'Insufficient evidence' to recommend DPP-IV inhibitor treatment in type 2 diabetes with COVID-19
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Insulin — not DPP-IV inhibitors or GLP-1 receptor agonists — should be the agent of choice for the management of severely ill patients with diabetes and coronavirus infections; this position is supported by extensive historical experience and the increased adoption of continuous glucose monitoring, according to a literature review published in Endocrine Reviews.
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 in hospitalized patients, Daniel J. Drucker, MD, a professor of medicine at the Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital and the University of Toronto, wrote in the updated review. However, there is “insufficient evidence” to suggest such agents might safely replace insulin for critically ill individuals with diabetes and coronavirus infection, he wrote.
“It has become clear over the last few months that people with diabetes, and people with obesity, are at greater risk for more severe COVID-19 infections,” Drucker told Healio. “We also know that GLP-1 levels and DPP-IV activity are regulated by infection and inflammation, and in turn, DPP-IV inhibitors and GLP-1 receptor agonists may also modulate inflammation. There is also science linking DPP-IV to coronavirus infection, specifically with MERS-CoV.”
Two coronavirus receptor proteins, angiotensin converting enzyme 2 (ACE2) and DPP-IV, are established transducers of metabolic signals and pathways regulating inflammation, renal and cardiovascular physiology, and glucose homeostasis; however, available evidence does not currently support clinically meaningful alterations in markers of immune function after administration of DPP-IV inhibitors in humans with or without type 2 diabetes.
“The severe acute respiratory syndrome SARS-CoV2 (also referred to as COVID-19) coronavirus pandemic highlights the importance of understanding shared disease pathophysiology potentially informing therapeutic choices in individuals with type 2 diabetes,” Drucker wrote.
In an interview, Drucker noted several important takeaways for clinicians:
- ACE2 and DPP-IV are coronavirus receptors. DPP-IV is a MERS-CoV receptor, but not a SARS-CoV-2 receptor, that is, not a COVID-19 receptor.
- ACE2 and DPP-IV control inflammation and cardiometabolic physiology.
- DPP-IV inhibitors do not meaningfully modify immune response in humans.
- COVID-19 hospitalizations are more common among people with diabetes and obesity.
- Acute COVID-19 illness requires reevaluation of any medications used for type 2 diabetes.
- Insulin is the glucose-lowering therapy of choice for acute coronavirus-related illness in hospital.
As Healio previously reported, adults with diabetes are no more likely to contract COVID-19 than people without diabetes, but could be up to twice as likely to die from complications of the disease. In an analysis of data from China and Italy published this month in the Journal of Endocrinological Investigation, the researchers wrote that, compared with adults who had a more favorable coronavirus disease course, the pooled rate ratio of diabetes among patients with an adverse coronavirus disease course was 2.26 (95% CI, 1.47-3.49).
Drucker said clinical trials are needed to better understand whether any diabetes drugs used today are uniquely safe, or possibly preferential, among people with active COVID-19 infection.
“A better understanding of how diabetes and obesity predisposes a person to severe infection, and what we might be able to do about this, from prevention, to therapeutic intervention, would be useful,” Drucker said. – by Regina Schaffer
For more information:
Daniel Drucker, MD, can be reached at 600 University Ave., Mailbox 39, TCP5-1004, Toronto, ON, Canada M5G 1X5; email: drucker@lunenfeld.ca.
Disclosure: Drucker reports he has received consultant or lectures fees within the past 12 months from Intarcia, Merck, Novo Nordisk and Pfizer, and has received grant support for his institution from Merck, Novo Nordisk and Shire/Takeda.
Perspective
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Gian P. Fadini, MD, PhD
Daniel Drucker, MD, is one of the researchers best positioned to comment upon the interplay between diabetes and the gut as a route of infection and a mediator of inflammation. This piece provides a comprehensive overview of many open issues on the relationships between diabetes and COVID-19. There are epidemiological aspects still not well understood about the links between diabetes and prevalence of the infection or severity of COVID-19. Drucker highlights evidence that diabetes is associated with impaired immune function; I believe this is going to be a major focus of upcoming research. In fact, we are understanding that, in addition to pneumonia and interstitial lung disease, COVID-19 causes gastrointestinal symptoms.
This review provides substantial insight into the molecular pathways that could link diabetes with SARS-CoV-2 infection and COVID-19 severity, with as a special focus on proteases ACE2, TMPRSS2 and DPP-IV. We know that other beta-coronaviruses use membrane-bound DPP-IV to enter the cell, although such evidence for SARS-CoV-2 is weak. DPP-IV is also shed from the membrane as a soluble protein, and how the soluble and membrane-bound DPP-IV interact to regulate coronavirus cycle is unclear. DPP-IV inhibitors would inhibit both the membrane-bound and soluble forms. Even if SARS-CoV-2 used mDPP-IV to enter the cell, it is quite hard to predict the antiviral effects of inhibiting DPP-IV enzymatic activity.
So far, in the absence of any clinical data that support the anti-COVID-19 effect of DPP-IV inhibitors, this remains a hypothesis. I anticipate data will be available in a few weeks. The hypothesis is fascinating, because DPP-IV inhibitors have an optimal safety profile even among older adults, who are particularly prone to COVID-19 progression. Even if DPP-IV inhibitors had no effect on viral infection, they remain a good therapy for older and fragile individuals with type 2 diabetes.
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