One-third reduction across multiple databases enhances confidence
“Collectively, among 128,861 patients with HIV-1 or hepatitis B, users of NRTIs had a 33% reduced hazard of developing type 2 diabetes,” Dr. Ambati and colleagues emphasize.
“The fact that the protective effect against the development of diabetes was replicated in multiple databases in studies from multiple institutions enhances confidence in the results,” Dr. Ambati noted in a statement from the University of Virginia.
Dr. Ambati and colleagues also showed that the NRTI lamivudine restores insulin sensitivity in human cells from type 2 diabetes patients.
That drug prevented induction of insulin resistance in human cells from people who did not have diabetes. It also prevented inflammasome activation in mice fed a high-fat diet.
“These investigations of human cell, mouse and population database systems collectively suggest a potential beneficial effect of NRTIs in forestalling diabetes onset,” they stressed.
Trial assessing kamuvudines slated to begin next year
In the interview, Dr. Ambati explained that inflammasomes are protein complexes that form a large superstructure within the cell. “When activated, they lead to the production of some very powerful inflammatory cytokines, including interleukin-1 beta and IL-18.”
Although there are many different types of inflammasomes, the one implicated in type 2 diabetes, as well as many other chronic diseases, including macular degeneration, is the NLRP3 inflammasome.
Activation of this molecule promotes insulin resistance, a key driver of type 2 diabetes, he explained.
Importantly, previous research showed that the way the NRTIs block this inflammasome has nothing to do with their anti-HIV activity.
After making a small chemical modification in the NRTIs, Dr. Ambati and colleagues were able to show that the resulting agents, which they have dubbed “kamuvudines,” are able to block inflammasome activation independently of their antiviral effects.
They hope that this modification will reduce the toxicities associated with the agents. This would be necessary if kamuvudines were to be more widely used in a noninfected, healthier population, Ambati stressed.
Dr. Ambati and his colleague, Paul Ashton, PhD, cofounder of Inflammasone Therapeutics, plan a clinical trial with one of these kamuvudines in macular degeneration, which they hope will begin early next year.
“We are trying to pick a disease where we can show efficacy fairly quickly in a small number of people,” Dr. Ashton explained in an interview. “We’re very enthusiastic about this as it looks really, really promising.”
Dr. Ambati and Dr. Ashton cofounded Inflammasone Therapeutics, located in Boston. Dr. Ashton is the CEO of the company.
A version of this article originally appeared on Medscape.com.