Patients taking the oral blood pressure medication not only required less daily insulin two years after first diagnosis of the disease, but also showed evidence of surprising immunomodulatory benefits.
Continuing medication was necessary. In the two-year study, subjects who stopped daily doses of verapamil at one year saw their disease at two years worsen at rates similar to those of the control group of diabetes patients who did not use verapamil at all.
Type 1 diabetes is an autoimmune disease that causes loss of pancreatic beta cells, which produce endogenous insulin. To replace that, patients must take exogenous insulin by shots or pump and are at risk of dangerous low blood sugar events. There is no current oral treatment for this disease.
The suggestion that verapamil might serve as a potential Type 1 diabetes drug was the serendipitous discovery of study leader Anath Shalev, M.D., director of the Comprehensive Diabetes Center at the University of Alabama at Birmingham. This finding stemmed from more than two decades of her basic research into a gene in pancreatic islets called TXNIP.
In 2014, Shalev’s UAB research lab reported that verapamil completely reversed diabetes in animal models, and she announced plans to test the effects of the drug in a human clinical trial. The United States Food and Drug Administration approved verapamil for the treatment of high blood pressure in 1981.
In 2018, Shalev and colleagues reported the benefits of verapamil in a one-year clinical study of Type 1 diabetes patients, finding that regular oral administration of verapamil enabled patients to produce higher levels of their own insulin, thus limiting their need for injected insulin to regulate blood sugar levels.
The current study extends on that finding and provides crucial mechanistic and clinical insights into the beneficial effects of verapamil in Type 1 diabetes, using proteomics analysis and RNA sequencing.
To examine changes in circulating proteins in response to verapamil treatment, the researchers used liquid chromatography-tandem mass spectrometry of blood serum samples from subjects diagnosed with Type 1 diabetes within three months of diagnosis and at one year of follow-up.
Fifty-three proteins showed significantly altered relative abundance over time in response to verapamil. These included proteins known to be involved in immune modulation and autoimmunity of Type 1 diabetes.
The top serum protein altered by verapamil treatment was chromogranin A, or CHGA, which was downregulated with treatment. CHGA is localized in secretory granules, including those of pancreatic beta cells, suggesting that changed CHGA levels might reflect alterations in beta cell integrity. In contrast, the elevated levels of CHGA at Type 1 diabetes onset did not change in control subjects who did not take verapamil.
CHGA levels were also easily measured directly in serum using a simple ELISA assay after a blood draw, and lower levels in verapamil-treated subjects correlated with better endogenous insulin production as measured by mixed-meal-stimulated C-peptide, a standard test of Type 1 diabetes progression.
Also, serum CHGA levels in healthy, non-diabetic volunteers were about twofold lower compared to subjects with Type 1 diabetes, and after one year of verapamil treatment, verapamil-treated Type 1 diabetes subjects had similar CHGA levels compared with healthy individuals. In the second year, CHGA levels continued to drop in verapamil-treated subjects, but they rose in Type 1 diabetes subjects who discontinued verapamil during year two.
“Thus, serum CHGA seems to reflect changes in beta cell function in response to verapamil treatment or Type 1 diabetes progression and therefore may provide a longitudinal marker of treatment success or disease worsening,” Shalev said. “This would address a critical need, as the lack of a simple longitudinal marker has been a major challenge in the Type 1 diabetes field.”
Other labs have identified CHGA as an autoantigen in Type 1 diabetes that provokes immune T cells involved in the autoimmune disease. Thus, Shalev and colleagues asked whether verapamil affected T cells.
They found that several proinflammatory markers of T follicular helper cells, including CXCR5 and interleukin 21, were significantly elevated in monocytes from subjects with Type 1 diabetes, as compared to healthy controls, and they found that these changes were reversed by verapamil treatment.
“This suggests that verapamil, and/or the Type 1 diabetes improvements achieved by it, can modulate some circulating proinflammatory cytokines and T helper cell subsets, which in turn may contribute to the overall beneficial effects observed clinically.”
To assess changes in gene expression, RNA sequencing of human pancreatic islet samples exposed to glucose, with or without verapamil was performed and revealed a large number of genes that were either upregulated or downregulated. Analysis of these genes showed that verapamil regulates the thioredoxin system, including TXNIP, and promotes an anti-oxidative, anti-apoptotic and immunomodulatory gene expression profile in human islets. Such protective changes in the pancreatic islets might further explain the sustained improvements in pancreatic beta cell function observed with continuous verapamil use.
Shalev and colleagues caution that their study, with its small number of subjects, needs to be confirmed by larger clinical studies, such as a current verapamil-Type 1 diabetes study ongoing in Europe.
But the preservation of some beta cell function is promising. “In humans with Type 1 diabetes, even a small amount of preserved endogenous insulin production—as opposed to higher exogenous insulin requirements—has been shown to be associated with improved outcomes and could help improve quality of life and lower the high costs associated with insulin use,” Shalev said.
“The fact that these beneficial verapamil effects seemed to persist for two years, whereas discontinuation of verapamil led to disease progression, provides some additional support for its potential usefulness for long-term treatment.”
At UAB, Shalev is a professor in the Department of Medicine Division of Endocrinology, Diabetes and Metabolism, and she holds the Nancy R. and Eugene C. Gwaltney Family Endowed Chair in Juvenile Diabetes Research.
Co-authors with Shalev, in the Nature Communications report “Exploratory study reveals far reaching systemic and cellular effects of verapamil treatment in subjects with type 1 diabetes,” are Guanlan Xu, Tiffany D. Grimes, Truman B. Grayson, Junqin Chen, Lance A. Thielen and Fernando Ovalle, UAB Department of Medicine, Division of Endocrinology, Diabetes and Metabolism; Hubert M. Tse, UAB Department of Microbiology; Peng Li, UAB School of Nursing; Matt Kanke and Praveen Sethupathy, College of Veterinary Medicine, Cornell University, Ithaca, New York; and Tai-Tu Lin, Athena A. Schepmoes, Adam C. Swensen, Vladislav A. Petyuk and Wei-Jun Qian, Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington.
Repurposing verapamil for prevention of cognitive decline in sporadic Alzheimer’s disease
Dementia is currently the only leading cause of death that is still on the rise, with its overall costs already surpassing those of cancer and heart disease combined, it has developed into a worldwide crisis. In response to its serious and far-reaching effects, the US government has established the “National Alzheimer’s Project Act” (Public Law 111-375), which aims to prevent and successfully manage Alzheimer’s disease (AD), the most common cause of dementia, by 2025.
Unfortunately, the incidence of this rapidly progressive, irreversible neurodegenerative cerebral disorder is expected to increase further in coming years, given its close connection with advanced age, yet there are no satisfactory therapies. All the available agents, currently approved by the Food and Drug Administration (FDA) for managing AD are merely palliative, their efficacy decreases over time and they are frequently associated with undesirable side effects.
Moreover, efforts to develop new and more efficacious treatments have been futile, despite all the time taken (nearly 20 years) and billions of dollars spent in the rigorous process of drug design, research, development, formulation, and testing.
This has resulted in a move geared towards the repurposing of existing mediations, licensed for other therapeutic indications, for their potential application in AD and related cognitive disorders. Such practice of “medication repurposing” aims to maximize use of resources and reduce unnecessary expenditure.
A repurposed medication has already passed the initial steps required for primary approval, a laborious process, which includes everything from in vitro and preclinical screening, chemical optimization, toxicological studies to bulk manufacturing and formulation. The safety and efficacy profile has hence already been established so it is quick to advance to the market, for the proposed indication (Ahmed and Ishrat, 2020).
Indeed, medication repurposing aka medication repositioning has shown therapeutic success in many other areas including cancer and cardiovascular disease (Corbett et al., 2012; Ahmed and Ishrat, 2020). As for the choice of medication, a substantial body of clinical and experimental evidence indicates that Ca2+ channel blocking drugs, especially verapamil can potentially be repurposed, for prevention of neurodegeneration and dementia in patients at high risk or in the early stages of disease.
This is because verapamil, a highly efficacious phenylalkylamine Ca2+ channel blocking, with antioxidant, anti-inflammatory and nonspecific TXNIP inhibiting properties, effectively targets the main factors involved in the pathophysiology of dementia. Verapamil is currently approved by the FDA for treatment of various cardiovascular conditions including angina, hypertension and arrhythmias. It is also used first line in prevention of cluster headaches (Petersen et al., 2019).
Furthermore, multiple pre-clinical studies indicate a positive effect of verapamil in ameliorating cognitive deficits and diminishing AD-like pathology in various animal models (Melone et al., 2018; Ponne et al., 2020; Popovic et al., 2020; Ahmed et al., 2021). These include models of familial “early-onset” AD (Melone et al., 2018), which account for only 5% of AD patients in addition to the more prevalent, late onset sporadic AD (sAD) (Chen et al., 2013; Kamat, 2015; Ahmed et al., 2021).
The former is mostly associated with rare genetic mutations to amyloid precursor protein, presenilin-1, and presenilin-2, that cause initial symptoms to occur as early as the person’s thirties, whereas the latter, which comprises over 95% of cases, typically occurs in subjects of advanced age (Ahmed and Ishrat, 2020).
This form was modeled in our most recent study, given its much higher prevalence. In brief, we conducted a long-term study, for which we utilized a well-established model of clinical sAD in aged animals. This was obtained by intracerebroventricular administration of streptozotocin, a glucosamine-nitrosourea compound known to induce sAD like pathology.
This model shares many biochemical and pathological features with clinical sAD, including acute neuroinflammation, impaired cerebral glucose metabolism, defective brain insulin signaling and central insulin resistance in addition to disturbed synaptic plasticity (Chen et al., 2013; Kamat, 2015; Ahmed et al., 2021). Moreover, the intracerebroventricular streptozotocin model of sporadic AD is reportedly associated with amyloid β plaques and hyperphosphorylated tau tangles in the later stages of disease (Chen et al., 2013).
In order to assess neurotherapeutic efficacy, we employed functional (cognitive/behavioral) and molecular outcomes. Our main focus was centered on preclinical functional measures, using tests established to simulate those implemented in the clinic. We believe that it is critical to target functional outcomes in any study assessing potential treatments for AD.
This is because AD is fundamentally a clinical diagnosis, with cognitive and neurobehavioral outcomes serving as the primary criteria (cornerstone for diagnosis) in clinical practice (McKhann et al., 2011; Ahmed and Ishrat, 2020). Moreover, the large clinical studies currently focus primarily on behavioral and functional outcomes as the main measure of therapeutic success (Ahmed and Ishrat, 2020).
We determined that long-term, low dose verapamil treatment effectively prevents cognitive decline and sustains synaptic plasticity in this valid animal model of age related sAD (Ahmed et al., 2021). The results of our investigation were in accordance with earlier findings supporting the beneficial effects of verapamil in other models (Kumar et al., 2016; Melone et al., 2018; Ponne et al., 2020; Popovic et al., 2020; Ahmed et al., 2021).
We also discovered the minimum effective dose of verapamil for cognitive support to be 1 mg/kg per day, which is much lower than that approved by the FDA for reduction of blood pressure. In fact, the dose used in our study is equivalent to a clinical dose of 80 mg/day, which is only 1/3 of the minimum clinical daily dose of verapamil (240 mg), calculated based on the average weight of an adult male ≈ 80 kg (176 pounds). Such a low dose, may effectively sustain cognitive function without affecting blood pressure, rendering it useful even for normotensive individuals. These findings indicate that long-term treatment with low dose verapamil may delay progression of sporadic AD in susceptible subjects of advanced age.
Although, the exact molecular mechanisms leading to such effect are not entirely understood, they are likely a result of not one but, a combination of favorable actions (Figure 1). Verapamil primarily functions to regulate Ca2+ and maintain homeostasis. This is essential since Ca2+ imbalance is known to be a critical factor in the pathogenesis of many neurodegenerative conditions and most notably AD. This Ca2+ imbalance leads to mitochondrial dysfunction, increases production of reactive oxygen species, impairs synaptic plasticity and mediates apoptosis. Verapamil also possesses acute anti-inflammatory activity, partly due to its early-stage downregulation of TXNIP and associated inhibition of the NLRP3 inflammasome pathway (Ahmed et al., 2021).
It is intuitive that complex, progressive conditions like AD would require a systematic approach for screening of patients in the early stages and initiating appropriate therapy, within a suitable time window of efficacy. Future trials should hence focus on identifying patients in the very early pre-symptomatic stages, using relatively simple albeit effective diagnostic techniques. This is because there is often a delay in the development of symptomatic cognitive decline.
This “preclinical phase” is likely the optimal stage for application of interventions to preserve cognition, as it would target their therapeutic time window of efficacy. While verapamil alone may not “cure” AD, there is reasonably consistent evidence supporting its benefit and potential application in prevention of dementia.
Its ease of administration (oral availability, desirable pharmacodynamic characteristics), great tolerability, favorable side-effect profile, reasonable cost and extensive use are amongst the criteria that make verapamil particularly attractive. Typically, a specialized treatment regimen must be established, as part of a complete set of clinical guidelines and recommendations, for therapeutic management of patients in the various stages of disease.
These should be periodically revised and updated as necessary to account for the most recent clinical findings. We believe that verapamil can potentially be repurposed for AD as part of a comprehensive therapeutic plan/regimen.
Further investigations using different models designed to explore the mechanism in greater depth would be useful. Nevertheless, irrespective of the complete mechanism, it is clear that verapamil appears to be a promising agent that may potentially be repurposed for prevention of cognitive decline and dementia in older adults who may be at risk.
reference link : https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8552840/
More information: Exploratory study reveals far reaching systemic and cellular effects of verapamil treatment in subjects with type 1 diabetes, Nature Communications (2022). DOI: 10.1038/s41467-022-28826-3