Also known as French lilac, the herb Galega officinalis was used as a traditional medicine in medieval Europe, apparently helpful against worms, epilepsy and fever. In 1772 it was used to treat thirst and frequent urination, both symptoms of diabetes (Bailey, 2017). Later found to be guanidine-rich, G. officinalis was shown in 1918 to lower blood glucose concentrations; the derivative metformin (dimethylbiguanide) was synthesised in 1922; and in 1957 the French physician Jean Sterne first reported the use of metformin to treat diabetes (Bailey, 2017).
Following improved morbidity and mortality in type 2 diabetes (T2D) demonstrated in the United Kingdom Prospective Diabetes Study, metformin has been the first-line recommended oral treatment for T2D diabetes by the American Diabetes Association and the European Association for the Study of Diabetes since 2009 (Thomas and Gregg, 2017). Metformin reduces the production of liver glycogen without raising insulin concentrations; inhibits glucose absorption in the intestinal tract; and increases the uptake and utilisation of glucose in the peripheral tissues, all of which increase insulin sensitivity (Liu et al, 2023).
Liu et al (2023) note that in addition to metformin's clinically approved hypoglycaemic effect, it also exerts positive metabolic regulatory effects on the body ‘that cannot be ignored. Such as anti-cancer, anti-aging, brain repair, cardiovascular protection, gastrointestinal regulation, hair growth and inhibition of thyroid nodules, and other nonclinical effects.’
And recent research is uncovering a further role for metformin in showing how metabolism can influence an increasingly diverse range of conditions. Psychiatrist Dr Georgia Ede recently highlighted the relationship between metabolism and mental health when she observed: ‘People with obesity, T2D, and cardiovascular disease are also far more likely to have psychiatric disorders like depression, bipolar disorder (BD), and schizophrenia, and this is no coincidence’ (Ede, 2024: 18). Adding to the burgeoning evidence base supporting this statement, Calkin et al (2022) addressed the relationship between insulin resistance (IR) and treatment-resistant bipolar disorder (TRBD). When 45 patients with TRBD and IR were randomised to receive metformin (20 patients) or placebo (25 patients), 50% of TRBD patients treated with metformin not only reversed their IR, but improvements in depression ratings first noted at 6 weeks were sustained up to 26 weeks.
Choo et al (2024), observing that IR may be an important factor in resistance to treatment and disease progression in BD, present ‘the first case study of metformin being implicated in relapse, and subsequent remission of mania in a patient with BD on maintenance treatment.’ A 55-year-old woman with T2D and BD had stopped taking metformin for over 3 months before being hospitalised with a manic relapse. Metformin was gradually re-instituted to her pre-admission dosage, and ‘[f]ifteen days after restarting metformin, her manic symptoms appeared to be in full remission, and she was discharged from the hospital’ (Choo et al, 2024).
The authors suggest that the treatment of impaired glucose metabolism with agents like metformin, may help to address ‘the more severe, chronic, or treatment-resistant types of BD, along with other modifiable lifestyle factors, such as dietary modification and exercise, that have the potential to improve IR and inflammatory changes’ (Choo et al, 2024).
A further application of metformin, which emphasises the central importance of nutrition in chronic disease, is described by Song et al (2022) who cite epidemiological studies that have found a 54% prevalence of osteoarthritis in patients with T2D, and state that high concentrations of glucose ‘not only promote chondrocyte catabolic gene expression and inhibit the differentiation of mesenchymal stem cells into chondrocytes, but also accelerate the damage of cartilage structures.’ The authors also refer to a prospective cohort study of 818 obese patients with knee osteoarthritis which ‘found that metformin use was associated with reduced knee cartilage volume over 4 years and a reduced risk of total knee replacement over 6 years’ (Song et al, 2022).
However, no drug is a panacea, and although digestive disorders like nausea, vomiting, diarrhoea, and stomach upsets are the commonest side effects of metformin, ‘the effect of metformin on gastrointestinal function may lead to vitamin B12 deficiency due to poor digestion and absorption of vitamin B12’ (Song et al, 2022).
Yet notwithstanding such caveats, it appears that the repertoire of metformin's possible beneficial effects on chronic disease is far from complete, reaffirming the importance of attaining and maintaining good metabolic health.