A drug used to treat type 2 diabetes could offer a simple and cheap solution to reduce dangerous side effects of steroid treatment, new research from Queen Mary University of London suggests.
The phase 2 clinical trial, funded by Barts Charity, looked at the effects of the diabetes drug metformin on patients currently receiving high doses of glucocorticoids, a type of steroids used to treat chronic inflammatory diseases.
The researchers analysed results from over 50 non-diabetic patients on glucocorticoid treatment from Barts Health NHS Trust and found that patients treated with metformin showed improved clinical outcomes.
This included a 30 percent reduction in the rate of infections and lower hospital admissions, in comparison to the placebo group.
They also observed that treatment with metformin strengthened the intended anti-inflammatory effects of glucocorticoids and had beneficial results on several cardiovascular, metabolic and bone markers over the 12-week trial period.
The study is published today in the journal The Lancet Diabetes & Endocrinology, funded as part of a wider £25m commitment by Barts Charity to support innovative medical research at Barts and the London School of Medicine and Dentistry at Queen Mary.
Since the discovery of their therapeutic effects in the 1950s glucocorticoids, such as prednisolone, have revolutionized treatment of patients with chronic inflammatory disease.
Now glucocorticoids are used to treat a range of conditions where the immune system is overactive, including rheumatoid arthritis, asthma, inflammatory diseases, and in cancer therapy.
However, prolonged use of these medicines at high doses can lead to serious metabolic side effects such as weight gain, high sugar levels, loss of bone and muscle mass, and increased risk of infection and thrombosis.
Long-term, these features can lead to Cushing’s syndrome, a potentially fatal disorder which also exists in patients where the body makes too much of the stress hormone cortisol.
Several biological medicines have been developed as alternatives to steroids but these drugs are expensive and can present their own adverse effects.
Previous research from Professor Márta Korbonits and colleagues found that steroids are able to influence a key metabolic protein, called AMP-kinase or AMPK.
Other experimental studies have suggested that metformin acts, at least partly, via the AMPK protein and in the opposite way to steroids.
Based on this evidence, the researchers reasoned that the diabetes drug held the potential to reverse the unwanted side effects of steroids.
Professor Márta Korbonits, Professor of Endocrinology at Barts and the London School of Medicine and Dentistry at Queen Mary, said: “Our findings are strikingly positive and suggest that a simple and immediately available intervention, treatment with the diabetes drug metformin, can improve the clinical status of patients on glucocorticoid treatment, even if they do not have diabetes.
The results could have a huge impact on the large number of patients on long-term glucocorticoids, improving treatment-related complications and their cardiovascular prognosis.
“Whilst developed countries may be increasing the use of biologics or other steroid-sparing agents, in many other parts of the world there’s still a heavy reliance on glucocorticoids.
Therefore, doctors and patients have been waiting for a safe, cheap and effective treatment that can prevent the major metabolic complications of these medicines, but does not affect, or could even improve, their anti-inflammatory properties. Our results suggest metformin has the potential to help these patients.”
Fiona Miller Smith, Chief Executive of Barts Charity, said: “At Barts Charity we are funding research to pioneer improvements in healthcare that not only enhance the lives of patients in our hospitals and local community but can also have an impact worldwide.
“Steroids are used to treat a vast range of conditions, from cancer to rheumatoid arthritis, and a large number of over 60s need to take these drugs to manage chronic conditions that could otherwise become extremely debilitating.
The promising findings of this study show how funding innovative research can help us rethink long-standing problems facing patients and healthcare professionals, and in this case, even deliver new, simple and cost-effective treatment options for the NHS.”
It is estimated that around three percent of the general adult population and up to 11 percent of over 80s are currently prescribed long-term steroid treatment for chronic inflammatory disease.
Obesity is an important public health problem, owing to the exponential increase in its prevalence in recent years [1]; indeed, the prevalence of pediatric obesity has tripled in one decade in Spain [2]. Obesity is an independent risk factor for metabolic (dyslipidemia, type 2 diabetes, metabolic syndrome) and cardiovascular diseases (hypertension, atherosclerosis) [3].
The mainstay of prevention and treatment of obesity in children is based on lifestyle modification including diet and physical activity; however, long-term compliance to these remains very poor.
While some of these programs have shown to be effective in improving anthropometric parameters, there is conflicting evidence about their effectiveness in improving the body composition and reversing the insulin resistance and metabolic derangements [4, 5]. Therefore, different pharmacological therapies have been used to treat childhood obesity and its complications [6].
Metformin is a biguanide widely used to treat type 2 diabetic patients [7]. It has been successfully used to reduce weight gain, hyperinsulinemia, and dyslipidemia in adults, and in patients with prediabetes, to prevent the progression from glucose intolerance to type 2 diabetes [8, 9].
These results have prompted the use of metformin in adolescents in the early phases of development of diabetes and metabolic syndrome, mainly in those patients with obesity and hyperinsulinemia, in order to reduce the risk for metabolic and cardiovascular diseases [10].
In pre-puberal girls with a history of low birth weight (LBW, who are at increased risk for metabolic syndrome in adulthood), increased visceral adiposity, and risk markers for metabolic syndrome, treatment with metformin before and throughout puberty decreases the gains in total, visceral, and hepatic adiposity and prevents the deterioration of endocrine-metabolic parameters [11].
In these girls, metformin treatment was followed by a delayed progression of puberty, a more normal menarcheal age, and a taller adult height [12, 13].
Recent reviews including a total of 15 randomized controlled trials (RCTs) with metformin treatment (1000–2000 mg/day) over 6 months in children and/or adolescents with obesity and hyperinsulinemia reported that more than 50% of the studies showed a greater reduction in body mass index (BMI) with metformin versus controls (average reduction of -1.3 kg/m2) and about 25% of the studies showed a significant reduction in HOMA-IR in the metformin versus control group (average reduction of -0.6) [6, 14].
Adverse events were reported to have occurred in all metformin trials, with gastrointestinal side effects the most commonly reported. A similar RCT in pre-puberal and pubertal children with obesity showed that metformin (1000 mg/day for 6 months) decreased the BMI z score and improved inflammatory and cardiovascular-related obesity parameters in pre-puberal children but not in pubertal children [15].
Puberty, together with prenatal and early postnatal life, are highly dynamic periods characterized by a plasticity of the body to adapt to the increased metabolic and growing demands of these phases of life [16].
Our previous studies in pre-puberal girls with LBW without obesity but with an increase in visceral adiposity and cardiometabolic risk markers showed that pre-puberal metformin treatment not only prevents the worsening of the metabolic profile in these girls but has persistent effects beyond this period of life, once the pharmacological treatment has been discontinued [17].
Although a post-pubertal onset of metformin treatment also improves the metabolic profile in these girls, metformin’s normalizing effects are reversed as soon as the drug is discontinued [18]. It has therefore been proposed that puberty offers a window of opportunity for reprogramming, the metabolic abnormalities of these patients in order to delay a potential development of metabolic syndrome.
The above-mentioned data obtained in patients with obesity provide enough evidence to sustain beneficial effects of metformin in pediatric populations. However, these RCTs evaluated the effect of 1000–2000 mg/day metformin over 6 months in pubertal children and/or adolescents with obesity, focusing on anthropometric and metabolic parameters. Only six of these RCTs had an intervention of more than 6 months, and they found no further improvement in BMI of metformin treated groups, though their BMI was lower than the controls [14].
Here, we performed a pilot study to ascertain whether a lower dose of metformin (850 mg/day) for 24 months normalizes the endocrine-metabolic abnormalities, improves body composition (specifically, decreases the excess of visceral and liver fat), and reduces carotid intima-media thickness in pre-puberal and early pubertal children with obesity.
More information:The Lancet Diabetes & Endocrinology (2020). DOI: 10.1016/S2213-8587(20)30021-8 , http://www.thelancet.com/journals/landia/article/PIIS2213-8587(20)30021-8/fulltext
