Metformin Therapy: Versatility in Action
Metformin (generic) or Glucophage (brand) has become a very popular therapeutic agent in multiple medical conditions. According to David McCulloch (UpToDate 19.3- January, 2012) two classes of oral hypoglycemic medications directly improve insulin action: biguanides (metformin) and thiazolodinediones. Metformin is widely considered to be the first choice for oral therapy of type 2 diabetes based on the 2006 (and updated in 2009) consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Metformin is the only oral hypoglycemic medication that is generally approved for use in children with type 2 diabetes. It also is used as adjunctive medication in type 1 diabetes for other pathological states in pediatrics (to be described shortly).
How does Metformin work?
Metformin is only effective in the presence of insulin and its primary action is to decrease the amount of glucose produced by the liver. Metformin also increases insulin-mediated glucose utilization in muscle and liver (peripheral tissues) especially after meals (increased insulin sensitivity). It decreases serum free fatty acid concentrations, which has the effect of reducing some of the building blocks for gluconeogenesis (production of glucose). Metformin increases glucose utilization when it is metabolized anaerobically (without oxygen) in experimental animals. The lactate that results is then used by the liver to produce more glucose (via gluconeogenesis) that, in theory, could protect against hypoglycemia.
In addition, the molecular mechanisms of metformin action are hypothesized to work with a protein that is a tumor suppressor and may play a role in inhibiting cell growth. There have been multiple reports in the oncology literature suggesting that in people with type 2 diabetes, metformin therapy has been associated with a reduced risk of cancer and lower cancer morbidity. A current online paper (American Journal of Gastroenterology, January 31, 2012) found that "significantly fewer women with a new diagnosis of pancreatic cancer had been taking metformin for at least a few years, compared to cancer-free women."
What is the relationship between Metformin and Pediatric Conditions?
1. Type 2 diabetes: We are experiencing an increase in the diagnosis of type 2 diabetes in children (even as young as 7 years of age) and adolescents. It is approved for use for children older than 10 years. The major side effect that may cause discontinuation in children (and adults) is gastrointestinal discomfort and diarrhea. However, these side effects often resolve after several weeks of therapy. Lactic acidosis is a serious side effect in the geriatric population. As the Thiazolodinedione class of oral hypoglycemic medications has many more side effects, it is rarely used in children. Metformin is the oral drug of choice in the treatment of type 2 diabetes in children. Generally, we will begin Metformin in children with a new diagnosis of type 2 diabetes if blood sugars are not extremely elevated and there is lack of ketones. Children who are more ill and appear with higher blood sugars or are admitted with diabetic ketoacidosis (can occur in type 2 diabetes) will be started on insulin initially and eventually weaned to oral Metformin after the "glucose toxicity" is resolved. Sometimes, children and adolescents receive both insulin therapy and Metformin together for treatment of type 2 diabetes. Metformin comes in both liquid (Riomet) and tablet form and may be packaged in combination with other type 2 diabetes oral medications. A huge benefit in oral Metformin for children is the lack of hypoglycemia in response to administration as opposed to other classes of oral diabetes agents such as the Sulfonylureas.
2. Type 1 diabetes: Metformin is sometimes prescribed as an adjunct to insulin therapy to "decrease insulin resistance" and thus increase insulin sensitivity. As a result, we are often able to decrease the amount of exogenous insulin required by the child or adolescent with type 1 diabetes.
3. Polycystic Ovary Syndrome (PCOS): This condition is the most frequent endocrinologic problem in women of reproductive age. The features of this syndrome include:
a. Lack of ovulation, which results in irregular menstruation, ovulation-related infertility, and amenorrhea and polycystic ovaries
b. Excessive hormones that masculinize (androgens), which result in acne and hirsuitism as well as insulin resistance
c. Obesity, type 2 diabetes and high cholesterol levels
d. There is variability of symptoms in affected women
We use Metformin to decrease insulin resistance and if the person with PCOS has diabetes it works to lower blood sugars as well. Metformin often has another bonus feature in the treatment of PCOS; it may restart ovulation and result in fertility. Oral contraceptive use is prescribed in those with PCOS to help with fertility and may be used in conjunction with Metformin.