2DM patients. It is known that T2DM patients often suffer from HF with preserved ejection fraction (HFpEF) [18]. NSAIDs may worsen HFpEF due to their potential to cause fluid retention and increase blood pressure, both of which can exacerbate the diastolic dysfunction commonly seen in HFpEF [18]. Additionally, the salt and water retention associated with NSAIDs use could potentially lead to increased preload, which may contribute to systolic dysfunction [19].

While there is limited literature available on the subject, it is currently challenging to definitively determine if and how NSAIDs predispose to T2DM patients to HF. However, existing studies suggest a significant association between HF and NSAIDs use in patients with T2DM. This potential correlation should be considered when prescribing NSAIDs to T2DM patients, particularly those aged 65 or older. Based on the limited data available, it can be hypothesized that NSAIDs use may be safe in patients with well-controlled T2DM who are under 65 years of age. However, further extensive research, such as randomized clinical trials, is needed to provide a more comprehensive understanding of this potential association. Physicians prescribing NSAIDs to T2DM patients for conditions such as rheumatologic complications, migraines, and chronic pain should be well-informed and up-to-date regarding the potential adverse effects of these medications. Managing pain in T2DM patients while minimizing the potential risk of HF involves carefully selecting less-harmful NSAIDs, such as naproxen, which have been associated with lower cardiovascular risks compared to others like diclofenac. Additionally, prescribing the lowest effective dose for the shortest necessary duration can help balance pain relief with minimizing potential cardiovascular risks. Greater awareness and understanding of this potentially harmful association could help save lives and address a significant public health concern. Investing in more in-depth research is essential to comprehend better the relationship between NSAIDs use and HF in T2DM patients. This will help guide clinical decision-making and empower healthcare providers to make more informed choices when treating patients with T2DM who require NSAIDs therapy.

Conflict of Interest Statement

The authors declare that they have no competing interests.

Funding Sources

The publication of this article was funded by the Qatar National Library.

Author Contributions

Manuscript writing and Editing: Shehroze Tabassum, Aroma Naeem, Uzzam Ahmed Khawaja, and Abdulqadir J. Nashwan. All authors read and approved the final manuscript, and all the authors meet the criteria for authorship as per the ICMJE criteria.

Funding Statement

The publication of this article was funded by the Qatar National Library.