Treating endocrine conditions in the age of COVID-19: What experts have learned
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Since early March, experts have undertaken a flurry of new study and guidance for treating endocrine conditions in the setting of COVID-19. Debate continues over the risks for worse disease outcomes, optimal management and best treatments.
As the Endocrine Society opened its first all-virtual meeting, three experts highlighted how diabetes and obesity influence COVID-19 outcomes, the increased risk for people with adrenal insufficiency and the role of endocrine-related targets in possibly treating COVID-19.
Impact of diabetes
Developed nations bearing the brunt of the COVID-19 epidemic tend to share another common problem — increasing numbers of people with type 2 diabetes and obesity, Manuel Puig-Domingo, MD, PhD, professor of endocrinology at Autonomous University of Barcelona, said during a presentation. Emerging research suggests those with diabetes and obesity who contract the novel coronavirus are far more likely to experience worse disease outcomes, including admission to the ICU, mechanical ventilation and death compared with adults without diabetes and obesity.
“This is certainly the perfect storm, the collision of two public health epidemics, mostly — but not just in — developed countries,” Puig-Domingo said.
Diabetes and obesity are associated with an increased risks for severe forms of bacterial and viral respiratory tract infections, including H1N1 influenza, SARS and MERS, Puig-Domingo said.
“Regarding COVID-19, we were worried about what might happen,” he said. “It seems with COVID-19 infection, things are similar or worse in terms of mortality.”
Early data from hospitals hard hit by COVID-19 suggest that people with diabetes and obesity are more prone to symptomatic disease, Puig-Domingo said. In an analysis of more than 4,100 patients with COVID-19 treated at NYU Langone Hospital, 15% had diabetes and 26% had obesity, he said. Data from the Spanish Society of Internal Medicine series showed that, among 6,430 patients hospitalized with COVID-19, 21.2% had obesity and 18.7% had diabetes.
“Is this a coincidence due to the fact that diabetes or obesity are very prevalent in the community? Or are there differences through which people with diabetes and obesity are more prone to get the disease?” Puig-Domingo said. “It is difficult to analyze all of the data, because there is great heterogeneity across studies and some of the papers published in highly qualified journals have been retracted.”
When assessing the pathophysiology of systemic failure in people with diabetes and COVID-19, Puig-Domingo said several facts are clear. Diabetes and obesity confer impaired pulmonary function, an exaggerated inflammasome response, aberrant protein glycation, increased coagulation and potential bacterial superinfection. Hyperglycemia is also associated with higher mortality, and multiorgan COVID-related injury is enhanced in diabetes.
“When you compared people with diabetes vs. people without diabetes, virtually all of the biomarkers we are using in the clinic show a higher level of organ injury in people with diabetes,” he said.
Mortality in COVID-19 is mostly age dependent, but also comorbidity dependent and, in particular, glucose dependent, Puig-Domingo said. Diabetes with obesity accounts for threefold to fivefold increased mortality risk in the setting of COVID-19, he said.
“We have all seen young, obese people who have died in our hospitals” from COVID-19, Puig-Domingo said. “This is also comorbidity dependent and, as I said, glucose dependent.”
Puig-Domingo said endocrinologists, diabetologists and internal medicine clinicians play an important role in providing proper insulin treatment and nutritional support, both of which likely decrease mortality risk in individuals diabetes and obesity infected by COVID-19, he said.
Guidance for adrenal insufficiency
Currently, there is no evidence that COVID-19 has a more severe course among individuals with primary and secondary adrenal insufficiency; however, those with adrenal insufficiency are at increased risk for respiratory and viral infections, and patients experiencing major inflammation and fever are at risk for life-threatening adrenal crisis, Wiebke Arlt, MD, DSC, FRCP, FMEDSCI, chair of medicine and director of the Institute of Metabolism and Systems Research at the University of Birmingham, U.K., said during a presentation.
“We have to think about whether these patients are at increased risk, and based on the data we have, we say that these patients are at an increased risk to catch COVID-19,” Arlt said, noting the risk is higher among those with primary adrenal insufficiency.
Individuals with primary adrenal insufficiency have impaired natural killer cell cytotoxicity compared with age- and sex-matched controls, Arlt said. This leads to deficient innate immunity defense against a viral infection.
“This is reduced to quite a significant extent, in such a way that a person with Addison’s disease has a natural killer cell function that is equivalent to an 85-year-old,” Arlt said. “That means that, in patients with primary adrenal insufficiency, innate immunity in a high percentage is compromised.”
Endocrinologists treating individuals with adrenal insufficiency should keep three key principles in mind: Educate, equip and empower, Arlt said. Educate patients about general “sick day” rules, as well as special COVID-19 sick day rules, and stress the importance of stringent social distancing to patients. Equip patients with sufficient hydrocortisone supplies, an up-to-date hydrocortisone emergency self-injection kit and an emergency phone number. Empower patients by providing them with a hydrocortisone steroid emergency card, Arlt said.
Role for diabetes medications
Despite emerging data that may lead some to think there is a role for DPP-IV inhibitors or other therapies in treating individuals with diabetes and COVID-19, insulin should remain the agent of choice for the management of severely ill patients with diabetes and coronavirus infections, Daniel J. Drucker, MD, professor of medicine at the Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital and the University of Toronto, said during the presentation.
“With the new coronavirus, there are some very familiar players for endocrinologists,” Drucker said. “The [angiotensin-converting enzyme 2, or ACE2] enzyme that is very familiar to us in cardiometabolic management and DPP-IV, and it really raises a question — how should we think about using the medications we have today in the context of people with a wide spectrum of coronavirus infections?”
Endocrinologists know that unopposed ACE activity is not good for end organs, Drucker said. ACE2 has been established as the predominant receptor for COVID-19, though data are conflicting regarding its clinical relevance. Similarly, the downstream transmembrane protease serine 2, or TMPRSS2, an enzyme encoded by the TMPRSS2 gene, is required for onward virus transmission and is highly androgen regulated. Clinical trials are ongoing to lower androgens in people with COVID-19 to see if this can improve outcomes, Drucker said.
DPP-IV inhibitors and GLP-1 receptor agonists, which are widely used in the treatment of type 2 diabetes, may exert anti-inflammatory actions in humans, and the agents have been used to control glucose among hospitalized patients, Drucker said. However, there is insufficient evidence to suggest such agents might safely replace insulin for critically ill individuals with diabetes and coronavirus infection.
Additionally, soluble DPP-IV has been shown to bind the MERS receptor, but not other coronavirus receptors, he said.
“A large number of substrates are modulated by DPP-IV, but not in a major way in people with diabetes,” Drucker said. “So far, we can’t see any evidence for harm or benefit with DPP-IV inhibitors.”
Prevention of COVID-19 infection continues to be the most important thing to do when approaching managing people with diabetes, Drucker said.
“If it turns out they develop coronavirus infection, the principles of good medical management that we are all familiar with in hospitalized people with diabetes [apply] — paying attention to hydration, nutrition, kidney function, liver function and careful monitoring, not only of glucose but of ketones and other medications being used,” Drucker said.
Perspective
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Jeffrey I. Mechanick, MD, FACP, MACE, FACN, ECNU
An overarching theme here is prevention. From a metabolic standpoint, this means preventing severe COVID-19 disease. To do that, we must look at three things — the epidemiology of the disease, the mechanisms and how one actually implements conventional options in a setting that is riddled with shortages and staff redeployment, all while decreasing the exposure of health care professionals.
Metabolically, we are talking about an epidemiologic association of hypertension, diabetes and obesity with a more severe COVID-19 course. If one looks at the patients who are hospitalized or in the ICU or have died of COVID-19, there is a disproportionate increased prevalence of hypertension, diabetes and obesity. The ramifications of prolonged hyperglycemia make the prothrombotic state in COVID-19 much worse. In obesity, abnormal adiposity, particularly epicardial adipose tissue, has a lot of angiotensin-converting enzyme 2, or ACE2, which has been established as the COVID-19 receptor. The coronavirus attacks the ACE2 receptor, potentially giving rise to myocardial injury. Those with obesity are also more prone to insulin resistance.
Finally, if you look at the ACE2 molecule, it is actually cardioprotective. But when COVID spikes the ACE2 receptor, you get a loss of number and function of the ACE2 molecule, leading to decreased cardioprotection, and so you are seeing severe respiratory distress, hyperglycemia, microthrombi, acute kidney failure and cardiac injury. When all those things are happening in full force, particularly among those already at high risk for worse complications, you have an accelerated clinical course.
We know how to treat hypertension. We know how to treat diabetes and obesity. Here is the problem — the system was overwhelmed. There were shortages of equipment and medicines. Health care professionals were at high risk for exposure. We had to come up with adaptive protocols, such as subcutaneous insulin instead of insulin drips for severe hyperglycemia, that would make implementation more feasible with these shortages and the attempts to decrease exposure to COVID-positive patients. We were successful with this, and we were managing.
Now we are entering a post-COVID or chronic phase, and we are starting to see a fair amount of lingering organ dysfunction and chronic critical illness, as well as encephalopathy. These are additional issues for which endocrinologists may be consulted, as there is a severe persistence of metabolic issues. Additionally, we may still see another wave of this virus. We need to learn as much as we can now, so we are much better prepared for the future.
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Puig-Domingo M, et al. The impact of COVID-19 on endocrinology. ENDO Online; June 8-19, 2020.
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