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Metformin

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Metformin belongs to a class of drugs called biguanides.  Guanidine itself is far too toxic to be used therapeutically, however, by linking two guanidine rings together, a relatively non-toxic class of drugs was created which have proved useful in the treatment of type II diabetes.   Metformin is the only remaining biguanide on the market, as the other biguanides phenformin and buformin were withdrawn from use in the 1970′s due to frequent lactic acidosis reactions and increased cardiac mortality.  Metformin has quite a long history of use, having first been discovered in 1922, although it was sidelined until the late 1940′s and it wasn’t until 1958 that it became available in Europe and 1995 that it was approved for use in the US.  The development of metformin stems from a long history of use of the herb Goat’s Rue or Galega officinalis in folk medicine.

How Does Metformin Work?

Metformin works by:

    • Increasing insulin sensitivity at a cellular level, especially enhancing peripheral glucose uptake (ie in your extremities).
    • Suppressing the production of glucose by your liver by more than 1/3.
    • Activating a liver enzyme called AMP-activated protein kinase which is very import in the insulin signalling process, the metabolism of glucose and fats as well as balancing the energy in your body.
    • Increasing the production of DCI-IPG in the liver in response to insulin.
    • Decreasing the absorption of glucose from the gastrointestinal tract.
    • Increasing fatty acid oxidation.

Metformin is contraindicated in people with pre-existing:

      • kidney disease
      • liver disease
      • lung disease and
      • heart disease

as these conditions increase the risk of the serious and life-threatening side effect lactic acidosis.

How Does Metformin Compare to Diet & Exercise?

A study published in the Annals of Internal Medicine in 2005 by a group of researchers working for the Diabetes Prevention Program Research Group found that in a large group of subjects (over 3200) who had impaired glucose tolerance, defined in this study as being a fasting plasma glucose level of more than 5.3 mmol/L or 95 mg/dL, and 53% of whom already had the metabolic syndrome (being overweight especially with increased central obesity leading to an increase in triglycerides, leading to the production of inflammatory cytokines eventually leading to insulin resistance and often high blood pressure) metformin prevented the development of full blown metabolic syndrome in those who did not already have it by 17% when compared with a placebo.

This sounds good, but compared to an intensive lifestyle program (150 minutes brisk walking a week, a healthy low calorie, low fat diet) it is decidedly inferior.  Diet and exercise prevented the development of full blown metabolic syndrome in those who only had impaired glucose tolerance at the outset of the study by 41%, more than double the protection offered by metformin.

For those participants who already met the criteria for metabolic syndrome at the beginning of the study, lifestyle interventions alone were found to resolve the syndrome in 38% of subjects after three years, compared to only 23% of those taking metformin.

The study also found that participants who took metformin had a much greater incident of gastrointestinal symptoms than those taking a placebo or undertaking the intensive lifestyle program. Another report of this study in the New England Journal of Medicine finds that lifestyle modification reduces the incidence of diabetes mellitus by 58% compared with a placebo treatment whereas metformin only reduces the incidence by 31%.

Clearly, these results indicate that diet and exercise interventions are far superior to treatment with metformin in treating impaired glucose tolerance.

When Is It Appropriate to Take Metformin?

Scientists at the Saint Vincent de Paul hospital in Paris have recently published a study in the French medical journal Annales d’Endocrinologie which makes 8 recommendations regarding the prescription of metformin in women with PCOS.

  1. Metformin is not efficient enough in order to regulate menstrual cycles.
  2. Metformin is not efficient enough in order to treat hyperandrogenism.
  3. Metformin should not be used as a first-line treatment in order to treat infertility. Clomiphene citrate (CC) is the reference treatment.
  4. Metformin in addition to CC is not recommended as a second line treatment, after the failure of CC alone.
  5. Metformin should not be used during pregnancy in non diabetic women with PCOS, in order to prevent the risk of gestational diabetes.
  6. Metformin should be prescribed to PCOS women when they are diabetic, in order to prevent their cardiovascular risk, after lifestyle modification.
  7. Metformin should not be used in PCOS non diabetic women in order to lose weight. Metformin should not be used in order to treat dyslipidemia in women with PCOS.
  8. In PCOS women, without diabetes, but with fasting hyperglycemia or carbohydrate intolerance, metformin should be prescribed if: BMI > 35.

Essentially it is saying that the side-effects outweigh the benefits for women with PCOS unless the condition is very severe and alternative methods have failed.  If blood glucose control has totally broken down to the point of frank diabetes, or if the woman is very obese, with a BMI of 35 or greater.  This would be equivalent to a weight of 225 lbs or just over 100 kg if you were 5’7″ tall or 170 cm.

Does Metformin Improve Fertility & Reduce Miscarriage Rates?

Many women take metformin, thinking that it will improve their rate of ovulation and increase their chances of becoming pregnant.  It has also been suggested that taking metformin throughout pregnancy will reduce the rate of miscarriage, which is common in women with PCOS, resulting in a higher rate of live births.

A meta-analysis published on 20 January 2010 has found that there is no evidence to support the notion that metformin, whether used by itself or in combination with clomiphene citrate, improve the live birth rate in women with PCOS.  Two large clinical studies published in 2006 and 2007  returned mostly negative results.  Metformin on its own was no more effective than a placebo and adding it to clomiphene did not increase clomiphene’s effectiveness.

What Side Effects Can Metformin Cause?

Gastrointestinal distress

Metformin is well known for causing a lot of problems with a person’s digestive system.  Over half of all people who take metformin experience diarrhoea, a quarter experience nausea and vomiting, 12% experience gas (belching or flatulence), with 5-10% experiencing abdominal discomfort and indigestion.These side effects occur less frequently or with less severity in people who take the extended release version and are worse after meals which contain a lot of fat or carbohydrates.  Starting with a small dose of metformin and working your way up slowly to the dose that is right for you may minimise any GI side effects.  For those who aren’t able to persuade themselves to eat a healthy diet using the ‘carrot’ approach, metformin can be the ‘stick’ as falling off the wagon when you are taking metformin will cause you a great deal of discomfort and likely pain and embarrassment as well.

General Malaise

Up to a quarter of people who take metformin find that they just feel unwell on it.  This can be constant or come in bouts lasting from days to weeks.  As metformin is known to cause kidney and liver damage in some people, it is very important if you suffer these symptoms whilst taking metformin, that you see your doctor and have tests run to evaluate your kidney and liver function.Metformin can also cause a very serious condition called lactic acidosis, which can be life threatening.

Low blood sugar

As metformin is designed to lower blood sugar, it can do this too efficiently in some people, resulting in dizziness, weakness, lethargy and even fainting.  These effects are rare, however, if this happens to you, you may need to reduce your dosage.

Vitamin B12 deficiency

Metformin is known to cause problems with the absorption of vitamin B12 in up to a third of people taking it.  This is because it impairs the ability of your cells to absorb intrinsic factor, which is produced in the stomach and binds to B12 making it available for absorption into the blood.  This problem can persist even after ceasing to take metformin.  Vitamin B12 is very important for a number of functions in the body and can be difficult to get enough of through diet, especially for vegans and vegetarians as it is largely found in animal products.

More Information:

Al-Inany H, Johnson N. Drugs for anovulatory infertility in polycystic ovary syndrome. BMJ. 2006;332(7556):1461–2.

http://www.bmj.com/content/332/7556/1461

Baillargeon JP, Iuorno MJ, Jakubowicz DJ, Apridonidze T, He N, Nestler JE.  Metformin therapy increases insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator in women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 2004 Jan;89(1):242-9.

http://www.ncbi.nlm.nih.gov/pubmed/14715857

Balen AH. Metformin Therapy for the Management of Infertility in Women with Polycystic Ovarian Sydnrome.  Royal College of Obstetricians and Gynaecologists Scientific Advisory Committee Opinion Paper 13, December 2008.

Cusi, K., and Defronzo, R.A. 1998. Metformin: a review of its metabolic effects. Diabetes Reviews.  6:89–131.

http://www.ncbi.nlm.nih.gov/pubmed/20091537

Duranteau L, Lefevre P, Jeandidier N, Simon T, Christin-Maitre S.  Should physicians prescribe metformin to women with polycystic ovary syndrome PCOS?, Ann Endocrinol (Paris). 2010 Jan 13  PMID:  20079483

http://www.ncbi.nlm.nih.gov/pubmed/20079483

Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group.  Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.  N Engl J Med. 2002 Feb 7;346(6):393-403.

http://content.nejm.org/cgi/content/full/346/6/393

Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356(6):551–66.

http://www.nejm.org/doi/full/10.1056/NEJMoa063971

Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1482338/

Orchard TJ, Temprosa M, Goldberg R, et al.: The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: The Diabetes Prevention Program randomized trial. Ann Intern Med 142:611–619, 2005.

http://www.annals.org/cgi/content/full/142/8/611#R5-9

Palomba S, Pasquali R, Orio F, Nestler JE. Clomiphene citrate, metformin or both as first-step approach in treating anovulatory infertility in patients with polycystic ovary syndrome (PCOS): a systematic review of head-to-head randomized controlled studies and meta-analysis. Clin. Endocrinol. (Oxf). 2009;70(2):311–21.

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2265.2008.03369.x/abstract

Palomba S, Orio F, Falbo A, Russo T, Tolino A, Zullo F. Clomiphene citrate versus metformin as first-line approach for the treatment of anovulation in infertile patients with polycystic ovary syndrome. J Clin Endocrinol Metab. 2007;92(9):3498–503.

http://jcem.endojournals.org/content/92/9/3498.full.pdf+html

Radosh L. Drug treatments for polycystic ovary syndrome. Am Fam Physician. 2009;79(8):671–6.

http://www.aafp.org/afp/2009/0415/p671.html

Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH.  Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility.Cochrane Database Syst Rev. 2010 Jan 20;(1):CD003053.

Ting R, Szeto C, Chan M, Ma K, Chow K (2006). “Risk factors of vitamin B(12) deficiency in patients receiving metformin”. Arch Intern Med 166 (18): 1975–9Metformin is one of the most commonly prescribed drugs in the treatment of PCOS, because it addresses the (currently theorised) root cause of PCOS – insulin resistance resulting in hyperinsulinaemia and hyperglycaemia.

The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod. 2008;23(3):462–77.

http://humrep.oxfordjournals.org/content/23/3/462.full.pdf+html

http://www.jbmr.org/details/journalArticle/572183

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