Endocrinology

Thyroid storm is a life-threatening endocrine emergency for which, remarkably, there are no definitive diagnostic tests, and the management of which is supported by a startlingly weak evidence base.

“What’s tricky is there really are no specific biochemical level cutoffs for thyroid storm, and also no unique laboratory abnormalities. So in the end, it’s a clinical diagnosis and a clinical judgment,” Stephanie B. Mayer, MD, MHSc, observed at HM20 Virtual, hosted by the Society of Hospital Medicine.

Moreover, there are no prospective clinical trials addressing the treatment of thyroid storm, and the 2016 American Thyroid Association clinical practice guidelines on the topic are based upon low-quality evidence from case reports and studies dating back to the 1970s and 1980s. UpToDate reached the same conclusion in 2020, noted Dr. Mayer, an endocrinologist at Virginia Commonwealth University, Richmond.

Thinking that perhaps the guideline writing panel had missed something, she asked a university medical research librarian to custom-build a comprehensive search for studies on thyroid storm management. The search proved unrewarding.

“The evidence is, unfortunately, a little disappointing,” Dr. Mayer said.

Thyroid storm is a rare condition, but one that hospitalists must be ready for. She highlighted current best practices in diagnosis and management.
 

A high-mortality emergency

Thyroid storm is an extreme manifestation of thyrotoxicosis, which is marked by multiorgan dysfunction and rapid decompensation. In a large, first-of-its-kind, national retrospective U.S. study, the incidence of thyroid storm was 0.57-0.76 cases per 100,000 persons per year. Thyroid storm accounted for 16% of the more than 121,000 hospital discharges featuring a primary diagnosis of thyrotoxicosis. The in-hospital mortality rate for patients with thyroid storm was 1.2%-3.6% during the 10-year study period, a rate 12-fold higher than that among patients with thyrotoxicosis without thyroid storm (Thyroid. 2019 Jan;29[1]:36-43).

Dr. Mayer highlighted a multicenter French study that underscored the current hefty morbidity and mortality associated with thyroid storm. Among 92 patients admitted to the ICU for thyroid storm, the in-ICU mortality rate was 17%, and the mortality rate 6 months after admission was 22%. Independent risk factors for in-ICU mortality were multiorgan failure and the occurrence of cardiogenic shock within the first 48 hours in the ICU (Crit Care Med. 2020 Jan;48[1]:83-90).
 

How to recognize thyroid storm

The most user-friendly system for assistance in diagnosing thyroid storm is the one put forth by the Japan Thyroid Association and the Japan Endocrine Society, in Dr. Mayer’s view. As a prerequisite to the diagnosis a patient must have thyrotoxicosis as evidenced by elevated free thyroxine (free T4) and free or total triiodothyronine (T3), which in the vast majority of cases, is accompanied by low thyroid stimulating hormone (TSH).

The Japanese diagnostic system for thyroid storm relies on five categories of organ system–based clinical features. This approach places greater weight on disturbances of consciousness – restlessness, delirium, agitation, psychosis, lethargy, coma – than the other four components, which consist of fever of at least 100.4° F, tachycardia of 130 or more beats per minute, heart failure signs and symptoms, and gastrointestinal/hepatic involvement as evidenced by nausea, vomiting, hyperdefecation, and/or a total bilirubin level of 3.0 mg/dL or more.

The Japanese approach offers two paths to a definite diagnosis of thyroid storm. One requires at least one CNS manifestation plus symptoms drawn from any one of the other four categories. The other route, for patients without evident CNS symptoms, requires the presence of symptoms from at least three of the other four categories.

A patient is categorized as having suspected rather than definite thyroid storm if the CNS criterion isn’t met but any two of the others are. A patient also qualifies for suspected thyroid storm when CNS manifestations plus symptoms from at least one other category are present, but thyroid hormone levels aren’t available (Endocr J. 2016 Dec 30;63[12]:1025-64).

Management of thyroid storm

There is usually a precipitating event that drives the transition from smoldering thyrotoxicosis to thyroid storm.

“The big thing is to look for and treat the underlying precipitating event,” the endocrinologist stressed.

It’s often a systemic insult: severe infection, trauma, surgery, an acute MI, diabetic ketoacidosis, pulmonary embolism, or perhaps having just gone through labor. Iodine exposure in the form of IV contrast or taking amiodarone, which contains 37% iodine by weight, can also fan thyrotoxicosis into thyroid storm. Abrupt discontinuation of antithyroid medication is another common cause.

Fluid and electrolyte replacement, oxygen if appropriate, cooling blankets, and other supportive measures are also important.

Medical management targets multiple steps in thyroid hormone production and action to quell thyroid storm. The first order of business is to inhibit synthesis of new thyroid hormone by prescribing a thioamide. Dr. Mayer favors propylthiouracil over methimazole for this purpose because, not only does it block the thyroid gland from synthesizing new hormone, it also reduces conversion of T4 to T3. Propylthiouracil is usually given orally as a 500- to 1,000-mg loading dose, then 250 mg every 4 hours. The drug can also be given rectally or by nasogastric tube.

One hour or more after starting the thioamide, inorganic iodine is started to inhibit release of preformed hormone from the thyroid gland. Five drops of saturated solution of potassium iodide given every 6 hours is the recommended dose; it provides 764 mg of iodide per day. Lugol’s solution dosed at four to eight drops every 6-8 hours is an effective alternative.

Simultaneous with starting the patient on inorganic iodine, a low-dose beta blocker is introduced to control adrenergic symptoms.

“Propranolol is first line because it also decreases T4 to T3 conversion and it’s noncardioselective, so it’s better than a cardioselective beta blocker at reducing sympathetic tone-related symptoms, such as agitation, fever, and psychosis,” the endocrinologist explained.

At the same time that propranolol at 60-80 mg is given orally every 4 hours and iodine are started, the patient is placed on glucocorticoids as another means of reducing peripheral conversion of T4 to T3. The options are intravenous hydrocortisone at 100-300 mg/day in divided doses or dexamethasone at 2 mg every 6 hours.

Aspirin and NSAIDs should be avoided as antipyretics because they can actually raise T3 and T4 levels. Acetaminophen is the right fever-lowering agent in the setting of thyroid storm.

Dr. Mayer has occasionally had to reach for one of several backup therapies. Prescribing a bile acid sequestrant – 20-30 g/day of cholestyramine or colestipol – will trap thyroid hormone in the intestine, preventing it from recirculating.

“Be careful to dose it away from the other medications,” she cautioned.

Also, therapeutic plasmapheresis is effective at rapidly removing circulating thyroid hormone in patients who don’t show early clinical improvement in response to multipronged medical therapy.

Dr. Mayer offered a couple of final tips to hospitalists regarding thyroid storm: Know who directs plasmapheresis at your hospital, and keep the American Thyroid Association management guidelines handy (Thyroid. 2016 Oct;26[10]:1343-421).

She reported receiving funding from both NovoNordisk and Astra Zeneca.

 

[email protected]

Thyroid storm is a life-threatening endocrine emergency for which, remarkably, there are no definitive diagnostic tests, and the management of which is supported by a startlingly weak evidence base.

“What’s tricky is there really are no specific biochemical level cutoffs for thyroid storm, and also no unique laboratory abnormalities. So in the end, it’s a clinical diagnosis and a clinical judgment,” Stephanie B. Mayer, MD, MHSc, observed at HM20 Virtual, hosted by the Society of Hospital Medicine.

Moreover, there are no prospective clinical trials addressing the treatment of thyroid storm, and the 2016 American Thyroid Association clinical practice guidelines on the topic are based upon low-quality evidence from case reports and studies dating back to the 1970s and 1980s. UpToDate reached the same conclusion in 2020, noted Dr. Mayer, an endocrinologist at Virginia Commonwealth University, Richmond.

Thinking that perhaps the guideline writing panel had missed something, she asked a university medical research librarian to custom-build a comprehensive search for studies on thyroid storm management. The search proved unrewarding.

“The evidence is, unfortunately, a little disappointing,” Dr. Mayer said.

Thyroid storm is a rare condition, but one that hospitalists must be ready for. She highlighted current best practices in diagnosis and management.
 

A high-mortality emergency

Thyroid storm is an extreme manifestation of thyrotoxicosis, which is marked by multiorgan dysfunction and rapid decompensation. In a large, first-of-its-kind, national retrospective U.S. study, the incidence of thyroid storm was 0.57-0.76 cases per 100,000 persons per year. Thyroid storm accounted for 16% of the more than 121,000 hospital discharges featuring a primary diagnosis of thyrotoxicosis. The in-hospital mortality rate for patients with thyroid storm was 1.2%-3.6% during the 10-year study period, a rate 12-fold higher than that among patients with thyrotoxicosis without thyroid storm (Thyroid. 2019 Jan;29[1]:36-43).

Dr. Mayer highlighted a multicenter French study that underscored the current hefty morbidity and mortality associated with thyroid storm. Among 92 patients admitted to the ICU for thyroid storm, the in-ICU mortality rate was 17%, and the mortality rate 6 months after admission was 22%. Independent risk factors for in-ICU mortality were multiorgan failure and the occurrence of cardiogenic shock within the first 48 hours in the ICU (Crit Care Med. 2020 Jan;48[1]:83-90).
 

How to recognize thyroid storm

The most user-friendly system for assistance in diagnosing thyroid storm is the one put forth by the Japan Thyroid Association and the Japan Endocrine Society, in Dr. Mayer’s view. As a prerequisite to the diagnosis a patient must have thyrotoxicosis as evidenced by elevated free thyroxine (free T4) and free or total triiodothyronine (T3), which in the vast majority of cases, is accompanied by low thyroid stimulating hormone (TSH).

The Japanese diagnostic system for thyroid storm relies on five categories of organ system–based clinical features. This approach places greater weight on disturbances of consciousness – restlessness, delirium, agitation, psychosis, lethargy, coma – than the other four components, which consist of fever of at least 100.4° F, tachycardia of 130 or more beats per minute, heart failure signs and symptoms, and gastrointestinal/hepatic involvement as evidenced by nausea, vomiting, hyperdefecation, and/or a total bilirubin level of 3.0 mg/dL or more.

The Japanese approach offers two paths to a definite diagnosis of thyroid storm. One requires at least one CNS manifestation plus symptoms drawn from any one of the other four categories. The other route, for patients without evident CNS symptoms, requires the presence of symptoms from at least three of the other four categories.

A patient is categorized as having suspected rather than definite thyroid storm if the CNS criterion isn’t met but any two of the others are. A patient also qualifies for suspected thyroid storm when CNS manifestations plus symptoms from at least one other category are present, but thyroid hormone levels aren’t available (Endocr J. 2016 Dec 30;63[12]:1025-64).

Management of thyroid storm

There is usually a precipitating event that drives the transition from smoldering thyrotoxicosis to thyroid storm.

“The big thing is to look for and treat the underlying precipitating event,” the endocrinologist stressed.

It’s often a systemic insult: severe infection, trauma, surgery, an acute MI, diabetic ketoacidosis, pulmonary embolism, or perhaps having just gone through labor. Iodine exposure in the form of IV contrast or taking amiodarone, which contains 37% iodine by weight, can also fan thyrotoxicosis into thyroid storm. Abrupt discontinuation of antithyroid medication is another common cause.

Fluid and electrolyte replacement, oxygen if appropriate, cooling blankets, and other supportive measures are also important.

Medical management targets multiple steps in thyroid hormone production and action to quell thyroid storm. The first order of business is to inhibit synthesis of new thyroid hormone by prescribing a thioamide. Dr. Mayer favors propylthiouracil over methimazole for this purpose because, not only does it block the thyroid gland from synthesizing new hormone, it also reduces conversion of T4 to T3. Propylthiouracil is usually given orally as a 500- to 1,000-mg loading dose, then 250 mg every 4 hours. The drug can also be given rectally or by nasogastric tube.

One hour or more after starting the thioamide, inorganic iodine is started to inhibit release of preformed hormone from the thyroid gland. Five drops of saturated solution of potassium iodide given every 6 hours is the recommended dose; it provides 764 mg of iodide per day. Lugol’s solution dosed at four to eight drops every 6-8 hours is an effective alternative.

Simultaneous with starting the patient on inorganic iodine, a low-dose beta blocker is introduced to control adrenergic symptoms.

“Propranolol is first line because it also decreases T4 to T3 conversion and it’s noncardioselective, so it’s better than a cardioselective beta blocker at reducing sympathetic tone-related symptoms, such as agitation, fever, and psychosis,” the endocrinologist explained.

At the same time that propranolol at 60-80 mg is given orally every 4 hours and iodine are started, the patient is placed on glucocorticoids as another means of reducing peripheral conversion of T4 to T3. The options are intravenous hydrocortisone at 100-300 mg/day in divided doses or dexamethasone at 2 mg every 6 hours.

Aspirin and NSAIDs should be avoided as antipyretics because they can actually raise T3 and T4 levels. Acetaminophen is the right fever-lowering agent in the setting of thyroid storm.

Dr. Mayer has occasionally had to reach for one of several backup therapies. Prescribing a bile acid sequestrant – 20-30 g/day of cholestyramine or colestipol – will trap thyroid hormone in the intestine, preventing it from recirculating.

“Be careful to dose it away from the other medications,” she cautioned.

Also, therapeutic plasmapheresis is effective at rapidly removing circulating thyroid hormone in patients who don’t show early clinical improvement in response to multipronged medical therapy.

Dr. Mayer offered a couple of final tips to hospitalists regarding thyroid storm: Know who directs plasmapheresis at your hospital, and keep the American Thyroid Association management guidelines handy (Thyroid. 2016 Oct;26[10]:1343-421).

She reported receiving funding from both NovoNordisk and Astra Zeneca.

 

[email protected]

Thyroid storm is a life-threatening endocrine emergency for which, remarkably, there are no definitive diagnostic tests, and the management of which is supported by a startlingly weak evidence base.

“What’s tricky is there really are no specific biochemical level cutoffs for thyroid storm, and also no unique laboratory abnormalities. So in the end, it’s a clinical diagnosis and a clinical judgment,” Stephanie B. Mayer, MD, MHSc, observed at HM20 Virtual, hosted by the Society of Hospital Medicine.

Moreover, there are no prospective clinical trials addressing the treatment of thyroid storm, and the 2016 American Thyroid Association clinical practice guidelines on the topic are based upon low-quality evidence from case reports and studies dating back to the 1970s and 1980s. UpToDate reached the same conclusion in 2020, noted Dr. Mayer, an endocrinologist at Virginia Commonwealth University, Richmond.

Thinking that perhaps the guideline writing panel had missed something, she asked a university medical research librarian to custom-build a comprehensive search for studies on thyroid storm management. The search proved unrewarding.

“The evidence is, unfortunately, a little disappointing,” Dr. Mayer said.

Thyroid storm is a rare condition, but one that hospitalists must be ready for. She highlighted current best practices in diagnosis and management.
 

A high-mortality emergency

Thyroid storm is an extreme manifestation of thyrotoxicosis, which is marked by multiorgan dysfunction and rapid decompensation. In a large, first-of-its-kind, national retrospective U.S. study, the incidence of thyroid storm was 0.57-0.76 cases per 100,000 persons per year. Thyroid storm accounted for 16% of the more than 121,000 hospital discharges featuring a primary diagnosis of thyrotoxicosis. The in-hospital mortality rate for patients with thyroid storm was 1.2%-3.6% during the 10-year study period, a rate 12-fold higher than that among patients with thyrotoxicosis without thyroid storm (Thyroid. 2019 Jan;29[1]:36-43).

Dr. Mayer highlighted a multicenter French study that underscored the current hefty morbidity and mortality associated with thyroid storm. Among 92 patients admitted to the ICU for thyroid storm, the in-ICU mortality rate was 17%, and the mortality rate 6 months after admission was 22%. Independent risk factors for in-ICU mortality were multiorgan failure and the occurrence of cardiogenic shock within the first 48 hours in the ICU (Crit Care Med. 2020 Jan;48[1]:83-90).
 

How to recognize thyroid storm

The most user-friendly system for assistance in diagnosing thyroid storm is the one put forth by the Japan Thyroid Association and the Japan Endocrine Society, in Dr. Mayer’s view. As a prerequisite to the diagnosis a patient must have thyrotoxicosis as evidenced by elevated free thyroxine (free T4) and free or total triiodothyronine (T3), which in the vast majority of cases, is accompanied by low thyroid stimulating hormone (TSH).

The Japanese diagnostic system for thyroid storm relies on five categories of organ system–based clinical features. This approach places greater weight on disturbances of consciousness – restlessness, delirium, agitation, psychosis, lethargy, coma – than the other four components, which consist of fever of at least 100.4° F, tachycardia of 130 or more beats per minute, heart failure signs and symptoms, and gastrointestinal/hepatic involvement as evidenced by nausea, vomiting, hyperdefecation, and/or a total bilirubin level of 3.0 mg/dL or more.

The Japanese approach offers two paths to a definite diagnosis of thyroid storm. One requires at least one CNS manifestation plus symptoms drawn from any one of the other four categories. The other route, for patients without evident CNS symptoms, requires the presence of symptoms from at least three of the other four categories.

A patient is categorized as having suspected rather than definite thyroid storm if the CNS criterion isn’t met but any two of the others are. A patient also qualifies for suspected thyroid storm when CNS manifestations plus symptoms from at least one other category are present, but thyroid hormone levels aren’t available (Endocr J. 2016 Dec 30;63[12]:1025-64).

Management of thyroid storm

There is usually a precipitating event that drives the transition from smoldering thyrotoxicosis to thyroid storm.

“The big thing is to look for and treat the underlying precipitating event,” the endocrinologist stressed.

It’s often a systemic insult: severe infection, trauma, surgery, an acute MI, diabetic ketoacidosis, pulmonary embolism, or perhaps having just gone through labor. Iodine exposure in the form of IV contrast or taking amiodarone, which contains 37% iodine by weight, can also fan thyrotoxicosis into thyroid storm. Abrupt discontinuation of antithyroid medication is another common cause.

Fluid and electrolyte replacement, oxygen if appropriate, cooling blankets, and other supportive measures are also important.

Medical management targets multiple steps in thyroid hormone production and action to quell thyroid storm. The first order of business is to inhibit synthesis of new thyroid hormone by prescribing a thioamide. Dr. Mayer favors propylthiouracil over methimazole for this purpose because, not only does it block the thyroid gland from synthesizing new hormone, it also reduces conversion of T4 to T3. Propylthiouracil is usually given orally as a 500- to 1,000-mg loading dose, then 250 mg every 4 hours. The drug can also be given rectally or by nasogastric tube.

One hour or more after starting the thioamide, inorganic iodine is started to inhibit release of preformed hormone from the thyroid gland. Five drops of saturated solution of potassium iodide given every 6 hours is the recommended dose; it provides 764 mg of iodide per day. Lugol’s solution dosed at four to eight drops every 6-8 hours is an effective alternative.

Simultaneous with starting the patient on inorganic iodine, a low-dose beta blocker is introduced to control adrenergic symptoms.

“Propranolol is first line because it also decreases T4 to T3 conversion and it’s noncardioselective, so it’s better than a cardioselective beta blocker at reducing sympathetic tone-related symptoms, such as agitation, fever, and psychosis,” the endocrinologist explained.

At the same time that propranolol at 60-80 mg is given orally every 4 hours and iodine are started, the patient is placed on glucocorticoids as another means of reducing peripheral conversion of T4 to T3. The options are intravenous hydrocortisone at 100-300 mg/day in divided doses or dexamethasone at 2 mg every 6 hours.

Aspirin and NSAIDs should be avoided as antipyretics because they can actually raise T3 and T4 levels. Acetaminophen is the right fever-lowering agent in the setting of thyroid storm.

Dr. Mayer has occasionally had to reach for one of several backup therapies. Prescribing a bile acid sequestrant – 20-30 g/day of cholestyramine or colestipol – will trap thyroid hormone in the intestine, preventing it from recirculating.

“Be careful to dose it away from the other medications,” she cautioned.

Also, therapeutic plasmapheresis is effective at rapidly removing circulating thyroid hormone in patients who don’t show early clinical improvement in response to multipronged medical therapy.

Dr. Mayer offered a couple of final tips to hospitalists regarding thyroid storm: Know who directs plasmapheresis at your hospital, and keep the American Thyroid Association management guidelines handy (Thyroid. 2016 Oct;26[10]:1343-421).

She reported receiving funding from both NovoNordisk and Astra Zeneca.

 

[email protected]

Case

A 45-year-old female with moderate persistent asthma is admitted for right lower extremity cellulitis. She has hyponatremia with a sodium of 129 mEq/L and reports a history of longstanding fatigue and lightheadedness on standing. An early morning serum cortisol was 10 mcg/dL, normal per the reference range for the laboratory. Has adrenal insufficiency been excluded in this patient?

Overview

Adrenal insufficiency (AI) is a clinical syndrome characterized by a deficiency of cortisol. Presentation may range from nonspecific symptoms such as fatigue, weight loss, and gastrointestinal concerns to a fulminant adrenal crisis with severe weakness and hypotension (Table 1). The diagnosis of AI is commonly delayed, negatively impacting patients’ quality of life and risking dangerous complications.^1,2

AI can occur due to diseases of the adrenal glands themselves (primary) or impairment of adrenocorticotropin (ACTH) secretion from the pituitary (secondary) or corticotropin-releasing hormone (CRH) secretion from the hypothalamus (tertiary). In the hospital setting, causes of primary AI may include autoimmune disease, infection, metastatic disease, hemorrhage, and adverse medication effects. Secondary and tertiary AI would be of particular concern for patients with traumatic brain injuries or pituitary surgery, but also are seen commonly as a result of adverse medication effects in the hospitalized patient, notably opioids and corticosteroids through suppression the hypothalamic-pituitary-adrenal (HPA) axis and immune checkpoint inhibitors via autoimmune hypophysitis.

Testing for AI in the hospitalized patient presents a host of challenges. Among these are the variability in presentation of different types of AI, high rates of exogenous corticosteroid use, the impact of critical illness on the HPA axis, medical illness altering protein binding of serum cortisol, interfering medications, the variation in assays used by laboratories, and the logistical challenges of obtaining appropriately timed phlebotomy.^2,3
 

Cortisol testing

An intact HPA axis results in ACTH-dependent cortisol release from the adrenal glands. Cortisol secretion exhibits circadian rhythm, with the highest levels in the early morning (6 a.m. to 8 a.m.) and the lowest at night (12 a.m.). It also is pulsatile, which may explain the range of “normal” morning serum cortisol observed in a study of healthy volunteers.³ Note that serum cortisol is equivalent to plasma cortisol in current immunoassays, and will henceforth be called “cortisol” in this paper.³

There are instances when morning cortisol may strongly suggest a diagnosis of AI on its own. A meta-analysis found that morning cortisol of < 5 mcg/dL predicts AI and morning cortisol of > 13 mcg/dL ruled out AI.⁴ The Endocrine Society of America favors dynamic assessment of adrenal function for most patients.²

Historically, the gold standard for assessing dynamic adrenal function has been the insulin tolerance test (ITT), whereby cortisol is measured after inducing hypoglycemia to a blood glucose < 35 mg/dL. ITT is logistically difficult and poses some risk to the patient. The corticotropin (or cosyntropin) stimulation test (CST), in which a supraphysiologic dose of a synthetic ACTH analog is administered parenterally to a patient and resultant cortisol levels are measured, has been validated against the ITT and is generally preferred.⁵ CST is used to diagnose primary AI as well as chronic secondary and tertiary AI, given that longstanding lack of ACTH stimulation causes atrophy of the adrenal glands. The sensitivity for secondary and tertiary AI is likely lower than primary AI especially in acute onset of disease.^6,7

In performance of the CST a baseline cortisol and ACTH are obtained, with subsequent cortisol testing at 30 and/or 60 minutes after administration of the ACTH analog (Figure 1). Currently, there is no consensus for which time point is preferred, but the 30-minute test is more sensitive for AI and the 60-minute test is more specific.^2,7,8

CST is typically performed using a “standard high dose” of 250 mcg of the ACTH analog. There has been interest in the use of a “low-dose” 1 mcg test, which is closer to normal physiologic stimulation of the adrenal glands and may have better sensitivity for early secondary or partial AI. However, the 250-mcg dose is easier to prepare and has fewer technical pitfalls in administration as well as a lower risk for false positive testing. At this point the data do not compellingly favor the use of low-dose CST testing in general practice.^2,3,7
 

Clinical decision making

Diagnostic evaluation should be guided by the likelihood of the disease (i.e., the pretest probability) (Figure 1). Begin with a review of the patient’s signs and symptoms, medical and family history, and medications with special consideration for opioids, exogenous steroids, and immune checkpoint inhibitors (Table 1).

For patients with low pretest probability for AI, morning cortisol and ACTH is a reasonable first test (Figure 1). A cortisol value of 18 mcg/dL or greater does not support AI and no further testing is needed.² Patients with morning cortisol of 13-18 mcg/dL could be followed clinically or could undergo further testing in the inpatient environment with CST, depending upon the clinical scenario.⁴ Patients with serum cortisol of <13 mcg/dL warrant CST.

For patients with moderate to high pretest probability for AI, we recommend initial testing with CST. While the results of high-dose CST are not necessarily impacted by time of day, if an a.m. cortisol has not yet been obtained and it is logistically feasible to do so, performing CST in the morning will provide the most useful data for clinical interpretation.

For patients presenting with possible adrenal crisis, it is essential not to delay treatment. In these patients, obtain a cortisol paired with ACTH and initiate treatment immediately. Further testing can be deferred until the time the patient is stable.²
 

Potential pitfalls

Interpreting cortisol requires awareness of multiple conditions that could directly impact the results.^2,3 (Table 2).

Currently available assays measure “total cortisol,” most of which is protein bound (cortisol-binding globulin as well as albumin). Therefore, conditions that lower serum protein (e.g., nephrotic syndrome, liver disease, inflammation) will lower the measured cortisol. Conversely, conditions that increase serum protein (e.g., estrogen excess in pregnancy and oral contraceptive use) will increase the measured cortisol.^2,3

It is also important to recognize that existing immunoassay testing techniques informed the established cut-off for exclusion of AI at 18 mcg/dL. With newer immunoassays and emerging liquid chromatography/tandem mass spectrometry, this cut-off may be lowered; thus the assay should be confirmed with the performing laboratory. There is emerging evidence that serum or plasma free cortisol and salivary cortisol testing for AI may be useful in certain cases, but these techniques are not yet widespread or included in clinical practice guidelines.^2,3,7
 

Population focus: Patients on exogenous steroids

Exogenous corticosteroids suppress the HPA axis via negative inhibition of CRH and ACTH release, often resulting in low endogenous cortisol levels which may or may not reflect true loss of adrenal function. In addition, many corticosteroids will be detected by standard serum cortisol tests that rely on immunoassays. For this reason, cortisol measurement and CST should be done at least 18-24 hours after the last dose of exogenous steroids.

Although the focus has been on higher doses and longer courses of steroids (e.g., chronic use of ≥ 5 mg prednisone daily, or ≥ 20 mg prednisone daily for > 3 weeks), there is increasing evidence that lower doses, shorter courses, and alternate routes (e.g., inhaled, intra-articular) can result in biochemical and clinical evidence of AI.⁹ Thus, a thorough history and exam should be obtained to determine all recent corticosteroid exposure and cushingoid features.
 

Application of the data to the case

To effectively assess the patient for adrenal insufficiency, we need additional information. First and foremost, is a description of the patient’s current clinical status. If she is demonstrating evidence of adrenal crisis, treatment should not be delayed for additional testing. If she is stable, a thorough history including use of corticosteroids by any route, pregnancy, oral contraceptives, recent surgery, and liver and kidney disease is essential.

Additional evaluation reveals the patient has been using her fluticasone inhaler daily. No other source of hyponatremia or lightheadedness is identified. The patient’s risk factors of corticosteroid use and unexplained hyponatremia with associated lightheadedness increase her pretest probability of AI and a single morning cortisol of 10 mcg/dL is insufficient to exclude adrenal insufficiency. The appropriate follow-up test is a standard high-dose cosyntropin stimulation test at least 18 hours after her last dose of fluticasone. A cortisol level > 18 mcg/dL at 30 minutes in the absence of other conditions that impact cortisol testing would not be suggestive of AI. A serum cortisol level of < 18 mcg/dL at 30 minutes would raise concern for abnormal adrenal reserve due to chronic corticosteroid therapy and would warrant referral to an endocrinologist.
 

Bottom line

An isolated serum cortisol is often insufficient to exclude adrenal insufficiency. Hospitalists should be aware of the many factors that impact the interpretation of this test.

Dr. Gordon is assistant professor of medicine at Tufts University, Boston, and a hospitalist at Maine Medical Center, Portland. She is the subspecialty education coordinator of inpatient medicine for the Internal Medicine Residency Program. Dr. Herrle is assistant professor of medicine at Tufts University and a hospitalist at Maine Medical Center. She is the associate director of medical student education for the department of internal medicine at MMC and a medical director for clinical informatics at MaineHealth.

References

1. Bleicken B et al. Delayed diagnosis of adrenal insufficiency is common: A cross-sectional study in 216 patients. Am J Med Sci. 2010;339(6):525-31. doi: 10.1097/MAJ.0b013e3181db6b7a.

2. Bornstein SR et al. Diagnosis and treatment of primary adrenal insufficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016 Feb;101(2):364-89.

3. El-Farhan N et al. Measuring cortisol in serum, urine and saliva – Are our assays good enough? Ann Clin Biochem. 2017 May;54(3):308-22. doi: 10.1177/0004563216687335.

4. Kazlauskaite R et al. Corticotropin tests for hypothalamic-pituitary-adrenal insufficiency: A metaanalysis. J Clin Endocrinol Metab. 2008;93:4245-53.

5. Wood JB et al. A rapid test of adrenocortical function. Lancet. 1965;191:243-5.

6. Singh Ospina N et al. ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J Clin Endocrinol Metab. 2016;101(2):427-34.

7. Burgos N et al. Pitfalls in the interpretation of the cosyntropin stimulation test for the diagnosis of adrenal insufficiency. Curr Opin Endocrinol Diabetes Obes. 2019;26(3):139-45.

8. Odom DC et al. A Single, post-ACTH cortisol measurement to screen for adrenal insufficiency in the hospitalized patient. J Hosp Med. 2018;13(8):526-30. doi: 10.12788/jhm.2928.

9. Broersen LHA et al. Adrenal insufficiency in corticosteroids use: Systematic review and meta-analysis. J Clin Endocrinol Metab. 2015;100(6): 2171-80.
 

Key points

• In general, random cortisol testing is of limited value and should be avoided.

• Serum cortisol testing in the hospitalized patient is impacted by a variety of patient and disease factors and should be interpreted carefully.

• For patients with low pretest probability of adrenal insufficiency, early morning serum cortisol testing may be sufficient to exclude the diagnosis.

• For patients with moderate to high pretest probability of adrenal insufficiency, standard high-dose (250 mcg) corticotropin stimulation testing is preferred.
 

Additional reading

Bornstein SR et al. Diagnosis and treatment of primary adrenal insufficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016 Feb;101(2):364-89.

Burgos N et al. Pitfalls in the interpretation of the cosyntropin stimulation test for the diagnosis of adrenal insufficiency. Curr Opin Endocrinol Diabetes Obes. 2019;26(3):139-45.
 

Quiz

An 82 y.o. woman with depression is admitted from her long-term care facility with worsening weakness and mild hypoglycemia. Her supine vital signs are stable, but she exhibits a drop in systolic blood pressure of 21 mm Hg upon standing. There is no evidence of infection by history, exam, or initial workup. She is not on chronic corticosteroids by any route.

What would be your initial workup for adrenal insufficiency?

A) Morning serum cortisol and ACTH

B) Insulin tolerance test

C) Corticotropin stimulation test

D) Would not test at this point

Answer: C. Although her symptom of weakness is nonspecific, her hypoglycemia and orthostatic hypotension are concerning enough that she would qualify as moderate to high pretest probability for AI. In this setting, one would acquire a basal serum total cortisol and ACTH then administer the standard high-dose corticotropin stimulation test (250 mcg) followed by repeat serum total cortisol at 30 or 60 minutes.

Case

A 45-year-old female with moderate persistent asthma is admitted for right lower extremity cellulitis. She has hyponatremia with a sodium of 129 mEq/L and reports a history of longstanding fatigue and lightheadedness on standing. An early morning serum cortisol was 10 mcg/dL, normal per the reference range for the laboratory. Has adrenal insufficiency been excluded in this patient?

Overview

Adrenal insufficiency (AI) is a clinical syndrome characterized by a deficiency of cortisol. Presentation may range from nonspecific symptoms such as fatigue, weight loss, and gastrointestinal concerns to a fulminant adrenal crisis with severe weakness and hypotension (Table 1). The diagnosis of AI is commonly delayed, negatively impacting patients’ quality of life and risking dangerous complications.^1,2

AI can occur due to diseases of the adrenal glands themselves (primary) or impairment of adrenocorticotropin (ACTH) secretion from the pituitary (secondary) or corticotropin-releasing hormone (CRH) secretion from the hypothalamus (tertiary). In the hospital setting, causes of primary AI may include autoimmune disease, infection, metastatic disease, hemorrhage, and adverse medication effects. Secondary and tertiary AI would be of particular concern for patients with traumatic brain injuries or pituitary surgery, but also are seen commonly as a result of adverse medication effects in the hospitalized patient, notably opioids and corticosteroids through suppression the hypothalamic-pituitary-adrenal (HPA) axis and immune checkpoint inhibitors via autoimmune hypophysitis.

Testing for AI in the hospitalized patient presents a host of challenges. Among these are the variability in presentation of different types of AI, high rates of exogenous corticosteroid use, the impact of critical illness on the HPA axis, medical illness altering protein binding of serum cortisol, interfering medications, the variation in assays used by laboratories, and the logistical challenges of obtaining appropriately timed phlebotomy.^2,3
 

Cortisol testing

An intact HPA axis results in ACTH-dependent cortisol release from the adrenal glands. Cortisol secretion exhibits circadian rhythm, with the highest levels in the early morning (6 a.m. to 8 a.m.) and the lowest at night (12 a.m.). It also is pulsatile, which may explain the range of “normal” morning serum cortisol observed in a study of healthy volunteers.³ Note that serum cortisol is equivalent to plasma cortisol in current immunoassays, and will henceforth be called “cortisol” in this paper.³

There are instances when morning cortisol may strongly suggest a diagnosis of AI on its own. A meta-analysis found that morning cortisol of < 5 mcg/dL predicts AI and morning cortisol of > 13 mcg/dL ruled out AI.⁴ The Endocrine Society of America favors dynamic assessment of adrenal function for most patients.²

Historically, the gold standard for assessing dynamic adrenal function has been the insulin tolerance test (ITT), whereby cortisol is measured after inducing hypoglycemia to a blood glucose < 35 mg/dL. ITT is logistically difficult and poses some risk to the patient. The corticotropin (or cosyntropin) stimulation test (CST), in which a supraphysiologic dose of a synthetic ACTH analog is administered parenterally to a patient and resultant cortisol levels are measured, has been validated against the ITT and is generally preferred.⁵ CST is used to diagnose primary AI as well as chronic secondary and tertiary AI, given that longstanding lack of ACTH stimulation causes atrophy of the adrenal glands. The sensitivity for secondary and tertiary AI is likely lower than primary AI especially in acute onset of disease.^6,7

In performance of the CST a baseline cortisol and ACTH are obtained, with subsequent cortisol testing at 30 and/or 60 minutes after administration of the ACTH analog (Figure 1). Currently, there is no consensus for which time point is preferred, but the 30-minute test is more sensitive for AI and the 60-minute test is more specific.^2,7,8

CST is typically performed using a “standard high dose” of 250 mcg of the ACTH analog. There has been interest in the use of a “low-dose” 1 mcg test, which is closer to normal physiologic stimulation of the adrenal glands and may have better sensitivity for early secondary or partial AI. However, the 250-mcg dose is easier to prepare and has fewer technical pitfalls in administration as well as a lower risk for false positive testing. At this point the data do not compellingly favor the use of low-dose CST testing in general practice.^2,3,7
 

Clinical decision making

Diagnostic evaluation should be guided by the likelihood of the disease (i.e., the pretest probability) (Figure 1). Begin with a review of the patient’s signs and symptoms, medical and family history, and medications with special consideration for opioids, exogenous steroids, and immune checkpoint inhibitors (Table 1).

For patients with low pretest probability for AI, morning cortisol and ACTH is a reasonable first test (Figure 1). A cortisol value of 18 mcg/dL or greater does not support AI and no further testing is needed.² Patients with morning cortisol of 13-18 mcg/dL could be followed clinically or could undergo further testing in the inpatient environment with CST, depending upon the clinical scenario.⁴ Patients with serum cortisol of <13 mcg/dL warrant CST.

For patients with moderate to high pretest probability for AI, we recommend initial testing with CST. While the results of high-dose CST are not necessarily impacted by time of day, if an a.m. cortisol has not yet been obtained and it is logistically feasible to do so, performing CST in the morning will provide the most useful data for clinical interpretation.

For patients presenting with possible adrenal crisis, it is essential not to delay treatment. In these patients, obtain a cortisol paired with ACTH and initiate treatment immediately. Further testing can be deferred until the time the patient is stable.²
 

Potential pitfalls

Interpreting cortisol requires awareness of multiple conditions that could directly impact the results.^2,3 (Table 2).

Currently available assays measure “total cortisol,” most of which is protein bound (cortisol-binding globulin as well as albumin). Therefore, conditions that lower serum protein (e.g., nephrotic syndrome, liver disease, inflammation) will lower the measured cortisol. Conversely, conditions that increase serum protein (e.g., estrogen excess in pregnancy and oral contraceptive use) will increase the measured cortisol.^2,3

It is also important to recognize that existing immunoassay testing techniques informed the established cut-off for exclusion of AI at 18 mcg/dL. With newer immunoassays and emerging liquid chromatography/tandem mass spectrometry, this cut-off may be lowered; thus the assay should be confirmed with the performing laboratory. There is emerging evidence that serum or plasma free cortisol and salivary cortisol testing for AI may be useful in certain cases, but these techniques are not yet widespread or included in clinical practice guidelines.^2,3,7
 

Population focus: Patients on exogenous steroids

Exogenous corticosteroids suppress the HPA axis via negative inhibition of CRH and ACTH release, often resulting in low endogenous cortisol levels which may or may not reflect true loss of adrenal function. In addition, many corticosteroids will be detected by standard serum cortisol tests that rely on immunoassays. For this reason, cortisol measurement and CST should be done at least 18-24 hours after the last dose of exogenous steroids.

Although the focus has been on higher doses and longer courses of steroids (e.g., chronic use of ≥ 5 mg prednisone daily, or ≥ 20 mg prednisone daily for > 3 weeks), there is increasing evidence that lower doses, shorter courses, and alternate routes (e.g., inhaled, intra-articular) can result in biochemical and clinical evidence of AI.⁹ Thus, a thorough history and exam should be obtained to determine all recent corticosteroid exposure and cushingoid features.
 

Application of the data to the case

To effectively assess the patient for adrenal insufficiency, we need additional information. First and foremost, is a description of the patient’s current clinical status. If she is demonstrating evidence of adrenal crisis, treatment should not be delayed for additional testing. If she is stable, a thorough history including use of corticosteroids by any route, pregnancy, oral contraceptives, recent surgery, and liver and kidney disease is essential.

Additional evaluation reveals the patient has been using her fluticasone inhaler daily. No other source of hyponatremia or lightheadedness is identified. The patient’s risk factors of corticosteroid use and unexplained hyponatremia with associated lightheadedness increase her pretest probability of AI and a single morning cortisol of 10 mcg/dL is insufficient to exclude adrenal insufficiency. The appropriate follow-up test is a standard high-dose cosyntropin stimulation test at least 18 hours after her last dose of fluticasone. A cortisol level > 18 mcg/dL at 30 minutes in the absence of other conditions that impact cortisol testing would not be suggestive of AI. A serum cortisol level of < 18 mcg/dL at 30 minutes would raise concern for abnormal adrenal reserve due to chronic corticosteroid therapy and would warrant referral to an endocrinologist.
 

Bottom line

An isolated serum cortisol is often insufficient to exclude adrenal insufficiency. Hospitalists should be aware of the many factors that impact the interpretation of this test.

Dr. Gordon is assistant professor of medicine at Tufts University, Boston, and a hospitalist at Maine Medical Center, Portland. She is the subspecialty education coordinator of inpatient medicine for the Internal Medicine Residency Program. Dr. Herrle is assistant professor of medicine at Tufts University and a hospitalist at Maine Medical Center. She is the associate director of medical student education for the department of internal medicine at MMC and a medical director for clinical informatics at MaineHealth.

References

1. Bleicken B et al. Delayed diagnosis of adrenal insufficiency is common: A cross-sectional study in 216 patients. Am J Med Sci. 2010;339(6):525-31. doi: 10.1097/MAJ.0b013e3181db6b7a.

2. Bornstein SR et al. Diagnosis and treatment of primary adrenal insufficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016 Feb;101(2):364-89.

3. El-Farhan N et al. Measuring cortisol in serum, urine and saliva – Are our assays good enough? Ann Clin Biochem. 2017 May;54(3):308-22. doi: 10.1177/0004563216687335.

4. Kazlauskaite R et al. Corticotropin tests for hypothalamic-pituitary-adrenal insufficiency: A metaanalysis. J Clin Endocrinol Metab. 2008;93:4245-53.

5. Wood JB et al. A rapid test of adrenocortical function. Lancet. 1965;191:243-5.

6. Singh Ospina N et al. ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J Clin Endocrinol Metab. 2016;101(2):427-34.

7. Burgos N et al. Pitfalls in the interpretation of the cosyntropin stimulation test for the diagnosis of adrenal insufficiency. Curr Opin Endocrinol Diabetes Obes. 2019;26(3):139-45.

8. Odom DC et al. A Single, post-ACTH cortisol measurement to screen for adrenal insufficiency in the hospitalized patient. J Hosp Med. 2018;13(8):526-30. doi: 10.12788/jhm.2928.

9. Broersen LHA et al. Adrenal insufficiency in corticosteroids use: Systematic review and meta-analysis. J Clin Endocrinol Metab. 2015;100(6): 2171-80.
 

Key points

• In general, random cortisol testing is of limited value and should be avoided.

• Serum cortisol testing in the hospitalized patient is impacted by a variety of patient and disease factors and should be interpreted carefully.

• For patients with low pretest probability of adrenal insufficiency, early morning serum cortisol testing may be sufficient to exclude the diagnosis.

• For patients with moderate to high pretest probability of adrenal insufficiency, standard high-dose (250 mcg) corticotropin stimulation testing is preferred.
 

Additional reading

Bornstein SR et al. Diagnosis and treatment of primary adrenal insufficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016 Feb;101(2):364-89.

Burgos N et al. Pitfalls in the interpretation of the cosyntropin stimulation test for the diagnosis of adrenal insufficiency. Curr Opin Endocrinol Diabetes Obes. 2019;26(3):139-45.
 

Quiz

An 82 y.o. woman with depression is admitted from her long-term care facility with worsening weakness and mild hypoglycemia. Her supine vital signs are stable, but she exhibits a drop in systolic blood pressure of 21 mm Hg upon standing. There is no evidence of infection by history, exam, or initial workup. She is not on chronic corticosteroids by any route.

What would be your initial workup for adrenal insufficiency?

A) Morning serum cortisol and ACTH

B) Insulin tolerance test

C) Corticotropin stimulation test

D) Would not test at this point

Answer: C. Although her symptom of weakness is nonspecific, her hypoglycemia and orthostatic hypotension are concerning enough that she would qualify as moderate to high pretest probability for AI. In this setting, one would acquire a basal serum total cortisol and ACTH then administer the standard high-dose corticotropin stimulation test (250 mcg) followed by repeat serum total cortisol at 30 or 60 minutes.

Case

A 45-year-old female with moderate persistent asthma is admitted for right lower extremity cellulitis. She has hyponatremia with a sodium of 129 mEq/L and reports a history of longstanding fatigue and lightheadedness on standing. An early morning serum cortisol was 10 mcg/dL, normal per the reference range for the laboratory. Has adrenal insufficiency been excluded in this patient?

Overview

Adrenal insufficiency (AI) is a clinical syndrome characterized by a deficiency of cortisol. Presentation may range from nonspecific symptoms such as fatigue, weight loss, and gastrointestinal concerns to a fulminant adrenal crisis with severe weakness and hypotension (Table 1). The diagnosis of AI is commonly delayed, negatively impacting patients’ quality of life and risking dangerous complications.^1,2

AI can occur due to diseases of the adrenal glands themselves (primary) or impairment of adrenocorticotropin (ACTH) secretion from the pituitary (secondary) or corticotropin-releasing hormone (CRH) secretion from the hypothalamus (tertiary). In the hospital setting, causes of primary AI may include autoimmune disease, infection, metastatic disease, hemorrhage, and adverse medication effects. Secondary and tertiary AI would be of particular concern for patients with traumatic brain injuries or pituitary surgery, but also are seen commonly as a result of adverse medication effects in the hospitalized patient, notably opioids and corticosteroids through suppression the hypothalamic-pituitary-adrenal (HPA) axis and immune checkpoint inhibitors via autoimmune hypophysitis.

Testing for AI in the hospitalized patient presents a host of challenges. Among these are the variability in presentation of different types of AI, high rates of exogenous corticosteroid use, the impact of critical illness on the HPA axis, medical illness altering protein binding of serum cortisol, interfering medications, the variation in assays used by laboratories, and the logistical challenges of obtaining appropriately timed phlebotomy.^2,3
 

Cortisol testing

An intact HPA axis results in ACTH-dependent cortisol release from the adrenal glands. Cortisol secretion exhibits circadian rhythm, with the highest levels in the early morning (6 a.m. to 8 a.m.) and the lowest at night (12 a.m.). It also is pulsatile, which may explain the range of “normal” morning serum cortisol observed in a study of healthy volunteers.³ Note that serum cortisol is equivalent to plasma cortisol in current immunoassays, and will henceforth be called “cortisol” in this paper.³

There are instances when morning cortisol may strongly suggest a diagnosis of AI on its own. A meta-analysis found that morning cortisol of < 5 mcg/dL predicts AI and morning cortisol of > 13 mcg/dL ruled out AI.⁴ The Endocrine Society of America favors dynamic assessment of adrenal function for most patients.²

Historically, the gold standard for assessing dynamic adrenal function has been the insulin tolerance test (ITT), whereby cortisol is measured after inducing hypoglycemia to a blood glucose < 35 mg/dL. ITT is logistically difficult and poses some risk to the patient. The corticotropin (or cosyntropin) stimulation test (CST), in which a supraphysiologic dose of a synthetic ACTH analog is administered parenterally to a patient and resultant cortisol levels are measured, has been validated against the ITT and is generally preferred.⁵ CST is used to diagnose primary AI as well as chronic secondary and tertiary AI, given that longstanding lack of ACTH stimulation causes atrophy of the adrenal glands. The sensitivity for secondary and tertiary AI is likely lower than primary AI especially in acute onset of disease.^6,7

In performance of the CST a baseline cortisol and ACTH are obtained, with subsequent cortisol testing at 30 and/or 60 minutes after administration of the ACTH analog (Figure 1). Currently, there is no consensus for which time point is preferred, but the 30-minute test is more sensitive for AI and the 60-minute test is more specific.^2,7,8

CST is typically performed using a “standard high dose” of 250 mcg of the ACTH analog. There has been interest in the use of a “low-dose” 1 mcg test, which is closer to normal physiologic stimulation of the adrenal glands and may have better sensitivity for early secondary or partial AI. However, the 250-mcg dose is easier to prepare and has fewer technical pitfalls in administration as well as a lower risk for false positive testing. At this point the data do not compellingly favor the use of low-dose CST testing in general practice.^2,3,7
 

Clinical decision making

Diagnostic evaluation should be guided by the likelihood of the disease (i.e., the pretest probability) (Figure 1). Begin with a review of the patient’s signs and symptoms, medical and family history, and medications with special consideration for opioids, exogenous steroids, and immune checkpoint inhibitors (Table 1).

For patients with low pretest probability for AI, morning cortisol and ACTH is a reasonable first test (Figure 1). A cortisol value of 18 mcg/dL or greater does not support AI and no further testing is needed.² Patients with morning cortisol of 13-18 mcg/dL could be followed clinically or could undergo further testing in the inpatient environment with CST, depending upon the clinical scenario.⁴ Patients with serum cortisol of <13 mcg/dL warrant CST.

For patients with moderate to high pretest probability for AI, we recommend initial testing with CST. While the results of high-dose CST are not necessarily impacted by time of day, if an a.m. cortisol has not yet been obtained and it is logistically feasible to do so, performing CST in the morning will provide the most useful data for clinical interpretation.

For patients presenting with possible adrenal crisis, it is essential not to delay treatment. In these patients, obtain a cortisol paired with ACTH and initiate treatment immediately. Further testing can be deferred until the time the patient is stable.²
 

Potential pitfalls

Interpreting cortisol requires awareness of multiple conditions that could directly impact the results.^2,3 (Table 2).

Currently available assays measure “total cortisol,” most of which is protein bound (cortisol-binding globulin as well as albumin). Therefore, conditions that lower serum protein (e.g., nephrotic syndrome, liver disease, inflammation) will lower the measured cortisol. Conversely, conditions that increase serum protein (e.g., estrogen excess in pregnancy and oral contraceptive use) will increase the measured cortisol.^2,3

It is also important to recognize that existing immunoassay testing techniques informed the established cut-off for exclusion of AI at 18 mcg/dL. With newer immunoassays and emerging liquid chromatography/tandem mass spectrometry, this cut-off may be lowered; thus the assay should be confirmed with the performing laboratory. There is emerging evidence that serum or plasma free cortisol and salivary cortisol testing for AI may be useful in certain cases, but these techniques are not yet widespread or included in clinical practice guidelines.^2,3,7
 

Population focus: Patients on exogenous steroids

Exogenous corticosteroids suppress the HPA axis via negative inhibition of CRH and ACTH release, often resulting in low endogenous cortisol levels which may or may not reflect true loss of adrenal function. In addition, many corticosteroids will be detected by standard serum cortisol tests that rely on immunoassays. For this reason, cortisol measurement and CST should be done at least 18-24 hours after the last dose of exogenous steroids.

Although the focus has been on higher doses and longer courses of steroids (e.g., chronic use of ≥ 5 mg prednisone daily, or ≥ 20 mg prednisone daily for > 3 weeks), there is increasing evidence that lower doses, shorter courses, and alternate routes (e.g., inhaled, intra-articular) can result in biochemical and clinical evidence of AI.⁹ Thus, a thorough history and exam should be obtained to determine all recent corticosteroid exposure and cushingoid features.
 

Application of the data to the case

To effectively assess the patient for adrenal insufficiency, we need additional information. First and foremost, is a description of the patient’s current clinical status. If she is demonstrating evidence of adrenal crisis, treatment should not be delayed for additional testing. If she is stable, a thorough history including use of corticosteroids by any route, pregnancy, oral contraceptives, recent surgery, and liver and kidney disease is essential.

Additional evaluation reveals the patient has been using her fluticasone inhaler daily. No other source of hyponatremia or lightheadedness is identified. The patient’s risk factors of corticosteroid use and unexplained hyponatremia with associated lightheadedness increase her pretest probability of AI and a single morning cortisol of 10 mcg/dL is insufficient to exclude adrenal insufficiency. The appropriate follow-up test is a standard high-dose cosyntropin stimulation test at least 18 hours after her last dose of fluticasone. A cortisol level > 18 mcg/dL at 30 minutes in the absence of other conditions that impact cortisol testing would not be suggestive of AI. A serum cortisol level of < 18 mcg/dL at 30 minutes would raise concern for abnormal adrenal reserve due to chronic corticosteroid therapy and would warrant referral to an endocrinologist.
 

Bottom line

An isolated serum cortisol is often insufficient to exclude adrenal insufficiency. Hospitalists should be aware of the many factors that impact the interpretation of this test.

Dr. Gordon is assistant professor of medicine at Tufts University, Boston, and a hospitalist at Maine Medical Center, Portland. She is the subspecialty education coordinator of inpatient medicine for the Internal Medicine Residency Program. Dr. Herrle is assistant professor of medicine at Tufts University and a hospitalist at Maine Medical Center. She is the associate director of medical student education for the department of internal medicine at MMC and a medical director for clinical informatics at MaineHealth.

References

1. Bleicken B et al. Delayed diagnosis of adrenal insufficiency is common: A cross-sectional study in 216 patients. Am J Med Sci. 2010;339(6):525-31. doi: 10.1097/MAJ.0b013e3181db6b7a.

2. Bornstein SR et al. Diagnosis and treatment of primary adrenal insufficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016 Feb;101(2):364-89.

3. El-Farhan N et al. Measuring cortisol in serum, urine and saliva – Are our assays good enough? Ann Clin Biochem. 2017 May;54(3):308-22. doi: 10.1177/0004563216687335.

4. Kazlauskaite R et al. Corticotropin tests for hypothalamic-pituitary-adrenal insufficiency: A metaanalysis. J Clin Endocrinol Metab. 2008;93:4245-53.

5. Wood JB et al. A rapid test of adrenocortical function. Lancet. 1965;191:243-5.

6. Singh Ospina N et al. ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J Clin Endocrinol Metab. 2016;101(2):427-34.

7. Burgos N et al. Pitfalls in the interpretation of the cosyntropin stimulation test for the diagnosis of adrenal insufficiency. Curr Opin Endocrinol Diabetes Obes. 2019;26(3):139-45.

8. Odom DC et al. A Single, post-ACTH cortisol measurement to screen for adrenal insufficiency in the hospitalized patient. J Hosp Med. 2018;13(8):526-30. doi: 10.12788/jhm.2928.

9. Broersen LHA et al. Adrenal insufficiency in corticosteroids use: Systematic review and meta-analysis. J Clin Endocrinol Metab. 2015;100(6): 2171-80.
 

Key points

• In general, random cortisol testing is of limited value and should be avoided.

• Serum cortisol testing in the hospitalized patient is impacted by a variety of patient and disease factors and should be interpreted carefully.

• For patients with low pretest probability of adrenal insufficiency, early morning serum cortisol testing may be sufficient to exclude the diagnosis.

• For patients with moderate to high pretest probability of adrenal insufficiency, standard high-dose (250 mcg) corticotropin stimulation testing is preferred.
 

Additional reading

Bornstein SR et al. Diagnosis and treatment of primary adrenal insufficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016 Feb;101(2):364-89.

Burgos N et al. Pitfalls in the interpretation of the cosyntropin stimulation test for the diagnosis of adrenal insufficiency. Curr Opin Endocrinol Diabetes Obes. 2019;26(3):139-45.
 

Quiz

An 82 y.o. woman with depression is admitted from her long-term care facility with worsening weakness and mild hypoglycemia. Her supine vital signs are stable, but she exhibits a drop in systolic blood pressure of 21 mm Hg upon standing. There is no evidence of infection by history, exam, or initial workup. She is not on chronic corticosteroids by any route.

What would be your initial workup for adrenal insufficiency?

A) Morning serum cortisol and ACTH

B) Insulin tolerance test

C) Corticotropin stimulation test

D) Would not test at this point

Answer: C. Although her symptom of weakness is nonspecific, her hypoglycemia and orthostatic hypotension are concerning enough that she would qualify as moderate to high pretest probability for AI. In this setting, one would acquire a basal serum total cortisol and ACTH then administer the standard high-dose corticotropin stimulation test (250 mcg) followed by repeat serum total cortisol at 30 or 60 minutes.

The latest findings regarding the risk for atypical femur fracture (AFF) with use of bisphosphonates for osteoporosis show a significant increase in risk when treatment extends beyond 5 years. The risk is notably higher risk among Asian women, compared with White women. However, the benefits in fracture reduction still appear to far outweigh the risk for AFF.

The research, published in the New England Journal of Medicine, importantly adds to findings from smaller studies by showing effects in a population of nearly 200,000 women in a diverse cohort, said Angela M. Cheung, MD, PhD.

“This study answers some important questions – Kaiser Permanente Southern California is a large health maintenance organization with a diverse racial population,” said Dr. Cheung, director of the Center of Excellence in Skeletal Health Assessment and osteoporosis program at the University of Toronto.

“This is the first study that included a diverse population to definitively show that Asians are at a much higher risk of atypical femur fractures than Caucasians,” she emphasized.

Although AFFs are rare, concerns about them remain pressing in the treatment of osteoporosis, Dr. Cheung noted. “This is a big concern for clinicians – they want to do no harm.”
 

Risk for AFF increases with longer duration of bisphosphonate use

For the study, Dennis M. Black, PhD, of the departments of epidemiology and biostatistics and orthopedic surgery at the University of California, San Francisco, and colleagues identified women aged 50 years or older enrolled in the Kaiser Permanente Southern California system who were treated with bisphosphonates and were followed from January 2007 to November 2017.

Among the 196,129 women identified in the study, 277 AFFs occurred.

After multivariate adjustment, compared with those treated for less than 3 months, for women who were treated for 3-5 years, the hazard ratio for experiencing an AFF was 8.86. For therapy of 5-8 years, the HR increased to 19.88, and for those treated with bisphosphonates for 8 years or longer, the HR was 43.51.

The risk for AFF declined quickly upon bisphosphonate discontinuation; compared with current users, the HR dropped to 0.52 within 3-15 months after the last bisphosphonate use. It declined to 0.26 at more than 4 years after discontinuation.

The risk for AFF with bisphosphonate use was higher for Asian women than for White women (HR, 4.84); this did not apply to any other ethnic groups (HR, 0.99).

Other risk factors for AFF included shorter height (HR, 1.28 per 5-cm decrement), greater weight (HR, 1.15 per 5-kg increment), and glucocorticoid use (HR, 2.28 for glucocorticoid use of 1 or more years).

Among White women, the number of fractures prevented with bisphosphonate use far outweighed the risk for bisphosphonate-associated AFFs.

For example, among White women, during a 3-year treatment period, there were two bisphosphonate-associated AFFs, whereas 149 hip fractures and 541 clinical fractures were prevented, the authors wrote.

After 5 years, there were eight AFFs, but 286 hip fractures and 859 clinical fractures were prevented.

Although the risk-benefit ratio among Asian women still favored prevention of fractures, the difference was less pronounced – eight bisphosphonate-associated AFFs had occurred at 3 years, whereas 91 hip fractures and 330 clinical fractures were prevented.

The authors noted that previous studies have also shown Asian women to be at a disproportionately higher risk for AFF.

An earlier Kaiser Permanente Southern California case series showed that 49% of 142 AFFs occurred in Asian patients, despite the fact that those patients made up only 10% of the study population.

Various factors could cause higher risk in Asian women

The reasons for the increased risk among Asian women are likely multifactorial and could include greater medication adherence among Asian women, genetic differences in drug metabolism and bone turnover, and, notably, increased lateral stress caused by bowed Asian femora, the authors speculated.

Further questions include whether the risk is limited to Asians living outside of Asia and whether cultural differences in diet or physical activity are risk factors, they added.

“At this early stage, further research into the cause of the increased risk among women of Asian ancestry is warranted,” they wrote.

Although the risk for AFF may be higher among Asian women, the incidence of hip and other osteoporotic fractures is lower among Asians as well as other non-White persons, compared with White persons, they added.

The findings have important implications in how clinicians should discuss treatment options with different patient groups, Dr. Cheung said.

“I think this is one of the key findings of the study,” she added. “In this day and age of personalized medicine, we need to keep the individual patient in mind, and that includes their racial/ethnic background, genetic characteristics, sex, medical conditions and medications, etc. So it is important for physicians to pay attention to this. The risk-benefit ratio of these drugs for Asians will be quite different, compared to Caucasians.”
 

No link between traditional fracture risk factors and AFF, study shows

Interestingly, although older age, previous fractures, and lower bone mineral density are key risk factors for hip and other osteoporotic fractures in the general population, they do not significantly increase the risk for AFF with bisphosphonate use, the study also showed.

“In fact, the oldest women in our cohort, who are at highest risk for hip and other fractures, were at lowest risk for AFF,” the authors wrote.

The collective findings “add to the risk-benefit balance of bisphosphonate treatment in these populations and could directly affect decisions regarding treatment initiation and duration.”

Notable limitations of the study include the fact that most women were treated with one particular bisphosphonate, alendronate, and that other bisphosphonates were underrepresented, Dr. Cheung said.

“This study examined bisphosphonate therapy, but the vast majority of the women were exposed to alendronate, so whether women on risedronate or other bisphosphonates have similar risks is unclear,” she observed.

“In addition, because they can only capture bisphosphonate use using their database, any bisphosphonate exposure prior to joining Kaiser Permanente will not be captured. So the study may underestimate the total cumulative duration of bisphosphonate use,” she added.

The study received support from Kaiser Permanente and discretionary funds from the University of California, San Francisco. The study began with a pilot grant from Merck Sharp & Dohme, which had no role in the conduct of the study. Dr. Cheung has served as a consultant for Amgen. She chaired and led the 2019 International Society for Clinical Densitometry Position Development Conference on Detection of Atypical Femur Fractures and currently is on the Osteoporosis Canada Guidelines Committee.

A version of this article originally appeared on Medscape.com.

The latest findings regarding the risk for atypical femur fracture (AFF) with use of bisphosphonates for osteoporosis show a significant increase in risk when treatment extends beyond 5 years. The risk is notably higher risk among Asian women, compared with White women. However, the benefits in fracture reduction still appear to far outweigh the risk for AFF.

The research, published in the New England Journal of Medicine, importantly adds to findings from smaller studies by showing effects in a population of nearly 200,000 women in a diverse cohort, said Angela M. Cheung, MD, PhD.

“This study answers some important questions – Kaiser Permanente Southern California is a large health maintenance organization with a diverse racial population,” said Dr. Cheung, director of the Center of Excellence in Skeletal Health Assessment and osteoporosis program at the University of Toronto.

“This is the first study that included a diverse population to definitively show that Asians are at a much higher risk of atypical femur fractures than Caucasians,” she emphasized.

Although AFFs are rare, concerns about them remain pressing in the treatment of osteoporosis, Dr. Cheung noted. “This is a big concern for clinicians – they want to do no harm.”
 

Risk for AFF increases with longer duration of bisphosphonate use

For the study, Dennis M. Black, PhD, of the departments of epidemiology and biostatistics and orthopedic surgery at the University of California, San Francisco, and colleagues identified women aged 50 years or older enrolled in the Kaiser Permanente Southern California system who were treated with bisphosphonates and were followed from January 2007 to November 2017.

Among the 196,129 women identified in the study, 277 AFFs occurred.

After multivariate adjustment, compared with those treated for less than 3 months, for women who were treated for 3-5 years, the hazard ratio for experiencing an AFF was 8.86. For therapy of 5-8 years, the HR increased to 19.88, and for those treated with bisphosphonates for 8 years or longer, the HR was 43.51.

The risk for AFF declined quickly upon bisphosphonate discontinuation; compared with current users, the HR dropped to 0.52 within 3-15 months after the last bisphosphonate use. It declined to 0.26 at more than 4 years after discontinuation.

The risk for AFF with bisphosphonate use was higher for Asian women than for White women (HR, 4.84); this did not apply to any other ethnic groups (HR, 0.99).

Other risk factors for AFF included shorter height (HR, 1.28 per 5-cm decrement), greater weight (HR, 1.15 per 5-kg increment), and glucocorticoid use (HR, 2.28 for glucocorticoid use of 1 or more years).

Among White women, the number of fractures prevented with bisphosphonate use far outweighed the risk for bisphosphonate-associated AFFs.

For example, among White women, during a 3-year treatment period, there were two bisphosphonate-associated AFFs, whereas 149 hip fractures and 541 clinical fractures were prevented, the authors wrote.

After 5 years, there were eight AFFs, but 286 hip fractures and 859 clinical fractures were prevented.

Although the risk-benefit ratio among Asian women still favored prevention of fractures, the difference was less pronounced – eight bisphosphonate-associated AFFs had occurred at 3 years, whereas 91 hip fractures and 330 clinical fractures were prevented.

The authors noted that previous studies have also shown Asian women to be at a disproportionately higher risk for AFF.

An earlier Kaiser Permanente Southern California case series showed that 49% of 142 AFFs occurred in Asian patients, despite the fact that those patients made up only 10% of the study population.

Various factors could cause higher risk in Asian women

The reasons for the increased risk among Asian women are likely multifactorial and could include greater medication adherence among Asian women, genetic differences in drug metabolism and bone turnover, and, notably, increased lateral stress caused by bowed Asian femora, the authors speculated.

Further questions include whether the risk is limited to Asians living outside of Asia and whether cultural differences in diet or physical activity are risk factors, they added.

“At this early stage, further research into the cause of the increased risk among women of Asian ancestry is warranted,” they wrote.

Although the risk for AFF may be higher among Asian women, the incidence of hip and other osteoporotic fractures is lower among Asians as well as other non-White persons, compared with White persons, they added.

The findings have important implications in how clinicians should discuss treatment options with different patient groups, Dr. Cheung said.

“I think this is one of the key findings of the study,” she added. “In this day and age of personalized medicine, we need to keep the individual patient in mind, and that includes their racial/ethnic background, genetic characteristics, sex, medical conditions and medications, etc. So it is important for physicians to pay attention to this. The risk-benefit ratio of these drugs for Asians will be quite different, compared to Caucasians.”
 

No link between traditional fracture risk factors and AFF, study shows

Interestingly, although older age, previous fractures, and lower bone mineral density are key risk factors for hip and other osteoporotic fractures in the general population, they do not significantly increase the risk for AFF with bisphosphonate use, the study also showed.

“In fact, the oldest women in our cohort, who are at highest risk for hip and other fractures, were at lowest risk for AFF,” the authors wrote.

The collective findings “add to the risk-benefit balance of bisphosphonate treatment in these populations and could directly affect decisions regarding treatment initiation and duration.”

Notable limitations of the study include the fact that most women were treated with one particular bisphosphonate, alendronate, and that other bisphosphonates were underrepresented, Dr. Cheung said.

“This study examined bisphosphonate therapy, but the vast majority of the women were exposed to alendronate, so whether women on risedronate or other bisphosphonates have similar risks is unclear,” she observed.

“In addition, because they can only capture bisphosphonate use using their database, any bisphosphonate exposure prior to joining Kaiser Permanente will not be captured. So the study may underestimate the total cumulative duration of bisphosphonate use,” she added.

The study received support from Kaiser Permanente and discretionary funds from the University of California, San Francisco. The study began with a pilot grant from Merck Sharp & Dohme, which had no role in the conduct of the study. Dr. Cheung has served as a consultant for Amgen. She chaired and led the 2019 International Society for Clinical Densitometry Position Development Conference on Detection of Atypical Femur Fractures and currently is on the Osteoporosis Canada Guidelines Committee.

A version of this article originally appeared on Medscape.com.

The latest findings regarding the risk for atypical femur fracture (AFF) with use of bisphosphonates for osteoporosis show a significant increase in risk when treatment extends beyond 5 years. The risk is notably higher risk among Asian women, compared with White women. However, the benefits in fracture reduction still appear to far outweigh the risk for AFF.

The research, published in the New England Journal of Medicine, importantly adds to findings from smaller studies by showing effects in a population of nearly 200,000 women in a diverse cohort, said Angela M. Cheung, MD, PhD.

“This study answers some important questions – Kaiser Permanente Southern California is a large health maintenance organization with a diverse racial population,” said Dr. Cheung, director of the Center of Excellence in Skeletal Health Assessment and osteoporosis program at the University of Toronto.

“This is the first study that included a diverse population to definitively show that Asians are at a much higher risk of atypical femur fractures than Caucasians,” she emphasized.

Although AFFs are rare, concerns about them remain pressing in the treatment of osteoporosis, Dr. Cheung noted. “This is a big concern for clinicians – they want to do no harm.”
 

Risk for AFF increases with longer duration of bisphosphonate use

For the study, Dennis M. Black, PhD, of the departments of epidemiology and biostatistics and orthopedic surgery at the University of California, San Francisco, and colleagues identified women aged 50 years or older enrolled in the Kaiser Permanente Southern California system who were treated with bisphosphonates and were followed from January 2007 to November 2017.

Among the 196,129 women identified in the study, 277 AFFs occurred.

After multivariate adjustment, compared with those treated for less than 3 months, for women who were treated for 3-5 years, the hazard ratio for experiencing an AFF was 8.86. For therapy of 5-8 years, the HR increased to 19.88, and for those treated with bisphosphonates for 8 years or longer, the HR was 43.51.

The risk for AFF declined quickly upon bisphosphonate discontinuation; compared with current users, the HR dropped to 0.52 within 3-15 months after the last bisphosphonate use. It declined to 0.26 at more than 4 years after discontinuation.

The risk for AFF with bisphosphonate use was higher for Asian women than for White women (HR, 4.84); this did not apply to any other ethnic groups (HR, 0.99).

Other risk factors for AFF included shorter height (HR, 1.28 per 5-cm decrement), greater weight (HR, 1.15 per 5-kg increment), and glucocorticoid use (HR, 2.28 for glucocorticoid use of 1 or more years).

Among White women, the number of fractures prevented with bisphosphonate use far outweighed the risk for bisphosphonate-associated AFFs.

For example, among White women, during a 3-year treatment period, there were two bisphosphonate-associated AFFs, whereas 149 hip fractures and 541 clinical fractures were prevented, the authors wrote.

After 5 years, there were eight AFFs, but 286 hip fractures and 859 clinical fractures were prevented.

Although the risk-benefit ratio among Asian women still favored prevention of fractures, the difference was less pronounced – eight bisphosphonate-associated AFFs had occurred at 3 years, whereas 91 hip fractures and 330 clinical fractures were prevented.

The authors noted that previous studies have also shown Asian women to be at a disproportionately higher risk for AFF.

An earlier Kaiser Permanente Southern California case series showed that 49% of 142 AFFs occurred in Asian patients, despite the fact that those patients made up only 10% of the study population.

Various factors could cause higher risk in Asian women

The reasons for the increased risk among Asian women are likely multifactorial and could include greater medication adherence among Asian women, genetic differences in drug metabolism and bone turnover, and, notably, increased lateral stress caused by bowed Asian femora, the authors speculated.

Further questions include whether the risk is limited to Asians living outside of Asia and whether cultural differences in diet or physical activity are risk factors, they added.

“At this early stage, further research into the cause of the increased risk among women of Asian ancestry is warranted,” they wrote.

Although the risk for AFF may be higher among Asian women, the incidence of hip and other osteoporotic fractures is lower among Asians as well as other non-White persons, compared with White persons, they added.

The findings have important implications in how clinicians should discuss treatment options with different patient groups, Dr. Cheung said.

“I think this is one of the key findings of the study,” she added. “In this day and age of personalized medicine, we need to keep the individual patient in mind, and that includes their racial/ethnic background, genetic characteristics, sex, medical conditions and medications, etc. So it is important for physicians to pay attention to this. The risk-benefit ratio of these drugs for Asians will be quite different, compared to Caucasians.”
 

No link between traditional fracture risk factors and AFF, study shows

Interestingly, although older age, previous fractures, and lower bone mineral density are key risk factors for hip and other osteoporotic fractures in the general population, they do not significantly increase the risk for AFF with bisphosphonate use, the study also showed.

“In fact, the oldest women in our cohort, who are at highest risk for hip and other fractures, were at lowest risk for AFF,” the authors wrote.

The collective findings “add to the risk-benefit balance of bisphosphonate treatment in these populations and could directly affect decisions regarding treatment initiation and duration.”

Notable limitations of the study include the fact that most women were treated with one particular bisphosphonate, alendronate, and that other bisphosphonates were underrepresented, Dr. Cheung said.

“This study examined bisphosphonate therapy, but the vast majority of the women were exposed to alendronate, so whether women on risedronate or other bisphosphonates have similar risks is unclear,” she observed.

“In addition, because they can only capture bisphosphonate use using their database, any bisphosphonate exposure prior to joining Kaiser Permanente will not be captured. So the study may underestimate the total cumulative duration of bisphosphonate use,” she added.

The study received support from Kaiser Permanente and discretionary funds from the University of California, San Francisco. The study began with a pilot grant from Merck Sharp & Dohme, which had no role in the conduct of the study. Dr. Cheung has served as a consultant for Amgen. She chaired and led the 2019 International Society for Clinical Densitometry Position Development Conference on Detection of Atypical Femur Fractures and currently is on the Osteoporosis Canada Guidelines Committee.

A version of this article originally appeared on Medscape.com.

Humira outsold all other drugs in 2019 in terms of revenue as cytokine inhibitor medications earned their way to three of the first four spots on the pharmaceutical best-seller list, according to a new analysis from the IQVIA Institute for Human Data Science.

Sales of Humira (adalimumab) amounted to $21.4 billion before discounting, Murray Aitken, the institute’s executive director, and associates wrote in their analysis. That’s more than double the total of the anticoagulant Eliquis (apixaban), which brought in $9.9 billion in its last year before generic forms became available.

The next two spots were filled by the tumor necrosis factor inhibitor Enbrel (etanercept) with $8.1 billion in sales and the interleukin 12/23 inhibitor Stelara (ustekinumab) with sales totaling $6.6 billion, followed by the chemotherapy drug Keytruda (pembrolizumab) close behind after racking up $6.5 billion in sales, the researchers reported.

Total nondiscounted spending on all drugs in the U.S. market came to $511 billion in 2019, an increase of 5.7% over the $484 billion spent in 2018, based on data from the July 2020 IQVIA National Sales Perspectives.

These figures are “not adjusted for estimates of off-invoice discounts and rebates,” the authors noted, but they include “prescription and insulin products sold into chain and independent pharmacies, food store pharmacies, mail service pharmacies, long-term care facilities, hospitals, clinics, and other institutional settings.”

Those “discounts and rebates” do exist, however, and they can add up. Drug sales for 2019, “after deducting negotiated rebates, discounts, and other forms of price concessions, such as patient coupons or vouchers that offset out-of-pocket costs,” were $235 billion less than overall nondiscounted spending, the report noted.

Now that we’ve shown you the money, let’s take a quick look at volume. The leading drugs by number of dispensed prescriptions in 2019 were, not surprisingly, quite different. First, with 118 million prescriptions, was atorvastatin, followed by levothyroxine (113 million), lisinopril (96), amlodipine (89), and metoprolol (85), Mr. Aitken and associates reported.

Altogether, over 4.2 billion prescriptions were dispensed last year, with a couple of caveats: 90-day and 30-day fills were both counted as one prescription, and OTC drugs were not included, they pointed out.

[email protected]

Humira outsold all other drugs in 2019 in terms of revenue as cytokine inhibitor medications earned their way to three of the first four spots on the pharmaceutical best-seller list, according to a new analysis from the IQVIA Institute for Human Data Science.

Sales of Humira (adalimumab) amounted to $21.4 billion before discounting, Murray Aitken, the institute’s executive director, and associates wrote in their analysis. That’s more than double the total of the anticoagulant Eliquis (apixaban), which brought in $9.9 billion in its last year before generic forms became available.

The next two spots were filled by the tumor necrosis factor inhibitor Enbrel (etanercept) with $8.1 billion in sales and the interleukin 12/23 inhibitor Stelara (ustekinumab) with sales totaling $6.6 billion, followed by the chemotherapy drug Keytruda (pembrolizumab) close behind after racking up $6.5 billion in sales, the researchers reported.

Total nondiscounted spending on all drugs in the U.S. market came to $511 billion in 2019, an increase of 5.7% over the $484 billion spent in 2018, based on data from the July 2020 IQVIA National Sales Perspectives.

These figures are “not adjusted for estimates of off-invoice discounts and rebates,” the authors noted, but they include “prescription and insulin products sold into chain and independent pharmacies, food store pharmacies, mail service pharmacies, long-term care facilities, hospitals, clinics, and other institutional settings.”

Those “discounts and rebates” do exist, however, and they can add up. Drug sales for 2019, “after deducting negotiated rebates, discounts, and other forms of price concessions, such as patient coupons or vouchers that offset out-of-pocket costs,” were $235 billion less than overall nondiscounted spending, the report noted.

Now that we’ve shown you the money, let’s take a quick look at volume. The leading drugs by number of dispensed prescriptions in 2019 were, not surprisingly, quite different. First, with 118 million prescriptions, was atorvastatin, followed by levothyroxine (113 million), lisinopril (96), amlodipine (89), and metoprolol (85), Mr. Aitken and associates reported.

Altogether, over 4.2 billion prescriptions were dispensed last year, with a couple of caveats: 90-day and 30-day fills were both counted as one prescription, and OTC drugs were not included, they pointed out.

[email protected]

Humira outsold all other drugs in 2019 in terms of revenue as cytokine inhibitor medications earned their way to three of the first four spots on the pharmaceutical best-seller list, according to a new analysis from the IQVIA Institute for Human Data Science.

Sales of Humira (adalimumab) amounted to $21.4 billion before discounting, Murray Aitken, the institute’s executive director, and associates wrote in their analysis. That’s more than double the total of the anticoagulant Eliquis (apixaban), which brought in $9.9 billion in its last year before generic forms became available.

The next two spots were filled by the tumor necrosis factor inhibitor Enbrel (etanercept) with $8.1 billion in sales and the interleukin 12/23 inhibitor Stelara (ustekinumab) with sales totaling $6.6 billion, followed by the chemotherapy drug Keytruda (pembrolizumab) close behind after racking up $6.5 billion in sales, the researchers reported.

Total nondiscounted spending on all drugs in the U.S. market came to $511 billion in 2019, an increase of 5.7% over the $484 billion spent in 2018, based on data from the July 2020 IQVIA National Sales Perspectives.

These figures are “not adjusted for estimates of off-invoice discounts and rebates,” the authors noted, but they include “prescription and insulin products sold into chain and independent pharmacies, food store pharmacies, mail service pharmacies, long-term care facilities, hospitals, clinics, and other institutional settings.”

Those “discounts and rebates” do exist, however, and they can add up. Drug sales for 2019, “after deducting negotiated rebates, discounts, and other forms of price concessions, such as patient coupons or vouchers that offset out-of-pocket costs,” were $235 billion less than overall nondiscounted spending, the report noted.

Now that we’ve shown you the money, let’s take a quick look at volume. The leading drugs by number of dispensed prescriptions in 2019 were, not surprisingly, quite different. First, with 118 million prescriptions, was atorvastatin, followed by levothyroxine (113 million), lisinopril (96), amlodipine (89), and metoprolol (85), Mr. Aitken and associates reported.

Altogether, over 4.2 billion prescriptions were dispensed last year, with a couple of caveats: 90-day and 30-day fills were both counted as one prescription, and OTC drugs were not included, they pointed out.

[email protected]

Rates of thyrotoxicosis are significantly higher among patients who are critically ill with COVID-19 than among patients who are critically ill but who do not not have COVID-19, suggesting an atypical form of thyroiditis related to the novel coronavirus infection, according to new research.

“We suggest routine assessment of thyroid function in patients with COVID-19 requiring high-intensity care because they frequently present with thyrotoxicosis due to a form of subacute thyroiditis related to SARS-CoV-2,” the authors wrote in correspondence published online in The Lancet Diabetes and Endocrinology.

However, notably, the study – which compared critically ill ICU patients who had COVID-19 with those who did not have COVID-19 or who had milder cases of COVID-19 – indicates that thyroid disorders do not appear to increase the risk of developing COVID-19, first author Ilaria Muller, MD, PhD, of the department of endocrinology, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Milan, said in an interview.

“It is important to highlight that we did not find an increased prevalence of preexisting thyroid disorders in COVID-19 patients (contrary to early media reports),” she said. “So far, clinical observations do not support this fear, and we need to reassure people with thyroid disorders, since such disorders are very common among the general population.”

Yet the findings add to emerging evidence of a COVID-19/thyroid relationship, Angela M. Leung, MD, said in an interview.

“Given the health care impacts of the current COVID-19 pandemic worldwide, this study provides some insight on the potential systemic inflammation, as well as thyroid-specific inflammation, of the SARS-Cov-2 virus that is described in some emerging reports,” she said.

“This study joins at least six others that have reported a clinical presentation resembling subacute thyroiditis in critically ill patients with COVID-19,” noted Dr. Leung, of the division of endocrinology, diabetes, and metabolism in the department of medicine at the University of California, Los Angeles.
 

Thyroid function analysis in those with severe COVID-19

Dr. Muller explained that preliminary data from her institution showed thyroid abnormalities in patients who were severely ill with COVID-19. She and her team extended the evaluation to include thyroid data and other data on 93 patients with COVID-19 who were admitted to high-intensity care units (HICUs) in Italy during the 2020 pandemic.

Those data were compared with data on 101 critically ill patients admitted to the same HICUs in 2019 who did not have COVID-19. A third group of 52 patients with COVID-19 who were admitted to low-intensity care units (LICUs) in Italy in 2020 were also included in the analysis.

The mean age of the patients in the HICU 2020 group was 65.3 years; in the HICU 2019 group, it was 73 years; and in the LICU group, it was 70 years (P = .001). In addition, the HICU 2020 group included more men than the other two groups (69% vs. 56% and 48%; P = .03).

Of note, only 9% of patients in the HICU 2020 group had preexisting thyroid disorders, compared with 21% in the LICU group and 23% in the HICU 2019 group (P = .017).

These findings suggest that “such conditions are not a risk factor for SARS-CoV-2 infection or severity of COVID-19,” the authors wrote.

The patients with the preexisting thyroid conditions were excluded from the thyroid function analysis.

A significantly higher proportion of patients in the HICU 2020 group (13; 15%) were thyrotoxic upon admission, compared with just 1 (1%) of 78 patients in the HICU 2019 group (P = .002) and one (2%) of 41 patients in the LICU group (P = .025).

Among the 14 patients in the two COVID-19 groups who had thyrotoxicosis, the majority were male (9; 64%)

Among those in the HICU 2020 group, serum thyroid-stimulating hormone concentrations were lower than in either of the other two groups (P = .018), and serum free thyroxine (free T4) concentrations were higher than in the LICU group (P = .016) but not the HICU 2019 group.
 

Differences compared with other infection-related thyroiditis

Although thyrotoxicosis relating to subacute viral thyroiditis can result from a wide variety of viral infections, there are some key differences with COVID-19, Dr. Muller said.

“Thyroid dysfunction related to SARS-CoV-2 seems to be milder than that of classic subacute thyroiditis due to other viruses,” she explained. Furthermore, thyroid dysfunction associated with other viral infections is more common in women, whereas there were more male patients with the COVID-19–related atypical thyroiditis.

In addition, the thyroid effects developed early with COVID-19, whereas they usually emerge after the infections by other viruses.

Patients did not demonstrate the neck pain that is common with classic viral thyroiditis, and the thyroid abnormalities appear to correlate with the severity of COVID-19, whereas they are seen even in patients with mild symptoms when other viral infections are the cause.

In addition to the risk for subacute viral thyroiditis, critically ill patients in general are at risk of developing nonthyroidal illness syndrome, with alterations in thyroid function. However, thyroid hormone measures in the patients severely ill with COVID-19 were not consistent with that syndrome.

A subanalysis of eight HICU 2020 patients with thyroid dysfunction who were followed for 55 days after discharge showed that two experienced hyperthyroidism but likely not from COVID-19; in the remaining six, thyroid function normalized.

Muller speculated that, when ill with COVID-19, the patients likely had a combination of SARS-CoV-2–related atypical thyroiditis and nonthyroidal illness syndrome, known as T4 toxicosis.
 

Will there be any long-term effects?

Importantly, it remains unknown whether the novel coronavirus has longer-term effects on the thyroid, Dr. Muller said.

“We cannot predict what will be the long-lasting thyroid effects after COVID-19,” she said.

With classic subacute viral thyroiditis, “After a few years ... 5%-20% of patients develop permanent hypothyroidism, [and] the same might happen in COVID-19 patients,” she hypothesized. “We will follow our patients long term to answer this question – this study is already ongoing.”

In the meantime, diagnosis of thyroid dysfunction in patients with COVID-19 is important, inasmuch as it could worsen the already critical conditions of patients, Muller stressed.

“The gold-standard treatment for thyroiditis is steroids, so the presence of thyroid dysfunction might represent an additional indication to such treatment in COVID-19 patients, to be verified in properly designed clinical trials,” she advised.
 

ACE2 cell receptors highly expressed in thyroid

Dr. Muller and colleagues also noted recent research showing that ACE2 – demonstrated to be a key host-cell entry receptor for both SARS-CoV and SARS-CoV-2 – is expressed in even higher levels in the thyroid than the lungs, where it causes COVID-19’s notorious pulmonary effects.

Dr. Muller said the implications of ACE2 expression in the thyroid remain to be elucidated.

“If ACE2 is confirmed to be expressed at higher levels, compared with the lungs in the thyroid gland and other tissues, i.e., small intestine, testis, kidney, heart, etc, dedicated studies will be needed to correlate ACE2 expression with the organs’ susceptibility to SARS-CoV-2 reflected by clinical presentation,” she said.

Dr. Leung added that, as a take-home message from these and the other thyroid/COVID-19 studies, “data are starting to show us that COVID-19 infection may cause thyrotoxicosis that is possibly related to thyroid and systemic inflammation. However, the serum thyroid function test abnormalities seen in COVID-19 patients with subacute thyroiditis are also likely exacerbated to a substantial extent by nonthyroidal illness physiology.”

The authors have disclosed no relevant financial relationships. Dr. Leung is on the advisory board of Medscape Diabetes and Endocrinology.

A version of this article originally appeared on Medscape.com.

Rates of thyrotoxicosis are significantly higher among patients who are critically ill with COVID-19 than among patients who are critically ill but who do not not have COVID-19, suggesting an atypical form of thyroiditis related to the novel coronavirus infection, according to new research.

“We suggest routine assessment of thyroid function in patients with COVID-19 requiring high-intensity care because they frequently present with thyrotoxicosis due to a form of subacute thyroiditis related to SARS-CoV-2,” the authors wrote in correspondence published online in The Lancet Diabetes and Endocrinology.

However, notably, the study – which compared critically ill ICU patients who had COVID-19 with those who did not have COVID-19 or who had milder cases of COVID-19 – indicates that thyroid disorders do not appear to increase the risk of developing COVID-19, first author Ilaria Muller, MD, PhD, of the department of endocrinology, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Milan, said in an interview.

“It is important to highlight that we did not find an increased prevalence of preexisting thyroid disorders in COVID-19 patients (contrary to early media reports),” she said. “So far, clinical observations do not support this fear, and we need to reassure people with thyroid disorders, since such disorders are very common among the general population.”

Yet the findings add to emerging evidence of a COVID-19/thyroid relationship, Angela M. Leung, MD, said in an interview.

“Given the health care impacts of the current COVID-19 pandemic worldwide, this study provides some insight on the potential systemic inflammation, as well as thyroid-specific inflammation, of the SARS-Cov-2 virus that is described in some emerging reports,” she said.

“This study joins at least six others that have reported a clinical presentation resembling subacute thyroiditis in critically ill patients with COVID-19,” noted Dr. Leung, of the division of endocrinology, diabetes, and metabolism in the department of medicine at the University of California, Los Angeles.
 

Thyroid function analysis in those with severe COVID-19

Dr. Muller explained that preliminary data from her institution showed thyroid abnormalities in patients who were severely ill with COVID-19. She and her team extended the evaluation to include thyroid data and other data on 93 patients with COVID-19 who were admitted to high-intensity care units (HICUs) in Italy during the 2020 pandemic.

Those data were compared with data on 101 critically ill patients admitted to the same HICUs in 2019 who did not have COVID-19. A third group of 52 patients with COVID-19 who were admitted to low-intensity care units (LICUs) in Italy in 2020 were also included in the analysis.

The mean age of the patients in the HICU 2020 group was 65.3 years; in the HICU 2019 group, it was 73 years; and in the LICU group, it was 70 years (P = .001). In addition, the HICU 2020 group included more men than the other two groups (69% vs. 56% and 48%; P = .03).

Of note, only 9% of patients in the HICU 2020 group had preexisting thyroid disorders, compared with 21% in the LICU group and 23% in the HICU 2019 group (P = .017).

These findings suggest that “such conditions are not a risk factor for SARS-CoV-2 infection or severity of COVID-19,” the authors wrote.

The patients with the preexisting thyroid conditions were excluded from the thyroid function analysis.

A significantly higher proportion of patients in the HICU 2020 group (13; 15%) were thyrotoxic upon admission, compared with just 1 (1%) of 78 patients in the HICU 2019 group (P = .002) and one (2%) of 41 patients in the LICU group (P = .025).

Among the 14 patients in the two COVID-19 groups who had thyrotoxicosis, the majority were male (9; 64%)

Among those in the HICU 2020 group, serum thyroid-stimulating hormone concentrations were lower than in either of the other two groups (P = .018), and serum free thyroxine (free T4) concentrations were higher than in the LICU group (P = .016) but not the HICU 2019 group.
 

Differences compared with other infection-related thyroiditis

Although thyrotoxicosis relating to subacute viral thyroiditis can result from a wide variety of viral infections, there are some key differences with COVID-19, Dr. Muller said.

“Thyroid dysfunction related to SARS-CoV-2 seems to be milder than that of classic subacute thyroiditis due to other viruses,” she explained. Furthermore, thyroid dysfunction associated with other viral infections is more common in women, whereas there were more male patients with the COVID-19–related atypical thyroiditis.

In addition, the thyroid effects developed early with COVID-19, whereas they usually emerge after the infections by other viruses.

Patients did not demonstrate the neck pain that is common with classic viral thyroiditis, and the thyroid abnormalities appear to correlate with the severity of COVID-19, whereas they are seen even in patients with mild symptoms when other viral infections are the cause.

In addition to the risk for subacute viral thyroiditis, critically ill patients in general are at risk of developing nonthyroidal illness syndrome, with alterations in thyroid function. However, thyroid hormone measures in the patients severely ill with COVID-19 were not consistent with that syndrome.

A subanalysis of eight HICU 2020 patients with thyroid dysfunction who were followed for 55 days after discharge showed that two experienced hyperthyroidism but likely not from COVID-19; in the remaining six, thyroid function normalized.

Muller speculated that, when ill with COVID-19, the patients likely had a combination of SARS-CoV-2–related atypical thyroiditis and nonthyroidal illness syndrome, known as T4 toxicosis.
 

Will there be any long-term effects?

Importantly, it remains unknown whether the novel coronavirus has longer-term effects on the thyroid, Dr. Muller said.

“We cannot predict what will be the long-lasting thyroid effects after COVID-19,” she said.

With classic subacute viral thyroiditis, “After a few years ... 5%-20% of patients develop permanent hypothyroidism, [and] the same might happen in COVID-19 patients,” she hypothesized. “We will follow our patients long term to answer this question – this study is already ongoing.”

In the meantime, diagnosis of thyroid dysfunction in patients with COVID-19 is important, inasmuch as it could worsen the already critical conditions of patients, Muller stressed.

“The gold-standard treatment for thyroiditis is steroids, so the presence of thyroid dysfunction might represent an additional indication to such treatment in COVID-19 patients, to be verified in properly designed clinical trials,” she advised.
 

ACE2 cell receptors highly expressed in thyroid

Dr. Muller and colleagues also noted recent research showing that ACE2 – demonstrated to be a key host-cell entry receptor for both SARS-CoV and SARS-CoV-2 – is expressed in even higher levels in the thyroid than the lungs, where it causes COVID-19’s notorious pulmonary effects.

Dr. Muller said the implications of ACE2 expression in the thyroid remain to be elucidated.

“If ACE2 is confirmed to be expressed at higher levels, compared with the lungs in the thyroid gland and other tissues, i.e., small intestine, testis, kidney, heart, etc, dedicated studies will be needed to correlate ACE2 expression with the organs’ susceptibility to SARS-CoV-2 reflected by clinical presentation,” she said.

Dr. Leung added that, as a take-home message from these and the other thyroid/COVID-19 studies, “data are starting to show us that COVID-19 infection may cause thyrotoxicosis that is possibly related to thyroid and systemic inflammation. However, the serum thyroid function test abnormalities seen in COVID-19 patients with subacute thyroiditis are also likely exacerbated to a substantial extent by nonthyroidal illness physiology.”

The authors have disclosed no relevant financial relationships. Dr. Leung is on the advisory board of Medscape Diabetes and Endocrinology.

A version of this article originally appeared on Medscape.com.

Rates of thyrotoxicosis are significantly higher among patients who are critically ill with COVID-19 than among patients who are critically ill but who do not not have COVID-19, suggesting an atypical form of thyroiditis related to the novel coronavirus infection, according to new research.

“We suggest routine assessment of thyroid function in patients with COVID-19 requiring high-intensity care because they frequently present with thyrotoxicosis due to a form of subacute thyroiditis related to SARS-CoV-2,” the authors wrote in correspondence published online in The Lancet Diabetes and Endocrinology.

However, notably, the study – which compared critically ill ICU patients who had COVID-19 with those who did not have COVID-19 or who had milder cases of COVID-19 – indicates that thyroid disorders do not appear to increase the risk of developing COVID-19, first author Ilaria Muller, MD, PhD, of the department of endocrinology, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Milan, said in an interview.

“It is important to highlight that we did not find an increased prevalence of preexisting thyroid disorders in COVID-19 patients (contrary to early media reports),” she said. “So far, clinical observations do not support this fear, and we need to reassure people with thyroid disorders, since such disorders are very common among the general population.”

Yet the findings add to emerging evidence of a COVID-19/thyroid relationship, Angela M. Leung, MD, said in an interview.

“Given the health care impacts of the current COVID-19 pandemic worldwide, this study provides some insight on the potential systemic inflammation, as well as thyroid-specific inflammation, of the SARS-Cov-2 virus that is described in some emerging reports,” she said.

“This study joins at least six others that have reported a clinical presentation resembling subacute thyroiditis in critically ill patients with COVID-19,” noted Dr. Leung, of the division of endocrinology, diabetes, and metabolism in the department of medicine at the University of California, Los Angeles.
 

Thyroid function analysis in those with severe COVID-19

Dr. Muller explained that preliminary data from her institution showed thyroid abnormalities in patients who were severely ill with COVID-19. She and her team extended the evaluation to include thyroid data and other data on 93 patients with COVID-19 who were admitted to high-intensity care units (HICUs) in Italy during the 2020 pandemic.

Those data were compared with data on 101 critically ill patients admitted to the same HICUs in 2019 who did not have COVID-19. A third group of 52 patients with COVID-19 who were admitted to low-intensity care units (LICUs) in Italy in 2020 were also included in the analysis.

The mean age of the patients in the HICU 2020 group was 65.3 years; in the HICU 2019 group, it was 73 years; and in the LICU group, it was 70 years (P = .001). In addition, the HICU 2020 group included more men than the other two groups (69% vs. 56% and 48%; P = .03).

Of note, only 9% of patients in the HICU 2020 group had preexisting thyroid disorders, compared with 21% in the LICU group and 23% in the HICU 2019 group (P = .017).

These findings suggest that “such conditions are not a risk factor for SARS-CoV-2 infection or severity of COVID-19,” the authors wrote.

The patients with the preexisting thyroid conditions were excluded from the thyroid function analysis.

A significantly higher proportion of patients in the HICU 2020 group (13; 15%) were thyrotoxic upon admission, compared with just 1 (1%) of 78 patients in the HICU 2019 group (P = .002) and one (2%) of 41 patients in the LICU group (P = .025).

Among the 14 patients in the two COVID-19 groups who had thyrotoxicosis, the majority were male (9; 64%)

Among those in the HICU 2020 group, serum thyroid-stimulating hormone concentrations were lower than in either of the other two groups (P = .018), and serum free thyroxine (free T4) concentrations were higher than in the LICU group (P = .016) but not the HICU 2019 group.
 

Differences compared with other infection-related thyroiditis

Although thyrotoxicosis relating to subacute viral thyroiditis can result from a wide variety of viral infections, there are some key differences with COVID-19, Dr. Muller said.

“Thyroid dysfunction related to SARS-CoV-2 seems to be milder than that of classic subacute thyroiditis due to other viruses,” she explained. Furthermore, thyroid dysfunction associated with other viral infections is more common in women, whereas there were more male patients with the COVID-19–related atypical thyroiditis.

In addition, the thyroid effects developed early with COVID-19, whereas they usually emerge after the infections by other viruses.

Patients did not demonstrate the neck pain that is common with classic viral thyroiditis, and the thyroid abnormalities appear to correlate with the severity of COVID-19, whereas they are seen even in patients with mild symptoms when other viral infections are the cause.

In addition to the risk for subacute viral thyroiditis, critically ill patients in general are at risk of developing nonthyroidal illness syndrome, with alterations in thyroid function. However, thyroid hormone measures in the patients severely ill with COVID-19 were not consistent with that syndrome.

A subanalysis of eight HICU 2020 patients with thyroid dysfunction who were followed for 55 days after discharge showed that two experienced hyperthyroidism but likely not from COVID-19; in the remaining six, thyroid function normalized.

Muller speculated that, when ill with COVID-19, the patients likely had a combination of SARS-CoV-2–related atypical thyroiditis and nonthyroidal illness syndrome, known as T4 toxicosis.
 

Will there be any long-term effects?

Importantly, it remains unknown whether the novel coronavirus has longer-term effects on the thyroid, Dr. Muller said.

“We cannot predict what will be the long-lasting thyroid effects after COVID-19,” she said.

With classic subacute viral thyroiditis, “After a few years ... 5%-20% of patients develop permanent hypothyroidism, [and] the same might happen in COVID-19 patients,” she hypothesized. “We will follow our patients long term to answer this question – this study is already ongoing.”

In the meantime, diagnosis of thyroid dysfunction in patients with COVID-19 is important, inasmuch as it could worsen the already critical conditions of patients, Muller stressed.

“The gold-standard treatment for thyroiditis is steroids, so the presence of thyroid dysfunction might represent an additional indication to such treatment in COVID-19 patients, to be verified in properly designed clinical trials,” she advised.
 

ACE2 cell receptors highly expressed in thyroid

Dr. Muller and colleagues also noted recent research showing that ACE2 – demonstrated to be a key host-cell entry receptor for both SARS-CoV and SARS-CoV-2 – is expressed in even higher levels in the thyroid than the lungs, where it causes COVID-19’s notorious pulmonary effects.

Dr. Muller said the implications of ACE2 expression in the thyroid remain to be elucidated.

“If ACE2 is confirmed to be expressed at higher levels, compared with the lungs in the thyroid gland and other tissues, i.e., small intestine, testis, kidney, heart, etc, dedicated studies will be needed to correlate ACE2 expression with the organs’ susceptibility to SARS-CoV-2 reflected by clinical presentation,” she said.

Dr. Leung added that, as a take-home message from these and the other thyroid/COVID-19 studies, “data are starting to show us that COVID-19 infection may cause thyrotoxicosis that is possibly related to thyroid and systemic inflammation. However, the serum thyroid function test abnormalities seen in COVID-19 patients with subacute thyroiditis are also likely exacerbated to a substantial extent by nonthyroidal illness physiology.”

The authors have disclosed no relevant financial relationships. Dr. Leung is on the advisory board of Medscape Diabetes and Endocrinology.

A version of this article originally appeared on Medscape.com.

Accumulating observational data suggest that metformin use in patients with type 2 diabetes might reduce the risk for death from COVID-19, but the randomized trials needed to prove this are unlikely to be carried out, according to experts.

The latest results, which are not yet peer reviewed, were published online July 31. The study was conducted by Andrew B. Crouse, PhD, of the Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, and colleagues.

The researchers found that among more than 600 patients with diabetes and COVID-19, use of metformin was associated with a nearly 70% reduction in mortality after adjustment for multiple confounders.

Data from four previous studies that also show a reduction in mortality among metformin users compared to nonusers were summarized in a “mini review” by André J. Scheen, MD, PhD, published Aug. 1 in Diabetes and Metabolism.

Dr. Scheen, of the division of diabetes, nutrition, and metabolic disorders and the division of clinical pharmacology at Liège (Belgium) University, discussed possible mechanisms behind this observation.

“Because metformin exerts various effects beyond its glucose-lowering action, among which are anti-inflammatory effects, it may be speculated that this biguanide might positively influence the prognosis of patients with [type 2 diabetes] hospitalized for COVID-19,” he said.

“However, given the potential confounders inherently found in observational studies, caution is required before drawing any firm conclusions in the absence of randomized controlled trials,” Dr. Scheen wrote.

Indeed, when asked to comment, endocrinologist Kasia Lipska, MD, of Yale University, New Haven, Conn., said in an interview: “Metformin users tend to do better in many different settings with respect to many different outcomes. To me, it is still unclear whether metformin is truly a miracle drug or whether it is simply used more often among people who are healthier and who do not have contraindications to its use.”

She added, “I don’t think we have enough data to suggest metformin use for COVID-19 mitigation at this point.”

Alabama authors say confounding effects ‘unlikely’

In the retrospective analysis of electronic health records from their institution, Dr. Crouse and colleagues reviewed data from 604 patients who were confirmed to have tested positive for COVID-19 between Feb. 25 and June 22, 2020. Of those individuals, 40% had diabetes.

Death occurred in 11% (n = 67); the odds ratio (OR) for death among those with, vs. without, diabetes was 3.62 (P < .0001).

Individuals with diabetes accounted for >60% of all deaths. In multiple logistic regression, age 50-70 vs. <50, male sex, and diabetes emerged as independent predictors of death.

Of the 42 patients with diabetes who died, 8 (19%) had used metformin, and 34 (81%) had not*, a significant difference (OR, 0.38; P = .0221). Insulin use, on the other hand, had no effect on mortality (P = .5728).

“In fact, with 11% [being] the mortality of metformin users, [this] was comparable to that of the general COVID-19-positive population and dramatically lower than the 23% mortality observed in subjects with diabetes and not on metformin,” the authors said.

The survival benefit observed with metformin remained after exclusion of patients with classic metformin contraindications, such as chronic kidney disease and heart failure (OR, 0.17; P = .0231).

“This makes any potential confounding effects from skewing metformin users toward healthier subjects without these additional comorbidities very unlikely,” Dr. Crouse and colleagues contended.

After further analysis that controlled for other covariates (age, sex, obesity status, and hypertension), age, sex, and metformin use remained independent predictors of mortality.

For metformin, the odds ratio was 0.33 (P = .0210).

But, Dr. Lipska pointed out, “Observational studies can take into account confounders that are measured. However, unmeasured confounders may still affect the conclusions of these studies ... Propensity score matching to account for the likelihood of use of metformin could be used to better account for differences between metformin users and nonusers.”

If metformin does reduce COVID-19 deaths, multiple mechanisms likely

In his article, Dr. Scheen noted that several mechanisms have been proposed for the possible beneficial effect of metformin on COVID-19 outcomes, including direct improvements in glucose control, body weight, and insulin resistance; reduction in inflammation; inhibition of virus penetration via phosphorylation of ACE2; inhibition of an immune hyperactivation pathway; and neutrophil reduction. All remain theoretical, he emphasized.

He noted that some authors have raised concerns about possible harms from the use of metformin by patients with type 2 diabetes who are hospitalized for COVID-19, particularly because of the potential risk for lactic acidosis in cases of multiple organ failure.

In totality, four studies suggest 25% death reduction with metformin

Taken together, the four observational studies that Dr. Scheen reviewed showed that metformin had a positive effect, with an overall 25% reduction in death (P < .00001), albeit with relatively high heterogeneity (I² = 61%).

The largest of these, from the United States, included 6,256 patients hospitalized with COVID-19 and involved propensity matching. A significant reduction in mortality with metformin use was seen in women but not men (odds ratio, 0.759).

The French Coronavirus-SARS-CoV-2 and Diabetes Outcomes (CORONADO) study of 1,317 patients with diabetes and confirmed COVID-19 who were admitted to 53 French hospitals also showed a significant survival benefit for metformin, although the study wasn’t designed to address that issue.

In that study, the odds ratio for death on day 7 in prior metformin users compared to nonusers was 0.59. This finding lost significance but remained a trend after full adjustments (0.80).

Two smaller observational studies produced similar trends toward survival benefit with metformin.

Nonetheless, Dr. Scheen cautioned: “Firm conclusions about the impact of metformin therapy can only be drawn from double-blind randomized controlled trials (RCTs), and such trials are almost impossible in the context of COVID-19.”

He added: “Because metformin is out of patent and very inexpensive, no pharmaceutical company is likely to be interested in planning a study to demonstrate the benefits of metformin on COVID-19-related clinical outcomes.”

Dr. Lipska agreed: “RCTs are unlikely to be conducted to settle these issues. In their absence, metformin use should be based on its safety and effectiveness profile.”

Dr. Scheen concluded, however, that “there are at least no negative safety indications, so there is no reason to stop metformin therapy during COVID-19 infection except in cases of severe gastrointestinal symptoms, hypoxia and/or multiple organ failure.”

Dr. Lipska has received grants from the National Institutes of Health and works under contract for the Centers for Medicare & Medicaid Services to develop publicly reported quality measures. Dr. Scheen has disclosed no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

*A previous version reversed these two outcomes in error. 

Accumulating observational data suggest that metformin use in patients with type 2 diabetes might reduce the risk for death from COVID-19, but the randomized trials needed to prove this are unlikely to be carried out, according to experts.

The latest results, which are not yet peer reviewed, were published online July 31. The study was conducted by Andrew B. Crouse, PhD, of the Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, and colleagues.

The researchers found that among more than 600 patients with diabetes and COVID-19, use of metformin was associated with a nearly 70% reduction in mortality after adjustment for multiple confounders.

Data from four previous studies that also show a reduction in mortality among metformin users compared to nonusers were summarized in a “mini review” by André J. Scheen, MD, PhD, published Aug. 1 in Diabetes and Metabolism.

Dr. Scheen, of the division of diabetes, nutrition, and metabolic disorders and the division of clinical pharmacology at Liège (Belgium) University, discussed possible mechanisms behind this observation.

“Because metformin exerts various effects beyond its glucose-lowering action, among which are anti-inflammatory effects, it may be speculated that this biguanide might positively influence the prognosis of patients with [type 2 diabetes] hospitalized for COVID-19,” he said.

“However, given the potential confounders inherently found in observational studies, caution is required before drawing any firm conclusions in the absence of randomized controlled trials,” Dr. Scheen wrote.

Indeed, when asked to comment, endocrinologist Kasia Lipska, MD, of Yale University, New Haven, Conn., said in an interview: “Metformin users tend to do better in many different settings with respect to many different outcomes. To me, it is still unclear whether metformin is truly a miracle drug or whether it is simply used more often among people who are healthier and who do not have contraindications to its use.”

She added, “I don’t think we have enough data to suggest metformin use for COVID-19 mitigation at this point.”

Alabama authors say confounding effects ‘unlikely’

In the retrospective analysis of electronic health records from their institution, Dr. Crouse and colleagues reviewed data from 604 patients who were confirmed to have tested positive for COVID-19 between Feb. 25 and June 22, 2020. Of those individuals, 40% had diabetes.

Death occurred in 11% (n = 67); the odds ratio (OR) for death among those with, vs. without, diabetes was 3.62 (P < .0001).

Individuals with diabetes accounted for >60% of all deaths. In multiple logistic regression, age 50-70 vs. <50, male sex, and diabetes emerged as independent predictors of death.

Of the 42 patients with diabetes who died, 8 (19%) had used metformin, and 34 (81%) had not*, a significant difference (OR, 0.38; P = .0221). Insulin use, on the other hand, had no effect on mortality (P = .5728).

“In fact, with 11% [being] the mortality of metformin users, [this] was comparable to that of the general COVID-19-positive population and dramatically lower than the 23% mortality observed in subjects with diabetes and not on metformin,” the authors said.

The survival benefit observed with metformin remained after exclusion of patients with classic metformin contraindications, such as chronic kidney disease and heart failure (OR, 0.17; P = .0231).

“This makes any potential confounding effects from skewing metformin users toward healthier subjects without these additional comorbidities very unlikely,” Dr. Crouse and colleagues contended.

After further analysis that controlled for other covariates (age, sex, obesity status, and hypertension), age, sex, and metformin use remained independent predictors of mortality.

For metformin, the odds ratio was 0.33 (P = .0210).

But, Dr. Lipska pointed out, “Observational studies can take into account confounders that are measured. However, unmeasured confounders may still affect the conclusions of these studies ... Propensity score matching to account for the likelihood of use of metformin could be used to better account for differences between metformin users and nonusers.”

If metformin does reduce COVID-19 deaths, multiple mechanisms likely

In his article, Dr. Scheen noted that several mechanisms have been proposed for the possible beneficial effect of metformin on COVID-19 outcomes, including direct improvements in glucose control, body weight, and insulin resistance; reduction in inflammation; inhibition of virus penetration via phosphorylation of ACE2; inhibition of an immune hyperactivation pathway; and neutrophil reduction. All remain theoretical, he emphasized.

He noted that some authors have raised concerns about possible harms from the use of metformin by patients with type 2 diabetes who are hospitalized for COVID-19, particularly because of the potential risk for lactic acidosis in cases of multiple organ failure.

In totality, four studies suggest 25% death reduction with metformin

Taken together, the four observational studies that Dr. Scheen reviewed showed that metformin had a positive effect, with an overall 25% reduction in death (P < .00001), albeit with relatively high heterogeneity (I² = 61%).

The largest of these, from the United States, included 6,256 patients hospitalized with COVID-19 and involved propensity matching. A significant reduction in mortality with metformin use was seen in women but not men (odds ratio, 0.759).

The French Coronavirus-SARS-CoV-2 and Diabetes Outcomes (CORONADO) study of 1,317 patients with diabetes and confirmed COVID-19 who were admitted to 53 French hospitals also showed a significant survival benefit for metformin, although the study wasn’t designed to address that issue.

In that study, the odds ratio for death on day 7 in prior metformin users compared to nonusers was 0.59. This finding lost significance but remained a trend after full adjustments (0.80).

Two smaller observational studies produced similar trends toward survival benefit with metformin.

Nonetheless, Dr. Scheen cautioned: “Firm conclusions about the impact of metformin therapy can only be drawn from double-blind randomized controlled trials (RCTs), and such trials are almost impossible in the context of COVID-19.”

He added: “Because metformin is out of patent and very inexpensive, no pharmaceutical company is likely to be interested in planning a study to demonstrate the benefits of metformin on COVID-19-related clinical outcomes.”

Dr. Lipska agreed: “RCTs are unlikely to be conducted to settle these issues. In their absence, metformin use should be based on its safety and effectiveness profile.”

Dr. Scheen concluded, however, that “there are at least no negative safety indications, so there is no reason to stop metformin therapy during COVID-19 infection except in cases of severe gastrointestinal symptoms, hypoxia and/or multiple organ failure.”

Dr. Lipska has received grants from the National Institutes of Health and works under contract for the Centers for Medicare & Medicaid Services to develop publicly reported quality measures. Dr. Scheen has disclosed no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

*A previous version reversed these two outcomes in error. 

Accumulating observational data suggest that metformin use in patients with type 2 diabetes might reduce the risk for death from COVID-19, but the randomized trials needed to prove this are unlikely to be carried out, according to experts.

The latest results, which are not yet peer reviewed, were published online July 31. The study was conducted by Andrew B. Crouse, PhD, of the Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, and colleagues.

The researchers found that among more than 600 patients with diabetes and COVID-19, use of metformin was associated with a nearly 70% reduction in mortality after adjustment for multiple confounders.

Data from four previous studies that also show a reduction in mortality among metformin users compared to nonusers were summarized in a “mini review” by André J. Scheen, MD, PhD, published Aug. 1 in Diabetes and Metabolism.

Dr. Scheen, of the division of diabetes, nutrition, and metabolic disorders and the division of clinical pharmacology at Liège (Belgium) University, discussed possible mechanisms behind this observation.

“Because metformin exerts various effects beyond its glucose-lowering action, among which are anti-inflammatory effects, it may be speculated that this biguanide might positively influence the prognosis of patients with [type 2 diabetes] hospitalized for COVID-19,” he said.

“However, given the potential confounders inherently found in observational studies, caution is required before drawing any firm conclusions in the absence of randomized controlled trials,” Dr. Scheen wrote.

Indeed, when asked to comment, endocrinologist Kasia Lipska, MD, of Yale University, New Haven, Conn., said in an interview: “Metformin users tend to do better in many different settings with respect to many different outcomes. To me, it is still unclear whether metformin is truly a miracle drug or whether it is simply used more often among people who are healthier and who do not have contraindications to its use.”

She added, “I don’t think we have enough data to suggest metformin use for COVID-19 mitigation at this point.”

Alabama authors say confounding effects ‘unlikely’

In the retrospective analysis of electronic health records from their institution, Dr. Crouse and colleagues reviewed data from 604 patients who were confirmed to have tested positive for COVID-19 between Feb. 25 and June 22, 2020. Of those individuals, 40% had diabetes.

Death occurred in 11% (n = 67); the odds ratio (OR) for death among those with, vs. without, diabetes was 3.62 (P < .0001).

Individuals with diabetes accounted for >60% of all deaths. In multiple logistic regression, age 50-70 vs. <50, male sex, and diabetes emerged as independent predictors of death.

Of the 42 patients with diabetes who died, 8 (19%) had used metformin, and 34 (81%) had not*, a significant difference (OR, 0.38; P = .0221). Insulin use, on the other hand, had no effect on mortality (P = .5728).

“In fact, with 11% [being] the mortality of metformin users, [this] was comparable to that of the general COVID-19-positive population and dramatically lower than the 23% mortality observed in subjects with diabetes and not on metformin,” the authors said.

The survival benefit observed with metformin remained after exclusion of patients with classic metformin contraindications, such as chronic kidney disease and heart failure (OR, 0.17; P = .0231).

“This makes any potential confounding effects from skewing metformin users toward healthier subjects without these additional comorbidities very unlikely,” Dr. Crouse and colleagues contended.

After further analysis that controlled for other covariates (age, sex, obesity status, and hypertension), age, sex, and metformin use remained independent predictors of mortality.

For metformin, the odds ratio was 0.33 (P = .0210).

But, Dr. Lipska pointed out, “Observational studies can take into account confounders that are measured. However, unmeasured confounders may still affect the conclusions of these studies ... Propensity score matching to account for the likelihood of use of metformin could be used to better account for differences between metformin users and nonusers.”

If metformin does reduce COVID-19 deaths, multiple mechanisms likely

In his article, Dr. Scheen noted that several mechanisms have been proposed for the possible beneficial effect of metformin on COVID-19 outcomes, including direct improvements in glucose control, body weight, and insulin resistance; reduction in inflammation; inhibition of virus penetration via phosphorylation of ACE2; inhibition of an immune hyperactivation pathway; and neutrophil reduction. All remain theoretical, he emphasized.

He noted that some authors have raised concerns about possible harms from the use of metformin by patients with type 2 diabetes who are hospitalized for COVID-19, particularly because of the potential risk for lactic acidosis in cases of multiple organ failure.

In totality, four studies suggest 25% death reduction with metformin

Taken together, the four observational studies that Dr. Scheen reviewed showed that metformin had a positive effect, with an overall 25% reduction in death (P < .00001), albeit with relatively high heterogeneity (I² = 61%).

The largest of these, from the United States, included 6,256 patients hospitalized with COVID-19 and involved propensity matching. A significant reduction in mortality with metformin use was seen in women but not men (odds ratio, 0.759).

The French Coronavirus-SARS-CoV-2 and Diabetes Outcomes (CORONADO) study of 1,317 patients with diabetes and confirmed COVID-19 who were admitted to 53 French hospitals also showed a significant survival benefit for metformin, although the study wasn’t designed to address that issue.

In that study, the odds ratio for death on day 7 in prior metformin users compared to nonusers was 0.59. This finding lost significance but remained a trend after full adjustments (0.80).

Two smaller observational studies produced similar trends toward survival benefit with metformin.

Nonetheless, Dr. Scheen cautioned: “Firm conclusions about the impact of metformin therapy can only be drawn from double-blind randomized controlled trials (RCTs), and such trials are almost impossible in the context of COVID-19.”

He added: “Because metformin is out of patent and very inexpensive, no pharmaceutical company is likely to be interested in planning a study to demonstrate the benefits of metformin on COVID-19-related clinical outcomes.”

Dr. Lipska agreed: “RCTs are unlikely to be conducted to settle these issues. In their absence, metformin use should be based on its safety and effectiveness profile.”

Dr. Scheen concluded, however, that “there are at least no negative safety indications, so there is no reason to stop metformin therapy during COVID-19 infection except in cases of severe gastrointestinal symptoms, hypoxia and/or multiple organ failure.”

Dr. Lipska has received grants from the National Institutes of Health and works under contract for the Centers for Medicare & Medicaid Services to develop publicly reported quality measures. Dr. Scheen has disclosed no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

*A previous version reversed these two outcomes in error. 

New guidance from the U.K. National Diabetes COVID-19 Response Group addresses glucose management in patients with COVID-19 who are receiving dexamethasone therapy.

Although there are already guidelines that address inpatient management of steroid-induced hyperglycemia, the authors of the new document wrote that this new expert opinion paper was needed “given the ‘triple insult’ of dexamethasone-induced–impaired glucose metabolism, COVID-19–induced insulin resistance, and COVID-19–impaired insulin production.”

RECOVERY trial spurs response

The document, which is the latest in a series from the Association of British Clinical Diabetologists, was published online Aug. 2 in Diabetic Medicine. The group is chaired by Gerry Rayman, MD, consultant physician at the diabetes centre and diabetes research unit, East Suffolk (England) and North East NHS Foundation Trust.

The guidance was developed in response to the recent “breakthrough” Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, which showed that dexamethasone reduced deaths in patients with COVID-19 on ventilators or receiving oxygen therapy. The advice is not intended for critical care units but can be adapted for that use.

The dose used in RECOVERY – 6 mg daily for 10 days – is 400%-500% greater than the therapeutic glucocorticoid replacement dose. High glucocorticoid doses can exacerbate hyperglycemia in people with established diabetes, unmask undiagnosed diabetes, precipitate hyperglycemia or new-onset diabetes, and can also cause hyperglycemic hyperosmolar state (HHS), the authors explained.

They recommended a target glucose of 6.0-10.0 mmol/L (108-180 mg/dL), although they say up to 12 mmol/L (216 mg/dL) is “acceptable.” They then gave advice on frequency of monitoring for people with and without known diabetes, exclusion of diabetic ketoacidosis and HHS, correction of initial hyperglycemia and maintenance of glycemic control using subcutaneous insulin, and prevention of hypoglycemia at the end of dexamethasone therapy (day 10) with insulin down-titration, discharge, and follow-up.

The detailed insulin guidance covers dose escalation for both insulin-treated and insulin-naive patients. A table suggests increasing correction doses of rapid-acting insulin based on prior total daily dose or weight.

Use of once- or twice-daily NPH insulin is recommended for patients whose glucose has risen above 12 mmol/L, in some cases with the addition of a long-acting analog. A second chart gives dose adjustments for those insulins. Additional guidance addresses patients on insulin pumps.

Guidance useful for U.S. physicians

Francisco Pasquel, MD, assistant professor of medicine in the division of endocrinology at Emory University, Atlanta, said in an interview that he believes the guidance is “acceptable” for worldwide use, and that “it’s coherent and consistent with what we typically do.”

However, Dr. Pasquel, who founded COVID-in-Diabetes, an online repository of published guidance and shared experience – to which this new document has now been added – did take issue with one piece of advice. The guidance says that patients already taking premixed insulin formulations can continue using them while increasing the dose by 20%-40%. Given the risk of hypoglycemia associated with those formulations, Dr. Pasquel said he would switch those patients to NPH during the time that they’re on dexamethasone.

He also noted that the rapid-acting insulin dose range of 2-10 units provided in the first table, for correction of initial hyperglycemia, are more conservative than those used at his hospital, where correction doses of up to 14-16 units are sometimes necessary.

But Dr. Pasquel praised the group’s overall efforts since the pandemic began, noting that “they’re very organized and constantly updating their recommendations. They have a unified system in the [National Health Service], so it’s easier to standardize. They have a unique [electronic health record] which is far superior to what we do from a public health perspective.”

Dr. Rayman reported no relevant financial relationships. Dr. Pasquel reported receiving research funding from Dexcom, Merck, and the National Institutes of Health, and consulting for AstraZeneca, Eli Lilly, Merck, and Boehringer Ingelheim.

A version of this article originally appeared on Medscape.com.

New guidance from the U.K. National Diabetes COVID-19 Response Group addresses glucose management in patients with COVID-19 who are receiving dexamethasone therapy.

Although there are already guidelines that address inpatient management of steroid-induced hyperglycemia, the authors of the new document wrote that this new expert opinion paper was needed “given the ‘triple insult’ of dexamethasone-induced–impaired glucose metabolism, COVID-19–induced insulin resistance, and COVID-19–impaired insulin production.”

RECOVERY trial spurs response

The document, which is the latest in a series from the Association of British Clinical Diabetologists, was published online Aug. 2 in Diabetic Medicine. The group is chaired by Gerry Rayman, MD, consultant physician at the diabetes centre and diabetes research unit, East Suffolk (England) and North East NHS Foundation Trust.

The guidance was developed in response to the recent “breakthrough” Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, which showed that dexamethasone reduced deaths in patients with COVID-19 on ventilators or receiving oxygen therapy. The advice is not intended for critical care units but can be adapted for that use.

The dose used in RECOVERY – 6 mg daily for 10 days – is 400%-500% greater than the therapeutic glucocorticoid replacement dose. High glucocorticoid doses can exacerbate hyperglycemia in people with established diabetes, unmask undiagnosed diabetes, precipitate hyperglycemia or new-onset diabetes, and can also cause hyperglycemic hyperosmolar state (HHS), the authors explained.

They recommended a target glucose of 6.0-10.0 mmol/L (108-180 mg/dL), although they say up to 12 mmol/L (216 mg/dL) is “acceptable.” They then gave advice on frequency of monitoring for people with and without known diabetes, exclusion of diabetic ketoacidosis and HHS, correction of initial hyperglycemia and maintenance of glycemic control using subcutaneous insulin, and prevention of hypoglycemia at the end of dexamethasone therapy (day 10) with insulin down-titration, discharge, and follow-up.

The detailed insulin guidance covers dose escalation for both insulin-treated and insulin-naive patients. A table suggests increasing correction doses of rapid-acting insulin based on prior total daily dose or weight.

Use of once- or twice-daily NPH insulin is recommended for patients whose glucose has risen above 12 mmol/L, in some cases with the addition of a long-acting analog. A second chart gives dose adjustments for those insulins. Additional guidance addresses patients on insulin pumps.

Guidance useful for U.S. physicians

Francisco Pasquel, MD, assistant professor of medicine in the division of endocrinology at Emory University, Atlanta, said in an interview that he believes the guidance is “acceptable” for worldwide use, and that “it’s coherent and consistent with what we typically do.”

However, Dr. Pasquel, who founded COVID-in-Diabetes, an online repository of published guidance and shared experience – to which this new document has now been added – did take issue with one piece of advice. The guidance says that patients already taking premixed insulin formulations can continue using them while increasing the dose by 20%-40%. Given the risk of hypoglycemia associated with those formulations, Dr. Pasquel said he would switch those patients to NPH during the time that they’re on dexamethasone.

He also noted that the rapid-acting insulin dose range of 2-10 units provided in the first table, for correction of initial hyperglycemia, are more conservative than those used at his hospital, where correction doses of up to 14-16 units are sometimes necessary.

But Dr. Pasquel praised the group’s overall efforts since the pandemic began, noting that “they’re very organized and constantly updating their recommendations. They have a unified system in the [National Health Service], so it’s easier to standardize. They have a unique [electronic health record] which is far superior to what we do from a public health perspective.”

Dr. Rayman reported no relevant financial relationships. Dr. Pasquel reported receiving research funding from Dexcom, Merck, and the National Institutes of Health, and consulting for AstraZeneca, Eli Lilly, Merck, and Boehringer Ingelheim.

A version of this article originally appeared on Medscape.com.

New guidance from the U.K. National Diabetes COVID-19 Response Group addresses glucose management in patients with COVID-19 who are receiving dexamethasone therapy.

Although there are already guidelines that address inpatient management of steroid-induced hyperglycemia, the authors of the new document wrote that this new expert opinion paper was needed “given the ‘triple insult’ of dexamethasone-induced–impaired glucose metabolism, COVID-19–induced insulin resistance, and COVID-19–impaired insulin production.”

RECOVERY trial spurs response

The document, which is the latest in a series from the Association of British Clinical Diabetologists, was published online Aug. 2 in Diabetic Medicine. The group is chaired by Gerry Rayman, MD, consultant physician at the diabetes centre and diabetes research unit, East Suffolk (England) and North East NHS Foundation Trust.

The guidance was developed in response to the recent “breakthrough” Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, which showed that dexamethasone reduced deaths in patients with COVID-19 on ventilators or receiving oxygen therapy. The advice is not intended for critical care units but can be adapted for that use.

The dose used in RECOVERY – 6 mg daily for 10 days – is 400%-500% greater than the therapeutic glucocorticoid replacement dose. High glucocorticoid doses can exacerbate hyperglycemia in people with established diabetes, unmask undiagnosed diabetes, precipitate hyperglycemia or new-onset diabetes, and can also cause hyperglycemic hyperosmolar state (HHS), the authors explained.

They recommended a target glucose of 6.0-10.0 mmol/L (108-180 mg/dL), although they say up to 12 mmol/L (216 mg/dL) is “acceptable.” They then gave advice on frequency of monitoring for people with and without known diabetes, exclusion of diabetic ketoacidosis and HHS, correction of initial hyperglycemia and maintenance of glycemic control using subcutaneous insulin, and prevention of hypoglycemia at the end of dexamethasone therapy (day 10) with insulin down-titration, discharge, and follow-up.

The detailed insulin guidance covers dose escalation for both insulin-treated and insulin-naive patients. A table suggests increasing correction doses of rapid-acting insulin based on prior total daily dose or weight.

Use of once- or twice-daily NPH insulin is recommended for patients whose glucose has risen above 12 mmol/L, in some cases with the addition of a long-acting analog. A second chart gives dose adjustments for those insulins. Additional guidance addresses patients on insulin pumps.

Guidance useful for U.S. physicians

Francisco Pasquel, MD, assistant professor of medicine in the division of endocrinology at Emory University, Atlanta, said in an interview that he believes the guidance is “acceptable” for worldwide use, and that “it’s coherent and consistent with what we typically do.”

However, Dr. Pasquel, who founded COVID-in-Diabetes, an online repository of published guidance and shared experience – to which this new document has now been added – did take issue with one piece of advice. The guidance says that patients already taking premixed insulin formulations can continue using them while increasing the dose by 20%-40%. Given the risk of hypoglycemia associated with those formulations, Dr. Pasquel said he would switch those patients to NPH during the time that they’re on dexamethasone.

He also noted that the rapid-acting insulin dose range of 2-10 units provided in the first table, for correction of initial hyperglycemia, are more conservative than those used at his hospital, where correction doses of up to 14-16 units are sometimes necessary.

But Dr. Pasquel praised the group’s overall efforts since the pandemic began, noting that “they’re very organized and constantly updating their recommendations. They have a unified system in the [National Health Service], so it’s easier to standardize. They have a unique [electronic health record] which is far superior to what we do from a public health perspective.”

Dr. Rayman reported no relevant financial relationships. Dr. Pasquel reported receiving research funding from Dexcom, Merck, and the National Institutes of Health, and consulting for AstraZeneca, Eli Lilly, Merck, and Boehringer Ingelheim.

A version of this article originally appeared on Medscape.com.

Italian patients with diabetic foot ulceration (DFUs) suffered mightily during the height of the coronavirus pandemic in that country, according to a newly published study.

Phalinn Ooi/CC-BY-2.0

Amid a mandatory national lockdown, the rates of amputations skyrocketed at a hospital far from the hardest-hit region as many patients developed gangrene.

The findings offer critical lessons for the United States, said wound care specialist William H. Tettelbach, MD, of Western Peaks Specialty Hospital near Salt Lake City. “It’s become more obvious that outpatient wound care is a critical care need for the community because of the risk of ignoring these chronic wounds and letting them remain open. We cannot let these services be closed down like some were when the pandemic started.”

The study, led by Paola Caruso, MD, of the University of Campania Luigi Vanvitelli in Naples, appeared in Diabetes Care.

The researchers launched the study to understand how patients with diabetes and DFU fared during the height of the pandemic in Italy, where tens of thousands of people died, mainly in the northern region of the country. They focused on patients in the southern region who were admitted to the division of endocrinology and metabolic diseases at the Teaching Hospital at the University of Campania Luigi Vanvitelli.

The study compared 25 patients who were admitted from March 9 to May 18, 2020, with 38 patients who were admitted from a longer period between January and May 2019. The demographics of the groups are similar, with average ages in the early 60s and more men than women (21:4, respectively, in 2020 and 23:15, respectively, in 2019.)

The results reveal high numbers of emergent and serious cases in 2020. Compared with 2019, fewer were outpatients (16% vs. 45%, P = .028) and more were emergency patients (76% vs. 26%, P < .001).

Clinically, gangrene was much more common in the 2020 group, compared with the 2019 group (64% vs. 29%, P = .009), as was amputation (60% vs. 18%, P = .001).

The researchers determined that amputation was more than three times more likely in the 2020 versus the 2019 group (relative risk, 3.26; 95% confidence interval, 1.55-6.84) even though the 2019 period was longer. After adjustment for gender, the heightened risk in 2020 was 2.50 (95% CI, 1.18-5.29).

There was no statistically significant increase in the risk of revascularization.

“The COVID-19 lockdown may have had a detrimental impact on amputation risk because of the sudden interruption of DFU care and lower-limb preservation pathways, resulting in delayed diagnosis and treatment,” the researchers wrote. “DFU is often characterized by progressive clinical course, which can rapidly lead patients to critical worsening of their ulcers.”

They added that “the higher risk of amputation observed during COVID-19 lockdown confirms the need for proper and timely management of DFU patients to prevent dramatic outcomes responsible for a reduction of quality of life and increased morbidity and mortality.”

The study authors didn’t discuss why more patients seemed to have stayed home and not gotten proper care. It’s not clear if they were scared to get treatment or couldn’t obtain it because of the national shutdown.

Both have been factors affecting diabetic foot care in the United States during the pandemic, said Dr. Tettelbach. He called the study “timely and pertinent,” and said it highlights how wound care is “a critical need” that must remain available even when other medical services such as elective surgeries are shut down.

Infection-control protocols such as allowing patients to wait for appointments in their cars instead of waiting rooms will alleviate the fears of certain patients about seeking in-person care during the pandemic, he said. But some patients will be afraid to come in no matter what, he said, and home health may be the best solution for their care.

Several of the study authors reported various disclosures. Dr. Tettelbach reported no relevant disclosures.

SOURCE: Caruso P et al. Diabetes Care. 2020 Jul 23. doi:10.2337/dc20-1347.

Italian patients with diabetic foot ulceration (DFUs) suffered mightily during the height of the coronavirus pandemic in that country, according to a newly published study.

Phalinn Ooi/CC-BY-2.0

Amid a mandatory national lockdown, the rates of amputations skyrocketed at a hospital far from the hardest-hit region as many patients developed gangrene.

The findings offer critical lessons for the United States, said wound care specialist William H. Tettelbach, MD, of Western Peaks Specialty Hospital near Salt Lake City. “It’s become more obvious that outpatient wound care is a critical care need for the community because of the risk of ignoring these chronic wounds and letting them remain open. We cannot let these services be closed down like some were when the pandemic started.”

The study, led by Paola Caruso, MD, of the University of Campania Luigi Vanvitelli in Naples, appeared in Diabetes Care.

The researchers launched the study to understand how patients with diabetes and DFU fared during the height of the pandemic in Italy, where tens of thousands of people died, mainly in the northern region of the country. They focused on patients in the southern region who were admitted to the division of endocrinology and metabolic diseases at the Teaching Hospital at the University of Campania Luigi Vanvitelli.

The study compared 25 patients who were admitted from March 9 to May 18, 2020, with 38 patients who were admitted from a longer period between January and May 2019. The demographics of the groups are similar, with average ages in the early 60s and more men than women (21:4, respectively, in 2020 and 23:15, respectively, in 2019.)

The results reveal high numbers of emergent and serious cases in 2020. Compared with 2019, fewer were outpatients (16% vs. 45%, P = .028) and more were emergency patients (76% vs. 26%, P < .001).

Clinically, gangrene was much more common in the 2020 group, compared with the 2019 group (64% vs. 29%, P = .009), as was amputation (60% vs. 18%, P = .001).

The researchers determined that amputation was more than three times more likely in the 2020 versus the 2019 group (relative risk, 3.26; 95% confidence interval, 1.55-6.84) even though the 2019 period was longer. After adjustment for gender, the heightened risk in 2020 was 2.50 (95% CI, 1.18-5.29).

There was no statistically significant increase in the risk of revascularization.

“The COVID-19 lockdown may have had a detrimental impact on amputation risk because of the sudden interruption of DFU care and lower-limb preservation pathways, resulting in delayed diagnosis and treatment,” the researchers wrote. “DFU is often characterized by progressive clinical course, which can rapidly lead patients to critical worsening of their ulcers.”

They added that “the higher risk of amputation observed during COVID-19 lockdown confirms the need for proper and timely management of DFU patients to prevent dramatic outcomes responsible for a reduction of quality of life and increased morbidity and mortality.”

The study authors didn’t discuss why more patients seemed to have stayed home and not gotten proper care. It’s not clear if they were scared to get treatment or couldn’t obtain it because of the national shutdown.

Both have been factors affecting diabetic foot care in the United States during the pandemic, said Dr. Tettelbach. He called the study “timely and pertinent,” and said it highlights how wound care is “a critical need” that must remain available even when other medical services such as elective surgeries are shut down.

Infection-control protocols such as allowing patients to wait for appointments in their cars instead of waiting rooms will alleviate the fears of certain patients about seeking in-person care during the pandemic, he said. But some patients will be afraid to come in no matter what, he said, and home health may be the best solution for their care.

Several of the study authors reported various disclosures. Dr. Tettelbach reported no relevant disclosures.

SOURCE: Caruso P et al. Diabetes Care. 2020 Jul 23. doi:10.2337/dc20-1347.

Italian patients with diabetic foot ulceration (DFUs) suffered mightily during the height of the coronavirus pandemic in that country, according to a newly published study.

Phalinn Ooi/CC-BY-2.0

Amid a mandatory national lockdown, the rates of amputations skyrocketed at a hospital far from the hardest-hit region as many patients developed gangrene.

The findings offer critical lessons for the United States, said wound care specialist William H. Tettelbach, MD, of Western Peaks Specialty Hospital near Salt Lake City. “It’s become more obvious that outpatient wound care is a critical care need for the community because of the risk of ignoring these chronic wounds and letting them remain open. We cannot let these services be closed down like some were when the pandemic started.”

The study, led by Paola Caruso, MD, of the University of Campania Luigi Vanvitelli in Naples, appeared in Diabetes Care.

The researchers launched the study to understand how patients with diabetes and DFU fared during the height of the pandemic in Italy, where tens of thousands of people died, mainly in the northern region of the country. They focused on patients in the southern region who were admitted to the division of endocrinology and metabolic diseases at the Teaching Hospital at the University of Campania Luigi Vanvitelli.

The study compared 25 patients who were admitted from March 9 to May 18, 2020, with 38 patients who were admitted from a longer period between January and May 2019. The demographics of the groups are similar, with average ages in the early 60s and more men than women (21:4, respectively, in 2020 and 23:15, respectively, in 2019.)

The results reveal high numbers of emergent and serious cases in 2020. Compared with 2019, fewer were outpatients (16% vs. 45%, P = .028) and more were emergency patients (76% vs. 26%, P < .001).

Clinically, gangrene was much more common in the 2020 group, compared with the 2019 group (64% vs. 29%, P = .009), as was amputation (60% vs. 18%, P = .001).

The researchers determined that amputation was more than three times more likely in the 2020 versus the 2019 group (relative risk, 3.26; 95% confidence interval, 1.55-6.84) even though the 2019 period was longer. After adjustment for gender, the heightened risk in 2020 was 2.50 (95% CI, 1.18-5.29).

There was no statistically significant increase in the risk of revascularization.

“The COVID-19 lockdown may have had a detrimental impact on amputation risk because of the sudden interruption of DFU care and lower-limb preservation pathways, resulting in delayed diagnosis and treatment,” the researchers wrote. “DFU is often characterized by progressive clinical course, which can rapidly lead patients to critical worsening of their ulcers.”

They added that “the higher risk of amputation observed during COVID-19 lockdown confirms the need for proper and timely management of DFU patients to prevent dramatic outcomes responsible for a reduction of quality of life and increased morbidity and mortality.”

The study authors didn’t discuss why more patients seemed to have stayed home and not gotten proper care. It’s not clear if they were scared to get treatment or couldn’t obtain it because of the national shutdown.

Both have been factors affecting diabetic foot care in the United States during the pandemic, said Dr. Tettelbach. He called the study “timely and pertinent,” and said it highlights how wound care is “a critical need” that must remain available even when other medical services such as elective surgeries are shut down.

Infection-control protocols such as allowing patients to wait for appointments in their cars instead of waiting rooms will alleviate the fears of certain patients about seeking in-person care during the pandemic, he said. But some patients will be afraid to come in no matter what, he said, and home health may be the best solution for their care.

Several of the study authors reported various disclosures. Dr. Tettelbach reported no relevant disclosures.

SOURCE: Caruso P et al. Diabetes Care. 2020 Jul 23. doi:10.2337/dc20-1347.

Women facing issues related to perimenopause and menopause can consult their primary care physicians or ob.gyns. through telemedicine visits, but a new online portal, the Cusp, offers an alternative model with a focus on menopause and access to experts for a monthly membership fee.

The Cusp doesn’t claim to replace routine gynecologic care. Rather, it focuses on perimenopause and menopause symptoms specifically, and states that its physicians, some of whom are certified by the North American Menopause Society, provide expertise in menopause beyond what patients might receive as part of a typical ob.gyn. visit.

The Cusp is a for-profit organization, a group of physicians, nurse practitioners, and technologists who focus on integrated care for women in perimenopause and beyond. The aim is to leverage technology as a way to connect women to the care platform to book physician and nurse practitioner visits virtually and to have all of the information about their care centralized in one place.

According to the website, most patients who sign up for a care plan check in with their providers at least once a month to monitor their symptoms and tweak treatment strategies. Patients who sign up are prompted to download an app, which then becomes the main tool for scheduling future visits, tracking symptoms, and communicating with providers.

The Cusp launched in early 2019, before the advent of the COVID-19 pandemic, but the pandemic has accelerated the acceptance across medical specialties, suggesting that telemedicine is here to stay, according to Mindy Goldman, MD, professor of gynecology and gynecologic surgery at the University of California, San Francisco, and director of the Gynecology Center for Cancer Survivors and At-Risk Women at UCSF, who also serves as a medical adviser to the Cusp.

Partnering with technology companies allows opportunities to provide care in areas where there are gaps, such as menopause management, she said. Many clinicians in primary care and ob.gyn. care don’t have the time or training to discuss menopause management in depth with patients, and patient interviews conducted by the Cusp before launching the site showed that this was an area of need.

“One thing that is really unique about the Cusp is that we brought together experts to provide care in both in an evidence-based and holistic fashion,” Dr. Goldman emphasized.

The Cusp’s medical team includes physician and nurse practitioner menopause experts with backgrounds including not only ob.gyn. but also psychiatry, integrative medicine, and naturopathic medicine, with plans to add endocrinology and dermatology as well. This holistic approach allows the Cusp to tailor care based on what each woman is looking for, with evidence-based expertise to support treatment decisions, said Dr. Goldman, whose advisory role includes helping to develop patient treatment protocols and services.

If a woman wants to begin treating symptoms with a naturopathic approach, the team will provide protocols that take current guidelines into account. Regular visits, approximately once a month or as needed, allow for collaboration with the Cusp’s specialists to provide consistent care that is very comprehensive, she said.

One of the benefits of the Cusp is the opportunity for “frequent touchpoints” in which providers reach out to patients via text, email, or video. Although a traditional medical visit may include some initial discussion of menopause and treatment plans, the Cusp offers “a more seamless way to address needs on an ongoing basis,” to provide more complete patient care, Dr. Goldman said.

“We are constantly asking women what they are looking for in menopause care,” and a recurring question was about hormone testing, she said. Nontraditional practitioners may offer hormone testing as a way of individualizing care that also involves compounded formulations, and other treatments that are not standard of care. “In all of our protocols we follow what is recommended by standard organizations such as ACOG [American College of Obstetricians and Gynecologists] and NAMS.”

The Cusp’s newest service is an at-home hormone test currently for women in New York and California, but the company plans to expand this service. The hormone test, while not essential, is another tool to guide menopause management, and having a sense of when menopause will occur “gives us a chance to talk to people about behavioral changes and time to personalize a treatment protocol,” Dr. Goldman said.

The test is based in part on the anti-Müllerian hormone, which recent studies have shown is useful in predicting time to menopause. This, in combination with other hormone tests and other clinical information, will allow the Cusp’s menopause specialists to help women in perimenopause gain perspective on their symptoms and design a treatment plan that can evolve as their needs change, she explained.

“The more information you know about when menopause is going to be happening, you can tailor your treatment plan,” Dr. Goldman said. For example, a woman who may be 2 years away from menopause might consider a naturopathic approach at first, and switch to a different therapy as menopause occurs. “We know that the risks of cardiovascular disease and bone loss increase after menopause, and knowing the time to menopause gives us more guidance when educating patients about healthy lifestyle habits such as exercise and dietary changes that can help reduce these risks.”

The Cusp allows patients to use money in flexible spending accounts or health savings accounts to pay for the program. If doctors require lab tests or other procedures, these are covered through the patients’ regular health insurance as they would be if requested by a primary care physician or other health care professional.

Lubna Pal, MBBS, director of the menopause program at Yale University, New Haven, Conn., commented that part of the value in a telehealth site such as the Cusp is to serve as “a resource for reproductively aging women to understand what is happening to them.”

Any way to improve education on the topic of menopause is empowering to women, said Dr. Pal, professor of obstetrics, gynecology, and reproductive sciences at Yale. “This is an opportunity for patients to have access to a directed evaluation” of menopause-related symptoms. Then, when women visit their regular health care provider in person, they are well-equipped with knowledge to ask more informed questions and discuss a wide range of treatment options.

Dr. Pal noted that the hormone test is less valuable than the interaction between physicians and patients, whether online or in person.

“Menopause is a Monday morning quarterback diagnosis,” she said, emphasizing that, not only is a year without menses part of the diagnosis of menopause, many women in perimenopause can have wide fluctuations in hormone levels, so a test is more of a snapshot than a diagnostic tool, and that the results might cause unnecessary angst and concerns for patients.

However, part of the value of a telehealth site that focuses on menopause is that it gives women a place to learn more about their biology and to clarify their questions about symptoms and become aware of a range of treatment options. Telehealth consultations also can help women recognize how other factors such as lifestyle modifications can play a role in menopause symptoms, and how modifying these factors may provide some relief, she said.

Dr. Pal said she would be cautious about the idea of prescribing without seeing the patient in person, but noted that telehealth sites such as the Cusp can be a win-win to enhance women’s health when used in combination with regular in-person visits to an ob.gyn. The added value in patients’ being able to discuss their concerns and to learn more about their symptoms means that they will be better informed to develop a menopause management strategy in partnership with their providers, said Dr. Pal, who is not associated with the Cusp.

Dr. Goldman disclosed receiving compensation from the Cusp for her advisory work. She also holds stock options in the company. Dr. Pal, who is a member of the Ob.Gyn. News editorial advisory board, had no financial conflicts to disclose.

Women facing issues related to perimenopause and menopause can consult their primary care physicians or ob.gyns. through telemedicine visits, but a new online portal, the Cusp, offers an alternative model with a focus on menopause and access to experts for a monthly membership fee.

The Cusp doesn’t claim to replace routine gynecologic care. Rather, it focuses on perimenopause and menopause symptoms specifically, and states that its physicians, some of whom are certified by the North American Menopause Society, provide expertise in menopause beyond what patients might receive as part of a typical ob.gyn. visit.

The Cusp is a for-profit organization, a group of physicians, nurse practitioners, and technologists who focus on integrated care for women in perimenopause and beyond. The aim is to leverage technology as a way to connect women to the care platform to book physician and nurse practitioner visits virtually and to have all of the information about their care centralized in one place.

According to the website, most patients who sign up for a care plan check in with their providers at least once a month to monitor their symptoms and tweak treatment strategies. Patients who sign up are prompted to download an app, which then becomes the main tool for scheduling future visits, tracking symptoms, and communicating with providers.

The Cusp launched in early 2019, before the advent of the COVID-19 pandemic, but the pandemic has accelerated the acceptance across medical specialties, suggesting that telemedicine is here to stay, according to Mindy Goldman, MD, professor of gynecology and gynecologic surgery at the University of California, San Francisco, and director of the Gynecology Center for Cancer Survivors and At-Risk Women at UCSF, who also serves as a medical adviser to the Cusp.

Partnering with technology companies allows opportunities to provide care in areas where there are gaps, such as menopause management, she said. Many clinicians in primary care and ob.gyn. care don’t have the time or training to discuss menopause management in depth with patients, and patient interviews conducted by the Cusp before launching the site showed that this was an area of need.

“One thing that is really unique about the Cusp is that we brought together experts to provide care in both in an evidence-based and holistic fashion,” Dr. Goldman emphasized.

The Cusp’s medical team includes physician and nurse practitioner menopause experts with backgrounds including not only ob.gyn. but also psychiatry, integrative medicine, and naturopathic medicine, with plans to add endocrinology and dermatology as well. This holistic approach allows the Cusp to tailor care based on what each woman is looking for, with evidence-based expertise to support treatment decisions, said Dr. Goldman, whose advisory role includes helping to develop patient treatment protocols and services.

If a woman wants to begin treating symptoms with a naturopathic approach, the team will provide protocols that take current guidelines into account. Regular visits, approximately once a month or as needed, allow for collaboration with the Cusp’s specialists to provide consistent care that is very comprehensive, she said.

One of the benefits of the Cusp is the opportunity for “frequent touchpoints” in which providers reach out to patients via text, email, or video. Although a traditional medical visit may include some initial discussion of menopause and treatment plans, the Cusp offers “a more seamless way to address needs on an ongoing basis,” to provide more complete patient care, Dr. Goldman said.

“We are constantly asking women what they are looking for in menopause care,” and a recurring question was about hormone testing, she said. Nontraditional practitioners may offer hormone testing as a way of individualizing care that also involves compounded formulations, and other treatments that are not standard of care. “In all of our protocols we follow what is recommended by standard organizations such as ACOG [American College of Obstetricians and Gynecologists] and NAMS.”

The Cusp’s newest service is an at-home hormone test currently for women in New York and California, but the company plans to expand this service. The hormone test, while not essential, is another tool to guide menopause management, and having a sense of when menopause will occur “gives us a chance to talk to people about behavioral changes and time to personalize a treatment protocol,” Dr. Goldman said.

The test is based in part on the anti-Müllerian hormone, which recent studies have shown is useful in predicting time to menopause. This, in combination with other hormone tests and other clinical information, will allow the Cusp’s menopause specialists to help women in perimenopause gain perspective on their symptoms and design a treatment plan that can evolve as their needs change, she explained.

“The more information you know about when menopause is going to be happening, you can tailor your treatment plan,” Dr. Goldman said. For example, a woman who may be 2 years away from menopause might consider a naturopathic approach at first, and switch to a different therapy as menopause occurs. “We know that the risks of cardiovascular disease and bone loss increase after menopause, and knowing the time to menopause gives us more guidance when educating patients about healthy lifestyle habits such as exercise and dietary changes that can help reduce these risks.”

The Cusp allows patients to use money in flexible spending accounts or health savings accounts to pay for the program. If doctors require lab tests or other procedures, these are covered through the patients’ regular health insurance as they would be if requested by a primary care physician or other health care professional.

Lubna Pal, MBBS, director of the menopause program at Yale University, New Haven, Conn., commented that part of the value in a telehealth site such as the Cusp is to serve as “a resource for reproductively aging women to understand what is happening to them.”

Any way to improve education on the topic of menopause is empowering to women, said Dr. Pal, professor of obstetrics, gynecology, and reproductive sciences at Yale. “This is an opportunity for patients to have access to a directed evaluation” of menopause-related symptoms. Then, when women visit their regular health care provider in person, they are well-equipped with knowledge to ask more informed questions and discuss a wide range of treatment options.

Dr. Pal noted that the hormone test is less valuable than the interaction between physicians and patients, whether online or in person.

“Menopause is a Monday morning quarterback diagnosis,” she said, emphasizing that, not only is a year without menses part of the diagnosis of menopause, many women in perimenopause can have wide fluctuations in hormone levels, so a test is more of a snapshot than a diagnostic tool, and that the results might cause unnecessary angst and concerns for patients.

However, part of the value of a telehealth site that focuses on menopause is that it gives women a place to learn more about their biology and to clarify their questions about symptoms and become aware of a range of treatment options. Telehealth consultations also can help women recognize how other factors such as lifestyle modifications can play a role in menopause symptoms, and how modifying these factors may provide some relief, she said.

Dr. Pal said she would be cautious about the idea of prescribing without seeing the patient in person, but noted that telehealth sites such as the Cusp can be a win-win to enhance women’s health when used in combination with regular in-person visits to an ob.gyn. The added value in patients’ being able to discuss their concerns and to learn more about their symptoms means that they will be better informed to develop a menopause management strategy in partnership with their providers, said Dr. Pal, who is not associated with the Cusp.

Dr. Goldman disclosed receiving compensation from the Cusp for her advisory work. She also holds stock options in the company. Dr. Pal, who is a member of the Ob.Gyn. News editorial advisory board, had no financial conflicts to disclose.

Women facing issues related to perimenopause and menopause can consult their primary care physicians or ob.gyns. through telemedicine visits, but a new online portal, the Cusp, offers an alternative model with a focus on menopause and access to experts for a monthly membership fee.

The Cusp doesn’t claim to replace routine gynecologic care. Rather, it focuses on perimenopause and menopause symptoms specifically, and states that its physicians, some of whom are certified by the North American Menopause Society, provide expertise in menopause beyond what patients might receive as part of a typical ob.gyn. visit.

The Cusp is a for-profit organization, a group of physicians, nurse practitioners, and technologists who focus on integrated care for women in perimenopause and beyond. The aim is to leverage technology as a way to connect women to the care platform to book physician and nurse practitioner visits virtually and to have all of the information about their care centralized in one place.

According to the website, most patients who sign up for a care plan check in with their providers at least once a month to monitor their symptoms and tweak treatment strategies. Patients who sign up are prompted to download an app, which then becomes the main tool for scheduling future visits, tracking symptoms, and communicating with providers.

The Cusp launched in early 2019, before the advent of the COVID-19 pandemic, but the pandemic has accelerated the acceptance across medical specialties, suggesting that telemedicine is here to stay, according to Mindy Goldman, MD, professor of gynecology and gynecologic surgery at the University of California, San Francisco, and director of the Gynecology Center for Cancer Survivors and At-Risk Women at UCSF, who also serves as a medical adviser to the Cusp.

Partnering with technology companies allows opportunities to provide care in areas where there are gaps, such as menopause management, she said. Many clinicians in primary care and ob.gyn. care don’t have the time or training to discuss menopause management in depth with patients, and patient interviews conducted by the Cusp before launching the site showed that this was an area of need.

“One thing that is really unique about the Cusp is that we brought together experts to provide care in both in an evidence-based and holistic fashion,” Dr. Goldman emphasized.

The Cusp’s medical team includes physician and nurse practitioner menopause experts with backgrounds including not only ob.gyn. but also psychiatry, integrative medicine, and naturopathic medicine, with plans to add endocrinology and dermatology as well. This holistic approach allows the Cusp to tailor care based on what each woman is looking for, with evidence-based expertise to support treatment decisions, said Dr. Goldman, whose advisory role includes helping to develop patient treatment protocols and services.

If a woman wants to begin treating symptoms with a naturopathic approach, the team will provide protocols that take current guidelines into account. Regular visits, approximately once a month or as needed, allow for collaboration with the Cusp’s specialists to provide consistent care that is very comprehensive, she said.

One of the benefits of the Cusp is the opportunity for “frequent touchpoints” in which providers reach out to patients via text, email, or video. Although a traditional medical visit may include some initial discussion of menopause and treatment plans, the Cusp offers “a more seamless way to address needs on an ongoing basis,” to provide more complete patient care, Dr. Goldman said.

“We are constantly asking women what they are looking for in menopause care,” and a recurring question was about hormone testing, she said. Nontraditional practitioners may offer hormone testing as a way of individualizing care that also involves compounded formulations, and other treatments that are not standard of care. “In all of our protocols we follow what is recommended by standard organizations such as ACOG [American College of Obstetricians and Gynecologists] and NAMS.”

The Cusp’s newest service is an at-home hormone test currently for women in New York and California, but the company plans to expand this service. The hormone test, while not essential, is another tool to guide menopause management, and having a sense of when menopause will occur “gives us a chance to talk to people about behavioral changes and time to personalize a treatment protocol,” Dr. Goldman said.

The test is based in part on the anti-Müllerian hormone, which recent studies have shown is useful in predicting time to menopause. This, in combination with other hormone tests and other clinical information, will allow the Cusp’s menopause specialists to help women in perimenopause gain perspective on their symptoms and design a treatment plan that can evolve as their needs change, she explained.

“The more information you know about when menopause is going to be happening, you can tailor your treatment plan,” Dr. Goldman said. For example, a woman who may be 2 years away from menopause might consider a naturopathic approach at first, and switch to a different therapy as menopause occurs. “We know that the risks of cardiovascular disease and bone loss increase after menopause, and knowing the time to menopause gives us more guidance when educating patients about healthy lifestyle habits such as exercise and dietary changes that can help reduce these risks.”

The Cusp allows patients to use money in flexible spending accounts or health savings accounts to pay for the program. If doctors require lab tests or other procedures, these are covered through the patients’ regular health insurance as they would be if requested by a primary care physician or other health care professional.

Lubna Pal, MBBS, director of the menopause program at Yale University, New Haven, Conn., commented that part of the value in a telehealth site such as the Cusp is to serve as “a resource for reproductively aging women to understand what is happening to them.”

Any way to improve education on the topic of menopause is empowering to women, said Dr. Pal, professor of obstetrics, gynecology, and reproductive sciences at Yale. “This is an opportunity for patients to have access to a directed evaluation” of menopause-related symptoms. Then, when women visit their regular health care provider in person, they are well-equipped with knowledge to ask more informed questions and discuss a wide range of treatment options.

Dr. Pal noted that the hormone test is less valuable than the interaction between physicians and patients, whether online or in person.

“Menopause is a Monday morning quarterback diagnosis,” she said, emphasizing that, not only is a year without menses part of the diagnosis of menopause, many women in perimenopause can have wide fluctuations in hormone levels, so a test is more of a snapshot than a diagnostic tool, and that the results might cause unnecessary angst and concerns for patients.

However, part of the value of a telehealth site that focuses on menopause is that it gives women a place to learn more about their biology and to clarify their questions about symptoms and become aware of a range of treatment options. Telehealth consultations also can help women recognize how other factors such as lifestyle modifications can play a role in menopause symptoms, and how modifying these factors may provide some relief, she said.

Dr. Pal said she would be cautious about the idea of prescribing without seeing the patient in person, but noted that telehealth sites such as the Cusp can be a win-win to enhance women’s health when used in combination with regular in-person visits to an ob.gyn. The added value in patients’ being able to discuss their concerns and to learn more about their symptoms means that they will be better informed to develop a menopause management strategy in partnership with their providers, said Dr. Pal, who is not associated with the Cusp.

Dr. Goldman disclosed receiving compensation from the Cusp for her advisory work. She also holds stock options in the company. Dr. Pal, who is a member of the Ob.Gyn. News editorial advisory board, had no financial conflicts to disclose.

The benefits from sodium-glucose cotransporter 2 inhibitor drugs proven during the past year for cutting heart failure hospitalization rates substantially in patients with heart failure with reduced ejection fraction and slowing progression of chronic kidney disease, all regardless of diabetes status, have thrust this drug class into the top tier of agents for potentially treating millions of patients with cardiac or renal disease.

The sodium-glucose cotransporter 2 (SGLT2) inhibitors, first licensed for U.S. marketing in 2013 purely for glycemic control, have, during the 5 years since the first cardiovascular outcome trial results for the class came out, shown benefits in a range of patients reminiscent of what’s been established for ACE inhibitors and angiotensin receptor blockers (ARBs).

The wide-reaching benefits of SGLT2 inhibitors have recently become even more relevant by showing clinically meaningful effects in patients without type 2 diabetes (T2D). And in an uncanny coincidence, the SGLT2 inhibitors appear to act in complementary harmony with the ACE inhibitors and ARBs for preserving heart and renal function. These properties have made the SGLT2 inhibitors especially attractive as a new weapon for controlling the ascendant disorder of cardiorenal syndrome.

“SGLT2 inhibitors have a relatively greater impact on cardiovascular outcomes, compared with ACE inhibitors and ARBs, but the effects [of the two classes] are synergistic and ideally patients receive both,” said Peter McCullough, MD, a specialist in treating cardiorenal syndrome and other cardiovascular and renal disorders at Baylor, Scott, and White Heart and Vascular Hospital in Dallas. The SGLT2 inhibitors are among the drugs best suited to both treating and preventing cardiorenal syndrome by targeting both ends of the disorder, said Dr. McCullough, who chaired an American Heart Association panel that last year issued a scientific statement on cardiorenal syndrome (Circulation. 2019 Apr 16;139[16]:e840-78).

Although data on the SGLT2 inhibitors “are evolving,” the drug class is “going in the direction” of being “reasonably compared” with the ACE inhibitors and ARBs, said Javed Butler, MD, professor and chair of medicine at the University of Mississippi Medical Center, Jackson. “There are certainly complementary benefits that we see for both cardiovascular and renal outcomes.”

“We’ll think more and more about the SGLT2 inhibitors like renin-angiotensin system [RAS] inhibitors,” said David Z. Cherney, MD, referring to the drug class that includes ACE inhibitors and ARBs. “We should start to approach SGLT2 inhibitors like RAS inhibitors, with pleiotropic effects that go beyond glucose,” said Dr. Cherney, a nephrologist and professor of medicine at the University of Toronto, during the virtual annual scientific sessions of the American Diabetes Association in June 2020.
 

Working together in the nephron

One of the clearest complementary interactions between the SGLT2 inhibitors and the RAS inhibitors is their ability to reduce intraglomerular pressure, a key mechanism that slows nephron loss and progression of chronic kidney disease. SGLT2 inhibitors reduce sodium absorption in the proximal tubule that causes, through tubuloglomerular feedback, afferent arteriole constriction that lowers intraglomerular pressure, while the RAS inhibitors inhibit efferent arteriole constriction mediated by angiotensin II, also cutting intraglomerular pressure. Together, “they almost work in tandem,” explained Janani Rangaswami, MD, a nephrologist at Einstein Medical Center in Philadelphia, vice chair of the Kidney Council of the AHA, and first author of the 2019 cardiorenal syndrome AHA statement.

“Many had worried that if we target both the afferent and efferent arterioles simultaneously, it might increase the risk for acute kidney injury. What has been reassuring in both the recent data from the DAPA-HF trial and in recent meta-analysis was no evidence of increased risk for acute kidney injury with use of the SGLT2 inhibitor,” Dr. Rangaswami said in an interview. For example, a recent report on more than 39,000 Canadian patients with T2D who were at least 66 years old and newly begun on either an SGLT2 inhibitor or a different oral diabetes drug (a dipeptidyl peptidase–4 inhibitor), found a statistically significant 21% lower rate of acute kidney injury during the first 90 days on treatment with an SGLT2 inhibitor in a propensity score–matched analysis (CMAJ. 2020 Apr 6;192: e351-60).

Sara Freeman/MDedge News

Much of the concern about possible acute kidney injury stemmed from a property that the SGLT2 inhibitors share with RAS inhibitors: They cause an initial, reversible decline in glomerular filtration rate (GFR), followed by longer-term nephron preservation, a pattern attributable to reduced intraglomerular pressure. The question early on was: “ ‘Does this harm the kidney?’ But what we’ve seen is that patients do better over time, even with this initial hit. Whenever you offload the glomerulus you cut barotrauma and protect renal function,” explained Silvio E. Inzucchi, MD, professor of medicine at Yale University, New Haven, Conn., and director of the Yale Medicine Diabetes Center.

Dr. Inzucchi cautioned, however, that a small number of patients starting treatment with an SGLT2 inhibitor may have their GFR drop too sharply, especially if their GFR was low to start with. “You need to be careful, especially at the lower end of the GFR range. I recheck renal function after 1 month” after a patient starts an SGLT2. Patients whose level falls too low may need to discontinue. He added that it’s hard to set a uniform threshold for alarm, and instead assess patients on a case-by-case basis, but “you need some threshold in mind, where you will stop” treatment.
 

A smarter diuretic

One of the most intriguing renal effects of SGLT2 inhibitors is their diuretic action. During a talk at the virtual ADA scientific sessions, cardiologist Jeffrey Testani, MD, called them “smart” diuretics, because their effect on diuresis is relatively modest but comes without the neurohormonal price paid when patients take conventional loop diuretics.

”Loop diuretics are particularly bad,” causing neurohormonal activation that includes norepinephrine, renin, and vasopressin, said Dr. Testani, director of heart failure research at Yale. They also fail to produce a meaningful drop in blood volume despite causing substantial natriuresis.

In contrast, SGLT2 inhibitors cause “moderate” natriuresis while producing a significant cut in blood volume. “The body seems content with this lower plasma volume without activating catecholamines or renin, and that’s how the SGLT2 inhibitors differ from other diuretics,” said Dr. Inzucchi.

The class also maintains serum levels of potassium and magnesium, produces significant improvements in serum uric acid levels, and avoids the electrolyte abnormalities, volume depletion, and acute kidney injury that can occur with conventional distal diuretics, Dr. Testani said.

In short, the SGLT2 inhibitors “are safe and easy-to-use diuretics,” which allows them to fill a “huge unmet need for patients with heart failure.” As evidence accumulates for the benefits of the drug class in patients with heart failure and renal disease, “uptake will be extensive,” Dr. Testani predicted, driven in part by how easy it is to add the class to existing cardiorenal drug regimens.

Other standard therapies for patients with heart failure with reduced ejection fraction (HFrEF) risk electrolyte abnormalities, renal dysfunction, significantly lower blood pressure, often make patients feel worse, and involve a slow and laborious titration process, Dr. Testani noted. The SGLT2 inhibitor agents avoid these issues, a property that has played out in quality of life assessments of patients with HFrEF who received a drug from this class.
 

Outcomes met in trial after trial

In the DAPA-HF trial, with 4,443 patients with HFrEF and divided roughly equally between those with or without T2D, treatment with dapagliflozin (Farxiga) linked with significant improvements in health status and quality of life measured by the Kansas City Cardiomyopathy Questionnaire (Circulation. 2020 Jan 14;141[2]:90-9). “Not all treatments for HFrEF improve symptoms,” but in this study the SGTL2 inhibitor dapagliflozin did, boosting the Kansas City Cardiomyopathy Questionnaire score by about the same magnitude as treatment with a cardiac resynchronization device in patients with HFrEF, said Mikhail N. Kosiborod, MD, director of Cardiometabolic Research at Saint Luke’s Mid America Heart Institute in Kansas City, Mo., speaking at the virtual ADA scientific sessions.

Two more recent renal observations have further solidified the growing role of these drugs for kidney protection. Results from the CREDENCE trial that looked at canagliflozin (Invokana) treatment in 4,401 patients with T2D and albuminuria and chronic kidney disease showed canagliflozin treatment cut the primary, composite renal endpoint by a statistically significant 30%, compared with placebo (N Engl J Med. 2019 Jun 13;380[24]:2295-306). The study stopped earlier than planned because of how effective canagliflozin appeared.

Sara Freeman/Frontline Medical News

“Never before has a renal protection clinical trial stopped for overwhelming efficacy,” noted nephrologist Katherine R. Tuttle, MD, executive director for research at Providence Health Care in Spokane, Wash. “It’s very exciting to have a treatment that works on both the heart and kidney, given their interrelationship,” she said during the ADA sessions. Dr. Tuttle called the cardiorenal effects from the SGLT2 inhibitors “amazing.”

Just as the DAPA-HF trial’s primary outcome showed the ability of at least one drug from the class, dapagliflozin, to improve outcomes in HFrEF patients without T2D, topline results recently reported from the DAPA-CDK trial showed for the first time renal protection by an SGLT2 inhibitor in patients with chronic kidney disease but no T2D, in a study with about 4,300 patients.

Although detailed results from DAPA-CKD are not yet available, so far the outcomes seem consistent with the CREDENCE findings, and the cumulative renal findings for the class show the SGLT2 inhibitors have “potential for a profound impact on the patients we see in every nephrology clinic, and with dual cardiorenal disease,” said Dr. Rangaswami. The class is now established as “standard of care for patients with chronic kidney disease. The CREDENCE results made that clear.”

The DAPA-CKD findings in patients with chronic kidney disease regardless of their diabetes status “are very important. We really have not had any advances in this space for some time, and chronic kidney disease patients have very poor outcomes, both cardiovascular and renal,” commented Dr. Butler. The advantage from using this drug class in these patients “is huge.”

The DAPA-CKD findings are a “major advance,” agreed Dr. McCullough.
 

SGLT2 inhibitor use needs to grow

Experts lament that although the evidence favoring the class has been very bullish, prescribing uptake has been slow, perhaps partly explained by the retail U.S. cost for most of these agents, generally about $17/day.

Cost is, unfortunately, an issue right now for these drugs, said Dr. Butler. Generic formulations are imminent, “but we cannot accept waiting. Providing this therapy when insurance coverage is available,” is essential.

The FDA has already granted tentative approval to some generic formulations, although resolution of patent issues can delay generics actually reaching the market. “Generic dapagliflozin will have a major impact; the marketplace for these drugs will shift very quickly,” predicted Dr. McCullough.

But price may not be the sole barrier, cautioned Dr. Rangaswami. “I don’t think it’s just a cost issue. Several factors explain the slow uptake,” of the SGLT2 inhibitors. “The biggest barrier is that this is a new drug class, and understanding how to use the class is not yet where it needs to be in the physician community.” One of the biggest problems is that the SGLT2 inhibitors are still primarily regarded as drugs to treat hyperglycemia.

Physicians who treat patients with heart or renal disease “need to wrap their head around the idea that a drug with antihyperglycemic effects is now in their practice territory, and something they need to prescribe,” she noted. Currently “there is a reluctance to prescribe these drugs given the perception that they are antihyperglycemic agents, and usually get deferred to primary care physicians or endocrinologists. This results in huge missed opportunities by cardiologists and nephrologists in initiating these agents that have major cardiorenal risk reduction effects.”

The key role that cardiologists need to play in prescribing the SGLT2 inhibitors was brought home in a recent study of two representative U.S. health systems that showed patients with T2D were far more likely to see a cardiologist than an endocrinologist (Cardiovasc Endocrinol Metab. 2020 Jun;9[2]:56-9).

“The SGLT2 inhibitors are definitely a game-changing drug class,” summed up Dr. Rangaswami. “We’re going to see a lot of use in patients with heart and kidney disease.”

Dr. Cherney has been a consultant to or has received honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe Pharma, and Sanofi. Dr. Butler has had financial relationships with numerous pharmaceutical companies. Dr. McCullough and Dr. Rangaswami had no disclosures. Dr. Inzucchi has been a consultant to or helped run trials for Abbott, AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics. Dr. Testani has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, cardionomic, FIRE1 Magenta Med, Novartis, Reprieve, Sanofi, and W.L. Gore. Dr. Kosiborod has been a consultant to or led trials for Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Glytec, Janssen, Eli Lilly, Merck, Novartis, Novo Nordisk, Sanofi, and Vifor. Dr. Tuttle has been a consultant to AstraZeneca, Boehringer Ingelheim, Gilead, Goldfinch Bio, Eli Lilly, and Novo Nordisk.

[email protected]

The benefits from sodium-glucose cotransporter 2 inhibitor drugs proven during the past year for cutting heart failure hospitalization rates substantially in patients with heart failure with reduced ejection fraction and slowing progression of chronic kidney disease, all regardless of diabetes status, have thrust this drug class into the top tier of agents for potentially treating millions of patients with cardiac or renal disease.

The sodium-glucose cotransporter 2 (SGLT2) inhibitors, first licensed for U.S. marketing in 2013 purely for glycemic control, have, during the 5 years since the first cardiovascular outcome trial results for the class came out, shown benefits in a range of patients reminiscent of what’s been established for ACE inhibitors and angiotensin receptor blockers (ARBs).

The wide-reaching benefits of SGLT2 inhibitors have recently become even more relevant by showing clinically meaningful effects in patients without type 2 diabetes (T2D). And in an uncanny coincidence, the SGLT2 inhibitors appear to act in complementary harmony with the ACE inhibitors and ARBs for preserving heart and renal function. These properties have made the SGLT2 inhibitors especially attractive as a new weapon for controlling the ascendant disorder of cardiorenal syndrome.

“SGLT2 inhibitors have a relatively greater impact on cardiovascular outcomes, compared with ACE inhibitors and ARBs, but the effects [of the two classes] are synergistic and ideally patients receive both,” said Peter McCullough, MD, a specialist in treating cardiorenal syndrome and other cardiovascular and renal disorders at Baylor, Scott, and White Heart and Vascular Hospital in Dallas. The SGLT2 inhibitors are among the drugs best suited to both treating and preventing cardiorenal syndrome by targeting both ends of the disorder, said Dr. McCullough, who chaired an American Heart Association panel that last year issued a scientific statement on cardiorenal syndrome (Circulation. 2019 Apr 16;139[16]:e840-78).

Although data on the SGLT2 inhibitors “are evolving,” the drug class is “going in the direction” of being “reasonably compared” with the ACE inhibitors and ARBs, said Javed Butler, MD, professor and chair of medicine at the University of Mississippi Medical Center, Jackson. “There are certainly complementary benefits that we see for both cardiovascular and renal outcomes.”

“We’ll think more and more about the SGLT2 inhibitors like renin-angiotensin system [RAS] inhibitors,” said David Z. Cherney, MD, referring to the drug class that includes ACE inhibitors and ARBs. “We should start to approach SGLT2 inhibitors like RAS inhibitors, with pleiotropic effects that go beyond glucose,” said Dr. Cherney, a nephrologist and professor of medicine at the University of Toronto, during the virtual annual scientific sessions of the American Diabetes Association in June 2020.
 

Working together in the nephron

One of the clearest complementary interactions between the SGLT2 inhibitors and the RAS inhibitors is their ability to reduce intraglomerular pressure, a key mechanism that slows nephron loss and progression of chronic kidney disease. SGLT2 inhibitors reduce sodium absorption in the proximal tubule that causes, through tubuloglomerular feedback, afferent arteriole constriction that lowers intraglomerular pressure, while the RAS inhibitors inhibit efferent arteriole constriction mediated by angiotensin II, also cutting intraglomerular pressure. Together, “they almost work in tandem,” explained Janani Rangaswami, MD, a nephrologist at Einstein Medical Center in Philadelphia, vice chair of the Kidney Council of the AHA, and first author of the 2019 cardiorenal syndrome AHA statement.

“Many had worried that if we target both the afferent and efferent arterioles simultaneously, it might increase the risk for acute kidney injury. What has been reassuring in both the recent data from the DAPA-HF trial and in recent meta-analysis was no evidence of increased risk for acute kidney injury with use of the SGLT2 inhibitor,” Dr. Rangaswami said in an interview. For example, a recent report on more than 39,000 Canadian patients with T2D who were at least 66 years old and newly begun on either an SGLT2 inhibitor or a different oral diabetes drug (a dipeptidyl peptidase–4 inhibitor), found a statistically significant 21% lower rate of acute kidney injury during the first 90 days on treatment with an SGLT2 inhibitor in a propensity score–matched analysis (CMAJ. 2020 Apr 6;192: e351-60).

Sara Freeman/MDedge News

Much of the concern about possible acute kidney injury stemmed from a property that the SGLT2 inhibitors share with RAS inhibitors: They cause an initial, reversible decline in glomerular filtration rate (GFR), followed by longer-term nephron preservation, a pattern attributable to reduced intraglomerular pressure. The question early on was: “ ‘Does this harm the kidney?’ But what we’ve seen is that patients do better over time, even with this initial hit. Whenever you offload the glomerulus you cut barotrauma and protect renal function,” explained Silvio E. Inzucchi, MD, professor of medicine at Yale University, New Haven, Conn., and director of the Yale Medicine Diabetes Center.

Dr. Inzucchi cautioned, however, that a small number of patients starting treatment with an SGLT2 inhibitor may have their GFR drop too sharply, especially if their GFR was low to start with. “You need to be careful, especially at the lower end of the GFR range. I recheck renal function after 1 month” after a patient starts an SGLT2. Patients whose level falls too low may need to discontinue. He added that it’s hard to set a uniform threshold for alarm, and instead assess patients on a case-by-case basis, but “you need some threshold in mind, where you will stop” treatment.
 

A smarter diuretic

One of the most intriguing renal effects of SGLT2 inhibitors is their diuretic action. During a talk at the virtual ADA scientific sessions, cardiologist Jeffrey Testani, MD, called them “smart” diuretics, because their effect on diuresis is relatively modest but comes without the neurohormonal price paid when patients take conventional loop diuretics.

”Loop diuretics are particularly bad,” causing neurohormonal activation that includes norepinephrine, renin, and vasopressin, said Dr. Testani, director of heart failure research at Yale. They also fail to produce a meaningful drop in blood volume despite causing substantial natriuresis.

In contrast, SGLT2 inhibitors cause “moderate” natriuresis while producing a significant cut in blood volume. “The body seems content with this lower plasma volume without activating catecholamines or renin, and that’s how the SGLT2 inhibitors differ from other diuretics,” said Dr. Inzucchi.

The class also maintains serum levels of potassium and magnesium, produces significant improvements in serum uric acid levels, and avoids the electrolyte abnormalities, volume depletion, and acute kidney injury that can occur with conventional distal diuretics, Dr. Testani said.

In short, the SGLT2 inhibitors “are safe and easy-to-use diuretics,” which allows them to fill a “huge unmet need for patients with heart failure.” As evidence accumulates for the benefits of the drug class in patients with heart failure and renal disease, “uptake will be extensive,” Dr. Testani predicted, driven in part by how easy it is to add the class to existing cardiorenal drug regimens.

Other standard therapies for patients with heart failure with reduced ejection fraction (HFrEF) risk electrolyte abnormalities, renal dysfunction, significantly lower blood pressure, often make patients feel worse, and involve a slow and laborious titration process, Dr. Testani noted. The SGLT2 inhibitor agents avoid these issues, a property that has played out in quality of life assessments of patients with HFrEF who received a drug from this class.
 

Outcomes met in trial after trial

In the DAPA-HF trial, with 4,443 patients with HFrEF and divided roughly equally between those with or without T2D, treatment with dapagliflozin (Farxiga) linked with significant improvements in health status and quality of life measured by the Kansas City Cardiomyopathy Questionnaire (Circulation. 2020 Jan 14;141[2]:90-9). “Not all treatments for HFrEF improve symptoms,” but in this study the SGTL2 inhibitor dapagliflozin did, boosting the Kansas City Cardiomyopathy Questionnaire score by about the same magnitude as treatment with a cardiac resynchronization device in patients with HFrEF, said Mikhail N. Kosiborod, MD, director of Cardiometabolic Research at Saint Luke’s Mid America Heart Institute in Kansas City, Mo., speaking at the virtual ADA scientific sessions.

Two more recent renal observations have further solidified the growing role of these drugs for kidney protection. Results from the CREDENCE trial that looked at canagliflozin (Invokana) treatment in 4,401 patients with T2D and albuminuria and chronic kidney disease showed canagliflozin treatment cut the primary, composite renal endpoint by a statistically significant 30%, compared with placebo (N Engl J Med. 2019 Jun 13;380[24]:2295-306). The study stopped earlier than planned because of how effective canagliflozin appeared.

Sara Freeman/Frontline Medical News

“Never before has a renal protection clinical trial stopped for overwhelming efficacy,” noted nephrologist Katherine R. Tuttle, MD, executive director for research at Providence Health Care in Spokane, Wash. “It’s very exciting to have a treatment that works on both the heart and kidney, given their interrelationship,” she said during the ADA sessions. Dr. Tuttle called the cardiorenal effects from the SGLT2 inhibitors “amazing.”

Just as the DAPA-HF trial’s primary outcome showed the ability of at least one drug from the class, dapagliflozin, to improve outcomes in HFrEF patients without T2D, topline results recently reported from the DAPA-CDK trial showed for the first time renal protection by an SGLT2 inhibitor in patients with chronic kidney disease but no T2D, in a study with about 4,300 patients.

Although detailed results from DAPA-CKD are not yet available, so far the outcomes seem consistent with the CREDENCE findings, and the cumulative renal findings for the class show the SGLT2 inhibitors have “potential for a profound impact on the patients we see in every nephrology clinic, and with dual cardiorenal disease,” said Dr. Rangaswami. The class is now established as “standard of care for patients with chronic kidney disease. The CREDENCE results made that clear.”

The DAPA-CKD findings in patients with chronic kidney disease regardless of their diabetes status “are very important. We really have not had any advances in this space for some time, and chronic kidney disease patients have very poor outcomes, both cardiovascular and renal,” commented Dr. Butler. The advantage from using this drug class in these patients “is huge.”

The DAPA-CKD findings are a “major advance,” agreed Dr. McCullough.
 

SGLT2 inhibitor use needs to grow

Experts lament that although the evidence favoring the class has been very bullish, prescribing uptake has been slow, perhaps partly explained by the retail U.S. cost for most of these agents, generally about $17/day.

Cost is, unfortunately, an issue right now for these drugs, said Dr. Butler. Generic formulations are imminent, “but we cannot accept waiting. Providing this therapy when insurance coverage is available,” is essential.

The FDA has already granted tentative approval to some generic formulations, although resolution of patent issues can delay generics actually reaching the market. “Generic dapagliflozin will have a major impact; the marketplace for these drugs will shift very quickly,” predicted Dr. McCullough.

But price may not be the sole barrier, cautioned Dr. Rangaswami. “I don’t think it’s just a cost issue. Several factors explain the slow uptake,” of the SGLT2 inhibitors. “The biggest barrier is that this is a new drug class, and understanding how to use the class is not yet where it needs to be in the physician community.” One of the biggest problems is that the SGLT2 inhibitors are still primarily regarded as drugs to treat hyperglycemia.

Physicians who treat patients with heart or renal disease “need to wrap their head around the idea that a drug with antihyperglycemic effects is now in their practice territory, and something they need to prescribe,” she noted. Currently “there is a reluctance to prescribe these drugs given the perception that they are antihyperglycemic agents, and usually get deferred to primary care physicians or endocrinologists. This results in huge missed opportunities by cardiologists and nephrologists in initiating these agents that have major cardiorenal risk reduction effects.”

The key role that cardiologists need to play in prescribing the SGLT2 inhibitors was brought home in a recent study of two representative U.S. health systems that showed patients with T2D were far more likely to see a cardiologist than an endocrinologist (Cardiovasc Endocrinol Metab. 2020 Jun;9[2]:56-9).

“The SGLT2 inhibitors are definitely a game-changing drug class,” summed up Dr. Rangaswami. “We’re going to see a lot of use in patients with heart and kidney disease.”

Dr. Cherney has been a consultant to or has received honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe Pharma, and Sanofi. Dr. Butler has had financial relationships with numerous pharmaceutical companies. Dr. McCullough and Dr. Rangaswami had no disclosures. Dr. Inzucchi has been a consultant to or helped run trials for Abbott, AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics. Dr. Testani has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, cardionomic, FIRE1 Magenta Med, Novartis, Reprieve, Sanofi, and W.L. Gore. Dr. Kosiborod has been a consultant to or led trials for Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Glytec, Janssen, Eli Lilly, Merck, Novartis, Novo Nordisk, Sanofi, and Vifor. Dr. Tuttle has been a consultant to AstraZeneca, Boehringer Ingelheim, Gilead, Goldfinch Bio, Eli Lilly, and Novo Nordisk.

[email protected]

The benefits from sodium-glucose cotransporter 2 inhibitor drugs proven during the past year for cutting heart failure hospitalization rates substantially in patients with heart failure with reduced ejection fraction and slowing progression of chronic kidney disease, all regardless of diabetes status, have thrust this drug class into the top tier of agents for potentially treating millions of patients with cardiac or renal disease.

The sodium-glucose cotransporter 2 (SGLT2) inhibitors, first licensed for U.S. marketing in 2013 purely for glycemic control, have, during the 5 years since the first cardiovascular outcome trial results for the class came out, shown benefits in a range of patients reminiscent of what’s been established for ACE inhibitors and angiotensin receptor blockers (ARBs).

The wide-reaching benefits of SGLT2 inhibitors have recently become even more relevant by showing clinically meaningful effects in patients without type 2 diabetes (T2D). And in an uncanny coincidence, the SGLT2 inhibitors appear to act in complementary harmony with the ACE inhibitors and ARBs for preserving heart and renal function. These properties have made the SGLT2 inhibitors especially attractive as a new weapon for controlling the ascendant disorder of cardiorenal syndrome.

“SGLT2 inhibitors have a relatively greater impact on cardiovascular outcomes, compared with ACE inhibitors and ARBs, but the effects [of the two classes] are synergistic and ideally patients receive both,” said Peter McCullough, MD, a specialist in treating cardiorenal syndrome and other cardiovascular and renal disorders at Baylor, Scott, and White Heart and Vascular Hospital in Dallas. The SGLT2 inhibitors are among the drugs best suited to both treating and preventing cardiorenal syndrome by targeting both ends of the disorder, said Dr. McCullough, who chaired an American Heart Association panel that last year issued a scientific statement on cardiorenal syndrome (Circulation. 2019 Apr 16;139[16]:e840-78).

Although data on the SGLT2 inhibitors “are evolving,” the drug class is “going in the direction” of being “reasonably compared” with the ACE inhibitors and ARBs, said Javed Butler, MD, professor and chair of medicine at the University of Mississippi Medical Center, Jackson. “There are certainly complementary benefits that we see for both cardiovascular and renal outcomes.”

“We’ll think more and more about the SGLT2 inhibitors like renin-angiotensin system [RAS] inhibitors,” said David Z. Cherney, MD, referring to the drug class that includes ACE inhibitors and ARBs. “We should start to approach SGLT2 inhibitors like RAS inhibitors, with pleiotropic effects that go beyond glucose,” said Dr. Cherney, a nephrologist and professor of medicine at the University of Toronto, during the virtual annual scientific sessions of the American Diabetes Association in June 2020.
 

Working together in the nephron

One of the clearest complementary interactions between the SGLT2 inhibitors and the RAS inhibitors is their ability to reduce intraglomerular pressure, a key mechanism that slows nephron loss and progression of chronic kidney disease. SGLT2 inhibitors reduce sodium absorption in the proximal tubule that causes, through tubuloglomerular feedback, afferent arteriole constriction that lowers intraglomerular pressure, while the RAS inhibitors inhibit efferent arteriole constriction mediated by angiotensin II, also cutting intraglomerular pressure. Together, “they almost work in tandem,” explained Janani Rangaswami, MD, a nephrologist at Einstein Medical Center in Philadelphia, vice chair of the Kidney Council of the AHA, and first author of the 2019 cardiorenal syndrome AHA statement.

“Many had worried that if we target both the afferent and efferent arterioles simultaneously, it might increase the risk for acute kidney injury. What has been reassuring in both the recent data from the DAPA-HF trial and in recent meta-analysis was no evidence of increased risk for acute kidney injury with use of the SGLT2 inhibitor,” Dr. Rangaswami said in an interview. For example, a recent report on more than 39,000 Canadian patients with T2D who were at least 66 years old and newly begun on either an SGLT2 inhibitor or a different oral diabetes drug (a dipeptidyl peptidase–4 inhibitor), found a statistically significant 21% lower rate of acute kidney injury during the first 90 days on treatment with an SGLT2 inhibitor in a propensity score–matched analysis (CMAJ. 2020 Apr 6;192: e351-60).

Sara Freeman/MDedge News

Much of the concern about possible acute kidney injury stemmed from a property that the SGLT2 inhibitors share with RAS inhibitors: They cause an initial, reversible decline in glomerular filtration rate (GFR), followed by longer-term nephron preservation, a pattern attributable to reduced intraglomerular pressure. The question early on was: “ ‘Does this harm the kidney?’ But what we’ve seen is that patients do better over time, even with this initial hit. Whenever you offload the glomerulus you cut barotrauma and protect renal function,” explained Silvio E. Inzucchi, MD, professor of medicine at Yale University, New Haven, Conn., and director of the Yale Medicine Diabetes Center.

Dr. Inzucchi cautioned, however, that a small number of patients starting treatment with an SGLT2 inhibitor may have their GFR drop too sharply, especially if their GFR was low to start with. “You need to be careful, especially at the lower end of the GFR range. I recheck renal function after 1 month” after a patient starts an SGLT2. Patients whose level falls too low may need to discontinue. He added that it’s hard to set a uniform threshold for alarm, and instead assess patients on a case-by-case basis, but “you need some threshold in mind, where you will stop” treatment.
 

A smarter diuretic

One of the most intriguing renal effects of SGLT2 inhibitors is their diuretic action. During a talk at the virtual ADA scientific sessions, cardiologist Jeffrey Testani, MD, called them “smart” diuretics, because their effect on diuresis is relatively modest but comes without the neurohormonal price paid when patients take conventional loop diuretics.

”Loop diuretics are particularly bad,” causing neurohormonal activation that includes norepinephrine, renin, and vasopressin, said Dr. Testani, director of heart failure research at Yale. They also fail to produce a meaningful drop in blood volume despite causing substantial natriuresis.

In contrast, SGLT2 inhibitors cause “moderate” natriuresis while producing a significant cut in blood volume. “The body seems content with this lower plasma volume without activating catecholamines or renin, and that’s how the SGLT2 inhibitors differ from other diuretics,” said Dr. Inzucchi.

The class also maintains serum levels of potassium and magnesium, produces significant improvements in serum uric acid levels, and avoids the electrolyte abnormalities, volume depletion, and acute kidney injury that can occur with conventional distal diuretics, Dr. Testani said.

In short, the SGLT2 inhibitors “are safe and easy-to-use diuretics,” which allows them to fill a “huge unmet need for patients with heart failure.” As evidence accumulates for the benefits of the drug class in patients with heart failure and renal disease, “uptake will be extensive,” Dr. Testani predicted, driven in part by how easy it is to add the class to existing cardiorenal drug regimens.

Other standard therapies for patients with heart failure with reduced ejection fraction (HFrEF) risk electrolyte abnormalities, renal dysfunction, significantly lower blood pressure, often make patients feel worse, and involve a slow and laborious titration process, Dr. Testani noted. The SGLT2 inhibitor agents avoid these issues, a property that has played out in quality of life assessments of patients with HFrEF who received a drug from this class.
 

Outcomes met in trial after trial

In the DAPA-HF trial, with 4,443 patients with HFrEF and divided roughly equally between those with or without T2D, treatment with dapagliflozin (Farxiga) linked with significant improvements in health status and quality of life measured by the Kansas City Cardiomyopathy Questionnaire (Circulation. 2020 Jan 14;141[2]:90-9). “Not all treatments for HFrEF improve symptoms,” but in this study the SGTL2 inhibitor dapagliflozin did, boosting the Kansas City Cardiomyopathy Questionnaire score by about the same magnitude as treatment with a cardiac resynchronization device in patients with HFrEF, said Mikhail N. Kosiborod, MD, director of Cardiometabolic Research at Saint Luke’s Mid America Heart Institute in Kansas City, Mo., speaking at the virtual ADA scientific sessions.

Two more recent renal observations have further solidified the growing role of these drugs for kidney protection. Results from the CREDENCE trial that looked at canagliflozin (Invokana) treatment in 4,401 patients with T2D and albuminuria and chronic kidney disease showed canagliflozin treatment cut the primary, composite renal endpoint by a statistically significant 30%, compared with placebo (N Engl J Med. 2019 Jun 13;380[24]:2295-306). The study stopped earlier than planned because of how effective canagliflozin appeared.

Sara Freeman/Frontline Medical News

“Never before has a renal protection clinical trial stopped for overwhelming efficacy,” noted nephrologist Katherine R. Tuttle, MD, executive director for research at Providence Health Care in Spokane, Wash. “It’s very exciting to have a treatment that works on both the heart and kidney, given their interrelationship,” she said during the ADA sessions. Dr. Tuttle called the cardiorenal effects from the SGLT2 inhibitors “amazing.”

Just as the DAPA-HF trial’s primary outcome showed the ability of at least one drug from the class, dapagliflozin, to improve outcomes in HFrEF patients without T2D, topline results recently reported from the DAPA-CDK trial showed for the first time renal protection by an SGLT2 inhibitor in patients with chronic kidney disease but no T2D, in a study with about 4,300 patients.

Although detailed results from DAPA-CKD are not yet available, so far the outcomes seem consistent with the CREDENCE findings, and the cumulative renal findings for the class show the SGLT2 inhibitors have “potential for a profound impact on the patients we see in every nephrology clinic, and with dual cardiorenal disease,” said Dr. Rangaswami. The class is now established as “standard of care for patients with chronic kidney disease. The CREDENCE results made that clear.”

The DAPA-CKD findings in patients with chronic kidney disease regardless of their diabetes status “are very important. We really have not had any advances in this space for some time, and chronic kidney disease patients have very poor outcomes, both cardiovascular and renal,” commented Dr. Butler. The advantage from using this drug class in these patients “is huge.”

The DAPA-CKD findings are a “major advance,” agreed Dr. McCullough.
 

SGLT2 inhibitor use needs to grow

Experts lament that although the evidence favoring the class has been very bullish, prescribing uptake has been slow, perhaps partly explained by the retail U.S. cost for most of these agents, generally about $17/day.

Cost is, unfortunately, an issue right now for these drugs, said Dr. Butler. Generic formulations are imminent, “but we cannot accept waiting. Providing this therapy when insurance coverage is available,” is essential.

The FDA has already granted tentative approval to some generic formulations, although resolution of patent issues can delay generics actually reaching the market. “Generic dapagliflozin will have a major impact; the marketplace for these drugs will shift very quickly,” predicted Dr. McCullough.

But price may not be the sole barrier, cautioned Dr. Rangaswami. “I don’t think it’s just a cost issue. Several factors explain the slow uptake,” of the SGLT2 inhibitors. “The biggest barrier is that this is a new drug class, and understanding how to use the class is not yet where it needs to be in the physician community.” One of the biggest problems is that the SGLT2 inhibitors are still primarily regarded as drugs to treat hyperglycemia.

Physicians who treat patients with heart or renal disease “need to wrap their head around the idea that a drug with antihyperglycemic effects is now in their practice territory, and something they need to prescribe,” she noted. Currently “there is a reluctance to prescribe these drugs given the perception that they are antihyperglycemic agents, and usually get deferred to primary care physicians or endocrinologists. This results in huge missed opportunities by cardiologists and nephrologists in initiating these agents that have major cardiorenal risk reduction effects.”

The key role that cardiologists need to play in prescribing the SGLT2 inhibitors was brought home in a recent study of two representative U.S. health systems that showed patients with T2D were far more likely to see a cardiologist than an endocrinologist (Cardiovasc Endocrinol Metab. 2020 Jun;9[2]:56-9).

“The SGLT2 inhibitors are definitely a game-changing drug class,” summed up Dr. Rangaswami. “We’re going to see a lot of use in patients with heart and kidney disease.”

Dr. Cherney has been a consultant to or has received honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe Pharma, and Sanofi. Dr. Butler has had financial relationships with numerous pharmaceutical companies. Dr. McCullough and Dr. Rangaswami had no disclosures. Dr. Inzucchi has been a consultant to or helped run trials for Abbott, AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics. Dr. Testani has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, cardionomic, FIRE1 Magenta Med, Novartis, Reprieve, Sanofi, and W.L. Gore. Dr. Kosiborod has been a consultant to or led trials for Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Glytec, Janssen, Eli Lilly, Merck, Novartis, Novo Nordisk, Sanofi, and Vifor. Dr. Tuttle has been a consultant to AstraZeneca, Boehringer Ingelheim, Gilead, Goldfinch Bio, Eli Lilly, and Novo Nordisk.

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