Metformin beyond it's blood sugar lowering properties

The flower is of course,the French lilac or goat's rue,the original source of that well known anti-diabetic drug Metformin. Believed to be the most widely prescribed diabetes drug in the world,it was introduced into Britain in 1958 but not licensed for use in T2 diabetes in the US until 1994.

It works by blocking the production of glucose in the liver and also by helping the body to utilise insulin properly.

It appears to be most effective in helping with weight loss and thus reducing insulin resistance. This effect is not maintained at the same rate after the initial period of weight loss and treatment, but many patients, including those not overweight at diagnosis ,continue to take it for the cardiovascular protection it is said to  afford. Although this cardiovascular protection, appears to be generally accepted; there does not appear to be conclusive proof. See below *

Reappraisal of Metformin Efficacy in the Treatment of Type 2 Diabetes: A Meta-Analysis of Randomised Controlled Trials  PLOS Medicine

This showed no evidence that metformin has any beneficial effect on all-cause mortality, on cardiovascular mortality, or on cardiovascular morbidity among patients with type 2 diabetes. These findings must be cautiously interpreted because only a few randomized controlled trials were included in this study, and only a few patients died or developed any cardiovascular illnesses. Importantly, however, from these findings, it is impossible to exclude beyond reasonable doubt, the possibility that metformin causes up to a 25% reduction or a 31% increase in all-cause mortality. Similarly, these findings cannot exclude the possibility that metformin causes up to a 33% reduction or a 64% increase in cardiovascular mortality. Given that a large number of patients take metformin for many years as a first-line treatment for diabetes, further studies are urgently needed to clarify this situation.

T2s and some T1s and other types may be prescribed metformin, as also - pre-diabetics, those suffering from polycystic ovary syndrome, and Gestational diabetes. It is also used in the treatment of nonfatty liver disease. Some studies appear to suggest that it can protect against certain cancers-mainly those to which diabetics appear to be more susceptible. This is very exciting and appears quite feasible  in the light of recent discoveries re sugar and insulin markers and receptors  but a great deal more needs to be done before this view can be substantiated.  The meta analysis

 =http://journals.sfu.ca/ijmbs/index.php/ijmbs/article/download/330/696 

will be of interest to those who are interested in the current thinking about this drug.

There are many studies concerning various aspects of metformin therapy, but the meta analyses referred to here are the most recent.*

*Metformin is accepted as the first line drug of choice, where diet and exercise and other lifestyle changes, are not sufficient to reduce blood glucose levels. There are of course contraindications. Metformin is not suitable for everyone. It is not currently prescribed to those with renal impairment or heart failure. Mainly because of the role it is thought to play in the development of Lactic acidosis - see below in ’side effects.* 

So what is the downside to this 'wonder drug'? Most patients would cite the gastro-intestinal upsets which can last for some time.  Switching to the slow release version is the answer for most people although there are some who cannot tolerate it in any form. 'Many studies will quote lactic acidosis as the worst side effect of metformin as it can be fatal.*

patient.co.uk/doctor/Lactic-Acidosis.

The reputation of the biguanide metformin for causing lactic acidosis may be overstated, and largely based on experience with its more toxic predecessor phenformin. It can cause lactic acidosis in overdose, or if continued in severely ill diabetics who become dehydrated, but seems to be well tolerated on the whole, with many of the current cautions for conditions such as heart failure, probably being overzealous and denying a safe and useful therapy to many patients.[5] A Cochrane systematic review found no evidence of an association with lactic acidosis, or hyperlactataemia in study-based use.[6]

*Lactic acidosis is quite rare in any event, the usual figure quoted is less than 1 in 10,000.This seems quite reassuring, until one considers that the same figure is given for the side effects, which appears to be on the increase in some groups and which is often misdiagnosed. The real reason in fact for this post.

We are two T2 diabetics who have been on metformin for a number of years.  Both naturally slim-so metformin probably makes very little difference to our HbAIC's and both have taken it mainly for the potential cardiovascular protection.

We are at an  age when we may not be able to absorb an important nutrient  from diet alone-some studies say this may be as low as age 50 although others estimate it as much later, and are concerned that we may be in danger of suffering Vitamin B12 deficiency.

It is very well documented that metformin use for an extended period, or in older age groups or at a high dosage can have this effect. The effects of Vit B12 deficiency can be serious if left untreated. It is also often misdiagnosed.. 

09 December 2013

Boots WebMD

Symptoms|Medicines|Conditions

Anaemia and anaemia caused by a lack of vitamin B12 can result in symptoms which include:

Extreme tiredness or fatigue

A lack of energy or lethargy

Being out of breath

Feeling faint

Headache

Ringing in the ears ( tinnitus)

Lack of appetite

More specific symptoms linked to a lack of vitamin B12 include:

Yellowing of the skin

Sore, red tongue

Mouth ulcers

Changes or loss of some sense of touch

Feeling less pain

Walking problems

Vision problems

Mood changes, irritability, depression or psychosis

Symptoms of dementia

Causes of vitamin B12 deficiency

Vitamin B12 deficiency is more common in older people and affects around one in 10 over 75s.

The most common cause of vitamin B12 deficiency is pernicious anaemia, an auto-immune condition that affects around one in 10,000 people. Pernicious anaemia is caused by a lack of a protein called intrinsic factor that’s needed to absorb vitamin B12 from food into the body from the gastro-intestinal tract. This condition is more common in people over 60, in women, in people with a family history of pernicious anaemia or some autoimmune conditions, including Addison’s disease and vitiligo.

Vitamin B12 deficiency is risk for people who follow a strict vegan diet who don't eat the major food sources of B12: meat, eggs and dairy products. Babies whose mums are vegetarians may have vitamin B12 deficiency.

Other causes of vitamin B12 deficiency include:

Atrophic gastritis, or thinning of the stomach lining

Stomach ulcers

Surgery to remove part of the stomach or small intestine

Digestive conditions such as Crohn's disease, coeliac disease, bacterial growth or a parasite.

Medication, including proton pump inhibitors (PPIs) for indigestion

Diagnosis of vitamin B12 deficiency

Blood tests and examination of blood cells under the microscope assess haemoglobin levels, the size of red blood cells and the level of vitamin B12 in the blood. The levels of folate are also usually checked for the related condition folate deficiency anaemia.

Once the diagnosis is confirmed, further tests may be carried out to try to find out what's causing the anaemia.

A referral may be made to a specialist, such as a haematologist for blood conditions, a gastroenterologist for digestive disorders or a dietitian for advice on eating food containing more vitamin B12.

The above does not mention metformin specifically but many other studies do.  Apparently up to 30% of metformin users go on to develop B12 deficiency. Misdiagnosis is common as Vit B12 deficiency can mimic several serious disorders.

Welcome to B12 Awareness!

Disorders With Possible Underlying B12 Deficiency

Dementia—Alzheimer’s disease

Multiple sclerosis

Depression

Post-partum depression/psychosis

Bipolar disorder

Neuropathy (diabetic, CIDP)  

Diagnosing and Treating Vitamin B12 Deficiency (video)

Vitamin B12 deficiency can sneak up on you, and can lead to a myriad of diseases and disorders. Know the signs and symptoms. You could be deficient yet still test in the so-called range of "normal B12" on a blood test, especially if you have taken an oral B12 supplement of uncertain quality, or you have been under-treating the deficiency. Oral B12 supplements do not work for all patients; patients with digestive/absorption problems benefit from B12 injections, as do patients with nerve damage.

http://youtu.be/BvEizypoyO0

*Conclusion

Despite the above and  recommendations from many studies over the years,  there is still no standard requirement or directive for routine testing for vitamin B12 deficiency  for long-term or high dosage metformin users  in the UK.

Diagnosis is fortuitous in many cases and this is a great pity because the condition is easily treated.

Universal screening is still not considered to be cost effective  but there is sufficient evidence, in our opinion, to justify routine testing of those on long term and/or high doses of metformin and of the elderly who cannot absorb sufficient B12 from their diet. Testing could easily be included with the blood tests for the annual review.

It would be worthwhile in order to raise awareness of possible Vit B12 deficiency for those on metformin who might by those at risk and aware of it raising the issue with their HCP and asking to be tested. It is not a question of causing extra expense to the NHS but of saving it by avoiding misdiagnoses and more costly treatment being required unnecessarily, where the condition mimics other disorders.

This is a serious matter and should be treated as such.  The mantra about metformin being safe and cheap and effective may be true, but it is not the whole story.

There are those like our own Paul and others, contributing to diabetes forums, who because they suffer from B12 deficiency, not caused by metformin, are yet able to recognise the symptoms in others and I am sure must have  been the means of helping many to a faster diagnosis.  If routine testing of certain groups is impossible, then it should be possible, surely, to include, in the annual review a few questions about possible symptoms as a marker for those who may require tests.

As the numbers diagnosed with diabetes continue to increase and as people live longer with the condition, this matter becomes more pressing and affects more people.

Please be aware of the risks for yourselves-diabetic or not-and help spread awareness of this potentially dangerous but easily treated condition.

Kath & Graham