tag:theconversation.com,2011:/fr/topics/metformin-26007/articlesmetformin – The Conversation2023-12-05T05:02:16Ztag:theconversation.com,2011:article/2165292023-12-05T05:02:16Z2023-12-05T05:02:16ZCould antivirals reduce your risk of long COVID? Where the research is up to on prevention and treatment<figure><img src="https://images.theconversation.com/files/563521/original/file-20231205-22-pubb03.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C4089%2C2152&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/young-man-lying-down-bed-falling-2371946363">Bricolage/Shutterstock</a></span></figcaption></figure><p>Evidence is continuing to accumulate on the burden and frequency of <a href="https://www.nature.com/articles/s41591-023-02521-2">chronic effects</a> after a COVID infection, which fall under the umbrella term “long COVID”.</p>
<p>At least <a href="https://www.aihw.gov.au/reports/covid-19/long-covid-in-australia-a-review-of-the-literature/summary">5%–10%</a> of people who contract COVID experience <a href="https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html">long COVID</a>. This can include symptoms (for example, fatigue, brain fog and breathlessness) or conditions (for example, <a href="https://www.nature.com/articles/s41591-022-01689-3">heart conditions</a>, <a href="https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(22)00260-7/fulltext">neurological conditions</a> and <a href="https://www.thelancet.com/journals/landia/article/PIIS2213-8587(22)00044-4/fulltext">diabetes</a>) after the initial infection that may be persisting, new or relapsing.</p>
<p>Studies show the symptoms and increased risk of chronic conditions can persist <a href="https://theconversation.com/long-covid-symptoms-can-improve-but-their-resolution-is-slow-and-imperfect-212015">for up to two years</a> after infection. The individual impact of long COVID can range from temporary to severely disabling, and the societal cost – for example due to <a href="https://ifs.org.uk/publications/long-covid-and-labour-market">reduced workforce</a> and increased health-care costs – <a href="https://scholar.harvard.edu/files/cutler/files/long_covid_update_7-22.pdf">is enormous</a></p>
<p>The lower risk of developing long COVID with up-to-date <a href="https://www.bmj.com/content/383/bmj-2023-076990">COVID vaccinations</a> is substantially offset by the high levels of infections and <a href="https://www.nature.com/articles/s41591-022-02051-3">re-infections</a> globally. As a result, the <a href="https://www.nature.com/articles/s41577-023-00904-7/figures/1">cumulative burden of long COVID</a> has increased, including in <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01685-9/fulltext">lower and middle income countries</a>. A conservative estimate suggests <a href="https://www.nature.com/articles/s41579-022-00846-2">65 million</a> people may be currently affected globally. </p>
<p>So where are we at with reducing the risk of, and treating, long COVID?</p>
<h2>Could antivirals reduce the risk of long COVID?</h2>
<p>COVID antiviral drugs, taken orally, continue to play an <a href="https://www.thelancet.com/journals/lanwpc/article/PIIS2666-6065(23)00235-3/fulltext">important role in reducing</a> acute severe disease after infection. In Australia, they’re available to those <a href="https://theconversation.com/covid-wave-whats-the-latest-on-antiviral-drugs-and-who-is-eligible-in-australia-218423">at highest risk</a> from COVID.</p>
<p><a href="https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2802878">Observational research</a> has suggested taking antivirals during a COVID infection can reduce the risk of long COVID in people with at least one risk factor for acute severe COVID. </p>
<p>In one study, <a href="https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2802878">nirmatrelvir and ritonavir</a>, known as Paxlovid, was associated with a 26% reduced risk of developing long COVID. It was also linked to a 47% reduced risk of death and a 24% reduced risk of hospitalisation after the acute infection phase. </p>
<p>A similar 14% reduction in long COVID risk has been reported for <a href="https://www.bmj.com/content/381/bmj-2022-074572">molnupiravir</a> (Lagevrio).</p>
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<img alt="A box of Paxlovid, blister pack and some pills on a surface." src="https://images.theconversation.com/files/563528/original/file-20231205-23-5xm56w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/563528/original/file-20231205-23-5xm56w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/563528/original/file-20231205-23-5xm56w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/563528/original/file-20231205-23-5xm56w.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/563528/original/file-20231205-23-5xm56w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/563528/original/file-20231205-23-5xm56w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/563528/original/file-20231205-23-5xm56w.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Some research suggests taking Paxlovid during a COVID infection could reduce the risk of long COVID.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/detroit-michigan-usa-october-26-2022-2219217999">J.A. Dunbar/Shutterstock</a></span>
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<p><a href="https://www.shionogi.com/content/dam/shionogi/global/investors/ir-library/presentation/2022/CROI20230222.pdf">Ensitrelvir</a> – a COVID antiviral available in Japan – could also reduce the risk of long COVID, preliminary analyses suggest. </p>
<p>More research is needed, but this data indicates antiviral medications may be a key approach to lessening the risk of long COVID.</p>
<p>The population most <a href="https://theconversation.com/long-covid-stemmed-from-mild-cases-of-covid-19-in-most-people-according-to-a-new-multicountry-study-195707">at risk of long COVID</a> (often working-age adults) differs from those most at risk of severe disease from a COVID infection (older adults or those with chronic medical conditions). <a href="https://www.health.gov.au/health-alerts/covid-19/treatments/eligibility">Eligibility criteria</a> to access antivirals do not currently include consideration of long COVID. </p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/long-covid-symptoms-can-improve-but-their-resolution-is-slow-and-imperfect-212015">Long COVID symptoms can improve, but their resolution is slow and imperfect</a>
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<p>Meanwhile, one randomised trial found <a href="https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(23)00299-2/fulltext">metformin</a>, a commonly prescribed diabetes medication, could also reduce long COVID risk. The study offered people with symptomatic COVID who were overweight or obese metformin for two weeks (beginning within a week of symptoms starting). This group was 41% less likely to develop long COVID compared with a placebo group that didn’t take metformin.</p>
<p>The way this works might involve an effect on the powerhouses of our cells, <a href="https://www.nih.gov/news-events/nih-research-matters/sars-cov-2-can-cause-lasting-damage-cells-energy-production">mitochondria</a>, or directly on the virus. Whatever the precise mechanism, further research should be priortised to fast-track this potential. </p>
<h2>We’re understanding more about long COVID</h2>
<p>There are no effective or approved treatments for long COVID at present. Currently about <a href="https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(23)00440-1/fulltext">12 clinical trials</a> are testing potential drugs. A number of <a href="https://www.nature.com/articles/s41579-022-00846-2/tables/1">candidate treatments</a> exist for certain components of long COVID that may be useful in subgroups of patients.</p>
<p>However, recently we’ve seen <a href="https://www.nature.com/articles/s41579-022-00846-2">major advances</a> <a href="https://www.nature.com/articles/s41586-023-06651-y">in understanding</a> what’s actually <a href="https://www.cell.com/cell/fulltext/S0092-8674(23)01034-6">driving long COVID</a> in the body. This knowledge opens up approaches for both diagnosis and <a href="https://www.nature.com/articles/s41577-023-00904-7">treatments or interventions</a>.</p>
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Read more:
<a href="https://theconversation.com/common-diabetes-drug-metformin-could-protect-against-long-covid-207460">Common diabetes drug metformin could protect against long COVID</a>
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</em>
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<h2>Research on treatments is lacking</h2>
<p>An Australian parliamentary inquiry into long COVID <a href="https://www.aph.gov.au/Parliamentary_Business/Committees/House/Health_Aged_Care_and_Sport/LongandrepeatedCOVID">stressed</a> the best way to avoid the condition is to lower the risk of getting infected with COVID in the first place (through protective behaviours such as vaccination, mask wearing and <a href="https://www.betterhealth.vic.gov.au/covid-19/improving-ventilation-stop-spread-covid-19">cleaner indoor air</a>). </p>
<p>While these are all important measures, we would benefit from having more tools at our disposal to prevent and treat long COVID. After all, COVID is still evolving rapidly and vast numbers of people are likely to be reinfected in the months and years ahead. </p>
<p>Overall, the quantity and speed of clinical trials into long COVID treatments <a href="https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(23)00440-1/fulltext">has been insufficient</a>. And most public health policy approaches are focused on preventing severe disease from a COVID infection, rather than the long-term effects. </p>
<p>That said, Australia recently announced an initial <a href="https://www.health.gov.au/news/MRFF-34-million-for-research-into-post-acute-sequelae-of-covid-19-long-covid-and-sleep-apnoea">A$22 million of funding</a> and a <a href="https://www.health.gov.au/resources/publications/mrff-post-acute-sequelae-of-covid-19-research-plan?language=en">plan for research</a> into long COVID through the Medical Research Future Fund. </p>
<p>In July 2023, the White House established the <a href="https://www.hhs.gov/about/news/2023/07/31/hhs-announces-formation-office-long-covid-research-practice-launch-long-covid-clinical-trials-through-recover-initiative.html">Office of Long COVID Research and Practice</a> which will coordinate the US government’s response to long COVID, as well as two <a href="https://trials.recovercovid.org/design">randomised trials</a> of <a href="https://medicine.yale.edu/cii/research/paxlc-study/">Paxlovid</a>. </p>
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<img alt="A woman in the supermarket wearing a mask." src="https://images.theconversation.com/files/563534/original/file-20231205-15-lrhnfj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/563534/original/file-20231205-15-lrhnfj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/563534/original/file-20231205-15-lrhnfj.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/563534/original/file-20231205-15-lrhnfj.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/563534/original/file-20231205-15-lrhnfj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/563534/original/file-20231205-15-lrhnfj.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/563534/original/file-20231205-15-lrhnfj.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">COVID is still a threat – so long COVID is too.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/woman-hygienic-mask-shopping-supply-buying-1675734979">eldar nurkovic/Shutterstock</a></span>
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<h2>What now?</h2>
<p>Given what we now know about long COVID, and the additional concern of what we don’t know (for example, could organ damage reveal itself many years down the track?), we desperately need diagnostic tools, clinical care pathways coupled with health worker training, and treatments to prevent and cure long COVID.</p>
<p>Unaddressed, long COVID may well lead to a new and substantial health and societal burden for many years to come. The response must involve prioritisation of research, such as that which led to the fast development of COVID vaccines and antivirals.</p>
<p>While there are some positive signs in the policy and research space, we need to see stronger recognition of long COVID and a greater sense of urgency around finding solutions.</p><img src="https://counter.theconversation.com/content/216529/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Suman Majumdar, through the Burnet Institute receives grant funding from the Australian Governemnt via the National Health & Medical Research Council of Australia, the Medical Research Future Fund and DFAT's Centre for Health Security.</span></em></p><p class="fine-print"><em><span>Brendan Crabb and the Institute he leads receives research grant funding from the National Health & Medical Research Council of Australia, the Medical Research Future Fund, DFAT's Centre for Health Security and other Australian federal and Victorian State Government bodies. He is the Chair of The Australian Global Health Alliance and the Pacific Friends of Global Health, both in an honorary capacity. And he serves on the Board of the Telethon Kids Institute, on advisory committees of mRNA Victoria, the Sanger Institute (UK), the Institute for Health Transformation (at Deakin University), The Brain Cancer Centre (Australia), the WHO Malaria Vaccine Advisory Committee; MALVAC, and is a member of OzSAGE and The John Snow Project, all honorary positions.</span></em></p><p class="fine-print"><em><span>Michelle Scoullar received funding from the RACP Foundation in 2018 and 2020 as part of her PhD. She is the lead paediatrician with Clinic Nineteen, a clinic specialised in the care and treatment of people with long COVID. </span></em></p><p class="fine-print"><em><span>Ziyad Al-Aly consulted for Pfizer (uncompensated) and Tonix pharmaceuticals. He receives funding from the US government. </span></em></p><p class="fine-print"><em><span>Emma Pakula does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>A promising collection of studies suggests taking antivirals such as Paxlovid during an infection could reduce the risk of developing long COVID.Suman Majumdar, Associate Professor and Chief Health Officer - COVID and Health Emergencies, Burnet InstituteBrendan Crabb, Director and CEO, Burnet InstituteEmma Pakula, Senior Research and Policy Officer, Burnet InstituteMichelle Scoullar, Senior Research Fellow, Burnet InstituteZiyad Al-Aly, Director Clinical Epidemiology Center, VA St. Louis Health Care System, Washington University in St. LouisLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2120152023-09-03T20:02:53Z2023-09-03T20:02:53ZLong COVID symptoms can improve, but their resolution is slow and imperfect<figure><img src="https://images.theconversation.com/files/545699/original/file-20230831-27-aw3r3u.jpg?ixlib=rb-1.1.0&rect=20%2C0%2C6689%2C4466&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.pexels.com/photo/woman-wearing-black-camisole-3356489/">Pexels/Engin Akyurt</a></span></figcaption></figure><p>Around <a href="https://www.aihw.gov.au/reports/covid-19/long-covid-in-australia-a-review-of-the-literature/summary">5–10%</a> of people who get infected with SARS-CoV-2 will experience symptoms that persist way beyond the initial acute period, a clinical syndrome we are learning more about, known widely as long COVID. </p>
<p>Shortness of breath, brain fog, lethargy and tiredness, loss of smell or taste are <a href="https://jamanetwork.com/journals/jama/fullarticle/2805540">common features of long COVID</a>, as is the development of new conditions such as diabetes, heart disease, stroke, depression and dementia. </p>
<p>But how long is the “long”? If and when do symptoms resolve? </p>
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<em>
<strong>
Read more:
<a href="https://theconversation.com/when-does-covid-become-long-covid-and-whats-happening-in-the-body-when-symptoms-persist-heres-what-weve-learnt-so-far-188976">When does COVID become long COVID? And what's happening in the body when symptoms persist? Here's what we've learnt so far</a>
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<p>A <a href="https://www.nature.com/articles/s41591-023-02521-2">recent study</a> has examined this in detail, following people for two years after their infection. This and other recently published studies on long COVID show that while symptoms do resolve in many people, their resolution is slow and imperfect.</p>
<h2>What did the study find?</h2>
<p>The key work, led by <a href="https://outlook.wustl.edu/real-world-reflections/">Ziyad Al-Aly</a>, examines the effect of SARS-CoV-2 two years after infection in a large group of US veterans. The researchers followed 139,000 people with COVID and almost six million uninfected controls for two years, tracking deaths, hospitalisations and 80 long-term impacts of COVID, categorised into ten organ systems. </p>
<p>They found that people who were initially hospitalised with COVID were 1.3 times more likely to die and 2.6 times more likely to be hospitalised again, compared to the control group (people without COVID), over the two years. After two years, this “hospitalised” group remained at increased risk of 50 conditions. </p>
<p>People who had milder COVID (who weren’t hospitalised with their initial COVID infection) had an increased risk of death for up to six months and increased risk of hospitalisation for up to 18 months. However, at two years, they remained at increased risk of 25 conditions. </p>
<p>So, while people who were initially hospitalised for COVID had worse outcomes over the two-year follow-up, there was still a substantial burden of illness in people who initially had milder COVID. This included a risk of clots and blood disorders, lung disease, fatigue, gut disorders, muscle and joint disorders and diabetes.</p>
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<a href="https://images.theconversation.com/files/545912/original/file-20230901-21-ebj1at.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/545912/original/file-20230901-21-ebj1at.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/545912/original/file-20230901-21-ebj1at.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=904&fit=crop&dpr=1 600w, https://images.theconversation.com/files/545912/original/file-20230901-21-ebj1at.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=904&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/545912/original/file-20230901-21-ebj1at.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=904&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/545912/original/file-20230901-21-ebj1at.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1136&fit=crop&dpr=1 754w, https://images.theconversation.com/files/545912/original/file-20230901-21-ebj1at.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1136&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/545912/original/file-20230901-21-ebj1at.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1136&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="attribution"><a class="source" href="https://twitter.com/erictopol/status/1693639185444253882?s=46&t=FooHfRKkxCeTub5OkqUyNA">X (formerley Twitter)</a></span>
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<h2>Findings from other recent research were similar</h2>
<p>A <a href="https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2808237">separate cohort study</a> followed more than 208,000 veterans with COVID over two years. It showed that overall, 8.7% died compared with 4.1% in the uninfected control group. The risk of death was concentrated in the first six months after infection. </p>
<p>A third, not yet peer-reviewed and <a href="https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4505315">smaller cohort study</a> of 341 people with long COVID from Spain, found only 7.6% of them recovered at two years. </p>
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Read more:
<a href="https://theconversation.com/what-is-pots-and-how-is-it-related-to-long-covid-208280">What is POTS? And how is it related to long COVID?</a>
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<p>Another significant <a href="https://www.medrxiv.org/content/10.1101/2023.08.07.23293778v1">(not yet peer-reviewed) study</a> from the United Kingdom assessed diabetes risk after COVID by following 15 million people in England from 2020–21. It found a 30–50% elevated risk of new type 2 diabetes after COVID. This increased risk persisted up to two years. But the risk for type 1 diabetes risk did not persist. </p>
<p>An <a href="https://www.medrxiv.org/content/10.1101/2023.08.27.23294704v1">Australian</a> (not yet peer-reviewed) study followed 31 people who developed long COVID and 31 matched controls who recovered from COVID for two years. It found that most of the concerning immunological dysfunction effects that had been present at eight months, had resolved by two years. While almost two-thirds of those with long COVID (62%) reported improved quality of life over the two years, one-third were still struggling in this regard two years after their infection. </p>
<p>Finally, a recent whole-body positron emission tomography (PET) imaging and biopsy <a href="https://pubmed.ncbi.nlm.nih.gov/37577714/">study</a> showed prolonged tissue level immune-activation and viral persistence in the gut for up to a remarkable two years after COVID. </p>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"1667027609287262208"}"></div></p>
<h2>These studies have some limitations</h2>
<p>It’s important to note the observational studies have some <a href="https://twitter.com/GidMK/status/1695220123437863123?s=20">inherent limitations</a>. </p>
<p>The US veterans cohort studied by Al-Aly is nearly 90% men, with an average age of 61 years, which is different to groups most at risk of long COVID. </p>
<p>They acquired their initial infection in 2020, before Omicron, before vaccination and before therapies – all of which are protective against long COVID to a degree. </p>
<p>Having said that, long COVID still <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00941-2/fulltext">frequently</a> <a href="https://www.medrxiv.org/content/10.1101/2023.08.06.23293706v1">occurs</a> in vaccinated people infected with Omicron.</p>
<h2>We still don’t have treatments for long COVID</h2>
<p>Increasing understanding about underlying mechanisms of long COVID, such as those involving persistent virus and effects on <a href="https://www.nih.gov/news-events/nih-research-matters/sars-cov-2-can-cause-lasting-damage-cells-energy-production">mitochondria – the powerhouse of the cells -</a> can lead to treatment options that need to be trialled.</p>
<p>In July 2023, the <a href="https://www.hhs.gov/about/news/2023/07/31/hhs-announces-formation-office-long-covid-research-practice-launch-long-covid-clinical-trials-through-recover-initiative.html">White House</a> established the Office of Long COVID Research and Practice. Two <a href="https://medicine.yale.edu/cii/research/paxlc-study/">randomised</a> <a href="https://trials.recovercovid.org/design">trials</a> are testing whether the antiviral nirmatrelvir-ritonavir (Paxlovid) can treat long COVID are currently recruiting patients. </p>
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<img alt="Man looks at pill" src="https://images.theconversation.com/files/545705/original/file-20230831-25-grdbqr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/545705/original/file-20230831-25-grdbqr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/545705/original/file-20230831-25-grdbqr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/545705/original/file-20230831-25-grdbqr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/545705/original/file-20230831-25-grdbqr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/545705/original/file-20230831-25-grdbqr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/545705/original/file-20230831-25-grdbqr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Research is underway to see if drugs can prevent long COVID.</span>
<span class="attribution"><a class="source" href="https://www.pexels.com/photo/man-taking-a-pill-9902269/">Pexels/Ron Lach</a></span>
</figcaption>
</figure>
<p>A separate <a href="https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(23)00299-2/fulltext">randomised, placebo-controlled trial</a> has shown that metformin, a commonly prescribed anti-diabetic medication, taken for two weeks (and taken within three days of testing positive for COVID) reduced the chance of developing long COVID by 41%. The mechanism may involve an effect on mitochondria or directly on the virus. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/paxlovid-is-australias-first-line-covid-antiviral-but-lagevrio-also-prevents-severe-disease-in-over-70s-195349">Paxlovid is Australia's first-line COVID antiviral but Lagevrio also prevents severe disease in over-70s</a>
</strong>
</em>
</p>
<hr>
<h2>But it’s still important to prevent COVID (re)infections</h2>
<p>Taken together, these studies on the longevity of long COVID add substantially to the case to fast-track the development of interventions and therapies to prevent and/or cure the condition. </p>
<p>In the meantime, it’s crucially important to <a href="https://www.aph.gov.au/Parliamentary_Business/Committees/House/Health_Aged_Care_and_Sport/LongandrepeatedCOVID/Report/Chapter_5_-_Prevention">prevent</a> (re)infections in the first place to reduce the future burden of long COVID, already estimated to be greater than <a href="https://www.nature.com/articles/s41579-022-00846-2">65 million</a> people <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01685-9/fulltext">globally</a>. </p>
<p>Breathe clean air by ensuring indoor spaces are <a href="https://www.coronavirus.vic.gov.au/ventilation">well-ventilated</a>. In poorly ventilated or crowded spaces, wear a well-fitted and high-quality mask (a P2, KN95 or N95 mask), and/or use <a href="https://sgeas.unimelb.edu.au/engage/air-cleaner-guide">air filtration devices</a> suitable for the space you are in.</p>
<p>Keep up to date with boosters. And get tested so you can get antiviral treatment if you’re eligible. </p>
<p>If you suspect you have long COVID, <a href="https://www.health.gov.au/resources/publications/getting-help-for-long-covid?language=en">discuss this with your GP</a>, who may refer you to specialised services or multidisciplinary care.</p><img src="https://counter.theconversation.com/content/212015/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Suman Majumdar, through the Burnet Institute receives grant funding from the Australian Governemnt via the National Health & Medical Research Council of Australia, the Medical Research Future Fund and DFAT's Centre for Health Security. </span></em></p><p class="fine-print"><em><span>Brendan Crabb and the Institute he leads receives research grant funding from the National Health & Medical Research Council of Australia, the Medical Research Future Fund, DFAT's Centre for Health Security and other Australian federal and Victorian State Government bodies. He is the Chair of The Australian Global Health Alliance and the Pacific Friends of Global Health, both in an honorary capacity. And he serves on the Board of the Telethon Kids Institute, on advisory committees of mRNA Victoria, the Sanger Institute (UK), the Institute for Health Transformation (at Deakin University), The Brain Cancer Centre (Australia), the WHO Malaria Vaccine Advisory Committee; MALVAC, and is a member of OzSAGE and The John Snow Project, all honorary positions.</span></em></p>How are people with long COVID faring two years after their initial infection? Many have recovered. Some still struggle with symptoms – this is more likely for those who were initially hospitalised.Suman Majumdar, Chief Health Officer, Burnet InstituteBrendan Crabb, Director and CEO, Burnet InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2074602023-07-12T15:18:09Z2023-07-12T15:18:09ZCommon diabetes drug metformin could protect against long COVID<figure><img src="https://images.theconversation.com/files/534052/original/file-20230626-25-dy3ijb.jpg?ixlib=rb-1.1.0&rect=0%2C10%2C6709%2C4456&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Metformin is a drug commonly taken by patients with type 2 diabetes.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/senior-man-taking-prescription-medicine-home-1768003094">pikselstock/Shutterstock</a></span></figcaption></figure><p>There are no drugs to treat long COVID – a condition that affects around <a href="https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/prevalenceofongoingsymptomsfollowingcoronaviruscovid19infectionintheuk/30march2023">2 million people</a> in the UK alone – so you can imagine the excitement when a cheap diabetes drug called metformin was shown to decrease the risk of getting the disease. </p>
<p>The <a href="https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(23)00299-2/fulltext">study</a>, published in The Lancet Infectious Diseases, showed that if you give people who are overweight or obese metformin when they are ill with COVID, they are 40% less likely to develop long COVID compared with people who are given a placebo (dummy pill).</p>
<p>We don’t know exactly what causes long COVID, but a variety of biological mechanisms <a href="https://www.science.org/content/article/what-causes-long-covid-three-leading-theories">have been suggested</a>, including an overactive immune response, the virus lingering in certain organs, and thrombosis (clots) causing tissue damage.</p>
<p>Finding a cure is clearly going to be difficult, so a better approach would be to prevent the condition from developing in the first place. Treatment given during the infection may be able to reduce the immune response or help the body eliminate the virus and so lessen its long-term effects. </p>
<h2>What the study did</h2>
<p>In a clinical trial in the US, overweight and obese people aged 30 and over were randomly allocated to receive metformin or a placebo. (Being overweight or obese are <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469321/">known risk factors</a> for long COVID.)</p>
<p>The participants were recruited remotely, for example, through online messaging, and people were selected for the study based on self-reported criteria, including age and weight. The trial did include women who were pregnant or breastfeeding, which is important as these groups are often excluded from drug trials.</p>
<p>Over 1,000 people were given either metformin or an identical placebo pill after testing positive for COVID between December 2020 and January 2022.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/covid-risk-of-diabetes-and-heart-disease-is-higher-after-infection-but-maybe-only-temporarily-186976">COVID: risk of diabetes and heart disease is higher after infection – but maybe only temporarily</a>
</strong>
</em>
</p>
<hr>
<p>The active drugs and placebos were mailed to patients by courier and treatment was initiated within seven days of COVID symptoms starting. Almost half of the participants began treatment within four days of their symptoms starting.</p>
<p>Participants were instructed to take the pills for two weeks. The researchers followed the participants for ten months to see if they developed long COVID. Participants reported their symptoms monthly via an online survey.</p>
<p>Neither the trial participants nor the researchers knew which treatment a participant had received. This is what’s known as a “double-blind” trial and it’s important for avoiding bias.</p>
<figure class="align-center ">
<img alt="A woman sitting on a couch, holding her head between her hands." src="https://images.theconversation.com/files/534053/original/file-20230626-15-bhfu8n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/534053/original/file-20230626-15-bhfu8n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=401&fit=crop&dpr=1 600w, https://images.theconversation.com/files/534053/original/file-20230626-15-bhfu8n.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=401&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/534053/original/file-20230626-15-bhfu8n.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=401&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/534053/original/file-20230626-15-bhfu8n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/534053/original/file-20230626-15-bhfu8n.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/534053/original/file-20230626-15-bhfu8n.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Long COVID affects millions of people around the world.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/young-sad-woman-broken-heart-sitting-2112452147">Srdjan Randjelovic/Shutterstock</a></span>
</figcaption>
</figure>
<h2>What the results showed</h2>
<p>The main outcome measure was the report of a doctor’s diagnosis of long COVID. Of the 564 people who received metformin, 35 developed long COVID (6.3%) compared with 58 out of 562 (10.4%) who took a placebo. This equates to a 41% lower risk of long COVID for patients who received metformin.</p>
<p>Those starting treatment earlier, by day four, had lower rates of long COVID compared with those who started treatment later. This lends weight to the proposition that metformin has a protective effect against long COVID.</p>
<p>However, because relatively few people developed long COVID, large numbers of people needed to take metformin to prevent a single case of long COVID. Roughly 24 people would need to take metformin to prevent one case of long COVID.</p>
<p>While metformin is a safe drug – as indicated by many decades of use worldwide for type 2 diabetes as well as its current prescribing <a href="https://www.nhs.uk/conditions/gestational-diabetes/treatment/">in pregnancy</a> to treat gestational diabetes – it’s nevertheless worth weighing up the risks and benefits carefully. Side-effects can include a rash and <a href="https://www.nhs.uk/medicines/metformin/side-effects-of-metformin/">diarrhoea</a>.</p>
<p>Further studies will also be required to determine whether similar benefit is seen in the UK, particularly in people from minority ethnic groups, who were underrepresented in this study (83% of participants were white). </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/long-covid-who-is-at-risk-151797">Long COVID: who is at risk?</a>
</strong>
</em>
</p>
<hr>
<p>While it’s not clear how exactly metformin might work to protect against long COVID, this study offers a promising glimpse of how we might prevent it from developing in future.</p><img src="https://counter.theconversation.com/content/207460/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Frances Williams receives funding from Versus Arthritis and the Kennedy Trust. </span></em></p>A recent study found that among people who were overweight or obese, taking metformin during a COVID infection reduced the risk of developing long COVID by 40%.Frances Williams, Professor of Genomic Epidemiology and Hon Consultant Rheumatologist, King's College LondonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1453122020-09-02T19:58:21Z2020-09-02T19:58:21ZWeekly injection could treat type 2 diabetes, new enzyme discovery suggests<figure><img src="https://images.theconversation.com/files/355991/original/file-20200902-14-1081wgo.jpg?ixlib=rb-1.1.0&rect=6%2C0%2C4239%2C2826&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>A newly discovered protein produced by the liver, and which helps to control blood sugar levels, could potentially revolutionise treatment for type 2 diabetes.</p>
<p>Our research, published today in <a href="https://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.aaz8048">Science Translational Medicine</a>, found that injecting this protein, called SMOC1, into diabetic mice helped them control their blood glucose much more easily.</p>
<p>We have also engineered a long-lasting form of SMOC1 which, if it works the same way in humans as in mice, would only need to be injected once a week, rather than given daily as is the case for many current diabetes medications.</p>
<p>Our results in mice suggest SMOC1 is more effective than metformin, the current frontline drug for type 2 diabetes, in improving blood glucose control and insulin sensitivity. It’s also without the risk of dangerously low blood sugar associated with current drugs.</p>
<p>Most of us have friends, family members or colleagues with type 2 diabetes. This is not surprising, given the disease affects <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)33015-0/fulltext">more than 400 million people</a> worldwide, and almost <a href="https://www.aihw.gov.au/reports/diabetes/diabetes/contents/how-many-australians-have-diabetes">one million</a> in Australia alone.</p>
<p>Type 2 diabetes is also closely linked to obesity, and with the reported incidence of obesity growing (<a href="https://www.sciencedaily.com/releases/2017/06/170612094128.htm">more than two billion</a> people worldwide are overweight or obese), <a href="https://www.diabetesresearchclinicalpractice.com/article/S0168-8227(19)31230-6/fulltext">it is forecast</a> 578 million adults will have diabetes by 2030, and 700 million by 2045.</p>
<p>People with diabetes have many complications that can impair their quality of life and reduce their life expectancy. A major problem for people with type 2 diabetes is high blood glucose, which if left unchecked and untreated, can cause the development of many serious health problems:</p>
<ul>
<li><p>people with diabetes are up to <a href="https://www.diabetesaustralia.com.au/heart-disease">four times more likely</a> to suffer heart attacks and strokes</p></li>
<li><p>they’re <a href="https://www.diabetesvic.org.au/diabetes-and-me-type?tags=Left-Mega-Nav%2FComplications%2FKidney%20health%2F">three times more likely</a> to suffer kidney failure</p></li>
<li><p>amputations are <a href="https://www.diabetes.co.uk/diabetes-and-amputation.html">15 times more common</a> in people with diabetes</p></li>
<li><p>diabetes is the <a href="https://www.diabetesaustralia.com.au/news/15230?type=articles">leading cause of preventable blindness</a> in Australia. </p></li>
</ul>
<p>Almost <a href="https://www.diabetesaustralia.com.au/depression-and-mental-health">every second person</a> with diabetes experiences a mental illness, such depression or anxiety.</p>
<p>Reducing blood glucose levels before any sign of diabetes damage is evident can help thwart this silent and underestimated killer.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/a-disease-that-breeds-disease-why-is-type-2-diabetes-linked-to-increased-risk-of-cancer-and-dementia-139298">A disease that breeds disease: why is type 2 diabetes linked to increased risk of cancer and dementia?</a>
</strong>
</em>
</p>
<hr>
<h2>Current diabetes medications aren’t good enough</h2>
<p>A healthy diet and exercise are the first lines of treatment for diabetes. But this has limited effectiveness in reducing blood glucose, particularly as the disease progresses. So it ultimately becomes necessary to use drugs to control blood glucose.</p>
<p>There are a range of drugs available to maintain blood glucose levels. The most common first-choice drug is <a href="https://www.healthdirect.gov.au/metformin">metformin</a>, which is prescribed to more than <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398862/">120 million people</a> worldwide. While metformin is generally safe and effective, it frequently causes gastrointestinal symptoms such as diarrhoea and flatulence. </p>
<figure class="align-center ">
<img alt="Metformin package and pills in blister pack" src="https://images.theconversation.com/files/355970/original/file-20200902-14-lrjf8v.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/355970/original/file-20200902-14-lrjf8v.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=530&fit=crop&dpr=1 600w, https://images.theconversation.com/files/355970/original/file-20200902-14-lrjf8v.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=530&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/355970/original/file-20200902-14-lrjf8v.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=530&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/355970/original/file-20200902-14-lrjf8v.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=666&fit=crop&dpr=1 754w, https://images.theconversation.com/files/355970/original/file-20200902-14-lrjf8v.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=666&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/355970/original/file-20200902-14-lrjf8v.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=666&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Metformin has long been doctors’ go-to drug for type 2 diabetes.</span>
<span class="attribution"><span class="source">Ash/Wikimedia Commons</span></span>
</figcaption>
</figure>
<p>All diabetes medications, without exception, have either limited effectiveness or unpleasant side effects. Many can also potentially cause very low blood sugar (hypoglycemia), which can cause shakiness, anxiety, sweating, chills, lightheadedness, confusion and, in severe cases, coma or even death. </p>
<p>Insulin is used to treat type 2 diabetes typically later in disease progression, after other anti-hyperglycemic medications become less effective at managing blood glucose levels. </p>
<p>So, we can see there is an urgent need to develop new approaches to treat patients with this disease.</p>
<h2>The next generation of diabetes therapies</h2>
<p>Our discovery of SMOC1, which is naturally produced by the liver and is released into the blood when glucose levels are high, could offer a new way to control blood glucose. </p>
<p>We initially discovered SMOC1 as a protein that was released from mouse liver cells (hepatocytes). Its release increased when liver cells accumulated excess fat. </p>
<p>We further found SMOC1 levels in the blood to be reduced in people that are insulin resistant (pre-diabetic). Based on our animal studies and studies using human liver cells, we anticipate SMOC1 could be effective in people with type 2 diabetes, whether advanced or newly diagnosed. SMOC1 could make daily medications a thing of the past, boosting a patient’s quality of life. </p>
<p>Given the prevalence of type 2 diabetes, this would help reduce the public health burden of the disease, with patients potentially needing fewer hospital visits and shorter hospital stays.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/weekly-dose-metformin-the-diabetes-drug-developed-from-french-lilac-64430">Weekly Dose: metformin, the diabetes drug developed from French lilac</a>
</strong>
</em>
</p>
<hr>
<p>What happens next? We will need to test SMOC1 in humans, and enlist the help of the pharmaceutical industry to help develop this potential new therapy. </p>
<p>With the right support, SMOC1 could move to human trials within six to eight years, helping us get closer to reducing the global public health toll of type 2 diabetes and obesity in general.</p><img src="https://counter.theconversation.com/content/145312/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Magdalene Montgomery receives funding from the National Health and Medical Research Council (APP1143224).</span></em></p><p class="fine-print"><em><span>Matthew Watt receives funding from the National Health and Medical Research Council of Australia and the Diabetes Australia Research Trust for this work.</span></em></p>We’ve discovered a new protein produced by the liver, and found it helps control blood sugar levels in mice. This could revolutionise the way we treat type 2 diabetes in the future.Magdalene Montgomery, NHMRC CDF Fellow, Senior Research Fellow, Head Metabolic Crosstalk Laboratory, The University of MelbourneMatthew Watt, Head, Department of Physiology, The University of MelbourneLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1423402020-07-20T19:51:11Z2020-07-20T19:51:11ZALS scientific breakthrough: Diabetes drug metformin shows promise in mouse study for a common type of ALS<figure><img src="https://images.theconversation.com/files/348256/original/file-20200719-31-apeztc.jpg?ixlib=rb-1.1.0&rect=1%2C2%2C555%2C437&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A man with ALS uses a head-mounted laser pointer to communicate with his wife, by pointing to letters and words on a communication board.</span> <span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Using_a_head_mounted_laser_to_point_to_a_communication_board.jpg">Fezcat via Wikipedia.com</a></span></figcaption></figure><p>An FDA-approved diabetes drug shows early signs of promise against the most common genetic form of amyotrophic lateral sclerosis, a devastating neurological condition that causes paralysis. </p>
<p>ALS is a <a href="http://doi.org/10.1056/NEJMra1603471">progressive disease that affects neurons in the brain and spinal cord</a>. Motor neurons transmit signals from our brain to our muscles and allow us to move. ALS causes these motor neurons to die, resulting in the loss of a patient’s ability to speak, eat, move and breathe. Notable ALS patients include New York Yankees baseball star Lou Gehrig (the disease is often called Lou Gehrig’s disease), physicist Stephen Hawking and New Orleans Saints football star Steve Gleason. There are currently <a href="https://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/als/conditions/als_amyotrophic_lateral_sclerosis.html">more than 30,000 cases of ALS in the United States</a>, and life expectancy after diagnosis is typically 2 to 5 years. There is currently <a href="http://doi.org/10.1056/NEJMra1603471">no cure for ALS</a>. </p>
<p><a href="https://neurogenetics.med.ufl.edu/faculty/dr-laura-p-w-ranum/">I am a scientist</a> who studies neurological diseases that run in families, and I have been working hard to find a treatment to stop ALS. Our team has made a discovery, <a href="https://www.pnas.org/cgi/doi/10.1073/pnas.2005748117">detailed in a scientific study</a> and highlighted in <a href="https://doi.org/10.1073/pnas.2012363117">a commentary by Nobel Prize winner Michael Rosbash</a>, that paves the way for further research for improving disease in a genetic type of ALS caused by <a href="http://doi.org/10.1016/j.neuron.2011.09.011">a mutation in a gene</a> <a href="https://doi.org/10.1016/j.neuron.2011.09.010">with the unwieldy name</a> <em>chromosome 9 open reading frame 72 (C9orf72)</em>, based on its location on chromosome 9. In addition to ALS, mutations in this gene can also cause frontotemporal dementia, which can cause apathy, loss of emotional control and cognitive decline. Some patients with the <a href="https://doi.org/10.3389/fnins.2020.00042">C9orf72 mutation develop ALS, others develop frontotemporal dementia and some develop both</a>. Together, these diseases are referred to here as C9-ALS/FTD. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/348257/original/file-20200719-31-16upzky.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/348257/original/file-20200719-31-16upzky.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=421&fit=crop&dpr=1 600w, https://images.theconversation.com/files/348257/original/file-20200719-31-16upzky.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=421&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/348257/original/file-20200719-31-16upzky.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=421&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/348257/original/file-20200719-31-16upzky.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=529&fit=crop&dpr=1 754w, https://images.theconversation.com/files/348257/original/file-20200719-31-16upzky.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=529&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/348257/original/file-20200719-31-16upzky.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=529&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">When motor neurons are damaged and die, muscles atrophy and patients lose the ability to speak, eat, move and breathe.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/amyotrophic-lateral-sclerosis-concept-royalty-free-illustration/997071088?adppopup=true">blueringmedia / Getty Images</a></span>
</figcaption>
</figure>
<h2>Repeating theme in ALS and other neurodegenerative diseases</h2>
<p>I have been focusing on C9-ALS, which is the most common genetic type of ALS which is caused by a <a href="http://doi.org/10.1016/j.neuron.2011.09.011">mutation in the C9orf72</a> <a href="https://doi.org/10.1016/j.neuron.2011.09.010">gene</a>. The mutation occurs when six letters of DNA that make up part of the gene’s genetic code – GGGGCC – are repeated hundreds of extra times. It is as if a single word is repeated hundreds of times in the same sentence.</p>
<p>[<em>Deep knowledge, daily.</em> <a href="https://theconversation.com/us/newsletters/the-daily-3?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=deepknowledge">Sign up for The Conversation’s newsletter</a>.]</p>
<p>The gene mutation that causes C9-ALS is part of a much larger family of diseases that are caused by similar expansions of short repeated segments of DNA. </p>
<p>Repeat expansion mutations were first discovered in 1991 as the cause of Fragile X syndrome and spinal bulbar muscular atrophy, and this type of mutation is now <a href="http://doi.org/10.1016/j.neuron.2013.02.022">known to cause more than 50</a> <a href="http://doi.org/10.3390/ijms20133365">different neurologic diseases</a>. </p>
<p>Over the past 30 years, I have been studying these types of expansion mutations, including those that cause a disease called spinocerebellar ataxia type 8 <a href="https://doi.org/10.1038/7710">that affects coordination</a> and the <a href="http://doi.org/10.1126/science.1062125">muscle disease myotonic dystrophy type 2</a>. I have been particularly interested in understanding how these gene mutations work, and there have been some big surprises. </p>
<h2>One mutation, two RNAs and six unexpected proteins</h2>
<p>Typically, a gene encoded in DNA makes a single copy of an intermediate molecule called RNA, which the cell uses to manufacture a protein. Also, portions of genes are typically not expressed as proteins. The repeat expansion mutation in C9-ALS and many other neurological diseases occurs in these gene regions not expected to produce proteins. But, when a repeat expansion is present, the mutated region <a href="http://doi.org/10.1146/annurev-neuro-070918-050405">produces up to six unexpected and toxic proteins</a>. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/348260/original/file-20200719-21-dxf9pr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/348260/original/file-20200719-21-dxf9pr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/348260/original/file-20200719-21-dxf9pr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=529&fit=crop&dpr=1 600w, https://images.theconversation.com/files/348260/original/file-20200719-21-dxf9pr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=529&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/348260/original/file-20200719-21-dxf9pr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=529&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/348260/original/file-20200719-21-dxf9pr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=664&fit=crop&dpr=1 754w, https://images.theconversation.com/files/348260/original/file-20200719-21-dxf9pr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=664&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/348260/original/file-20200719-21-dxf9pr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=664&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This expansion mutation was previously thought to be silent and not produce any proteins. Now we know it produces two RNAs and six RAN proteins.</span>
<span class="attribution"><span class="source">Laura Ranum</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>In 2006, we started to unravel how this happens by discovering that the spinocerebellar ataxia type 8 repeat expansion mutation produces <a href="https://doi.org/10.1038/ng1827">two RNAs instead of just one</a>. This <a href="https://doi.org/10.1016/j.molcel.2005.09.002">double-the-trouble scenario</a> was also found in myotonic dystrophy type 1 and is now known to occur for <a href="https://doi.org/10.1146/annurev-neuro-070918-050405">many repeat expansion disorders</a>. </p>
<p>In 2011, we discovered that these repeat-expansion mutations also break the previously established dogma that a start signal embedded in the genetic code is required to make proteins. In contrast, we showed that when a repeat expansion mutation is present, proteins are produced without a start signal and extra, unexpected proteins are made – <a href="https://doi.org/10.1073/pnas.1013343108">up to six for each expansion mutation</a>. </p>
<p>We called these rogue proteins <a href="https://doi.org/10.1073/pnas.1013343108">repeat associated non-AUG (RAN) proteins</a>. These proteins accumulate in neurons and other brain cells, damaging them and causing disease. RAN proteins have now been found in 10 different repeat expansion diseases, including <a href="http://doi.org/10.1146/annurev-neuro-070918-050405">Huntington’s disease and Fragile X tremor ataxia syndrome</a>.</p>
<p>In C9-ALS mice, we have shown that <a href="http://doi.org/10.1016/j.neuron.2019.11.007">destroying RAN proteins using antibodies in mice</a> improves lifespan, the survival of motor neurons and other key aspects of the disease. </p>
<p>In the newly published study in the Proceedings of the National Academy of Sciences, our team discovered a cellular switch that, when turned on, hijacks the cell and forces it into making RAN proteins. <a href="https://www.pnas.org/cgi/doi/10.1073/pnas.2005748117">RNA copies of the expansion mutations turn on this switch</a>, called the protein kinase R pathway. </p>
<p>Turning off the protein kinase R pathway switch blocks RAN protein production for multiple types of disease-causing repeat expansions, making protein kinase R a possible Achilles heel for RAN protein diseases. These results had me and my colleague <a href="https://neurogenetics.med.ufl.edu/faculty/tao-zu/">Tao Zu</a>, a research assistant professor, tremendously excited. </p>
<h2>Metformin shows promise for C9-ALS/FTD and other expansion diseases</h2>
<p>I decided that we should test the FDA-approved diabetes drug metformin after hearing <a href="https://www.mcgill.ca/biochemistry/about-us/department/faculty-members/sonenberg">Nahum Sonenberg</a>, a longtime collaborator, present data showing that this drug improved disease in mice with Fragile X syndrome, <a href="http://doi.org/10.1038/nm.4335">a disease involving a missing protein</a>. Even though Fragile X disrupts protein production in a completely different way, I thought that because metformin normalized protein production in Fragile X syndrome, maybe it could do the same for RAN protein diseases.</p>
<p>Although it was a long shot, I asked Dr. Zu to test metformin in cells to see if the drug would lower RAN protein levels. The results in cells very clearly showed that it did. We went on to <a href="https://www.pnas.org/cgi/doi/10.1073/pnas.2005748117">show that metformin inhibits protein kinase R, reduces RAN proteins and improves disease in C9-ALS/FTD mice</a>. It is important to emphasize that this approach is thought to work for this particular genetic form of ALS and frontotemporal dementia because the <em>C9orf72</em> mutation makes RAN proteins. In a previous research study conducted by a different group, metformin treatment was <a href="https://doi.org/10.1371/journal.pone.0024189">not effective in mice with a different form of ALS that does not produce RAN proteins</a>. </p>
<p>Typically, it takes a decade or more to move promising research from the lab to the clinic. Metformin was introduced in 1957 in France and approved in 1995 in the United States. Because metformin is widely used as a <a href="https://doi.org/10.2147/DDDT.S141675">safe and effective treatment for Type 2 diabetes</a> with few side effects, we can skip the arduous drug-development process and immediately test if the benefits of metformin treatment in mice are also found in people with C9-ALS. </p>
<p>My colleagues and I at the University of Florida have already <a href="https://clinicaltrials.gov/ct2/show/NCT04220021">started a Phase 2 open-label trial</a> to test the effects of metformin in C9-ALS patients. In this first open-label trial, in which everyone will receive the drug, we will be testing to see if the drug is safe for patients with C9-ALS and if it lowers RAN protein levels in the cerebrospinal fluid. </p>
<p>If the results are promising, the next step would be to test the potential benefits of the drug in a larger, placebo-controlled trial. We are especially excited about metformin as a potential treatment for C9-ALS/FTD and other repeat expansion disorders, because by reducing RAN proteins, it could address a fundamental problem common to many of these diseases.</p><img src="https://counter.theconversation.com/content/142340/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Dr. Laura Ranum has received research funding from the National Institutes of Health (RO1 NS098819, R37NS040389 and PO1-NS058901), the Department of Defense (W81XWH1910654), Target ALS, ALS Association, Muscular Dystrophy Association, Myotonic Dystrophy Foundation, National Ataxia Foundation and Packard Center. She is an inventor on patents on RAN translation and is a co-founder of RanTran Inc. and has served as a scientific advisor to Biogen. She is a full time employee of the University of Florida, where she directs the Center for NeuroGenetics and is the Kitzman Family Professor in the Department of Molecular Genetics and Microbiology in the College of Medicine at the University of Florida.
</span></em></p>Amyotrophic lateral sclerosis, Lou Gehrig’s disease, is a crippling, progressive neurodegenerative disease for which there is no cure. Now it seems that a diabetes drug may help some cases.Laura P.W. Ranum, Director, Center for NeuroGenetics and Kitzman Family Professor of Molecular Genetics & Microbiology, University of FloridaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/990512018-07-04T11:57:55Z2018-07-04T11:57:55ZI nearly died from sepsis – and ignorance of this condition is killing millions<figure><img src="https://images.theconversation.com/files/226012/original/file-20180703-116123-1btt1vm.jpg?ixlib=rb-1.1.0&rect=31%2C101%2C967%2C473&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/532149166?src=A23XOMyvhe9QvY2XhnCk2g-1-3&size=medium_jpg">napocska/Shutterstock.com</a></span></figcaption></figure><p>A visit to family in Glasgow for Christmas in 2015 nearly had a tragic ending for me. Two days earlier I had been repairing the lock on my garden gate, when I scratched my hand on a nail. By the time I arrived in Glasgow I was feeling unwell. Twenty-four hours later I was in University Hospital Hairmyres in a coma. I had developed sepsis. My family were told that I had almost no chance of surviving the night.</p>
<p>I woke from my coma three months later and spent another year getting back to full health. I’m one of the lucky ones. Sepsis affects more than <a href="http://www.who.int/news-room/fact-sheets/detail/sepsis">30m people</a> a year worldwide and kills an estimated 6m people, of whom nearly 2m are children. Of those who do survive, 40% will have <a href="https://academic.oup.com/intqhc/advance-article/doi/10.1093/intqhc/mzy137/5040109">post-sepsis syndrome</a>, which leaves them with lasting physical and mental symptoms.</p>
<p>Sepsis starts with a viral or bacterial infection, usually of the <a href="https://books.google.co.uk/books?id=73pYBAAAQBAJ&pg=PA914&redir_esc=y#v=onepage&q&f=false">lungs, abdomen or urinary tract</a>, but it can also begin in a whole host of other ways, including a scratch (as happened in my case) or a bite. It’s not the bug that causes the potentially life-threatening condition, however, it’s the body’s response to the infection. A complex cascade of events is triggered to <a href="http://needtoknow.nas.edu/id/infection/how-pathogens-make-us-sick/">fight an infection</a> – in <a href="https://www.sepsis.org/sepsis/definition/">sepsis</a>, this process becomes uncontrolled, rapidly accelerating and resulting in the failure of vital organs in the body, including the kidneys, heart and lungs.</p>
<p>Like a match being lit, a tiny spark at one end of the match head spreads out rapidly, the flame grows quickly and the match is destroyed by the flame, unless it’s blown out in time. The “flame” of sepsis in a body moves very quickly, and if my brother had not spotted those critical signs in time, or my treatment in the hospital had been delayed by even an hour, I would have died.</p>
<p>Sepsis <a href="https://www.healthline.com/health/sepsis">symptoms</a> can include pale and mottled skin, severe breathlessness, severe shivering or severe muscle pain, not urinating all day, nausea or vomiting. If you or someone you know has one or more of these symptoms, you should call the emergency services immediately and ask: “Could it be sepsis?”</p>
<p>Anyone can get sepsis, although research suggests that people with a <a href="https://www.webmd.com/diet/guide/vitamin-d-deficiency#1">vitamin D deficiency</a> have a higher risk of contracting sepsis than most. Vitamin D deficiency has also been <a href="https://www.sciencedirect.com/science/article/pii/S1201971217302059?via%3Dihub">linked</a> to an increased risk of <a href="https://www.webmd.com/cold-and-flu/news/20170216/vitamin-d-linked-to-lower-risk-of-respiratory-infections">getting an infection</a>, which may then go on to cause sepsis.</p>
<h2>Promising avenues</h2>
<p>Unfortunately, while it may be possible to treat the original infection with antibiotics, there is no specific cure for sepsis – only the symptoms can be treated. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6000220/">New research</a>, however, shows that metformin, a drug used to treat type 2 diabetes, can reduce the impact of sepsis by limiting the body’s immune reaction and protecting it from damage by <a href="https://www.livescience.com/54901-free-radicals.html">free radicals</a> (oxygen-rich molecules that can damage cells).</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/226013/original/file-20180703-116132-z62k2a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/226013/original/file-20180703-116132-z62k2a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/226013/original/file-20180703-116132-z62k2a.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/226013/original/file-20180703-116132-z62k2a.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/226013/original/file-20180703-116132-z62k2a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/226013/original/file-20180703-116132-z62k2a.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/226013/original/file-20180703-116132-z62k2a.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">New research suggests that the diabetes drug, metformin, might help to reduce the impact of sepsis.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/524812273?src=QYLitJJ5B31olxoor9Yt6w-1-1&size=medium_jpg">Sherry Yates Young/Shutterstock.com</a></span>
</figcaption>
</figure>
<p>Other promising <a href="https://www.sciencedirect.com/science/article/pii/S0014299918303637?via%3Dihub">research</a> suggests that gene therapy may prove important in tackling sepsis, by <a href="https://www.khanacademy.org/science/biology/gene-expression-central-dogma/translation-polypeptides/a/protein-targeting-and-traffic">targeting a protein</a> produced in the body called <a href="https://en.wikipedia.org/wiki/NF-%CE%BAB">NF-kB</a>, which malfunctions during sepsis. If successful, these and other treatments in development have the potential to save lives and reduce the long-term impact of the disease on survivors. </p>
<p>The latest research seems promising, but the greatest defence we have against sepsis is awareness of the condition in medical professionals and the public. But at the moment <a href="https://www.huffingtonpost.co.uk/entry/sepsis-in-america-us_us_57083401e4b014223249196d?guccounter=1">awareness</a> is alarmingly low across the world. </p>
<p><a href="https://www.nejm.org/doi/full/10.1056/NEJMp1707170">Surveys suggest</a> that only 40% of people in Australia have heard of sepsis and only one-third of this group are able to identify a single symptom. Figures are even lower in Brazil where only <a href="https://www.nejm.org/doi/full/10.1056/NEJMp1707170">14% of the public</a> know what it is. And, although <a href="https://www.bbc.co.uk/news/uk-scotland-42943092">campaigning in the UK</a> and Germany has created an awareness in over 60% of people, knowledge of the warning signs is still limited.</p>
<p>As you’d expect, awareness is higher among <a href="https://ccforum.biomedcentral.com/articles/10.1186/cc2959">healthcare professionals</a> – but there is a need for greater education within this group. A definite diagnosis is <a href="https://www.medicinenet.com/sepsis/article.htm">often difficult</a>, and efforts are being made to establish clear guidance for healthcare workers across the world, including the roll-out of an internationally recognised protocol called <a href="https://bestpractice.bmj.com/topics/en-gb/245/management-approach">Sepsis6</a>.</p>
<p>With time, scientific research may provide new treatments – but in the short term, greater awareness of the condition among the public and medical professionals is likely to have the biggest effect on saving lives and minimising harm. So always ask: “Could it be sepsis?”</p><img src="https://counter.theconversation.com/content/99051/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Michael Porter does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Sepsis can maim or kill within hours. Here’s how to identify the condition.Michael Porter, Lecturer in Molecular Genetics, University of Central LancashireLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/886642017-12-18T12:17:42Z2017-12-18T12:17:42ZOne in three people failing to take important diabetes drug for fear of side effects<figure><img src="https://images.theconversation.com/files/199458/original/file-20171215-17860-1wlgdoa.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://commons.wikimedia.org/w/index.php?curid=38698964">Ash/Wikimedia Commons </a></span></figcaption></figure><p>Up to a third of people prescribed metformin – the most commonly prescribed drug for treating type 2 diabetes – are not taking the drug, our <a href="http://onlinelibrary.wiley.com/doi/10.1111/dom.13160/abstract">latest research</a> shows. Not only is this putting a large number of people with diabetes at increased risk of serious complications, it is also a huge waste of money. </p>
<p>If people with diabetes don’t control their blood sugar, it eventually leads to complications including blindness, kidney failure and heart disease. Metformin helps to lower blood sugar levels by lowering the amount of sugar made by the liver. The drug also increases the sensitivity of muscle cells to insulin.</p>
<p>However, metformin isn’t the only drug that people with type 2 diabetes are able to use. There is a wide range of drugs that can be used to improve blood sugar regulation. Some are taken in pill form, others are injected. Some can be used once weekly, whereas others must be taken several times a day. All of these things can influence how likely a person is to take their medicine as prescribed. </p>
<p>Each drug has a unique way of working and also comes with a unique set of side effects. Despite this abundance of choice, it was not previously clear which drugs people with diabetes find easiest to take and which are more likely to be left in the medicine cabinet.</p>
<p>For our review, we looked for studies comparing medication use in people with type 2 diabetes. We found 48 relevant studies describing medication use in a total of 1.7m people with diabetes. </p>
<h2>Lots to choose from</h2>
<p>Our analysis of the combined data (a meta-analysis) found that around 30% of metformin doses never get taken. For other medication types the proportion of missed doses was much lower, with 23% of sulfonylureas (such as gliclazide) and 20% of pioglitazone going untaken. DPP4 inhibitors (gliptins), one of the newer medication classes, have the highest rates of use, with only 10-20% of medication doses not taken. </p>
<p>When comparing injectable drugs, we found that people are twice as likely to stop taking GLP1 receptor agonists (such as exenatide), compared with insulin.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/199462/original/file-20171215-17842-11vchgg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/199462/original/file-20171215-17842-11vchgg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/199462/original/file-20171215-17842-11vchgg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/199462/original/file-20171215-17842-11vchgg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/199462/original/file-20171215-17842-11vchgg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/199462/original/file-20171215-17842-11vchgg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/199462/original/file-20171215-17842-11vchgg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Some diabetes drugs, like gliptins, are less likely to be left in the medicine cabinet.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/323515223?size=medium_jpg">Kwangmoozaa/Shutterstock.com</a></span>
</figcaption>
</figure>
<p>We were surprised to find such large differences in the number of missed doses between the different classes of drugs. We were also surprised to find that the use of metformin was so low. </p>
<p>Metformin can cause diarrhoea and flatulence, which may be part of the reason so many people stop taking it, but it is a worrying result nonetheless. Also, to get a good effect from metformin it may have to be taken two or three times a day. The good news is that there are some drugs that people with diabetes find easier to take.</p>
<p>Gliptins (such as sitaglitpin) have very few side effects and are usually only taken once a day, so it’s understandable why fewer doses of this drug class are missed.</p>
<p>Pioglitazone is one of the older diabetes drugs, and its use has fallen out of favour since its sister drug rosiglitazone was found to <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa072761">cause heart disease</a> and was withdrawn from the market. Pioglitazone has since been confirmed to be safe but is still less commonly prescribed. It was very interesting to see that this older drug – out of favour with doctors – was one of the most well tolerated by patients.</p>
<p>Although metformin is known to have some advantages over other diabetes drugs, particularly in protecting against heart disease, these effects can’t be achieved if people aren’t taking it. As there are lots of treatment options for type 2 diabetes, switching to a different medication – one that is easier to take – is a much better option than taking no drug at all.</p><img src="https://counter.theconversation.com/content/88664/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andrew McGovern previously received research funding from AstraZeneca and Eli Lilly. </span></em></p>People with type 2 diabetes are putting their health at risk by not taking their medication because of side effects.Andrew McGovern, Clinical researcher, University of SurreyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/867732017-12-07T19:17:28Z2017-12-07T19:17:28ZLosing weight is hard, but it’s not any harder if you have type 2 diabetes<figure><img src="https://images.theconversation.com/files/198061/original/file-20171207-31517-phkuys.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Medications to help with type 2 diabetes have been associated with weight gain.</span> <span class="attribution"><span class="source">from shutterstock.com</span></span></figcaption></figure><p>A <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33102-1/fulltext">study has found</a> weight loss could reverse type 2 diabetes. The UK clinical trial showed that 46% of people who followed a low-calorie diet, among other measures, for 12 months were able to stop their type 2 diabetes medications.</p>
<p>This confirms a <a href="https://www.ncbi.nlm.nih.gov/pubmed/28903916">position</a> outlined in a previous paper that people can beat diabetes into remission if they lost about 15 kilograms. Another <a href="https://www.ncbi.nlm.nih.gov/pubmed/27421729">study showed</a> that prediabetes (a blood sugar level that is high, but lower than necessary for diabetes diagnosis) can be prevented by losing as little as 2kg.</p>
<p>If weight loss isn’t already hard enough, many people think <a href="http://www.detroitnews.com/story/life/advice/2015/05/15/keith-roach-health-type-diabetes/27390969/">it’s more difficult</a> if you have diabetes. <a href="https://www.ncbi.nlm.nih.gov/pubmed/3677974">One small study</a> perhaps sowed the seed for this defeatist idea. A dozen overweight diabetic subjects and their overweight non-diabetic spouses were treated together in a behavioural weight-control program. After 20 weeks, the diabetic group lost 7.4kg on average while their non-diabetic spouses lost 13.4kg.</p>
<p>But there’s more to this story than meets the eye. In fact, losing weight with type 2 diabetes is no harder than it is without it.</p>
<h2>Where does this idea comes from?</h2>
<p>Type 2 diabetes <a href="http://www.nytimes.com/2008/07/01/health/01well.html">triples the risk of heart attack</a> and stroke, and is the leading cause of blindness, amputations and kidney failure. Treatment with modern drugs improves the outlook, but complications still develop and life expectancy is <a href="https://link.springer.com/article/10.1007%2Fs00125-017-4478-x">substantially reduced</a>, especially for younger people. So beating it into remission is the ultimate goal of management.</p>
<p>If weight loss helps reach that goal, people need to know if it’s harder to achieve than without diabetes. From all the information out there you might think it is. In diabetes, the <a href="https://www.ncbi.nlm.nih.gov/pubmed/28551803">fat-burning mitochondria</a> (the powerhouse of our cells) may be more sluggish and <a href="https://www.ncbi.nlm.nih.gov/pubmed/22029981">hunger hormones</a> may be out of whack.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/explainer-what-are-mitochondria-and-how-did-we-come-to-have-them-83106">Explainer: what are mitochondria and how did we come to have them?</a>
</strong>
</em>
</p>
<hr>
<p>Then there’s the insulin angle. In response to high levels of blood sugar (glucose), the pancreas pumps out insulin and packs glucose away into tissues like muscle to store or use for energy. Type 2 diabetes is characterised by <a href="http://www.joslin.org/info/what_is_insulin_resistance.html">insulin resistance</a>, because the muscle cells are not sensitive to insulin. So glucose accumulates in the blood or is taken up into fat cells where it can be made into more fat.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/198064/original/file-20171207-31555-1jg4fx2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/198064/original/file-20171207-31555-1jg4fx2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/198064/original/file-20171207-31555-1jg4fx2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/198064/original/file-20171207-31555-1jg4fx2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/198064/original/file-20171207-31555-1jg4fx2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/198064/original/file-20171207-31555-1jg4fx2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/198064/original/file-20171207-31555-1jg4fx2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/198064/original/file-20171207-31555-1jg4fx2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Insulin therapy has been associated with weight gain.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<p>Most people with type 2 diabetes are eventually <a href="http://www.diabetes.co.uk/about-insulin.html">given insulin</a> to help control the disease, but this has been associated with <a href="https://www.ncbi.nlm.nih.gov/pubmed/28509408">weight gain</a>. Other drugs that stimulate insulin production, such as <a href="http://www.diabetes.co.uk/diabetes-medication/sulphonylureas.html">sulfonylureas</a> and <a href="http://www.diabetes.co.uk/diabetes-medication/thiazolidinediones.html">thiazolidendiones</a>, can both <a href="https://www.ncbi.nlm.nih.gov/pubmed/19538102/">increase weight</a>. And medications <a href="https://www.diabetes.co.uk/diabetes-medication/metformin-weight-loss.html">such as metformin</a> (the mostly widely used drug to treat type 2 diabetes) can contribute to <a href="https://www.ncbi.nlm.nih.gov/pubmed/19538102">weight loss</a>. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/weekly-dose-metformin-the-diabetes-drug-developed-from-french-lilac-64430">Weekly Dose: metformin, the diabetes drug developed from French lilac</a>
</strong>
</em>
</p>
<hr>
<p>So it seems both physiology and anti-diabetic drugs may be conspiring against people with diabetes trying to lose weight.</p>
<h2>But it’s not true</h2>
<p>Earlier this year, <a href="https://www.ncbi.nlm.nih.gov/pubmed/28290463">a systematic review</a> explored whether it is harder to lose weight if you have type 2 diabetes. Researchers combined data from five studies, totalling 150 people with diabetes and 387 non-diabetic subjects, who all used a low-energy liquid formula diet. </p>
<p>They concluded that weight loss was the same – around 0.5kg per week – for both groups.</p>
<p>A recent <a href="https://www.ncbi.nlm.nih.gov/pubmed/28800932">large study</a>, also using a liquid formula diet for weight management, had similar findings. There were 339 patients with diabetes, 1,669 non-diabetics and a third group of 225 patients with impaired fasting glucose (indicative of insulin-resistant prediabetes). </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/health-check-whats-the-best-diet-for-weight-loss-21557">Health Check: what's the best diet for weight loss?</a>
</strong>
</em>
</p>
<hr>
<p>Weight loss over six months was comparable between the three groups (around 0.9kg per week), with most of the weight lost in the first six weeks. The substantial weight loss achieved by the prediabetic group is notable, given insulin resistance is often blamed for weight gain. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/198065/original/file-20171207-31539-lez9z0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/198065/original/file-20171207-31539-lez9z0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/198065/original/file-20171207-31539-lez9z0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=409&fit=crop&dpr=1 600w, https://images.theconversation.com/files/198065/original/file-20171207-31539-lez9z0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=409&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/198065/original/file-20171207-31539-lez9z0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=409&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/198065/original/file-20171207-31539-lez9z0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=514&fit=crop&dpr=1 754w, https://images.theconversation.com/files/198065/original/file-20171207-31539-lez9z0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=514&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/198065/original/file-20171207-31539-lez9z0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=514&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Real food diets are enough for less extreme weight loss.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<p>This study also <a href="https://www.ncbi.nlm.nih.gov/pubmed/28800932">found no discernible differences</a> in the rates or overall weight loss with medications associated with weight gain relative to those that aren’t. </p>
<p>So the good news is that by using intensive modern formula diets, people with diabetes can lose weight as readily as those without this disease. And concerns about potential confounding by insulin resistance or medications may be unfounded. </p>
<p>As for the <a href="https://www.ncbi.nlm.nih.gov/pubmed/28800932">spouse study</a>, it turns out they ate less than their diabetic partners. This is of course <a href="http://www.bmj.com/content/349/bmj.g7257">key to any successful diet</a>, along with moving more. In fact, reducing body weight by 7% through eating less and moving more (at least 2.5 hours of physical activity per week) <a href="https://www.ncbi.nlm.nih.gov/pubmed/28757449">helps prevent diabetes</a>.</p>
<h2>Tips to lose weight</h2>
<p>Although liquid formula diets are increasingly recommended for remission of diabetes, real food diets can be enough for less extreme weight loss. Also it’s <a href="https://www.ncbi.nlm.nih.gov/m/pubmed/28954840/">necessary to resume</a> a <a href="https://www.ncbi.nlm.nih.gov/pubmed/28958344">food-based diet</a> after a period on formula diets.</p>
<p>Most <a href="http://apps.who.int/iris/bitstream/10665/204871/1/9789241565257_eng.pdf">guidelines</a> for managing type 2 diabetes with lifestyle measures agree on the following recommendations: </p>
<ul>
<li>eat fewer calories than previously, but more vegetables and dietary fibre</li>
<li>replace saturated with unsaturated fats</li>
<li>avoid added sugars and excess alcohol</li>
<li>combine aerobic exercise with resistance training for regular physical activity</li>
<li>avoid tobacco smoke</li>
<li>develop a plan with a qualified health professional and <a href="https://www.ncbi.nlm.nih.gov/pubmed/27911049">a support network</a> to <a href="https://www.ncbi.nlm.nih.gov/pubmed/26608510">stay motivated</a>.</li>
</ul>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/do-you-even-lift-why-lifting-weights-is-more-important-for-your-health-than-you-think-58635">Do you even lift? Why lifting weights is more important for your health than you think</a>
</strong>
</em>
</p>
<hr>
<p>What should help is knowing that although losing weight might be hard, it really is no harder with diabetes.</p><img src="https://counter.theconversation.com/content/86773/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The authors do not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Losing weight is an effective treatment for type 2 diabetes, as well as a prudent preventive measure. Beliefs that it’s harder to lose weight when diabetic are unfounded.Andrew Brown, Professor and Head, School of Biotechnology and Biomolecular Sciences, UNSW SydneyMike Lean, Chair of Human Nutrition, University of GlasgowWilma Leslie, Research Associate, Nutrition, University of GlasgowLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/751272017-03-31T03:18:44Z2017-03-31T03:18:44ZThe search to extend lifespan is gaining ground, but can we truly reverse the biology of ageing?<figure><img src="https://images.theconversation.com/files/163244/original/image-20170330-30352-mw7sx5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A potential anti-ageing drug is likely to be more effective at maintaining health than extending lifespan.</span> <span class="attribution"><a class="source" href="https://unsplash.com/search/ageing?photo=q3FihXQ-13M">Christina Gottardi/Unsplash</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span></figcaption></figure><p><em>This is a long read. Enjoy!</em></p>
<hr>
<p>It was once a fringe topic for scientists and a pseudo-religious dream for others. But research into the biology of ageing, and consequently extending the lifespan of humans and animals, has become a serious endeavour.</p>
<p>Ageing research is often promoted as the key to the “eternal fountain of youth”, or an “elixir of immortality”. But the true promise of ageing research is that rather than tackling individual diseases one at a time, a single drug would treat all the diseases that arise in old age, at once. </p>
<p>There would be cost savings from keeping elderly patients out of specialist appointments for each condition. And a single health-maintaining pill would avoid the problem of <a href="https://theconversation.com/medicines-to-treat-side-effects-of-other-medicines-sometimes-less-is-more-beneficial-62981">drug overuse and interactions</a> common in older people who have to medicate each condition individually.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/163256/original/image-20170330-15578-123qua9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/163256/original/image-20170330-15578-123qua9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/163256/original/image-20170330-15578-123qua9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/163256/original/image-20170330-15578-123qua9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/163256/original/image-20170330-15578-123qua9.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/163256/original/image-20170330-15578-123qua9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/163256/original/image-20170330-15578-123qua9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/163256/original/image-20170330-15578-123qua9.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Antibiotics have increased life expectancy - can they be considered ‘anti-ageing’?</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<p>The idea of extending human life makes some uneasy, as preventing death seems unnatural. Certainly, were lifespan to be drastically increased, there would be challenges in funding the age pension, <a href="https://theconversation.com/on-eternal-life-why-an-anti-ageing-pill-might-sour-the-pleasures-of-existence-48755">among other issues</a>.</p>
<p>But this is already happening. Drugs and interventions developed over the past century that have almost doubled human lifespan could be considered as anti-ageing. Think of antibiotics, which have <a href="https://www.ncbi.nlm.nih.gov/pubmed/6757513">added anywhere between two and ten years to human life expectancy</a>. There is no debate that these are an essential part of modern medicine. </p>
<p>But when we talk about an anti-ageing pill, we mean one that targets the process of ageing itself. There is already a list of such drugs shown to extend the lives of lab animals. Many of these work through mimicking the effects of a near-starvation diet.</p>
<h2>Calorie restriction</h2>
<p>Calorie restriction has for <a href="https://www.ncbi.nlm.nih.gov/pubmed/2520283">over 80 years</a> been the most well-studied intervention known to delay ageing. </p>
<p>The willpower required to maintain a near-starvation diet for an entire lifetime is beyond most. But regular, short-term calorie restriction (such as the “5:2” diet of eating normally for five days and reducing calorie intake for two) has strong <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3017674/">benefits for metabolic health</a>, which helps control obesity and diabetes. </p>
<p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4547605/">Animal studies</a> show a reliable extension in lifespan during intermittent fasting. Other studies have shown genetically altering the body’s ability to respond to insulin, which is released when we eat a meal, <a href="https://www.ncbi.nlm.nih.gov/pubmed/8247153">doubles lifespan in worms</a>. A similar <a href="https://www.ncbi.nlm.nih.gov/pubmed/12543978">experiment in mice</a> revealed a less dramatic, but still significant, 18% increase in lifespan.</p>
<p>Early on, the effectiveness of restricting calories led scientists to hunt for genes that mediated these effects. In the late 1990s and early 2000s, scientists became interested in <a href="http://www.nature.com/nrm/journal/v13/n4/full/nrm3293.html">sirtuins</a> – a class of enzymes that turn on defence mechanisms during starvation.</p>
<figure class="align-left ">
<img alt="" src="https://images.theconversation.com/files/163258/original/image-20170330-15578-1c5ctxs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/163258/original/image-20170330-15578-1c5ctxs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=900&fit=crop&dpr=1 600w, https://images.theconversation.com/files/163258/original/image-20170330-15578-1c5ctxs.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=900&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/163258/original/image-20170330-15578-1c5ctxs.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=900&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/163258/original/image-20170330-15578-1c5ctxs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1130&fit=crop&dpr=1 754w, https://images.theconversation.com/files/163258/original/image-20170330-15578-1c5ctxs.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1130&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/163258/original/image-20170330-15578-1c5ctxs.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1130&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Resveratrol is a compound found in red wine and considered a candidate for anti-ageing.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<p>Drugs such as the now-infamous compound resveratrol, present in red wine, can <a href="https://www.ncbi.nlm.nih.gov/pubmed/12939617">activate</a> one member of the sirtuins, called SIRT1, to <a href="https://www.ncbi.nlm.nih.gov/pubmed/17086191">extend lifespan in mice</a> and slow markers of ageing. The SIRT1 enzyme <a href="https://www.ncbi.nlm.nih.gov/pubmed/10693811">requires</a> a fuel for its activity, called NAD+, the levels of which <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407129/">decline</a> with old age. </p>
<p>Given the importance of NAD+ to SIRT1, the idea of raising NAD+ levels has <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616312/">attracted attention</a>. But NAD+ is used by other cell processes that could be involved in ageing. For example, Dr Jun Li recently showed NAD+ levels are essential to <a href="http://science.sciencemag.org/content/355/6331/1312">turn on DNA repair machinery</a>, which wanes as we age. These findings could also be used to reduce DNA damage caused by radiation exposure – such as in childhood cancer survivors – and cosmic radiation encountered by <a href="https://www.sciencedaily.com/releases/2017/03/170323150518.htm">astronauts in outer space</a>. </p>
<p>The long-term effects of restricting calories on ageing in humans have yet to be fully characterised, and such a study in humans would be difficult to perform.</p>
<hr>
<p><em>Further reading - <a href="https://theconversation.com/explainer-how-do-drugs-work-48665"><strong>Explainer: how do drugs work?</strong></a></em></p>
<hr>
<h2>Protein restriction</h2>
<p>It may be that the anti-ageing effect of calorie restriction isn’t in overall calorie intake, but rather the intake of the protein component of diets. Researchers have <a href="https://www.ncbi.nlm.nih.gov/pubmed/24606899">measured</a> health and lifespan in an array of diets with different ratios of protein to carbohydrate to fats. They discovered protein restriction, rather than overall calorie restriction, is more important to lifespan. </p>
<p>Translated to human diets, this would be the exact opposite of the <a href="https://www.ncbi.nlm.nih.gov/pubmed/26269362">“paleo” diet</a>, a high-protein diet that emphasises meat and unprocessed vegetables over grains. The concept behind this diet is to mimic that of early Paleolithic humans living a hunter-gatherer existence. It is worth noting, however, that Paleolithic humans are <a href="http://onlinelibrary.wiley.com/doi/10.1002/1520-6505(2000)9:4%3C156::AID-EVAN5%3E3.0.CO;2-7/abstract">thought to have had a lifespan</a> of only 33 years. </p>
<p>The one population with the <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30752-3/fulltext?elsca1=tlpr">lowest recorded levels</a> of heart disease in the world are the Tsimane, a tribal group leading a gatherer-horticulturalist existence in the Bolivian Amazon. This group has a high-carbohydrate, low-protein diet. </p>
<p>Consistent with the idea that lowering protein intake extends lifespan, turning off the enzyme mTOR, which senses protein intake, with the drug rapamycin is the most powerful drug intervention we have so far to extend lifespan. </p>
<p>Rapamycin is used in the clinic to suppress the immune system during organ transplants. It extends life in animal species such as <a href="http://www.cell.com/cell-metabolism/fulltext/S1550-4131(12)00147-7">worms</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824086/">fruit flies</a> and mice, even when delivered briefly in <a href="https://www.ncbi.nlm.nih.gov/pubmed/27549339">middle age</a> or <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2786175/">late in life</a>. The downside, of course, is that one must live with a suppressed immune system, which is a bit of a drag if you’re not living in a sterile lab environment. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/163231/original/image-20170330-8597-4tij90.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/163231/original/image-20170330-8597-4tij90.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/163231/original/image-20170330-8597-4tij90.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/163231/original/image-20170330-8597-4tij90.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/163231/original/image-20170330-8597-4tij90.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/163231/original/image-20170330-8597-4tij90.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/163231/original/image-20170330-8597-4tij90.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/163231/original/image-20170330-8597-4tij90.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The Bolivian Tsimane have a high carbohydrate and low protein diet.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/rnw/5883542473/in/photolist-9XUGcx-9XUGct/">Photo RNW.org/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>In addition to simulating protein restriction, <a href="https://www.jci.org/articles/view/73939">mTOR inhibition with rapamycin also promotes</a> a process called <a href="http://www.nature.com/nrm/journal/v16/n8/full/nrm4024.html">autophagy</a>. This is where the cell essentially “eats” itself, breaking down and destroying the old and damaged parts of the cell into its raw materials, which can be recycled into new structures. A compound called spermidine, discovered in semen and present in trace quantities in cheese, has been found to <a href="http://www.nature.com/nm/journal/v22/n12/full/nm.4222.html">extend lifespan in mice </a>by 10%. It’s thought this is due to spermidine’s ability to <a href="http://www.nature.com/ncb/journal/v11/n11/abs/ncb1975.html">turn on autophagy</a>. </p>
<h2>Out with the old</h2>
<p>Another anti-ageing strategy is one called <a href="https://www.ncbi.nlm.nih.gov/pubmed/26646499">“senolysis”</a>: that is, killing off old and damaged or “senescent” cells. These cells take up space, grow larger and <a href="http://annualreviews.org/doi/abs/10.1146/annurev-pathol-121808-102144">release substances</a> that cause inflammation. When mice are genetically engineered so that it is possible to kill off senescent cells, <a href="http://www.nature.com/nature/journal/v530/n7589/abs/nature16932.html">health is drastically improved</a> and animals live 20 to 30% longer. </p>
<p>The hunt is now on for <a href="https://www.ncbi.nlm.nih.gov/pubmed/26646499">“senolytic”</a> drugs that can selectively kill off senescent cells. One company, Unity Biotech, recently <a href="https://www.wsj.com/articles/unity-biotechnology-in-battle-against-aging-raises-116m-1477591201">raised US$116 million</a> to achieve this. </p>
<h2>DNA changes</h2>
<p>There is strong evidence that ageing is literally part of our DNA. So-called <a href="http://www.the-scientist.com/?articles.view/articleNo/42274/title/Wrangling-Retrotransposons/">“jumping genes”</a> are DNA parasites, caused by ancient viral infections in our evolutionary ancestors, and make up almost half of our genetic material. These genes can actually “cut and paste” themselves so that they jump around to a different part of our DNA, and in doing so make our genomes less stable. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/163259/original/image-20170330-15599-wm4jby.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/163259/original/image-20170330-15599-wm4jby.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/163259/original/image-20170330-15599-wm4jby.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=575&fit=crop&dpr=1 600w, https://images.theconversation.com/files/163259/original/image-20170330-15599-wm4jby.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=575&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/163259/original/image-20170330-15599-wm4jby.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=575&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/163259/original/image-20170330-15599-wm4jby.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=722&fit=crop&dpr=1 754w, https://images.theconversation.com/files/163259/original/image-20170330-15599-wm4jby.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=722&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/163259/original/image-20170330-15599-wm4jby.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=722&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Telomeres, that cap the ends of our chromosomes, shorted as we age.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<p>Another sirtuin enzyme called SIRT6 normally <a href="http://www.nature.com/articles/ncomms6011">turns off these genes</a>. Animals genetically engineered to have an extra copy of this gene <a href="http://www.nature.com/nature/journal/v483/n7388/full/nature10815.html">live longer and in better health</a>. </p>
<p>Our DNA changes as we get older. For example, structures that cap the ends of our chromosomes (which carry our genes), called telomeres, <a href="http://www.pnas.org/content/101/49/17312.short">shorten with old age or stress</a>. Lengthening telomeres has been suggested as a way to restore youth. The trouble is the gene that does this, called telomerase, is normally only turned on in adults who have cancer.</p>
<p>Genetically engineered animals that over-produce telomerase from birth <a href="http://www.pnas.org/content/99/12/8191.full.pdf">develop cancer</a>. But, to add confusion, using genetically engineered viruses to force old mice to make more telomerase results in a <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494070/">longer lifespan with improved late-life health</a>, without an increased risk of cancer. </p>
<p>Elizabeth Parrish, who is the CEO of Bioviva – a company working to develop anti-ageing treatments – recently travelled to Colombia to <a href="https://www.theguardian.com/science/2016/jul/24/elizabeth-parrish-gene-therapy-ageing">receive gene therapy</a> to extend her telomeres. </p>
<p>Another drastic way to reverse ageing might be to turn adult cells back into youthful stem cells. This is possible by turning on so-called <a href="http://www.sciencedirect.com/science/article/pii/S0092867407014717">“Yamanaka factors”</a>. These work through turning certain genes “on” or “off”.</p>
<p>The problem is that turning “Yamanaka factors” on too much again <a href="http://www.nature.com/nature/journal/v502/n7471/abs/nature12586.html">causes cancer</a>. Instead, turning these genes on briefly appears to <a href="https://www.ncbi.nlm.nih.gov/pubmed/27984723">reverse ageing and extend lifespan</a> in short-lived mice. This could be a powerful but risky strategy for reversing ageing. </p>
<h2>Is it already here?</h2>
<p>In the end, the first anti-ageing drug likely to reach the market will be one we’re already familiar with: <a href="https://theconversation.com/weekly-dose-metformin-the-diabetes-drug-developed-from-french-lilac-64430">metformin</a>. It’s used to treat diabetes, has been around since the 1950s and is used by tens of millions of people. </p>
<p>In animals, <a href="https://www.ncbi.nlm.nih.gov/pubmed/23900241">metformin extends lifespan and maintains health</a>, while population-wide studies show <a href="http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071583">it reduces cancer risk</a>. Metformin is <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398862/">thought to work</a> by turning on an energy sensor in cells called <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249400/">“AMPK”</a>, which senses situations of low energy and alters metabolism in response. </p>
<figure class="align-left zoomable">
<a href="https://images.theconversation.com/files/163373/original/image-20170330-4578-1unazgv.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/163373/original/image-20170330-4578-1unazgv.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/163373/original/image-20170330-4578-1unazgv.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=491&fit=crop&dpr=1 600w, https://images.theconversation.com/files/163373/original/image-20170330-4578-1unazgv.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=491&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/163373/original/image-20170330-4578-1unazgv.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=491&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/163373/original/image-20170330-4578-1unazgv.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=617&fit=crop&dpr=1 754w, https://images.theconversation.com/files/163373/original/image-20170330-4578-1unazgv.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=617&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/163373/original/image-20170330-4578-1unazgv.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=617&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Metformin is likely to be the first ever anti-ageing drug to reach the market.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<p>The effect of metformin on health and lifespan in older, non-diabetic individuals is the subject of the <a href="https://www.ncbi.nlm.nih.gov/pubmed/27304507">TAME trial</a> in New York. If successful, this trial may lead to the first ever “gero-protective” or “anti-ageing” pill, which would be taken as a widely used prophylactic by the older population.</p>
<p>The drug industry is <a href="http://www.pharmaceutical-journal.com/news-and-analysis/features/why-the-use-of-anti-ageing-drugs-could-delay-the-development-of-chronic-diseases/20200663.article">keenly watching</a> the TAME trial. Regulatory authorities do not yet recognise ageing as a disease, which makes potential therapies that treat ageing less commercially viable. </p>
<p>Any such drug will instead be targeted towards specific diseases of ageing – for example, arthritis or type 2 diabetes. </p>
<p>Regardless of whether any of the drugs above are eventually shown to be safe and effective in humans, the current advice for maintaining health in old age is predictable but effective. Exercise, a varied and moderate diet, maintaining social contact and avoiding stress have profound health benefits, beyond anything that will ever be available in a pill.</p>
<hr>
<p><em>For anyone wishing to hear more about this research, the upcoming <a href="http://www.ageingbiologyaustralia.org/">Australian Biology of Ageing Conference</a> on 27-28th April 2017 will feature a public lecture.</em></p><img src="https://counter.theconversation.com/content/75127/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Lindsay Wu owns shares in Hydra Capital Pte Ltd, EdenRoc Sciences, Intravital Pty Ltd, and Continuum Biosciences Pty Ltd. He is a director of MetroBiotech NSW Pty Ltd, and Liberty Biosecurity Pty Ltd. Through the above he has a financial interest in NAD+ raising compounds, which are mentioned in this article.
His lab receives funding from the National Health and Medical Research Council (NHMRC) of Australia, MetroBiotech NSW Pty Ltd, and has in the past received funding from Cancer Institute NSW. His salary is paid from an NHMRC RD Wright (Biomedical) Career Development Fellowship, which funds his employment at UNSW Australia, where he is an NHMRC Senior Research Fellow.
He is a founding organiser of the Australian Biology of Ageing Conference series.</span></em></p>The true promise of ageing research is that rather than tackling individual diseases one at a time, a single drug to treat ageing would treat all of the diseases that arise in old age, at once.Lindsay Wu, NHMRC Senior Lecturer, School of Medical Sciences, UNSW SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/644302016-10-05T01:59:54Z2016-10-05T01:59:54ZWeekly Dose: metformin, the diabetes drug developed from French lilac<figure><img src="https://images.theconversation.com/files/140206/original/image-20161003-20217-1bqbxvj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Metformin was originally developed from natural compounds found in the plant known as French lilac.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/evergestis/14755129566/in/photolist-f53VB7-knNu4-f4NEY6-f53WnU-f53WLA-f53Vdu-ou2PVN-eo8vmw-ou2QgY-nXnEdz-fdVFFa-ocKcep-f9cDq4-cfyKeL-ouePbD-phNTVh-oTngVd-6qciLK-cRNFbh-cSifP9-otRTXC-wdReZL-J7MpWf-2EA72-53WPXo">Vlad Proklov/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span></figcaption></figure><p>Metformin is the most widely used drug to treat type 2 diabetes globally. In Australia, approximately <a href="http://www.ncbi.nlm.nih.gov/pubmed/17565410">two-thirds of patients</a> with type 2 diabetes are prescribed metformin, either alone or in combination with other pills, or with insulin injections. </p>
<p>Alongside diet and exercise, metformin is considered the <a href="http://www.racgp.org.au/your-practice/guidelines/diabetes/8-managing-glycaemia/83-glucose-lowering-agents/">first-choice drug</a> to improve glucose control in type 2 diabetes. </p>
<p>Metformin hydrochloride is the <a href="http://www.nhs.uk/chq/pages/1003.aspx?categoryid=73">scientific or generic name</a> for the active ingredient in tablets sold in Australia under 40 different <a href="https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/PICMI?OpenForm&t=&q=metformin">proprietary or brand names</a>.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/140417/original/image-20161005-15886-zrlnzp.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/140417/original/image-20161005-15886-zrlnzp.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=870&fit=crop&dpr=1 600w, https://images.theconversation.com/files/140417/original/image-20161005-15886-zrlnzp.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=870&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/140417/original/image-20161005-15886-zrlnzp.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=870&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/140417/original/image-20161005-15886-zrlnzp.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1093&fit=crop&dpr=1 754w, https://images.theconversation.com/files/140417/original/image-20161005-15886-zrlnzp.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1093&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/140417/original/image-20161005-15886-zrlnzp.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1093&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption"></span>
</figcaption>
</figure>
<h2>History</h2>
<p>Metformin was originally developed from natural compounds found in the plant <em>Galega officinalis</em>, known as French lilac or goat’s rue. </p>
<p>Synthetic biguanides were developed in the 1920s in Germany, but their use was limited due to side effects. During the 1940s, however, French physician <a href="http://onlinelibrary.wiley.com/doi/10.1002/pdi.606/pdf">Jean Sterne</a> examined a new biguanide called dimethylbiguanide or metformin. At the time, it was being studied for the treatment of influenza, but Sterne recognised it had glucose-lowering properties. He proposed calling it glucophage, meaning glucose eater, a name with which it is still commercially associated today.</p>
<p>Metformin has been used to treat diabetes since the late 1950s. It is now on the World Health Organisation’s <a href="http://www.who.int/medicines/publications/essentialmedicines/en/">List of Essential Medicines</a> needed for a basic health care system. </p>
<h2>How does it work?</h2>
<p>Insulin suppresses the production of glucose by the liver. One reason glucose levels remain high in those with type 2 diabetes is due to insufficient insulin. The liver continues to inappropriately make large amounts of glucose, even when glucose levels are already high. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/138385/original/image-20160920-11131-12u3ppo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/138385/original/image-20160920-11131-12u3ppo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/138385/original/image-20160920-11131-12u3ppo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/138385/original/image-20160920-11131-12u3ppo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/138385/original/image-20160920-11131-12u3ppo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/138385/original/image-20160920-11131-12u3ppo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/138385/original/image-20160920-11131-12u3ppo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">A French physician pioneered metformin for the treatment of diabetes and proposed calling it glucophage, meaning glucose eater.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<p>Metformin is able to reduce glucose production by the liver by approximately one-third, through <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676264/">mechanisms that remain to be fully understood</a>. When taken as directed, it will reduce the HbA1c, a marker of glucose control, by approximately <a href="http://www.ncbi.nlm.nih.gov/pubmed/27088241">0.5% to 1%</a>. </p>
<h2>Who uses it?</h2>
<p>Metformin is only indicated for lowering glucose levels in people with type 2 diabetes. However, it is also used off-label (<a href="https://theconversation.com/explainer-why-are-off-label-medicines-prescribed-44783">when medications are prescribed for conditions other than what they’ve been approved for</a>) to treat women with polycystic ovarian syndrome (PCOS) where it can be <a href="http://www.ncbi.nlm.nih.gov/pubmed/26060208">effective in some cases</a>.</p>
<p>Metformin is not used to treat people with gestational diabetes or type 1 diabetes, who must take insulin injections as required to control their glucose levels.</p>
<h2>How is it used?</h2>
<p>To work effectively, most people will take <a href="http://care.diabetesjournals.org/content/35/2/446">two to three grams of metformin</a> every day. To fit this much into a tablet, all medications containing metformin are the size of a small bullet and easily the biggest tablets people with type 2 diabetes will have to take. </p>
<p>Most people take their metformin twice a day (morning and night), although extended release formulations also allow for <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006121/">once-daily dosing</a>. </p>
<p>Because metformin is most commonly <a href="http://www.ncbi.nlm.nih.gov/pubmed/17565410">used in combination</a> with other glucose-lowering drugs to manage type 2 diabetes, <a href="https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/PICMI?OpenForm&t=&q=metformin">fixed-dose combinations</a> combining metformin with other oral glucose-lowering agents are also available. </p>
<h2>What are the side effects?</h2>
<p>The most commonly reported side effects from metformin are gastrointestinal disturbances, such as nausea, diarrhoea, cramping and flatulence. These effect around <a href="http://www.nps.org.au/conditions/hormones-metabolism-and-nutritional-problems/diabetes-type-2/for-individuals/medicines-and-treatments/metformin">one in five people to some degree</a>. </p>
<p>Usually the symptoms are mild and seen when people use high doses, when first starting metformin or increasing doses.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/140254/original/image-20161004-20213-158cq1f.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/140254/original/image-20161004-20213-158cq1f.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/140254/original/image-20161004-20213-158cq1f.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=530&fit=crop&dpr=1 600w, https://images.theconversation.com/files/140254/original/image-20161004-20213-158cq1f.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=530&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/140254/original/image-20161004-20213-158cq1f.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=530&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/140254/original/image-20161004-20213-158cq1f.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=666&fit=crop&dpr=1 754w, https://images.theconversation.com/files/140254/original/image-20161004-20213-158cq1f.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=666&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/140254/original/image-20161004-20213-158cq1f.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=666&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Around one in five people taking metformin will experience side effects to some degree.</span>
<span class="attribution"><a class="source" href="https://upload.wikimedia.org/wikipedia/commons/d/db/Metformin_500mg_Tablets.jpg">Wikimedia Commons</a></span>
</figcaption>
</figure>
<p>The likelihood of developing side effects can be reduced by starting off with low doses and increasing them gradually. It is also recommended to take metformin with or after meals to reduce the initial risk of side effects. But even despite these precautions, side effects <a href="http://www.nps.org.au/conditions/hormones-metabolism-and-nutritional-problems/diabetes-type-2/for-individuals/medicines-and-treatments/metformin">prevent about 10% of people</a> with type 2 diabetes from taking meformin.</p>
<p>Metformin is associated with a rare but life-threatening condition known as <a href="http://www.ncbi.nlm.nih.gov/pubmed/26773926">lactic acidosis</a>, where the body builds up too much lactic acid. This can be caused by factors such as heart, liver or kidney failure. There is still controversy over whether metformin is the cause of lactic acidosis or whether it exacerbates the condition. </p>
<p>Unlike <a href="http://www.racgp.org.au/your-practice/guidelines/diabetes/11-glycaemic-emergencies/">some other anti-diabetic medications</a>, low blood-glucose levels are seldom observed when metformin is used on its own. Metformin also has the advantage over other agents in that it does not cause weight gain and in some people (especially women) with type 2 diabetes it may reduce their weight slightly.</p>
<p>Because metformin is largely removed from the body by the kidneys, people with type 2 diabetes who have impaired kidney function will <a href="http://www.nps.org.au/medical-tests/tests-by-conditions/for-individuals/kidney-problems-and-disorders-tests/for-health-professionals/medicines-to-be-aware-of/metformin-and-gfr">require lower doses</a> to maintain safe levels and prevent side effects. </p>
<h2>How much does it cost</h2>
<p>Metformin is fully funded through the <a href="http://www.pbs.gov.au/medicine/item/1801T">Pharmaceutical Benefits Scheme</a> for use in people with type 2 diabetes, with a maximum consumer price of A$19.08. </p>
<h2>Drug interactions</h2>
<p>Metformin competes for clearance by the kidneys with drugs including <a href="https://theconversation.com/weekly-dose-digoxin-the-heart-medicine-that-may-have-given-us-van-goghs-starry-night-57980">digoxin</a> (for heart rhythm problems) trimethoprim and vancomycin (antibiotics), ranitidine and cimetidine (for heartburn), nifedipine and furosemide (for blood pressure) which all have the potential to modestly increase metformin levels. </p>
<p>In practice, metformin can be safely given in people taking these other agents with cautious observation.</p>
<h2>Controversies</h2>
<p>Metformin was not approved by the United States Federal Drug Agency (FDA) until <a href="https://web.archive.org/web/20070929152824/http://www.fda.gov/bbs/topics/ANSWERS/ANS00627.html">late 1994</a>. This was because one arm of a large clinical trial was stopped prematurely in 1971 when participants receiving a potent biguanide (known as phenformin) <a href="http://jama.jamanetwork.com/article.aspx?articleid=338569">died more often</a> and had an increased risk of lactic acidosis. </p>
<p>It remains controversial as to whether metformin can be used to prevent diabetes as well as treat it. Some clinical trials have shown that metformin is at least as effective as diet and exercise for <a href="http://www.ncbi.nlm.nih.gov/pubmed/22442395">preventing diabetes</a> in those at high risk of developing it.</p>
<p>The requirement to always discontinue metformin in patients with renal impairment has also undergone a <a href="http://www.ncbi.nlm.nih.gov/pubmed/27330130">rethink</a> in the last few years, as the risks of its use appear to be less than those associated with alternative therapies that expose patients to risk of hypoglycaemia, fluid retention or other side effects.</p><img src="https://counter.theconversation.com/content/64430/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Merlin Thomas has received honoraria for educational symposia conducted on behalf of pharmaceutical companies that manufacture drugs for the management of diabetes, including metformin. He has received funding from NHMRC and JDRF for research into diabetes. </span></em></p>Metformin has been used to treat diabetes since the late 1950s. It is now on the World Health Organisation’s List of Essential Medicines needed for a basic health care system.Merlin Thomas, Adjunct Professor of Preventive Medicine, Baker Heart and Diabetes InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/566952016-03-23T04:04:16Z2016-03-23T04:04:16ZThe fight against TB shifts to fixing the immune system, not only bacteria<figure><img src="https://images.theconversation.com/files/116045/original/image-20160322-32320-bavjy6.png?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A pair of lungs infected with TB. </span> <span class="attribution"><span class="source">shutterstock</span></span></figcaption></figure><p>Tuberculosis (TB) has managed to remain a major global health problem, despite 100 years of research and more than 50 years of treatment being available. It still claims up to 1.5 million lives each year.</p>
<p>Although there have been ongoing efforts that provide some hope in the fight against the disease, the TB drug pipeline remains thin and vaccine development slow as resistance grows. </p>
<p>More than 9.6 million new TB cases were recorded in 2014. This prompted the Stop TB Partnership and the World Health Assembly to set a target of reducing TB-related deaths by 95% and cases by 90% by <a href="http://stm.sciencemag.org/content/7/276/276fs8.full">2035</a>. But new therapeutic and diagnostic interventions – including an effective vaccine – are urgently needed if these goals are to be achieved. </p>
<p>Recently there has been an increasing focus on alternative treatment strategies known as <a href="https://www.ncbi.nlm.nih.gov/pubmed/26184493">host-directed therapies</a>. These are mostly drugs and therapies that have been developed to treat other diseases and conditions such as diabetes or inflammation and then re-purposed to tackle TB.</p>
<p>What makes these therapies unique and important is that after 60 years of targeting the bacteria that kills TB, these treatments open a new door in the fight against infection. They focus on fixing the body rather than the bacteria. </p>
<p>If successful, these alternative treatments will add huge value by addressing the clinical demands around treating TB. </p>
<h2>Alternative approaches</h2>
<p>Host-directed therapies work differently from TB drug treatments. TB treatment drugs target the bacteria that causes TB. Host-directed therapies focus on areas in the lung that encourage the TB infection. They have two major goals: </p>
<ul>
<li><p>to improve the state of the immune system, which must be intact to fight off TB; and</p></li>
<li><p>to limit lung tissue destruction.</p></li>
</ul>
<p>Limiting tissue destruction is important because it prevents the disease from progressing. Tissue destruction can be the result of an overwhelming inflammation that destroys important cells in the immune system where the infection occurs. This may lead to cavities forming in the lung. The bacteria that causes TB is then able to disseminate throughout the lung and is coughed out through the airway. </p>
<p>A number of host-directed therapies currently being investigated could potentially be used for <a href="https://www.ncbi.nlm.nih.gov/pubmed/26184493">adjunctive TB therapy</a>. These include:</p>
<ul>
<li><p><a href="https://www.ncbi.nlm.nih.gov/pubmed/21998409">vitamin D</a>, which induces specific immune molecules that have protective effects against the TB bacteria;</p></li>
<li><p>the diabetes drug, <a href="https://www.ncbi.nlm.nih.gov/pubmed/25411472">metformin</a>, which has been shown to enhance the body’s immune responses and decrease the TB bacterial loads in the lung;</p></li>
<li><p>non-steroidal <a href="https://www.ncbi.nlm.nih.gov/pubmed/25986592">anti-inflammatory drugs</a> that limit inflammation and tissue pathology. Inflammation leads to lung damage and progression of the disease; and</p></li>
<li><p><a href="https://www.ncbi.nlm.nih.gov/pubmed/24133190">statins</a> that reduce cholesterol levels and limit bacterial growth in the body’s immune cells. Cholesterol is known to encourage the growth of bacteria. </p></li>
</ul>
<p>When these therapies are used in combination with standard treatment regimens that target the bacteria, they are likely to shorten the current course of treatment. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/1mRTm6qPu1c?wmode=transparent&start=110" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Mohlopheni Marakalala speaks about host directed therapies at the Next Einstein Forum.</span></figcaption>
</figure>
<h2>Why we need alternatives</h2>
<p>There are several challenges that affect TB eradication. </p>
<p>First, the TB burden has been aggravated by HIV co-infection. HIV compromises the immune response required to protect a person against TB. This increases vulnerability to the disease. The World Health Organisation’s most recent <a href="http://www.who.int/tb/publications/global_report/gtbr2015_executive_summary.pdf">global TB report</a> shows that of the TB-related deaths in 2014, just under 27% of patients were HIV-positive. This is a slight increase <a href="http://apps.who.int/iris/bitstream/10665/91355/1/9789241564656_eng.pdf">from 2012</a>.</p>
<p>A second challenge is drug resistance. </p>
<p>First-line drug regimens have saved millions of lives but have been marred by non compliance and inconsistent use. TB patients who fail to adhere to their drug regimens often develop drug resistant TB. This means they have to go onto second-line drugs which are more expensive and may take even longer to complete.</p>
<p>Further resistance to second-line drugs leads to extensively drug-resistant TB (XDR-TB). This is more difficult to treat. </p>
<p>Drug resistance has led to a number of patients not responding to current treatment protocols, which is why there is a dire need for more treatment options.</p>
<p>The third challenge is that there is no adequate vaccine for adults.</p>
<p>The only approved TB vaccine, Bacille Calmette-Guérin, introduced 95 years ago, reduces the risk of TB in children. But it does not help adults with lung TB. An efficacious vaccine that provides a reliable protection against pulmonary TB is essential to eradicate TB. </p>
<p>In the past ten years, there has been some progress in developing a vaccine. A new candidate, <a href="https://www.ncbi.nlm.nih.gov/pubmed/23391465">MVA85A</a>, reached a phase 2b clinical trial. </p>
<p>Although MVA85A failed the clinical end point trial due to limited efficacy, several lessons were gained from the study. These will be highly beneficial in guiding future vaccine development efforts. </p>
<p>Currently over a dozen preventive vaccine candidates are progressing through the <a href="https://www.ncbi.nlm.nih.gov/pubmed/21798463">development pipeline</a>, providing some hope in achieving the 2035 targets.</p>
<h2>Other interventions that could help</h2>
<p>There are several other areas that need to be looked at to help eradicate TB. </p>
<p>First, the rapid diagnostic tools that can detect latent TB, drug-susceptible TB and drug-resistant TB need to be improved to detect the disease earlier. </p>
<p>Second, patients that do not respond to current treatments due to drug resistance do not have any other alternatives. A new strategy is needed here. </p>
<p>Finally, combination therapy hasn’t been cracked. This would shorten treatment protocols, thus improving adherence.</p><img src="https://counter.theconversation.com/content/56695/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Mohlopheni Marakalala has previously received funding from the South African National Research Foundation and the Medical Research Council. </span></em></p>There is an increasing focus on alternative treatment strategies, developed to treat other diseases and conditions but re-purposed to tackle TB.Mohlopheni Jackson Marakalala, Senior Lecturer and Group Leader in the Division of Immunology, University of Cape TownLicensed as Creative Commons – attribution, no derivatives.