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.

Figure 1: Hyperglucagonemia mitigates the effect of metformin on glucose production in prediabetes. (Konopka AR, et al. Cell Reports. 2016;15:1394.)

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.

Figure 2: Clinical picture of polycystic ovarian syndrome (Rocha AL, Oliveira FR, Azevedo RC, Silva VA, Peres TM, Candido AL, Gomes KB, Reis FM. Recent advances in the understanding and management of polycystic ovary syndrome. F1000Res. 2019 Apr 26;8:F1000 Faculty Rev-565. doi: 10.12688/f1000research.15318.1. PMID: 31069057; PMCID: PMC6489978.)

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.

Figure 3: Metformin side effects. (Metformin and the Liver: Unlocking the Full Therapeutic Potential – Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Most-common-side-effects-and-contraindications-of-metformin-and-metformin-associated_fig2_379291357 [accessed 14 Jul, 2024])

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.

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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Dr Louise Johnson helps us understand how the big M (menopause) may affect the management of diabetes.

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Menopause is a normal condition involving the permanent end of the menstrual cycles due to the cessation of the production hormones from the ovaries for at least 12 consecutive months.

The name menopause comes from the Greek word pausis which means pause, and men which means month. Menopause occurs in all menstruating females due to oestrogen deficiency, usually between the ages of 45 and 56 in most women. The median age of natural menopause is 51 years.

As women live longer, they spend roughly 40% of their lives in the post-menopausal years which equates to more than 30 years for most women.¹

About 5% of women experience early natural menopause, occurring between the ages of 40 and 45 years.

Symptoms related to oestrogen deficiency

1. Vasomotor symptoms

These are the most common symptoms during menopause. Up to 80% of women experience vasomotor symptoms consisting of night sweat, palpitations, migraine, and hot flushes.

Hot flushes occur day and night at unpredictable intervals, often lasting approximately three to four minutes each. A hot flash starts with a sensation of flushing that spreads to the upper body due to the central nervous system changes specific to thermoregulation.

The vasomotor symptoms last on average one to six years but can last 15 years in 10 to 15% of post-menopausal women. They may be worsened by smoking, alcohol, obesity, physical inactivity, and emotional stress. If untreated, vasomotor symptoms will eventually dissipate after approximately 7.4 years.

2. Genitourinary symptoms

Approximately 50 – 75% of women experience genitourinary syndrome. The vagina lining thins and there is reduced elasticity. It causes vagina dryness, burning, pruritus (itchiness,) and irritation.

Urinary symptoms of frequently passing urine and the urge to go immediately occurs as well as burning urination. The low oestrogen levels in the bladder also cause frequent urinary tract infection.

Urinary incontinence is not related to menopause. The causes are overweight, diabetes, and increasing age. A decline in sexual function and libido is also part of the syndrome.³

3. Psychogenic symptoms

Up to 70% of women experience psychogenic symptoms associated with peri-menopause and menopause. These symptoms include anger, irritability, anxiety, tension, depression, loss of concentration, and loss of self-esteem and confidence.

Sleep apnoea, insomnia, and restless leg syndrome may cause further sleep disturbance that aren’t explained by night sweats. The risk of depressive symptoms and a higher level of depression severity are noted in the peri-menopausal women compared to pre-menopausal women.

Making a diagnosis

Physical examination

The following abnormalities are observed:

• Blood pressure is elevated.
• Weight gain is noted and an additional decrease in height associated with osteoporosis.
• Breasts have an increase in fatty deposition.
• Vagina has increase dryness and atrophy (wasting) of urethra (bladder pipe opening).
• Arthralgias (joint pains) and sarcopenia (loss of muscle mass, function and strength).

Lab tests

Tests are typically not needed to diagnose menopause. Under certain circumstances the following tests can be done:

• Follicle-stimulating hormone (FSH) will be increased. An elevated serum FSH greater than 30mIU/ml is an objective indicator of menopause.
• Oestrogen will be decreased. An oestrogen value less than 20pg/ml is suggestive of menopause.
• Thyroid stimulating hormone (TSH) to rule out an underactive thyroid since it can cause similar symptoms to those of menopause.

Staging

In 2011, The Stage of Reproductive Aging Workshop (STRAW) divided the female reproductive cycle into three categories:

1. Reproductive stage

This start with the beginning of menstruation. During these years the menstrual cycle is regular.

2. Menopausal transition stage

This is when peri-menopause occurs. During this stage, the menstrual cycle undergoes variability in duration of menstruation. As this stage progresses, women can experience no menstruation (amenorrhea) for a time of up to 60 days.

3. Post-menopausal stage

This stage begins when menstruation has ceased for up to one year.

Menopause and Type 2 diabetes

These are both conditions that often occur in midlife. Menopause causes a sharp drop in oestrogen levels, leading to various changes that can affect body weight, fat distribution, and insulin sensitivity. These changes can raise the risk for Type 2 diabetes or make managing your diabetes more challenging.

Menopause may increase the risk of developing Type 2 diabetes due to:

• Hormonal changes – Oestrogen and progesterone affect how cells respond to the hormone insulin. When oestrogen and progesterone levels drop, cells may not be as sensitive to insulin. This can lead to high glucose levels.
• Blood glucose fluctuations – Hormonal changes can cause blood glucose to fluctuate throughout the day. This can make managing diabetes a challenge.
• Weight gain – Menopause is commonly associated with weight gain, up to 7.5 kg. Excess weight is a known risk factor for Type 2 diabetes.
• Disturbed sleep – Menopause can lead to restless sleep due to night sweats and palpitations. A lack of sleep has been linked with a higher risk of Type 2 diabetes.
• Depression – Depression is more common in menopause than before it. People who are depressed may have an increased risk of diabetes due to increase eating and less exercise.²

Treatment

Menopause requires no medical treatment. Instead, treatment focus on relieving signs and symptoms and managing chronic conditions that may occur with aging. Treatments may include:

• Hormone therapy

Oestrogen therapy is the most effective therapy for relieving menopausal hot flashes. Your doctor may recommend the lowest dose for the shortest time frame to provide symptomatic relief. If you still have a uterus, you will require progesterone as well to prevent endometrium increase. Oestrogen helps bone loss, but the long-term use should be carefully considered due to the risk of breast cancer and blood clotting, such as deep venous thrombosis and pulmonary emboli (blood clot to the lung).

• Vaginal oestrogen

Oestrogen can be delivered directly to the vagina to prevent dryness, discomfort with intercourse, and some urinary symptoms. This modality is a lot safer than oral oestrogen and has a lot less complications.

• Low-dose antidepressant

Certain antidepressants related to the class SSRI, such as paroxetine, escitalopram or venlafaxine, may decrease hot flashes and help with depression and mood stabilising.

• Gabapentin

This drug is approved for seizures but has shown to reduce hot flashes.

• Clonidine

This tablet is typically used in high blood pressure but has shown to relieve hot flushes.

Lifestyle remedies

1. Drink enough cold water and dress in layers. Try to pinpoint your trigger that may include alcohol, caffeine, stress, and spicy food.
2. Decrease vaginal discomfort with a vaginal lubricant.
3. Get enough sleep by avoiding caffeine and too much alcohol.
4. Strengthen your pelvic floor by doing Kegel exercises.
5. Adopt a balanced diet.
6. Don’t smoke.
7. Exercise regularly. Do aerobic exercises, such as walking 30 minutes per day five days a week and weight-bearing exercises twice a week.

Remember that hormonal therapy comes with risks such as stroke, heart attacks, blood clots, and breast- and uterus cancer. Discuss with your healthcare provider and choose the correct treatment specific for you. Menopause is a condition that can be effectively managed by your health team.

References

1. Mangiome CM, Barry MJ et. al. “Hormone therapy for the primary prevention of chronic conditions in postmenopausal persons” JAMA 2022;328 (17):1740-46
2. Slopien R, Wender-Ozegowska E et. al. “Menopause and diabetes” Maturitas, 2018;117:6-10
3. Talauliker V.”Menopause transition:Physiology and symptoms” Best Praxct Res Clin Obstet Gynaecol. 2022,81:3-7

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