In the absence of contraindications, metformin is considered the first choice for oral treatment of type 2 diabetes. A 2006 consensus statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), updated in 2009, proposed that metformin therapy (in the absence of contraindications) be initiated, concurrent with lifestyle intervention, at the time of diabetes diagnosis.
MECHANISM OF ACTION
- Metformin is effective only in the presence of insulin, and its major effect is to decrease hepatic glucose output.
- In addition, metformin increases insulin-mediated glucose utilization in peripheral tissues (such as muscle and liver), particularly after meals, and has an antilipolytic effect that lowers serum free fatty acid concentrations, thereby reducing substrate availability for gluconeogenesis.
- As a result of the improvement in glycemic control, serum insulin concentrations decline slightly.
EFFICACY
Monotherapy
Monotherapy
- Metformin typically lowers fasting blood glucose concentrations by approximately 20 percent and A1C by 1.5 percent, a response similar to that achieved with a sulfonylurea.
- In those who are obese, metformin promotes modest weight reduction or at least weight stabilization. This is in contrast to the weight gain often associated with insulin or sulfonylurea treatment.
- Metformin is less likely to cause hypoglycemia than sulfonylureas and insulin.
- It has lipid-lowering activity, resulting in a decrease in serum triglyceride and free fatty acid concentrations, a small decrease in serum low-density-lipoprotein (LDL) cholesterol concentrations, and a very modest increase in serum high-density-lipoprotein (HDL) cholesterol concentrations.
Combination therapy
- Combinations of drugs are often necessary to achieve optimal glycemic control.
- Metformin can be given in combination with sulfonylureas, insulin, glinides, alpha-glucosidase inhibitors, thiazolidinediones, exenatide, and DPP-IV inhibitors.
SIDE EFFECTS
- The most common side effects of metformin are gastrointestinal, including: metallic taste in the mouth, mild anorexia, nausea, abdominal discomfort, and soft bowel movements or diarrhea.
- These symptoms are usually mild, transient, and reversible after dose reduction or discontinuation of the drug.
- The dose and duration of use of metformin correlates with the risk of vitamin B12 deficiency due to reduce absorption in the ileum.
PHARMACOLOGY
- Onset of action: Within days; maximum effects up to 2 weeks.
- Distribution: Vd: 654 ± 358 L; partitions into erythrocytes.
- Protein binding: Negligible.
- Metabolism: Not metabolized by the liver.
- Bioavailability: Absolute: Fasting: 50% to 60%.
- Half-life elimination: Plasma: 4-9 hours.
- Time to peak, serum:
- Immediate release: 2-3 hours;
- Extended release: 7 hours (range: 4-8 hours).
- Excretion: Urine (90% as unchanged drug; active secretion) .
DOSAGE FORMS
- Metformin is available as 500, 850, or 1000 mg tablets, and should be taken with meals.
- Extended release tablets are also available.
- Combination tablets of metformin and sulfonylureas, thiazolidinediones, or DPP-IV inhibitors are also available.
DOSING
- Begin with 500 mg once daily with the evening meal and, if tolerated, add a second 500 mg dose with breakfast.
- The dose can be increased slowly (one tablet every one to two weeks) as necessary.
- The usual effective dose is 1500 to 2000 mg/day per day.
- The maximum dose of 2550 mg/day (850 mg TID) provides only marginally better glycemic control and is often not tolerated due to GI side effects.
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