NSAID Use Increased First Heart Failure Hospitalization Risk In Those With Type 2 Diabetes Mellitus

A study in Denmark found that short-term use of non-steroidal anti-inflammatory drugs (NSAIDs) increases heart failure hospitalization risk in type 2 diabetes patients, especially new users, those over 80 years old, and those with high A1c on 0-1 antidiabetic treatment.

Clinical Landscape

Type 2 Diabetes Mellitus (T2DM) is a major global health concern. According to the International Diabetes Federation (IDF), around 382 million people worldwide were estimated to have T2DM in 2013, with this number expected to rise to 592 million by 2035 [1]. More than 60% of those affected live in Asia, with almost one-third residing in China [1]. 

T2DM and Heart Failure 

T2DM is associated with macrovascular complications, including the development of structural heart disease and heart failure (HF) via systemic, myocardial, and cellular mechanisms [2]. The Framingham Heart Study has shown that T2DM increases the risk of HF up to 2-fold in men and 5-fold in women [3,4] independently.

Hyperglycemia and hyperinsulinemia accelerate atherosclerosis and increase atherogenic dyslipidemia, leading to endothelial dysfunction, leukocyte and platelet adhesion, thrombosis, inflammation, and coronary plaque ulceration [2]. Even in the absence of a major epicardial coronary heart disease, there is evidence of DM causing myocardial diseases such as cardiomegaly (diabetic cardiomyopathy) [2]. 

Insulin resistance and hyperinsulinemia have been found to contribute to left ventricular hypertrophy [2], while hyperglycemia increases fibrosis, and myocardial stiffness, and impairs cardiac relaxation [2] via the formation of advanced glycation end products that cause cross-links in collagen molecules. 

Other mechanisms, such as maladaptive calcium homeostasis and endoplasmic reticular stress, may result in cardiomyocyte fibrosis and diastolic dysfunction. Furthermore, hyperglycemia activates the renin-angiotensin-aldosterone system (RAAS), leading to the overproduction of angiotensin II and aldosterone, further aggravating diastolic dysfunction due to cardiac hypertrophy and fibrosis [2]. 

Non-steroidal anti-inflammatory medications and heart failure

Non-steroidal anti-inflammatory medications (NSAIDs), the most widely used medications worldwide [5], have long been associated with adverse cardiovascular events [6]. NSAIDs are cyclooxygenase (COX) inhibitors that affect various cell signalling pathways, including dysregulating the production of prostaglandins H2 (PGH-2) which is then converted to prostanoids (prostaglandins, prostacyclins, thromboxanes). Prostanoids regulate inflammation and pain under pathologic conditions, and the dysregulation of their formation by NSAIDs can lead to increased thrombotic events and arterial blood pressure [6] (figure 1). 

NSAIDs also reduce glomerular filtration and excretion of sodium and water by inhibiting prostanoid production in the kidney. This increases the risk of hypervolemia, worsening heart failure [6]. This risk is increased in those with impaired renal or cardiac function [6], with NSAID use predisposing patients to kidney insult due to reduced glomerular filtration. 

Therefore, the use of NSAIDs in patients with T2DM is expected to increase the risk of HF by aggravating fluid imbalances and/or prevalent subclinical HF [8]. However, specific recommendations for the short-term use of NSAIDs in T2DM patients are limited [8]. 

Use of NSAIDs in T2DM [8]

A study conducted in Denmark aimed to determine the short-term effect of NSAID use on the subsequent development of incident HF in patients with T2DM. Using Danish registers, the study recruited 331,189 patients aged 18 to 100 years old (median 62 years, IQR: 52 – 71 years) diagnosed with T2DM from 1998 to 2021. Patients with existing HF history or rheumatic diseases with long-term NSAID use, and patients filling a prescription of NSAIDs 120 days before inclusion were excluded to filter out persistent users. 

The follow-up duration started 120 days after the patient’s diagnosis of T2DM and lasted until their first HF hospitalization, death, or December 31, 2021, whichever was earlier. Exposure to NSAIDs was defined as the use of celecoxib, diclofenac, ibuprofen, or naproxen, as “these are the NSAIDs used primarily in Denmark”.   

The patients served as their own controls, where the index period was day 0 to 28 days before the HF event, and the reference period was 56 to 84 days before the event (day 56 – 84 prior to the HF incident as exposure and day 28 – 56 as the washout for the reference period). 

A total of 23,308 patients with T2DM and no HF history experienced their first HF hospitalization, with 17.2% below the age of 65 years old (n = 4,007), a median age of 76 years old, and 39.3% being females.  

The study found that short-term use of NSAIDs increased the risk of first HF hospitalization (OR: 1.43; 95% CI: 1.27 – 1.63) in a period as short as a month. Subgroups at elevated risks included those above the age of 80 years, elevated haemoglobin (Hb) A1c levels treated with 0 to 1 antidiabetic drug, and those without previous use of NSAIDs (new users). Both subgroups aged < 65 years and 65 – 79 years demonstrated increased risk respectively (OR: 1.14, 95% CI: 0.88 – 1.48; OR: 1.42; 95% CI: 1.19 – 1.71), though the result for the < 65 years subgroup is not statistically significant. 

The researchers also noted that a sizeable 16% of the patients with T2DM filled at least one prescription of NSAIDs, despite T2DM patients being a patient group with a well-established cardiovascular risk. 

Recommendations

As advanced age, HbA1c levels, and being a new user of NSAIDs were associated with the highest risk of developing incident HF hospitalization, these results suggest the need for increased vigilance and closer follow-up [8]. Cardiotoxicity is a class effect, but the magnitude of risk varies between individual NSAID drugs [6], and the extent of pre-existing structural heart disease in patients [8]. Healthcare professionals are therefore advised to continue practising individual risk assessment when using NSAIDs for patients with T2DM [8]. 

References

1. Arun Nanditha, Ronald C.W. Ma, Ambady Ramachandran, Chamukuttan Snehalatha, Juliana C.N. Chan, Kee Seng Chia, Jonathan E. Shaw, Paul Z. Zimmet; Diabetes in Asia and the Pacific: Implications for the Global Epidemic. Diabetes Care 1 March 2016; 39 (3): 472-485. https://doi.org/10.2337/dc15-1536
2. Dunlay SM, Givertz MM, Aguilar D, Allen LA, Chan M, Desai AS, Deswal A, Dickson VV, Kosiborod MN, Lekavich CL, McCoy RG, Mentz RJ, Piña IL; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; and the Heart Failure Society of America. Type 2 Diabetes Mellitus and Heart Failure: A Scientific Statement From the American Heart Association and the Heart Failure Society of America: This statement does not represent an update of the 2017 ACC/AHA/HFSA heart failure guideline update. Circulation. 2019 Aug 13;140(7):e294-e324. doi: 10.1161/CIR.0000000000000691. Epub 2019 Jun 6. Erratum in: Circulation. 2019 Sep 17;140(12):e692. PMID: 31167558
3. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis.Am J Cardiol. 1972; 30:595-602.
4. Echouffo-Tcheugui JB, Xu H, DeVore AD, Schulte PJ, Butler J, Yancy CW, Bhatt DL, Hernandez AF, Heidenreich PA, Fonarow GC. Temporal trends and factors associated with diabetes mellitus among patients hospitalized with heart failure: findings from Get With The Guidelines-Heart Failure registry.Am Heart J. 2016; 182:9–20. doi: 10.1016/j.ahj.2016.07.025
5. Use of non-steroidal anti-inflammatory drugs that elevate cardiovascular risk: an examination of sales and essential medicines lists in low-, middle-, and high-income countries. McGettigan P, Henry D. PLoS Med. 2013;10:1001388.
6. Varga Z, Sabzwari SRA, Vargova V. Cardiovascular Risk of Nonsteroidal Anti-Inflammatory Drugs: An Under-Recognized Public Health Issue. Cureus. 2017 Apr 8;9(4):e1144. doi: 10.7759/cureus.1144. PMID: 28491485; PMCID: PMC5422108.
7. Ghosh R, Alajbegovic A, Gomes AV. NSAIDs and Cardiovascular Diseases: Role of Reactive Oxygen Species. Oxid Med Cell Longev. 2015;2015:536962. doi: 10.1155/2015/536962. Epub 2015 Sep 20. PMID: 26457127; PMCID: PMC4592725.
8. Anders Holt, Jarl E. Strange, Nina Nouhravesh, Sebastian Kinnberg Nielsen, Mariam Elmegaard Malik, Anne-Marie Schjerning, Lars Køber, Christian Torp-Pedersen, Gunnar H. Gislason, Patricia McGettigan, Morten Schou, Morten Lamberts, Heart Failure Following Anti-Inflammatory Medications in Patients With Type 2 Diabetes Mellitus, Journal of the American College of Cardiology, Volume 81, Issue 15, 2023, Pages 1459-1470, ISSN 0735-1097, https://doi.org/10.1016/j.jacc.2023.02.027.