Pandemic Parallels: Glycemic Control in COVID-19 Patients

As the COVID-19 pandemic continues to roil the world’s healthcare systems, endocrinologists may have unique insights that could save lives and improve outcomes in these patients who present with elevated glucose levels and other underlying comorbidities such as obesity and diabetes.

When this issue went to press, the U.S. had the most cases of COVID-19 in the world, with close to 800,000 cases and 40,000 deaths. Those numbers have more than doubled since. It’s nothing new to call this a global pandemic, a catastrophe that has forced many people to make some very tough decisions, all while retaining hope that we’ll come through this yet.

Diabetes was already a global pandemic in its own right – more than 10% of the U.S. population has diabetes, and while endocrinologists have been studying and treating diabetes for decades now, the novel coronavirus has added some novel complications for patients with diabetes.

Patients with diabetes and obesity are already at an increased risk for infections, and that includes COVID-19. What’s worse, these patients are also at a higher risk of hospitalization and more severe clinical illness should they contract coronavirus. New research even suggests that patients with no history of diabetes hospitalized with COVID-19 could develop hyperglycemia in the hospital, increasing their mortality risks.

Endocrinology has long been at the crossroads of many other specialties, and the COVID-19 pandemic has created some opportunities and challenges for physicians and researchers for looking at how the biology of the coronavirus and diabetes might intersect, as well has how glucose-lowering therapies for hospitalized patients could save lives. The coronavirus pandemic has impacted virtually every facet of life, including treatment for patients with diabetes, and while the information (and misinformation) about this rampant infection is capricious at best, some evidence about how to care for some of our most vulnerable patients is beginning to emerge.

Insulin: “Your 99-Year-Old Friend”

Last month, Daniel J. Drucker, MD, of Mount Sinai Hospital in Toronto, published a paper in Endocrine Reviews that that looked at how the pathophysiology of diabetes and obesity might intersect with COVID-19 biology and found key shared pathways and mechanisms linked to the development and treatment of type 2 diabetes. “Cells within the lung and gut are major sites for coronavirus entry and inflammation,” Drucker says. “These cells express key proteins like Angiotensin Converting Enzyme 2 (ACE2) and Dipeptidyl Peptidase-4 (DPP4) that are also present in the development of type 2 diabetes.”

Drucker has been studying the biology of gut hormones and DPP4 for years now and found that glucagon-like peptide-1 (GLP-1) controls inflammation and DPP4 is actually a coronavirus receptor for MERS-CoV. However, in his review, Drucker points out that DPP4 is not a receptor for SARS-CoV-2 (COVID-19; this novel coronavirus), and therefore can’t conclude that a DPP4 inhibitor might modify the course of critically ill patients with coronavirus infection. “My interpretation of the available data on DPP4 inhibitors does not support a unique possible benefit, nor any safety concern, when using these drugs in someone with active infection,” he says.

Still, Drucker isn’t ruling anything out. Clinical trials could show promise for DPP4 inhibitors, but many more studies are needed before the medical community thoroughly understands the risks and benefits of using these diabetes medications in patients with coronavirus infections severe enough to require hospitalizations. “None of the available glucose-lowering therapies we have for type 2 diabetes have been ‘road tested’ or thoroughly studied in the context of active coronavirus infection,” he says. “There are special considerations for many of the drug classes, ranging from discontinuation to dose-adjustment, in regard to hypoglycemia, declining renal function, and ketoacidosis, that must be considered, particularly in ill patients, and in those hospitalized. Some people with SARS-CoV2 have gastrointestinal symptoms that may impair absorption of ingested food or oral tablets. So lots to think about.”

“Much of what I have written [in my review] is based on theory, and as noted, we obviously don’t have years of learnings from clinical randomized controlled trials studying SARS-CoV-2 and diabetes. So many of my colleagues may have different perspectives, hypotheses, and opinions. I will always listen and try and learn.” – Daniel J. Drucker, MD, professor of medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, Canada

For now, for patients with diabetes in the hospital with coronavirus, the classics are hard to beat. As Drucker (who is prolific on social media) tweeted: “Insulin is your 99-year-old friend.”

CGMs in the Hospital

The stress of contracting an infection and then being hospitalized with said infection can be a lot for anyone to handle, and that stress can wreak havoc on a body’s metabolism. According to David Klonoff, MD, medical director of the Diabetes Research Institute at Mills-Peninsula Medical Center in San Mateo, Calif., the body then produces hormones that cause resistance to insulin, leading to hyperglycemia. “These people might not have any diabetes once their COVID-19 illness is over, but while in the hospital, they are said to have uncontrolled hyperglycemia,” Klonoff says. “They should be treated with insulin to normalize their glucose levels, just like people with a history of diabetes should be treated with insulin to get their blood glucose down to a safe target range.”

Klonoff and his colleagues from Glytec and the Atlanta Diabetes Associates last month published a paper in Journal of Diabetes Science and Technology that concluded patients with diabetes or uncontrolled hyperglycemia hospitalized with COVID-19 had an in-hospital mortality rate of 29% — four times higher than patients without diabetes or hyperglycemia. The Glytec-initiated study evaluated 1,122 COVID-19 patients from 88 hospitals in the US between March 1 and April 6, 2020, using data transmitted to the Glytec database from 88 hospitals in 11 states, representing every part of the US. All patients had a laboratory-confirmed diagnosis of COVID-19 and 451 patients (40%) were designated as having diabetes, uncontrolled hyperglycemia, or A1C ≥ 6.5%. For this study, uncontrolled hyperglycemia was defined as two or more blood glucoses > 180 mg/dl within any 24-hour period after admission. “Patients with COVID-19, who are admitted with diabetes or who develop elevated glucose levels during hospitalization, have a greater risk of increased length of stay and mortality,” Klonoff says. “In general, bringing elevated blood glucose levels down to normal or near-normal significantly improves a person’s odds of surviving a serious hospitalization.”

But that may not always be so easy. Klonoff and his colleagues write in the Discussion section of their paper that hospitals are already buckling under the weight of this pandemic, especially with the scarcity of personal protection equipment (PPE), which can cause some hospital workers to fear they might also catch COVID-19. “As a result, the medical team might try to reduce caregiver-patient contact, with attendant risk of decreasing the frequency of BG assessments and avoiding IV insulin” the authors write.

Things may be looking up on that front. This month, the FDA announced during the current pandemic that they would not object to the use of certain continuous glucose monitors in the hospital (where these products have traditionally not been cleared for use) to make decisions for insulin dosing. “That decision will free up nurses from doing so much glucose testing at the bedside and will save a lot of time, effort, and supplies of PPE,” Klonoff says. “In the ICU, patients with elevated glucose levels usually require intravenous insulin, and in the wards, they usually require subcutaneous basal-bolus therapy.”

Listening & Learning

Again, what we know about COVID-19 and what it means for these strange days changes like the wind, a fierce torrent that’s sometimes tempting to get swept up in. “The rapid flow of new clinical information stemming from the SARS-CoV-2 epidemic requires ongoing scrutiny to understand the prudent use, risks and benefits of individual glucose-lowering agents and related medications commonly used in subjects with diabetes at risk of, or hospitalized with coronavirus-related infections,” Drucker writes in the conclusion of his review. “Moreover, the current pandemic highlights the importance of opportunities for continuing and expanding innovative delivery of diabetes care, through use of wearable and portable monitoring devices, and regular communication between people with diabetes, and their healthcare providers.”

“Much of what I have written [in my review] is based on theory,” Drucker says, “and as noted, we obviously don’t have years of learnings from clinical randomized controlled trials studying SARS-CoV-2 and diabetes. So many of my colleagues may have different perspectives, hypotheses, and opinions. I will always listen and try and learn.”

Klonoff says that data from hospitalized patients is being analyzed at this time to look for associations between effectively treating elevated glucose levels and improved outcomes. He tells Endocrine News that there are methods for retrospectively following the course of a hospitalization using real-world evidence (RWE) to look for a relationship between lowering glucose levels and improved survival. When the number of patients being studied with a carefully constructed RWE analysis is very large, and the variables of the treatment intervention are limited (which will be the case with this type of COVID-19 data analysis), then researchers will be able to reach conclusions.

“The answers to many of our key questions will come from solid science, from the laboratory to randomized clinical trials. It has never been more important to respect and invest in science. It is the foundation for our future on this planet.” – Daniel J. Drucker, MD, professor of medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, Canada

“I believe that in the case of hyperglycemia treatment during COVID-19, it will not be necessary to determine a relationship with a potentially expensive and time-consuming randomized control trial (RCT),” Klonoff says. “Furthermore, there would be ethical concerns if intensive insulin therapy were to be withheld from some patients in an RCT because this approach is so well-established for other causes of hyperglycemia in the hospital besides COVID-19.”

Still, everyone agrees that optimal glycemic control is crucial to the care of these patients. Careful, thoughtful adjustments to insulin dosing should be considered, and physicians should anticipate challenges with dehydration, because again, the stress of simply being in the hospital can take enough of a toll on the body to lead to poorer outcomes, Drucker says.

“The first step in improving outcomes for people with diabetes is to recognize that there is a problem with being admitted with COVID-19 and diabetes or uncontrolled hyperglycemia,” Klonoff says.

The next step is to determine whether treating the elevated glucose levels brings down the excess risk. Klonoff believes the existing data already justifies the need to bring down elevated glucose levels in the hospital in COVID-19 patients, since elevated glucose levels lead to poor outcomes for other diseases. “The second step of the research project will likely demonstrate for COVID-19, not only that there is benefit from lowering elevated blood glucose levels, but exactly how much benefit can be attained by lowering elevated blood glucose levels,” he says.

Science: The Foundation of Our Future

Since the coronavirus pandemic swept over the world, a popular refrain has been, “We’re all in this together” – an affirmation of community even as people are separated by the walls of their homes and social distancing policies. It’s no different for all those on the front lines of delivering healthcare, even if there may be some disagreement about research conclusions or study parameters. This is a hectic time for everyone, and for now, clinical trials will continue, as well as the hope we’ll be on the other side of this soon. “Most of us take one day at a time, try to stay healthy, and accomplish as much as we can, given major constraints on our activities,” Drucker says. “My own lab will try and learn much more about infection, diabetes, and interactions with gut hormone therapies.”

“Patients with COVID-19, who are admitted with diabetes or who develop elevated glucose levels during hospitalization, have a greater risk of increased length of stay and mortality. In general, bringing elevated blood glucose levels down to normal or near-normal significantly improves a person’s odds of surviving a serious hospitalization.” – David Klonoff, MD, medical director, Diabetes Research Institute, Mills-Peninsula Medical Center, San Mateo, Calif.

Endocrinologists are especially uniquely positioned to save lives and improve outcomes in patients hospitalized with COVID-19. Close to half of patients in intensive care have elevated blood glucose levels or a history of diabetes. “Endocrinologists understand the risks of abnormal blood glucose levels and have the knowledge and experience to use insulin and other drugs to safely bring elevated blood glucose levels down to normal while avoiding excessive therapy that can lead to low blood glucose levels,” Klonoff says.

But it’s not over yet. At press time, the COVID-19 death toll stands at around 2,000 a day, even as some ignore or outright reject scientific evidence and demand to “reopen the country,” even at the cost of more human lives. “The answers to many of our key questions will come from solid science, from the laboratory to randomized clinical trials,” Drucker says. “It has never been more important to respect and invest in science. It is the foundation for our future on this planet.”

— Bagley is the senior editor of Endocrine News. He wrote the profile of incoming Endocrine Society president Gary D. Hammer, MD, PhD, in the April issue.

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