NEW YORK (Reuters Health) – The oral blood pressure drug verapamil may delay type 1 diabetes (T1D) progression, lower insulin requirements and reduce proinflammatory cytokines for at least two years, researchers say.
In addition to these benefits, “Continuous use of oral verapamil downregulates the detrimental protein TXNIP and promotes an anti-oxidative, anti-apoptotic and immunomodulatory gene expression profile in human islets,” Dr. Anath Shalev of the University of Alabama at Birmingham told Reuters Health by email.
“Oral verapamil also reverses increases in proinflammatory factors (interleukin-21 levels and T-follicular-helper cells),” she noted. “This is the first indication that verapamil may also affect the autoimmunity of T1D, in addition to its effects on beta cell survival. As such, this could also help explain why verapamil is successful even without additional bona fide immunomodulation.”
However, the benefits are lost if the drug is discontinued, Dr. Shalev and colleagues note in their report in Nature Communications.
The team’s previous randomized placebo-controlled trial in adults with recent-onset T1D, published in 2018, showed that oral verapamil had short-term beneficial effects; however, the duration and underlying mechanisms were unclear.
For the current study, the researchers performed global proteomics analyses of blood samples from 10 subjects with T1DM, at baseline and after at least one year of receiving verapamil (360 mg sustained-release daily) or placebo. Patients were not receiving any diabetes medication other than insulin.
Fifty-three proteins showed altered abundance over time in response to verapamil, including proteins involved in immune modulation and autoimmunity. The analysis identified chromogranin A (CHGA), a T1D-autoantigen, as the primary protein altered by verapamil and as a potential therapeutic marker.
The analysis also showed that verapamil normalizes serum CHGA levels and reverses T1D-induced elevations in circulating proinflammatory T-follicular-helper cell markers. Lower CHGA levels also correlated with better endogenous insulin production, as measured by mixed-meal-stimulated C-peptide, a standard test of T1D progression.
After a year of treatment, T1D patients had similar CHGA levels to controls – about two-fold lower than in T1D.
RNA-sequencing further confirmed that verapamil regulates the thioredoxin system, including TXNIP, and, as Dr. Shalev indicated, promotes an anti-oxidative, anti-apoptotic and immunomodulatory gene expression profile in human islets.
These mechanistic and clinical findings help explain the beneficial effects of verapamil in T1D and will inform further study, according to the authors.
Dr. Shalev said, “Off-label use of once daily, oral, slow-release verapamil provides an additional approach that can be considered at a one-by-one basis to delay diabetes progression and reduce insulin requirements in subjects who don’t have any specific contraindications.”
Further, she noted, “Serum CHGA seems to provide a useful biomarker for monitoring the effectiveness of verapamil in subjects with T1D.”
The team is continuing to study verapamil’s effects in T1D, as well as TXNIP inhibition, including the commercialization with TIXiMED (Birmingham, Alabama) of a patented, TXNIP inhibitor.
Dr. David Harlan, Co-Director of the Diabetes Center of Excellence at the UMass Chan Medical School in Worcester, commented in an email to Reuters Health, “Sadly, the current insulin-based approaches (for T1D) can be complicated, expensive, and potentially dangerous, since too much insulin can cause dangerous low blood glucose levels.”
“Many efforts over the past 40+ years have attempted to weaken the autoimmune process that is believed to kill the individual’s pancreatic insulin producing cells,” he said. “But (to date) none of those immune-based therapies have been sufficiently safe and effective to enter standard practice.”
“The new studies show that verapamil can preserve insulin-producing capacity for up to two years, and have identified circulating markers of insulin-producing cell ‘stress,’ and immune parameters that are also influenced by the verapamil treatment,” he noted. “While the number of individuals studied is small, these results are very exciting since verapamil is known to be safe and inexpensive so could be approved with relative speed for those with new-onset T1D. The results open many questions worthy of further pursuit.”
“Prior to Dr. Shalev’s work,” he added, “no one would have considered the TXNIP pathway or an antihypertensive agent in wide use as worthy of scientific inquiry in T1D.”
SOURCE: https://go.nature.com/3MMkI35 Nature Communications, online March 3, 2022.