Evidence
Alert

Even low doses of steroids increase the risk of cardiovascular disease in people with inflammatory diseases

People who take steroids to treat long-term inflammatory diseases such as rheumatoid arthritis or inflammatory bowel disease have an increased risk of heart disease, stroke, and other cardiovascular disease. 

New research found that the risk of cardiovascular disease increases with the dose and duration of steroid treatment. A surprising finding was that even low daily doses increase the risk. 

There are few effective treatment options for many inflammatory diseases. Even so, this study suggests that doctors should seek to prescribe the minimum effective dose for the shortest time.  

The researchers also suggest that people taking steroids, even those on low doses, would benefit from regular monitoring and extra support to reduce their risk of cardiovascular disease. With the help of their GP, many people may be able to reduce their risk through lifestyle changes such as stopping smoking or losing weight. 

What’s the issue?

Glucocorticoids are steroids that are commonly prescribed to treat a range of long-term inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. About 1 in 100 people take this medication to reduce inflammation and other symptoms. For some of these diseases, treatment options are limited. 

One known risk of glucocorticoids is that long-term use in high doses may increase a person’s chance of developing cardiovascular disease, including heart disease and stroke. Before this study, the impact of low to moderate doses was less clear. 

The researchers assessed the cardiovascular disease risk in people with six inflammatory diseases taking lower doses of glucocorticoids. 

What’s new?

The researchers analysed the medical records of 87,794 patients treated in 389 primary care practices in the UK between 1998 and 2017. They were 56 years’ old on average and had all been diagnosed with one or more of six inflammatory diseases. These long-term diseases affect different parts of the body and can be debilitating. 

The six diseases and some typical symptoms are:

    • rheumatoid arthritis (pain and stiffness of joints)
    • inflammatory bowel disease (abdominal pain, bloating, diarrhoea)
    • giant cell arteritis (headache, jaw pain and vision problems)
    • polymyalgia rheumatica (pain and stiffness often in shoulders and hips; tiredness, and low mood)
    • lupus (joint pain, tiredness and skin rashes) 
    • vasculitis (skin rash; more seriously, problems with heart, kidney and other organs). 

None of the people in the study had cardiovascular disease when they were first treated for their inflammatory disease. 

The researchers assessed their risk of six common cardiovascular diseases. They considered:

    • atrial fibrillation (irregular heart beat)
    • heart failure (heart is unable to pump blood properly)
    • heart attack 
    • stroke and other diseases affecting blood vessels supplying the brain
    • peripheral arterial disease (reduced blood flow to leg muscles)
    • abdominal aortic aneurysm (swelling in the aorta, the main blood vessel leaving the heart).

Most glucocorticoid prescriptions (96%) were for prednisolone. The study found that the risk of developing all six cardiovascular diseases increased with higher daily dose and duration of prednisolone. This increased risk was present even at a low dose of 5 mg/day. 

After a year of treatment:

    • people taking a daily dose of less than 5 mg prednisolone had twice their original risk of developing cardiovascular disease
    • people taking daily doses of 25 mg or more had six times their original risk of developing cardiovascular disease (increased from 1.4% to 8.9%).

Why is this important?

A low daily dose of prednisolone (5 mg or less) was previously believed to be safe long-term. This study suggests that prednisolone increases the risk of a range of fatal and nonfatal cardiovascular diseases. It concludes that this risk increases with the dose and duration of steroid treatment. People on high doses develop a risk similar to those with diabetes.

The findings highlight how important it is for primary care clinicians to prescribe patients the minimal effective dose of steroids for the shortest duration of time. 

The researchers call on GPs to regularly monitor and help reduce cardiovascular risk for patients taking glucocorticoids, even those on low doses. Many people may be able to reduce their risk by making lifestyle changes such as stopping smoking or losing weight. 

The researchers stress that people currently taking glucocorticoids should not suddenly stop taking them. This can lead to life-threatening complications or flare-ups in their condition. Anyone concerned with taking this medication should speak to their doctor. 

What’s next?

Tools for scoring cardiovascular risk do not take into account glucocorticoid dose. Refining methods of risk prediction may help doctors identify which patients would benefit from taking steps to reduce their risk. 

The study highlights the need for new treatment approaches for long-term inflammatory diseases. These should avoid or minimise long-term glucocorticoid treatment and have less effect on the risk of developing cardiovascular disease.  When new potential therapies are identified, their benefits and risks need to be compared to those resulting from glucocorticoid treatment.

Further research is needed into why glucocorticoids appear to have a negative impact on the cardiovascular system. 

You may be interested to read

The full paper: Pujades-Rodríguez M, and others. Dose-dependent oral glucocorticoid cardiovascular risks in people with immune-mediated inflammatory diseases: a population-based cohort study. PLoS Medicine 2020;17:e1003432 

A paper by the same research group about Type 2 diabetes and glucocorticoid use: Wu J, and others. Glucocorticoid dose-dependent risk of type 2 diabetes in six immune-mediated inflammatory diseases: a population-based cohort analysis. BMJ Open Diabetes Research & Care 2020;8:e001220 

A paper by the same group about hypertension and glucocorticoid use: Mebrahtu TF, and others. Oral glucocorticoids increase the risk of hypertension in people with chronic inflammatory diseases: findings from a population-based cohort study in England. CMAJ 2020;192

Funding: This research was supported by the NIHR Leeds In Vitro Diagnostics Cooperative (NIHR Leeds MIC) and the NIHR Biomedical Research Centre at Leeds. 

Conflicts of Interest: One of the authors has received grants and personal fees from pharmaceutical companies. Another author is employed by IQVIA.

Disclaimer: NIHR Alerts are not a substitute for professional medical advice. They provide information about research which is funded or supported by the NIHR. Please note that views expressed in NIHR Alerts are those of the author(s) and reviewer(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Commentaries

Study author

Previously, it was believed that taking 5 mg glucocorticoid over the long-term was safe, but our findings suggest that even patients taking low doses have double the risk of developing cardiovascular disease. We were surprised to find a strong dose-response for all types of cardiovascular diseases studied, including heart failure, atrial fibrillation, and peripheral arterial disease. 

Targeted intensive interventions to protect cardiovascular health are essential – even when prescribing a low glucocorticoid dose. These interventions should be evaluated.

For some conditions, low-dose steroids may be needed for many months or years. One might expect that glucocorticoids would also reduce inflammation in the heart and blood vessels. Theoretically this would reduce heart attack and stroke (by reducing atherosclerosis, in which blood vessels become clogged up) and heart failure and rhythm disturbances (by reducing inflammation in the heart). 

However, glucocorticoids have many other direct and indirect effects on the cardiovascular system, which could plausibly be detrimental. Our data cannot define these processes but highlight the need to address this important question with further research.

Mar Pujades-Rodríguez, Research Fellow, University of Leeds 

The National Rheumatoid Arthritis Society  

The National Rheumatoid Arthritis Society (NRAS) welcomes this research in highlighting the risk of cardiovascular issues when using even low dose steroids to manage inflammatory arthritis.

The monitoring of CVD risks in those living with rheumatoid arthritis is patchy at best and completely absent at worst. I have had far too many conversations with hundreds of RA patients who are completely unaware of high risk of cardiovascular disease associated with inflammatory arthritis. Then for patients to be put at even greater risk with the use of steroids in their disease management is of great concern. Many people struggle to come off their low dose steroids and have found little or no support to do so. 

There is most definitely a time and a place for glucocorticoids as a bridging therapy or in response to flares in rheumatoid arthritis. But it is unacceptable for people to be left on them for many years. More support on managing pain via lifestyle changes needs to be promoted but busy GP practices can only offer so much. This is where patient organisations can really help with information, support and practical help.

Clare Jacklin, Chief Executive, National Rheumatoid Arthritis Society 

Member of the public 

I have severe respiratory problems and have had to take steroids in the past. I feel strongly that patients should know about any risks associated with their medication. It is their healthcare professionals’, as well as their own responsibility, to learn about these and act accordingly. 

The findings in this paper could prompt conversations between patients and their carers or doctors, and could lead to closer monitoring, dose reduction or even a change in medication if glucocorticoids are not strictly necessary. 

From personal experience, repeat prescription systems at GP clinics do not always monitor patients’ current list of medications and sometimes mean patients receive medications or doses they no longer need. Repeat prescription systems could be improved so that patients do not receive steroids after clinicians have adjusted or halted their prescription. 

The information in these findings could be included in leaflets at clinics, and/or shared with patients verbally by their carer or doctor.

Laura Zabala Findlay, Public contributor, Aberdeen

Clinician 

Findings from the study are likely to encourage corticosteroid sparing strategies for the management of immune-mediated inflammatory disease including those patients on relatively low doses of glucocorticoid.

The findings also confirm the importance of careful monitoring for cardiovascular disease in these conditions, especially in patients receiving corticosteroid therapy.

Neil McHugh, Head of the Department of Pharmacy & Pharmacology, University of Bath