Long COVID - 3 years and counting.... (Part 2)

New emerging research

As a specialist nurse working in one of the NHS long COVID clinics I had started to develop a hypothesis about metformin. This sparked my curiosity, and I wondered if Metformin was providing some protection to developing long COVID. In fact this conversation and curiosity was the first meeting with my fellow co-founder Rachel Jessy.? So, it was with interest that I read the new randomised placebo-controlled trial of metformin and the results indicating that this is the first drug to help prevent long COVID. In this trial over a thousand people with mild to moderate COVID were randomly assigned to 3 drugs, metformin, ivermectin, and fluvoxamine.? Inclusion criteria included those aged between 30-85 years with overweight or obesity. Those that were assigned to 2 weeks of metformin (500mg x 1 on day 1, increasing to 500mg x2 for four days and then 500mg in the AM with 1000mg in the evening for 9 days) showed a significant reduction of 42% in developing long COVID.? The effect of metformin was consistent across subgroups, including viral variants. The trial also reinforced the higher risk for unvaccinated v’s vaccinated status in the placebo arm with 14% vs 7%.?

The mechanism that metformin helps to reduce long COVID is not entirely understood but it is postulated that it helps to reduce oxidative stress and inflammation and/or helps with suppressing viral replication.? If it does suppress the virus, there is some hope that it may be beneficial as a treatment for long COVID if this condition is caused by remnants of the virus lingering in the body.?

Eric Topal shared his thoughts about this trial in substack claiming it was of significant rigour to now recommend metformin in clinical practice. The risks of prescribing metformin remain very low (it has been used consistently over many years) and the drug costs are minimal for a 2-week course (approximately ￡1-￡1.50).??

A further review identified that people with diabetes, both type 1 and type 2 appear more likely to develop long COVID compared to people who did not have diabetes. Additionally, long COVID also increases the risk of new-onset diabetes of both type 1 and type 2. It is hypothesised? that long COVID can exacerbate microvascular dysfunction through inflammatory or immunological mechanisms which may precipitate new onset diabetes and impact those with pre-existing diabetes. The ramifications of the socioeconomic burden of this bidirectional association between long COVID and diabetes should be considered and further studies are needed before we can draw definitive conclusions. It would be interesting to see if metformin could reduce long COVID developing in those most at risk and if it reduces risk in those who are more susceptible to developing COVID 19 complications. At present we are not aware of metformin being used outside of clinical trials.? The other factor which may hamper further larger studies is the reduction in testing of COVID 19 amongst the general population.??

Following a preprint in November looking at the use of Paxlovid and long COVID a further publication of the data with an increased sample showed that this drug was associated with a 26% reduction of long COVID in individuals treated within 5 days.? Results indicate that this benefit was seen across multiple organ systems but with no effect seen for reducing liver disease or diabetes.?

Interesting future studies are planned to look at using Paxlovid to treat people affected by long COVID in a small-randomised trial with 15 days of Paxlovid or placebo.? A Canadian randomised trial is underway looking at utilising naltrexone as a treatment for long COVID with results expected next year.? Finally, there is some emerging data which suggests that people are far less likely to develop long COVID if they tested positive for COVID 19 during Omicron waves.? This study is about to be published in April but tested 1,200 health care workers in Switzerland.? A previous study in the UK, involving the health records of 97,000 people found that those who were infected with Omicron variants were about half as likely to report continued symptoms after 4 weeks or more compared with those infected with the Delta variant. These differences in findings may be related to the populations studied and the size of the studies.

We have much more to discover about long COVID, learning how we move forward and adapt to the risks it poses. Innovative policies and practices are needed to help us transition, improving the health of the nation, reducing inequality, and protecting our more vulnerable members of society.? One thing is certain, long COVID is not disappearing any time soon and we should not ignore its impact.? By failing to accurately measure this we are at risk of being blind to the actual socioeconomic costs of long COVID.?