As COVID-19 spread across the globe, scientists are hunting for drugs that could be repurposed as a quick way to tackle the disease. Among them is a University of Miami researcher who has pointed to previous studies of other coronaviruses to back up his suggestion that a class of diabetes medications known as DPP-4 inhibitors might help.
In a commentary published recently in the journal Diabetes Research and Clinical Practice, endocrinologist Gianluca Iacobellis, M.D., Ph.D., argued that the DPP-4 enzyme represents a potential target that deserves further analysis for its role in COVID-19 respiratory disease.
Several DPP-4 inhibitors are already on the market, including Boehringer Ingelheim and Eli Lilly’s Tradjenta, Merck & Co.’s Januvia and the related combo Janumet. Iacobellis suggests that these drugs be tested in clinical trials for their ability to lower inflammation in COVID-19 patients with Type 2 diabetes, a group that’s disproportionally suffering from severe disease.
The DPP-4 enzyme is expressed in many tissues, but perhaps it’s best known for its role in glucose and insulin metabolism. By degrading GLP-1, DPP-4 can reduce insulin secretion. It’s also involved in immune regulation by activating T cells and increasing CD86 expression, Iacobellis said in the article.
In a 2013 Nature study, scientists in the Netherlands identified DPP-4 as a functional receptor for the spike protein of a MERS coronavirus. MERS-CoV binds to the receptor and interacts with T cells and nuclear factors that are involved with inflammatory responses. Both MERS-CoV and the current SARS-CoV-2 use the spike protein on their surfaces to latch onto and infect host cells.
In a 2019 JCI Insight study, scientists at the University of Maryland and Johns Hopkins University developed a mouse model that was susceptible to MERS-CoV by expressing human DPP-4. Upon infection with MERS-CoV, mice fed a high-fat diet that developed a Type 2 diabetes-like condition and suffered from severe symptoms of the infection for a longer period than did control mice.
However, these DPP-4 mice had fewer inflammatory molecules such as monocytes, CD4+ T cells and lower expression of TNF-alpha and IL-6. The researchers speculate that the immune response may have contributed to the more severe manifestation of MERS-CoV in diabetic mice.
Patients with underlying diseases, including Type 2 diabetes, are at higher risk of serious disease in the current pandemic. Data from the Chinese city of Wuhan and Italy show diabetes patients have accounted for a large proportion of intensive care admission and deaths related to COVID-19.
Other existing drugs have been pushed into COVID-19 clinical trials. Roche is examining its arthritis drug Actemra, and Sanofi and Regeneron are testing their rival IL-6 inhibitor Kevzara. AstraZeneca is preparing to start investigating its BTK blood cancer drug Calquence in the same setting.
DPP-4 inhibition doesn't seem to block viruses. A meta-analysis of 74 studies showed the risk of overall infection was comparable between DPP-4 inhibitor treatment and placebo or active comparator in diabetes patients. And the 2013 Nature study also showed that MERS-CoV infection could not be blocked by Januvia, AstraZeneca’s Onglyza or other DPP-4 inhibitors.
But the use of DPP-4 inhibitors and GLP-1 analogs has been associated with anti-inflammatory effects. Iacobellis argues that might be helpful in helping diabetes patients control COVID-19-related immune overreaction.
All told, DPP-4 “may represent a potential target for preventing and reducing the risk and the progression of the acute respiratory complications that Type 2 diabetes may add to the COVID-19 infection,” Iacobellis wrote in his article.
“The body is overreacting with this inflammatory response to the virus,” he said in a statement. “This could be partially mediated by DPP-4. The virus [potentially] binds to the enzyme and the enzymatic activity of DPP4 overexpresses inflammatory cytokines, exaggerating the inflammatory response.”
Editor's note: Iacobellis' statement at the bottom of the story has been editorially added "potentially" to reflect that the interaction between the COVID-19 spike glycoprotein and DPP-4 is a prediction based on scientific research, not a proven fact.