Metformin…. Is it a Wonder Drug?

Written by: Mandy Reece, PharmD, CDE; Freddi Mehlhorn, 2019 Doctor of Pharmacy Candidate Philadelphia College of Osteopathic Medicine (PCOM) Georgia Campus School of Pharmacy; Dong Kim, 2019 Doctor of Pharmacy Candidate PCOM Georgia Campus School of Pharmacy

Meet Meg

Meg, 28 year old Caucasian female with polycystic ovarian syndrome (PCOS), phones me on a Friday afternoon around 4 pm as she curious as to learn more about metformin. She has an appointment on Monday morning with gynecologist to discuss increasing her odds of pregnancy in light of her having PCOS. She had heard from a few friends that metformin could assist with getting pregnant in presence of PCOS. She and her husband have been trying to conceive for eight months.

When is it helpful?

In PCOS

Polycystic ovary syndrome (PCOS) is the most common endocrinological disorder, comprised of both reproductive and metabolic characteristics. Approximately 88% of women with PCOS are either overweight or obese. Insulin resistance is widely recognized as a common feature of PCOS, independent of obesity. Whether the role of insulin resistance is directly related to PCOS or associated through obesity, it undoubtedly raises a clinical concern with providers and patients. Metformin was originally introduced in the management of PCOS to establish the extent to which hyperinsulinemia (increased circulating insulin levels) influences the development of the syndrome. Today, metformin works in PCOS by increasing insulin sensitivity in peripheral tissues, therefore reducing circulating insulin levels. Other reported effects of metformin in PCOS include restoring ovulation, reducing weight, reducing circulating androgen levels, reducing risk of miscarriage, and reducing risk of gestational diabetes.

In Prediabetes
Patients at an increased risk for the development of type 2 diabetes mellitus (T2DM) are commonly characterized as having “prediabetes.” Prediabetes is defined as having a fasting plasma glucose of 100-125 mg/dL, a 2-hour post-prandial glucose of 140-199 mg/dL, or an A1C of 5.7-6.4%. While its use in prediabetes has not yet been approved by the FDA, recent guidelines recommend considering the use of Metformin to prevent or delay the onset of diabetes in patients with prediabetes (especially those who are < 60-years-old, have a BMI > 35 kg/m2, or have a history of gestational diabetes). In the Diabetes Prevention Program (DPP) trial, Metformin was shown to reduce the risk of developing T2DM by 31% as compared to a placebo group.

In Type 2 Diabetes
Metformin is the preferred initial pharmacologic agent for the treatment of type 2 diabetes mellitus (T2DM). It is well established as an effective, safe, and inexpensive medication. Along with increasing insulin sensitivity and reducing the amount of glucose that the liver produces, metformin has also shown beneficial effects on lowering A1C, promoting weight loss, and reducing cardiovascular events and death. While Metformin may be used alone in the treatment of T2DM, it can also be used in combination with almost all other available agents for the treatment of T2DM.

Perfection Not Quite
Metformin overall has relatively few adverse effects which are gastrointestinal related. Diarrhea is the most common adverse effect that I see in practice. Practical tips for decreasing risk of diarrhea are starting with low dose (500 mg) and gradually increasing dose as well as using extended release (ER) product. Personally, I found taking a probiotic while also taking metformin to prevent diarrhea.

What to monitor?
While metformin is a safe drug with a strong track record, there are still a few lab values that must be monitored. In terms of renal (kidney) lab values, estimated glomerular filtration rate (eGFR) should be checked before starting metformin then at least annually or more often for those with at risk for renal impairment (i.e. senior adults). When eGFR is below 30 mL/min/1.73m2, metformin must be discontinued.

When on metformin for longer than a year, a slight risk for vitamin B12 deficiency exists. Therefore, it is advised to have vitamin B12 level checked. There are typically no symptoms associated with mild vitamin B12 deficiency. With more severe cases of vitamin B12 deficiency, the possible symptoms include fatigue, pale skin, shortness of breath, vision loss and mood changes.

Back to Meg
Good news! Meg became pregnant after several months of metformin and additional infertility medication therapy. She was able to tolerate metformin without any side effects. She is now a mom to a healthy little boy, TJ.

Personal Note
I was diagnosed with prediabetes a couple of years ago due to extended lack of exercise following foot surgery and unhealthy eating. As a side note, I have always struggled with overeating and having a giant sweet tooth. I discussed with PCP about taking metformin and working on improving my lifestyle. I am thankful that increased physical activity, healthier eating and metformin returned my blood sugar to normal range. Today, I no longer have prediabetes.

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References
1. Lashen H. Role of metformin in the management of polycystic ovary syndrome. Therapeutic Advances in Endocrinology and Metabolism. 2010;1(3):117-128. doi:10.1177/2042018810380215.
2. Metformin for Prediabetes. JAMA. 2017;317(11):1171. doi:10.1001/jama.2016.17844
3. American Diabetes Association. Standards of Medical Care in Diabetes-2018. Diabetes Care 2018;41:S1-S141.

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