Corticosteroids even short term increase adverse events

Corticosteroids, prescribed for as many as one in five Americans in commercial insurance plans, can significantly increase the risk for adverse effects even when given short term, as found in a study recently published in BMJ (British Medical Journal). The authors note that though the severe adverse effects of longer term use or oral corticosteroids is well known, little has been understood about short term risks.

“…long term use of corticosteroids is generally avoided, given the risks of serious acute complications such as infection, venous thromboembolism, avascular necrosis, and fracture, as well as chronic diseases such as diabetes mellitus, hypertension, osteoporosis, and other features of iatrogenic Cushing’s syndrome…Indeed, corticosteroids are one of the most common reasons for admission to hospital for drug related adverse events…In contrast with long term use, however, the risk of complications from short term use is much less understood, and evidence is generally insufficient to guide clinicians.”

Corticosteroids often used where evidence is lacking

Until now little is know about the potential harms of short term use for the range of outpatient conditions for which they are often prescribed.

“…anecdotally corticosteroids are also used often in the short term to treat many other prevalent conditions where evidence is lacking, such as non-specific musculoskeletal pain and rashes. Despite such pervasive indications for use of oral corticosteroids, little is known about the prescribing patterns of short term use of these drugs in the general adult population, or their potential harm.”

Thus they set out to correlate short term use in an outpatient population and the risk of acute adverse events by analyzing data for 1,548,945 subjects who were prescribed oral corticosteroids for less than 30 days (non-oral forms were excluded from this study).

“We chose three acute events listed as adverse events on the Food and Drug Administration mandated drug label for oral corticosteroids (sepsis, venous thromboembolism, fracture). Given the inherent challenges related to confounding, we employed a self controlled case series (SCCS) design. This design has been used to examine drug and vaccine safety.”

The most common prescription was a six day methylprednisolone “dosepak”, most commonly given for upper respiratory tract infections, spinal conditions, and intervertebral disc disorders, allergies, bronchitis, and (non-bronchitic) lower respiratory tract disorders by family medicine and general internal medicine practitioners, but also by specialists in emergency medicine, otolaryngology, and orthopedics.

Significantly higher rates of sepsis, venous thromboembolism, and fracture

The authors identified a serious risk:

“Within 30 days of drug initiation, there was an increase in rates of sepsis (incidence rate ratio 5.30, 95% confidence interval 3.80 to 7.41), venous thromboembolism (3.33, 2.78 to 3.99), and fracture (1.87, 1.69 to 2.07), which diminished over the subsequent 31-90 days. The increased risk persisted at prednisone equivalent doses of less than 20 mg/day (incidence rate ratio 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P<0.001).”

It defies common sense to use an agent that suppresses the immune system during an infection in all but the rare cases of severe immune excess, especially when there are numerous, more benign alternatives.

Quoted in Medscape Family Medicine, lead author Akbar K. Waljee, MD, an assistant professor of gastroenterology at the University of Michigan in Ann Arbor, states:

“On the basis of these findings, Dr Waljee recommended prescribing the smallest possible amount of corticosteroids for treating the condition in question. “If there are alternatives to steroids, we should be use those when possible,” he said in the release. “Steroids may work faster, but they aren’t as risk-free as you might think.”

From the study:

  • This study of 1.5 million privately insured adults (18-64 years) in the US found that one in five patients in an outpatient setting used short term oral corticosteroid over a three year period (2012-14)

  • Within 30 days of corticosteroid initiation, the incidence of acute adverse events that result in major morbidity and mortality (sepsis, venous thromboembolism, fracture) increased by twofold, to fivefold above background rates

  • Greater attention to initiating prescriptions of these drugs and monitoring for adverse events may potentially improve patient safety

The authors conclude:

“Oral corticosteroids are frequently prescribed for short term use in the US for a variety of common conditions and by numerous provider specialties. Over a three year period, approximately one in five American adults in a commercially insured plan used oral corticosteroids for less than 30 days. The short term use of these drugs was associated with increased rates of sepsis, venous thromboembolism, and fracture; even at relatively low doses.”

Adrenal suppression by inhaled steroids is common

European Journal of EndocrinologyInhaled steroids (glucocorticoids/corticosteroids) are commonly prescribed for asthma but their systemic effect is often overlooked. A clinical study just published in the European Journal of Endocrinology offers evidence that inhaled steroids such as fluticasone (Flovent®), budesonide (Pulmicort®), and beclomethasone (Qvar®) frequently cause serious adrenal suppression. They also show that simply measuring morning cortisol can help indicate whether adrenal insufficiency is occurring. The authors state:

“Up to 3% of US & UK populations are prescribed glucocorticoids (GC). Suppression of the hypothalamo-pituitary-adrenal axis with the potential risk of adrenal crisis is a recognized complication of therapy.”

A better way to measure adrenal suppression due to inhaled steroids

The definitive test for adrenal failure or insufficiency due to autoimmunity (Addison’s disease), oral or inhaled steroids is stimulate the adrenals with ACTH (adrenocorticotropic hormone, known as Synacthen.cosyntropin, and tetracosactide), then measure after 30 and 60 minutes the amount of cortisol produced. This is inconvenient and costly as a screening test for patients using inhaled steroids.

“The 250_g short Synacthen stimulation test (SST) is the most commonly used dynamic assessment to diagnose adrenal insufficiency. There are challenges to the use of the SST in routine clinical practice, including both the staff and time constraints and a significant recent increase in Synacthen cost.”

So the authors investigated to determine whether measuring morning cortisol could be validated as a quicker and easier assessment.

“We performed a retrospective analysis to determine the prevalence of adrenal suppression due to prescribed GCs and the utility of a morning serum cortisol for rapid assessment of adrenal reserve in the routine clinical setting.”

Inhaled steroids suppress adrenal function in a dose dependent manner

In their data 20% of patients on inhaled steroids had adrenal suppression as shown by Synacthen stimulation:

“2773 patients underwent 3603 SSTs in a large secondary/tertiary centre between 2008-2013 and 17.9% (n=496) failed the SST. Of 404 patients taking oral, topical, intranasal or inhaled GC therapy for non-endocrine conditions, 33.2% (n=134) had a subnormal SST response. In patients taking inhaled GCs, without additional GC therapy, 20.5% (34/166) failed an SST and suppression of adrenal function increased in a dose-dependent fashion.”

Moreover, this did in fact correspond to the morning cortisol measurements:

“Using receiver operating characteristic curve analysis in patients currently taking inhaled GCs, a basal cortisol ≥348nmol/L provided 100% specificity for passing the SST; a cortisol value <34nmol/L had 100% sensitivity for SST failure. Using these cut-offs, 50% (n=83) of SSTs performed on patients prescribed inhaled GCs were unnecessary.”

Clinical implications

Too often patients are left in the dark about the systemic effects of inhaled steroids. This helpful study reminds practitioners that there can be global adverse effects stemming from adrenal suppression with possible long-term consequences for case management of a wide variety of disorders; and that this can be screened by simply measuring morning cortisol. The authors conclude:

Adrenal suppression due to GC treatment, particularly inhaled GCs, is common. A basal serum cortisol concentration has utility in helping determine, which patients should undergo dynamic assessment of adrenal function.”

Do inhaled corticosteroids for asthma increase diabetes risk?

Oral corticosteroids such as prednisone have well-known side effects that include increased insulin resistance and risk for diabetes, but what if they are inhaled for chronic inflammatory respiratory conditions such as asthma? A study recently published in The American Journal of Medicine addresses this question. The authors first observe:

“Systemic corticosteroids are known to increase diabetes risk, but the effects of high-dose inhaled corticosteroids are unknown. We assessed whether the use and dose of inhaled corticosteroids increase the risk of diabetes onset and progression.”

The authors examined a cohort of 388,584 patients treated for respiratory disease during 1990-2005, then followed them through 2007 or until diabetes onset. (A subcohort treated with oral blood sugar lowering medication was followed until they developed diabetes.) They evaluated their data to estimate the rate ratios of diabetes onset and progression associated with ‘current’ inhaled corticosteroid use and adjusted for the relevant variables. Their data showed that among their study cohort…

“…30,167 had diabetes onset during 5.5 years of follow-up (incidence rate 14.2/1000/year), and 2099 subsequently progressed from oral hypoglycemic treatment to insulin (incidence rate 19.8/1000/year). Current use of inhaled corticosteroids was associated with a 34% increase in the rate of diabetes and in the rate of diabetes progression. The risk increases were greatest with the highest inhaled corticosteroid doses, equivalent to fluticasone 1000 μg per day or more.”

The authors’ conclusion should be considered not only for the case management of asthma (before significant markers for pre-diabetes and diabetes emerge), but for the metabolic and endocrine effects beyond respiratory disease:

In patients with respiratory disease, inhaled corticosteroid use is associated with modest increases in the risks of diabetes onset and diabetes progression. The risks are more pronounced at the higher doses currently prescribed in the treatment of chronic obstructive pulmonary disease.”