Marvellous metformin

Dr Angela Murphy backs why metformin is still the drug of choice for treating Type 2 diabetes.

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Metformin was first described in the 1920s, but it was forgotten for years after the discovery of insulin. It was registered as a treatment for diabetes in the United Kingdom in 1958 and remains the most widely prescribed oral anti-diabetic medication.

Metformin is classified as a biguanide medication and was originally derived from the plant Galega officinalis, also known as French lilac.  It has several mechanisms of action which result in the lowering of blood glucose levels.

1. Decreases the production of glucose in the liver. It’s important to remember that the source of glucose in the blood is both from food and from the production of glucose in the liver.
2. Decreases the absorption of glucose from the gut.
3. Increases the uptake and utilisation of glucose by muscles. This is what improves insulin sensitivity.

Metformin doesn’t act on the pancreas to affect insulin production, so it’s unlikely to cause low blood glucose. Rather it helps to lower high glucose levels back to the normal range.

Metformin is registered in South Africa as a treatment for Type 2 diabetes. However, it can be used ‘off-label’ for other conditions, namely:

• Prediabetes
• Type 1 diabetes
• Polycystic ovarian syndrome

Prediabetes

Prediabetes is defined as one or both of the following being present:

• Impaired fasting glucose – This is a glucose level from 6.1mmol/L to 6.9mmol/L on a fasting blood sample.
• Impaired glucose tolerance – This is a glucose level from 7.8mmol/L to 11.1mmol/L on a blood sample taken two hours after a 75g glucose drink.

Metformin is often considered a reasonable treatment to introduce for prediabetes when attempts to normalise blood glucose with lifestyle interventions over a three to six-month period haven’t worked.

A strong family history of Type 2 diabetes (parents and siblings) would also increase the likelihood of metformin being offered in the setting of prediabetes.

Evidence from two large studies, the US Diabetes Prevention Program (DPP) and the Diabetes Prevention Program Outcome Study (DPPOS), has shown that metformin can prevent the onset of Type 2 diabetes in patients at risk. However, lifestyle intervention did give better results and should be encouraged first.

Type 1 diabetes

Type 1 diabetes is an autoimmune disorder that results in absolute insulin deficiency. This implies that, at diagnosis, the person with diabetes (PWD) must be given insulin injections. However, it’s possible for people with Type 1 diabetes to also be insulin resistant, particularly in the presence of obesity, sedentary lifestyle, and puberty.

The actions of metformin as described above, improving both liver and muscle insulin resistance as well as decreasing the absorption of glucose from the intestine, can improve the efficacy of insulin being injected in the person living with Type 1 diabetes. This would translate into lower insulin doses being required while glucose control improves.

One study found that people with Type 1 diabetes given metformin in addition to insulin showed better glucose concentrations, reduced insulin dose requirements, and some weight loss (on average 0.5kg).

Polycystic ovarian syndrome

Polycystic ovarian syndrome (PCOS) is diagnosed in women of reproductive age who have two of the following three criteria:

• Irregular menstrual cycles indicating irregular ovulation.
• Features of high male hormone levels: excess hair growth on face and body (hirsutism), acne, and baldness.
• An ultrasound scan showing polycystic ovaries.

An estimated 88% of women with PCOS are overweight or obese and almost three quarters have insulin resistance. Metformin has direct effects on the function of both the ovaries and the pituitary gland; the latter controls hormone functions in the body. This leads to improved menstrual cycles and fertility.

Metformin has been shown to induce ovulation either alone or with other hormonal drugs. Studies have suggested that metformin is more effective in women with PCOS who are also either overweight or obese. However, there are no specific predictors to show which women will respond better to metformin treatment.

The International Evidence-based Guideline for the Assessment and Management of Polycystic Ovarian Syndrome 2023 guideline states:

1. Metformin alone should be considered in adults with PCOS and a BMI ≥ 25 kg/m2.
2. Metformin alone could be considered in adolescents at risk of or with PCOS for cycle regulation, acknowledging limited evidence.
3. Metformin alone may be considered in adults with PCOS and BMI < 25 kg/m2, acknowledging limited evidence.

Metformin side effects

Gastrointestinal: Diarrhoea, nausea, vomiting, abdominal pain, and flatulence. In these instances, the extended-release formulation of metformin can be tried (metformin XR). Especially taken at night, this is found to be better tolerated. If any of these gastrointestinal symptoms continue then metformin should be stopped, and another diabetic medication used.

Vitamin B12 deficiency: It’s important for patients using metformin over many years to have their vitamin B12 levels checked as metformin reduces the uptake of vitamin B12.

Low vitamin B12 causes neuropathy and particularly balance problems. This might be blamed on the diabetes whereas a more reversible cause could be present.

Kidney function: If a PWD’s kidney function drops too low, metformin dose will be reduced or even discontinued.

Lactic acidosis: A rare side effect of metformin when lactic acid builds up in the bloodstream, which usually only occurs when metformin continues to be given to critically ill patients.

Less common side effects include a loss of appetite and a metallic taste.

Facts and myths

In recent months there have been queries from PWD regarding the safety and benefit of metformin. There was obvious concern with the reporting of the presence of N-nitrosodimethylamine (NDMA) in metformin manufactured in the USA. Our own regulatory authority has been checking metformin in South Africa and to date no contamination has been found here.

The second wave of doubt arose, in my opinion, from an advertising campaign driving to sell supplements to treat diabetes. To create this market, they denounced the benefits of metformin.

Metformin has, in recent years, shown promise in augmenting the treatment of cardiovascular disease and stroke, cancer, Alzheimer’s and other dementias. It has anti-aging effects which may lead to longevity. None of these conditions are primary indications to use metformin, but for PWD taking metformin, they may derive extra benefits. We know for sure that less cancer is seen in people living with Type 2 diabetes taking metformin than in people living with Type 2 diabetes not taking metformin.

Metformin is still marvellous

In global diabetes management guidelines, including South Africa, metformin remains the first-line medication for the treatment of Type 2 diabetes.

Many new medications with multiple benefits to heart, brain and kidneys have been launched in the last two decades, but they have not dislodged metformin from its first-line spot.

Metformin remains an important treatment for Type 2 diabetes, has some accepted off-label indications and there is ongoing research to look at possible other clinical benefits.

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References

1. Beysel S, Unsal IO, Kizilgul M, Caliskan M, Ucan B, Cakal E. The effects of metformin in type 1 diabetes mellitus. BMC Endocr Disord. 2018 Jan 16;18(1):1. doi: 10.1186/s12902-017-0228-9. PMID: 29338714; PMCID: PMC5771191.
2. org.uk 21 February 2023
3. Lashen H. Role of metformin in the management of polycystic ovary syndrome. Ther Adv Endocrinol Metab. 2010 Jun;1(3):117-28. doi: 10.1177/2042018810380215. PMID: 23148156; PMCID: PMC3475283.
4. https://www.monash.edu/__data/assets/pdf_file/0003/3379521/Evidence-Based-Guidelines-2023.pdf
5. https://www.health.harvard.edu/blog/is-metformin-a-wonder-drug-202109222605

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