Tag: metformin

Metformin Found to Slow Ageing in Primate Trial

Photo by Andre Mouton on Unsplash

An exhaustive four year-long study has shown that metformin reduces the effect of ageing. Using a wide array of ageing indicators, the researchers found that metformin resulted in about six year regression in brain ageing. They reported their findings in Cell.

Prior research and anectodal evidence suggested that metformin had an anti-ageing effect. Given to flies, worms and rodents, the drug showed evidence of rejuvenation. People taking metformin also reported feeling younger the longer they took it for.

In a rigorous 40-month study, the researchers gave metformin to 12 elderly male cynomolgus macaques and 18 other cynomolgus monkeys the drug daily. They were aged 13–16 years, equivalent to 40–50 in human years. A control group was used, as well as middle-aged and younger controls to account for ageing effects.

The study encompassed a comprehensive suite of physiological, imaging, histological, and molecular evaluations, substantiating metformin’s influence on delaying age-related phenotypes at the organismal level.

Tissue samples were taken at regular intervals, we leveraged pan-tissue transcriptomics, DNA methylomics, plasma proteomics, and metabolomics to develop innovative monkey aging clocks and applied these to gauge metformin’s effects on ageing.

The results highlighted a significant slowing of aging indicators. A number of organs that seemed to benefit included the kidneys, lungs and the skin. The greatest effect was seen in the brain, however. Metformin exerts a substantial neuroprotective effect, preserving brain structure and enhancing cognitive ability. In this case, treated monkeys had brain activity comparable to those six years younger.

The geroprotective effects on primate neurons were partially mediated by the activation of Nrf2, a transcription factor with anti-oxidative capabilities. The researchers say that this work pioneers the systemic reduction of multi-dimensional biological age in primates through metformin, paving the way for advancing pharmaceutical strategies against human aging.

The researchers have also started a much larger phase 2 human trial, with 120 participants.

Metformin Use Linked to Lower Risk of Developing Blood Cancers

Depiction of multiple myeloma. Credit: Scientific Animations

People who use metformin are less likely to develop a myeloproliferative neoplasm (MPN) over time, indicating that the treatment may help prevent the development of certain types of cancers, according to a study published in Blood Advances.

Metformin is a therapy used to treat high blood sugar in people with type 2 diabetes that increases the effect of insulin, reduces how much glucose is released from the liver and helps the body absorb glucose. A meta-analysis of previous studies connected the therapy with a reduction in the risk of gastrointestinal, breast, and urologic cancers, while a retrospective study of US veterans found that metformin users have a reduced risk for solid and haematological cancers.

Metformin’s anti-inflammatory properties in focus

“Our team was interested in understanding what other effects we see with commonly prescribed treatments like metformin,” said Anne Stidsholt Roug, MD, PhD, chief physician at Aarhus University Hospital and clinical associate professor at Aalborg University Hospital in Denmark. “The anti-inflammatory effect of metformin interested us, as MPNs are very inflammatory diseases. This is the first study to investigate the association between metformin use and risk of MPN.”

MPNs are a group of diseases that affect how bone marrow produces blood cells, resulting in an overproduction of red blood cells, white blood cells, or platelets that can lead to bleeding problems, a greater risk of stroke or heart attack, and organ damage.

Surprisingly strong association

The researchers compared metformin use among patients diagnosed with MPNs and a matched population from the Danish general population between 2010 and 2018. Of the 3816 MPN cases identified from the sample, a total of 268 (7.0%) individuals with MPN had taken metformin as compared to 8.2% (1573 out of 19 080) of the control group of people who had taken metformin but were not diagnosed with MPN. Just 1.1% of MPN cases had taken metformin for more than five years, as compared to 2.0% of controls. The protective effect of metformin was seen in all subtypes of MPN when adjusting for potential confounders.

“We were surprised by the magnitude of the association we saw in the data,” said Daniel Tuyet Kristensen, MD, PhD student, at Aalborg University Hospital and lead author of the study. “We saw the strongest effect in people who had taken metformin for more than five years as compared to those who had taken the treatment for less than a year.” Dr Kristensen added that this makes clinical sense, as MPNs are diseases that develop over a long period of time, like other types of cancer.

The researchers noted that while the protective effect of long-term metformin use was seen in all subtypes of MPN, the study was limited by its registry-based retrospective design. Further, they could not account for risk-modifying lifestyle factors, such as smoking, obesity, and dietary habits.

Dr Roug noted that while the study team were unable to assess exactly why metformin seems to protect against the development of MPN, they hope additional research will be conducted to better understand why this may be. Moving forward, the researchers aim to identify any similar trends with myelodysplastic syndromes and acute myeloid leukaemia in population-level data for future study.

Source: American Society of Hematology

Metformin for Gestational Diabetes may Negatively Impact Offspring

Photo by SHVETS production

With the rise in gestational diabetes and metabolic disorders during pregnancy, metformin is also being prescribed more frequently. Although it is known that the oral antidiabetic agent can cross the placental barrier, the impacts on the brain development of the child are largely unknown. Now, researchers have been able to demonstrate in a mouse model that although metformin has positive effects in pregnant animals, it does not in the offspring. The researchers, from German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), published their findings in Molecular Metabolism.

Around one in six pregnant women worldwide are affected by gestational diabetes. According to the Robert Koch Institute, 63 000 women in Germany were affected by the disease in 2021, and the trend is increasing. Excessively high blood sugar levels during pregnancy are associated with negative consequences for mother and child. It increases the risk of affected women developing type 2 diabetes later on and their children have a higher risk of developing metabolic disorders and being overweight.

Long-term effect of metformin on offspring is unclear

The placenta-crossing oral antidiabetic agent metformin has been gaining importance as an alternative to insulin administration when lifestyle changes fail to treat gestational diabetes. But there are currently only a few studies on the long-term effects of metformin on the health of offspring. It is known that metformin has an impact on the AMPK signaling pathway, which regulates the networking of nerve cells during brain development.

The interdisciplinary team of DIfE researchers led by Junior Research Group Leader Dr Rachel Lippert therefore grappled with two central questions:

Firstly, is metformin treatment only beneficial for the mother or also the child?

Secondly, does metformin treatment lead to long-term negative physiological changes in the offspring, especially in connection with the development of neuronal circuits in the hypothalamus, a critical region in the regulation of energy homeostasis?

Mouse models shed some light

To answer the key questions, the researchers used two mouse models with high-fat or control diets to represent the main causes of gestational diabetes, ie, severe obesity of the mother before pregnancy and excessive weight gain during pregnancy. The antidiabetic treatment of female mice and their offspring took place during the lactation period as this corresponds to the third trimester of a human pregnancy in terms of brain development.

The mice were treated with insulin, metformin, or a placebo, with dosage based on standard human treatments. The research team collected data on the body weight of the mice, analysed various metabolic parameters and hormones, and examined molecular signaling pathways in the hypothalamus.

Maternal metabolic state is crucial

“As a result of antidiabetic treatment in the early postnatal period, we were able to identify alterations in the weight gain and hormonal status of the offspring, which were critically dependent on the metabolic state of the mother,” explains Lippert. Furthermore, sex-specific changes in hypothalamic AMPK signalling in response to metformin exposure were also observed. Together with the metformin-induced shift in the examined hormone levels, the results indicate that the maternal metabolic state must be taken into account before starting the treatment of gestational diabetes.

Focusing on prevention

According to Rachel Lippert, treatment of gestational diabetes in future could entail developing a medication that is available for all and does not cross the placenta. “Given the increasing prevalence, education about gestational diabetes and preventive measures are of vital importance. If we can find a way to manage lifestyle and diet more proactively, we are in a better position to exploit the potential of gestational diabetes treatment,” says Lippert.

Source: Deutsches Zentrum fuer Diabetesforschung DZD

Metformin’s Weight Loss Tied to “Anti-hunger” Molecule

A new study finds that the modest weight loss from taking metformin is attributable to an appetite-suppressing molecule that is abundant after exercise

Photo by I Yunmai on Unsplash

An “anti-hunger” molecule produced after vigorous exercise is responsible for the moderate weight loss caused by the diabetes medication metformin, according to a new study in mice and humans. The anti-hunger molecule, lac-phe, was discovered by Stanford Medicine researchers in 2022.

The finding, made jointly by researchers at Stanford Medicine and at Harvard Medical School and published in Nature Metabolism, further cements the critical role the molecule, called lac-phe, plays in metabolism, exercise and appetite. It may pave the way to a new class of weight loss drugs.

“Until now, the way metformin, which is prescribed to control blood sugar levels, also brings about weight loss has been unclear,” said Jonathan Long, PhD, an assistant professor of pathology. “Now we know that it is acting through the same pathway as vigorous exercise to reduce hunger. Understanding how these pathways are controlled may lead to viable strategies to lower body mass and improve health in millions of people.”

Many people with diabetes who are prescribed metformin lose around 2% to 3% of their body weight within the first year of starting the drug. Although this amount of weight loss is modest when compared with the 15% or more often seen by people taking semaglutide, the discoveries that led to those drugs also grew from observations of relatively minor, but reproducible, weight loss in people taking first-generation versions of the medications.

Post-workout appetite loss

When Long and colleagues at Baylor University discovered lac-phe in 2022, they were on the hunt for small molecules responsible for curtailing hunger after vigorous exercise. What they found was a mishmash of lactate and an amino acid called phenylalanine. They dubbed the hybrid molecule lac-phe and went on to show that it’s not only more abundant after exercise but it also causes people (as well as mice and even racehorses) to feel less hungry immediately after a hard workout.

“There is an intimate connection between lac-phe production and lactate generation,” Long said. “Once we understood this relationship, we started to think about other aspects of lactate metabolism.”

Metformin was an obvious candidate because as it stimulates the breakdown of glucose (thus reducing blood sugar levels) it can trigger the generation of lactate.

The researchers found that obese laboratory mice given metformin had increased levels of lac-phe in their blood. They ate less than their peers and lost about 2 grams of body weight during the nine-day experiment.

Long and his colleagues also analysed stored blood plasma samples from people with Type 2 diabetes before and 12 weeks after they had begun taking metformin to control their blood sugar. They saw significant increases in the levels of lac-phe in people after metformin compared with their levels before treatment. Finally, 79 participants in a large, multi-ethnic study of atherosclerosis who were also taking metformin had significantly higher levels of lac-phe circulating in their blood than those who were not taking the drug.

“It was nice to confirm our hunch experimentally,” Long said. “The magnitude of effect of metformin on lac-phe production in mice was as great as or greater than what we previously observed with exercise. If you give a mouse metformin at levels comparable to what we prescribe for humans, their lac-phe levels go through the roof and stay high for many hours.”

Further research revealed that lac-phe is produced by intestinal epithelial cells in the animals; blocking the ability of mice to make lac-phe erased the appetite suppression and weight loss previously observed.

Finally, a statistical analysis of the people in the atherosclerosis study who lost weight during the several-year study and follow-up period found a meaningful association between metformin use, lac-phe production and weight loss.

“The fact that metformin and sprint exercise affect your body weight through the same pathway is both weird and interesting,” Long said. “And the involvement of the intestinal epithelial cells suggests a layer of gut-to-brain communication that deserves further exploration. Are there other signals involved?”

Long noted that, while semaglutide drugs are injected into the bloodstream, metformin is an oral drug that is already prescribed to millions of people. “These findings suggest there may be a way to optimize oral medications to affect these hunger and energy balance pathways to control body weight, cholesterol and blood pressure. I think what we’re seeing now is just the beginning of new types of weight loss drugs.”

Source: Stanford Medicine

Metformin Trial Offers Hope for Women with Gestational Diabetes

Source: Pixabay CC0

A significant step forward has been taken in the management of gestational diabetes mellitus after a clinical trial involving pregnant women provided new hope for expectant mothers suffering the condition. The findings from the trial are published in the Journal of American Medical Association.

Gestational diabetes affects almost 3 million pregnant women worldwide every year. It is a condition characterised by elevated blood sugar levels during pregnancy, posing increased health risks for both mothers and their babies.

The EMERGE, randomised, placebo-controlled trial, was conducted by the University of Galway and involved more than 500 pregnant women.

The trial results showed that:

  • Women assigned to metformin were 25% less likely to need insulin, and when insulin was necessary, it was started later in the pregnancy.
  • Fasting and post-meal glycaemic values in the mother were significantly lower in the metformin exposed group at weeks 32 and 38.
  • Women receiving metformin gained less weight throughout the trial and maintained this weight difference at the 12-week post-delivery visit.
  • Importantly, delivery occurred at the same mean gestational age (39.1 weeks) in both groups. There was no evidence of any increase in preterm birth (defined as birth before 37 weeks) among those who received metformin.
  • Infants born to mothers who received metformin weighed, on average, 113g less at birth, with significantly fewer infants classified as large at birth, or weighing over 4kg.
  • While there was a slight reduction in infant length (0.7cm), there were no other significant differences in baby measurements.
  • There were slightly more babies who were small at birth but this did not reach statistical significance.

The study also revealed no differences in adverse neonatal outcomes, including the need for intensive care treatment for new-borns, respiratory support, jaundice, congenital anomalies, birth injuries or low sugar levels.

Additionally there were no variations in rates of labour induction, caesarean delivery, maternal haemorrhage, infection or blood pressure issues during or after birth.

Professor Fidelma Dunne managed the trial, and presented the results at the 59th Annual Meeting of the European Association for the Study of Diabetes in Hamburg, Germany.

Professor Dunne said, “While there is convincing evidence that improved sugar control is associated with improved pregnancy outcomes, there was uncertainty about the optimal management approach following a diagnosis of gestational diabetes.

“In our pursuit of a safe and effective treatment option we explored an alternative approach – administering the drug metformin. A previous trial compared metformin to insulin and found it to be effective, yet concerns remained, especially regarding preterm birth and infant size.”

To address concerns comprehensively, the team at University of Galway conducted a ground-breaking placebo-controlled-trial, filling a critical gap in the gestational diabetes treatment landscape.

  • 535 pregnant women took part, with 268 receiving metformin and 267 a placebo.
  • 98% of women remained in the trial until delivery, with 88% completing the 12-week post-delivery follow up assessment.
  • Only 4.9% of women discontinued medication due to side effects, highlighting the safety of the interventions.

Professor Dunne said, “Traditionally, gestational diabetes has been managed initially through dietary advice and exercise, with insulin introduced if sugar levels remain sub optimal. While effective in reducing poor pregnancy outcomes, insulin use is associated with challenges, including low sugars in both the mother and infant which may require neonatal intensive care, excess weight gain for mothers, and higher caesarean birth rates.” Professor Dunne added: “The results from the EMERGE study are a significant step forward for women with gestational diabetes. Metformin has emerged as an effective alternative for managing gestational diabetes, offering new hope for expectant mothers and healthcare providers worldwide.”

Source: University of Galway

In Animal Studies, Metformin Extends Lifespan

Photo by Towfiqu Barbhuiya on Unsplash

Researchers have discovered that the common antidiabetic drug metformin not only lowers blood sugar levels but has revealed to extend lifespan in C. Elegans, an animal model that shares similar metabolic systems with humans and are often used to model human diseases.

This study, led by investigators at Massachusetts General Hospital (MGH), reveals that metformin promotes longevity by stimulating the body’s production of ether lipids, a major structural component of cell membranes.

The findings, which are published in eLife, suggest that boosting production of ether lipids in humans may support healthy aging and reduce the impact of aging-related diseases.

To identify the genes required to enable lifespan extension in response to metformin and its sister drug phenformin (drugs called biguanides), the scientists silenced individual genes in the roundworm Caenorhabditis elegans (which shares over 80% of its proteins with humans and has an average lifespan of about two weeks) and examined what happens to the altered worms after exposure to the medications.

The experiments reveal that genes that increase production of ether lipids are required to extend lifespan in response to the biguanides. Inactivation of the genes that encode for these enzymes completely prevented the longevity-promoting effects of biguanides. Importantly, inactivation of these genes prevented lifespan extension in a variety of situations that are also known to promote longevity, including dietary restriction.

The team also found that increasing ether lipid synthesis alone (by overexpressing a single, key ether lipid biosynthetic enzyme called fard-1) was sufficient to extend C. elegans’ lifespan, orchestrating a metabolic stress defense response through a factor called SKN-1, which is the worm counterpart to the mammalian protein Nrf. This response altered metabolism to promote a longer lifespan.

“Our study implicates promotion of ether lipid biosynthesis as a novel therapeutic target to promote healthy aging. This suggests that dietary or pharmacologic intervention to promote ether lipid synthesis might one day represent a strategy to treat aging and aging-related diseases,” says senior author Alexander A. Soukas, MD, PhD, an Associate Professor at Harvard Medical School.

“Because our studies focused solely on interventions in C. elegans, further studies in mammalian models (such as human cells and mice), epidemiological observation, and rigorous clinical trials are required to determine the viability of promoting ether lipid synthesis to promote human health-span and lifespan.”

Source: Massachusetts General Hospital

Metformin Also Seems to Protect Against Muscle Atrophy and Fibrosis

Photo by Barbara Olsen on Pexels

Diabetes and muscle function might seem like they don’t have much to do with each other. But University of Utah Health researchers have discovered that metformin can also prevent muscle atrophy and muscular fibrosis – which can help the elderly bounce back faster from injury or illness. Their findings were published in the journal Aging Cell.

Metformin, the researchers found, actually has surprising applications on a cellular level. It can target senescent cells which impact muscle function. Senescent cells secrete factors associated with inflammation that may underlie fibrotic tissue, a hardening or scarring of tissues. They also discovered that metformin also reduces muscle atrophy.

“We’re interested in clinical application of this research,” says Micah Drummond, PhD, senior author of the study and professor of physical therapy and athletic training at the College of Health. “For example, knee surgeries in the elderly are notoriously hard to recover from. If we give a metformin-type agent during the recovery period, could we help the muscles get back to normal faster?”

Reinvigorating muscle recovery

Ageing comes with the risks of falls, hospitalisation, or developing chronic disease, which are more likely with muscle disuse. The research team wanted to find a therapeutic solution that could properly target both disuse atrophy and muscle recovery.

There’s an optimal level of senescent cells that are beneficial, no matter your age. In younger, healthier people, short-term senescence is required for a proper recovery from injury, and completely blocking the senescent effect impedes the body’s efforts to heal. Typically, a younger person can bounce back more easily after muscle disuse without the use of an intervention such as Metformin.

“In the case of aging, we know that there’s immune dysfunction,” says Drummond. “As you get older, it becomes harder for your body to clear senescent cells and they accumulate. That’s one reason recovery is much slower for the elderly after periods of disuse.”

Metformin’s anti-senescent properties have been demonstrated through pre-clinical studies. To test the intervention in humans, the team recruited 20 healthy male and female older adults for a multi-week study. They had participants undergo a muscle biopsy and MRI before the intervention, which involved five days of bed rest. One group of 10 received metformin and the other 10 received placebo pills during a two-week run-in period, then each group continued the placebo or metformin treatment during bed rest.

After the bed rest, participants received another muscle biopsy and MRI, then ceased treatments. All patients completed a seven-day re-ambulation period followed by a final muscle biopsy.

“We saw two things in our study,” Drummond says. “When participants took Metformin during a bed rest, they had less muscle atrophy. During the recovery period, their muscles also had less fibrosis or excessive collagen. That build-up can make it harder for the muscle to properly function.”

Tying these results to senescence, the research team examined muscle biopsies from study participants. They found that the participants who took Metformin had fewer markers of cellular senescence.

“This is the first paper that has made the direct connection between a therapy targeting cellular senescence and improved muscle recovery following disuse in aging,” says lead author Jonathan Petrocelli, PhD He explains that metformin helps muscle cells better remodel and repair tissue during periods of recovery after inactivity.

“Our real goal is to have patients maintain their muscle mass and function as they age, because atrophy and weakness are some of the strongest predictors of disease development and death,” he says.

Drummond’s team is following up on these findings by examining combining the drug with leucine, an amino acid that promotes growth and could accelerate recovery even further. They’ve already demonstrated the potency of this combination in preclinical animal studies.

“Metformin is cheap, effective and quite safe, so it’s exciting to see that we can use it to accelerate recovery for older individuals,” adds Drummond.

Source: University of Utah Health

Great SCOT! Repurposing Old Antipsychotics as Diabetes Treatments

Photo by Myriam Zilles on Unsplash

Researchers have found that a class of older antipsychotic drugs could be a promising new therapeutic option for people with type 2 diabetes, helping fill a need among patients who aren’t able to take other currently available treatments. The drugs interact with the metabolic enzyme succinyl CoA:3-ketoacid CoA transferase (SCOT), preventing the muscles from using ketones for fuel.

“There is a growing need to find new therapies for type 2 diabetes,” says John Ussher, professor in the Faculty of Pharmacy & Pharmaceutical Sciences and lead author of the recent study published in the journal Diabetes.

Metformin is one of the most common therapeutics for type 2 diabetes, but about 15% of patients aren’t able to take it. Iinsulin secretagogues, another commonly used drug class, isn’t as effective for later-stage patients.

“For the patients who can’t take metformin, patients with late-stage diabetes where their beta cells aren’t working as well, when you’re trying to find new therapies or new combination therapies as the disease progresses, it becomes more important to find new drug classes that target new mechanisms so then you have more options to try and lower blood sugar in those individuals,” Ussher explains.

The mechanism Ussher and his team turned their attention to is SCOT, which is an enzyme involved in the body’s process of making energy from ketones. Using computer modelling to find drugs that could potentially interact with SCOT, they landed on an older generation of antipsychotic drugs, a drug class called diphenylbutylpiperidines, or DPBP for short.

Ussher and his team had previously found that a specific drug within this class called pimozide could be repurposed to help treat diabetes, but they’ve since expanded their focus to see whether more of the DPBP class could also be useful for treating the disease.

“We’ve tested three drugs now, and they all interact with this enzyme,” says Ussher. “They all improve blood sugar control by preventing the muscle from burning ketones as a fuel source.”

“We believe this SCOT inhibition is the reason these antipsychotics might actually have a second life for repurposing as an anti-diabetic agent,” he adds.

Developing a drug is a complicated, time-consuming and expensive process. It involves clinical trials to test the safety and efficacy of the drug, and can easily cost hundreds of millions of dollars. Not to mention, it can take years to go from development in the laboratory to use in the clinic or hospital. Repurposing an existing drug may help fast-track the process, Ussher notes.

“With something that’s an older drug which we used historically in humans that we no longer use, we know what the adverse effects are, we know in general that it’s safe,” he says.

Though clinical trials are still needed, repurposing a drug allows researchers to focus specifically on the efficacy and safety of the new intended use, offering a quicker and cheaper path to a new therapy.

“As you already have safety data, it somewhat accelerates the process,” says Ussher. “And from an economic standpoint, often because a lot of these drugs being pursued for repurposing are older, they’re off patent and cheaper.”

Repurposing is effective because it capitalises on a main characteristic of most drugs, ie not being restricted to just one target in the body. As Ussher explains, most drugs actually have numerous targets they can influence.

“That’s where repurposing comes in,” he says. “Can we identify the other targets that a drug may interact with, and by identifying those other targets, can this drug serve a purpose for a different disease?”

This is what Ussher’s lab did in recognising the DPBP drug class could target SCOT activity as well as the dopamine receptors it targets in its original intended use to treat psychosis.

Knowledge of these original targets can also provide valuable context when refining and improving the repurposed drug. Since DPBP drugs were originally antipsychotics, many of their potential side-effects such as drowsiness, dizziness or fatigue arise from their effects on their original target: the dopamine receptors in the brain. Ussher’s lab is planning to try creating a modified version of the drug class that doesn’t reach the brain and has fewer potential adverse effects.

“For us, the excitement is that it looks like the entire family of these compounds interacts with this protein [SCOT] and can improve blood sugar control in type 2 diabetes.”

Source: University of Alberta

Could Metformin be Used to Treat Atrial Fibrillation?

Photo by Towfiqu Barbhuiya on Pexels

Cleveland Clinic researchers have identified metformin as a possible treatment for atrial fibrillation (AF). In the study, published in Cell Reports Medicine, researchers used advanced computation and genetic sequencing to determine that metformin’s targets overlap significantly with genes that are dysregulated in AF.

“Finding drugs or procedures to treat atrial fibrillation is difficult because of potential serious side effects,” said Mina Chung, MD, senior study author. “There is a significant need for new treatments for atrial fibrillation as there have been no new drugs approved in more than a decade.”

“It’s not that we’ve found a new drug target where it takes 20 years to test this in individuals,” said Jessica Castrillon Lal, first author and graduate student.

“We can cut off 10+ years in the drug development pipeline. We already have the information there. We just have to test it in a very computationally efficient way, such as artificial intelligence technology,” said Feixiong Cheng, PhD, co-senior study author.

The analysis found metformin targeted 30 genes associated with AF, with direct effects on gene expression for eight. Eight other candidate drugs surfaced in the analysis, but further testing and patient data review identified metformin as the most promising candidate.

Castrillon Lal conducts research in Dr Cheng’s lab, which uses network medicine approaches to find candidate drugs for repurposing, creating vast networks of molecular interactions. For this study, researchers narrowed down a list of 2800 FDA-approved treatments by analysing three data sources: a map of interactions between proteins called an “interactome”; a network of genes associated with atrial fibrillation; and each medicine’s molecular or genetic targets.

Atrial fibrillation is the most common type of heart arrhythmia in the world and can lead to complications, including stroke and heart failure. Treatments have been primarily directed toward trying to prevent the arrhythmia using drugs targeting the electrical system, including ion channels in the heart, or using catheter ablation to isolate the pulmonary veins where initiating beats of atrial fibrillation occur.

However, side effects, limited success and potential complications can limit these approaches.

Source: Cleveland Clinic

Trial Suggests Early Metformin is Effective in COVID Treatment

Image from Pixabay

In a study published in the New England Journal of Medicine, researchers have found that metformin, a commonly prescribed diabetes medication, lowers the odds of emergency department visits, hospitalisations, or death due to COVID by over 40%; and over 50% if prescribed early in onset of symptoms. The study also found no positive effect from treatment with either ivermectin or low-dose fluvoxamine.

“Our trial suggests that metformin may reduce the likelihood of needing to go to the emergency room or be hospitalised for COVID,” said Carolyn Bramante, MD, principal investigator of the study.

The primary outcome was in fact low oxygen on a home oxygen monitor, which none of the medications in the trial prevented.

The COVID-OUT trial studied whether metformin, low-doses of the antidepressant fluvoxamine, the controversial antiparasitic ivermectin, or their combinations could serve as possible treatments to prevent ER visits or hospitalisation, as well as Long COVID.

Patients were randomised to receive one of the three drugs individually: placebo, or a combination of metformin and fluvoxamine or metformin and ivermectin. Although the study was placebo-controlled with exact-matching placebo pills, Dr Bramante said that 83% of volunteers received medications supported by existing data because of the six-arm design. Each participant received 2 types of pills to keep their treatment assignment masked, for 3 to 14 days of treatment. Each volunteer tracked their symptoms, and after 14 days, they completed a survey.

The 1323 participants in the trial were limited to adults with a body mass index greater than or equal to 25 kg/m2, which qualifies as overweight. To qualify for the study, volunteers enrolled within three days after receiving a positive COVID test. It was among the first randomised clinical trials for COVID to include pregnant women.

The study included those who were vaccinated and those who were not. This is the first published trial where the majority of participants were vaccinated. 

“Although we know COVID vaccines are highly effective, we know that some new strains of the virus may evade immunity and vaccines may not be available worldwide. So we felt we should study safe, available and inexpensive outpatient treatment options as soon as possible,” said Dr Bramante. “Understanding whether outpatient treatments could ensure more people survive the illness if they contract it and have fewer long-term symptoms is an important piece of the pandemic response.”

The clinical trial launched in January 2021 after researchers noticed that outpatient metformin use appeared to decrease the likelihood of mortality from, or being hospitalised for COVID. Their research was published in the Journal of Medical Virology and in The Lancet Healthy Longevity. Test-tube studies also found that metformin inhibited the -CoV-2 in lab settings. These findings, along with additional prospective studies supporting the use of higher-dose fluvoxamine and ivermectin, provided the evidence to include all three medications as well as combination arms.

Source: University of Minnesota