During DPP and DPPOS, the pharmacological intervention is metformin 850 mg bid, as tolerated. DPP participants who had been randomized to active metformin and are still eligible to take medication will remain in the medication arm of the follow up study. This will allow the longest possible period of continued exposure to metformin to determine its longer-term effects. Metformin is an investigational drug for the treatment of IGT and is used under an Investigational New Drug (IND 49,782) application with the Food and Drug Administration (FDA).
Metformin is an antihyperglycemic drug of the biguanide class used in the management of Type 2 diabetes in over 90 countries for over 30 years. It was approved for use in the U.S. in 1995 and is distributed by Bristol Myers-Squibb under the trade name Glucophage, and manufactured by Lipha, a French pharmaceutical firm. Generic products are now available as well.
Effects and Side Effects
Metformin reduces the excess hepatic glucose production that characterizes Type 2 diabetes without increasing insulin secretion. With reduced hyperglycemia, glucose uptake by muscle and other insulin sensitive tissues is enhanced while insulin levels remain stable or decline. In addition to its antihyperglycemic action, metformin also has antihyperlipidemic effects; particularly the lowering of serum triglyceride levels and is associated with weight loss. Metformin has been found to cause lactic acidosis rarely (about 0.03 cases per 1,000 person years) and then only when used in persons with renal or hepatic insufficiency or during episodes of hypoxia or circulatory failure.
Before its 1995 release in the U.S., and after review of extensive metformin use in Canada, Europe and other parts of the world, Bristol-Myers Squibb issued an FDA approved package insert providing detailed contraindications, precautions and safety monitoring recommendations for its use in Ty2DM. During the DPP all of these recommendations (including periodic assessment of serum creatinine) were strictly adhered to and the maximum dosage used (1.7 gm/day) was less than the maximum recommended (2.55 gm/day).
Metformin As Prevention
Metformin is not currently approved for use as a preventive medication for the development of Ty2DM. However, the DPP demonstrated that metformin is effective in persons with impaired glucose tolerance, reducing the development of diabetes by 31%. The most common side effects associated with metformin are gastrointestinal. As many as 30% of persons report diarrhea, nausea, metallic taste, abdominal bloating, flatulence or anorexia. These symptoms are generally transient, resolve spontaneously and can be avoided by gradual escalation of dosage. Metformin is not associated with hypoglycemia unless used in conjunction with other glucose-lowering medications (sulfonylurea or insulin). About 4% of participants were unable to continue metformin in U.S. clinical trials. About 6-9% of persons on metformin develop reduced vitamin B12 levels. However, megaloblastic anemia is rare and metformin use has not been reported to cause peripheral neuropathy.
DPP Dosing Schedule
Administration of metformin will be 850 mg twice each day, taken with food, and with doses recommended to be at least eight hours apart.
Medication Adherence Interview, Form and Code Sheet