Glyburide and Metformin Tablets (Glucovance)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The FDA recently approved a fixed combination of glyburide and metformin for the treatment of type 2 diabetes mellitus. The product, marketed under the trade name Glucovance, combines two of the most popular antidiabetic medications in one tablet. With metformin losing its patent next year, Bristol-Myers Squibb is hoping for success with this product and its recently approved long-acting form of metformin (Glucophage XL).
Indications
Glyburide/metformin is indicated as initial therapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes who are inadequately managed by diet and exercise.1
It is also indicated for second-line therapy when diet, exercise, and initial therapy with a sulfonylurea or metformin do not achieve adequate glycemic control.1
Dosage
Glucovance is available in three strengths: 1.25 mg/250 mg, 2.5 mg/500 mg, and 5 mg/500 mg of glyburide and metformin, respectively. As initial therapy, the recommended starting dose is 1.25 mg glyburide and 250 mg metformin once or twice daily with meals. Dosage may be increased in 1.25 mg/250 mg increments per day every two weeks up to a maximum of 10 mg/2000 mg per day. For second-line therapy, the recommended starting dose is 2.5 mg/250 mg or 5 mg/500 mg twice daily with meals.2
Potential Advantages
A fixed combination may improve medication adherence in those currently taking the drugs separately.
Potential Disadvantages
A fixed combination is less flexible than titration of the separate agents.
Comments
The combination of a sulfonylurea and metformin has been widely used and studied. These drugs have different mechanisms of action—one addresses insufficient insulin release while the other modulates insulin resistance.
A lower-dose combination may achieve comparable or better glycemic control than higher-dose monotherapy with potentially fewer side effects.1,2,4,5 Fewer episodes of hypoglycemia and weight gain than glyburide alone and a lower incidence of gastrointestinal side effects compared to metformin alone have been reported.2,5 In a large 20-week, double-blind placebo, U.S. multicenter trial (n = 806) reported by the manufacturer, the fixed-dose combination resulted in a reduction in HbA1c of 1.48-1.53% compared to 1.03% for metformin alone (P < 0.05) or 1.24% for glyburide alone (P < 0.05).1
Fasting blood sugar (FBS) was reduced 40.1-41.5 mg/dL compared to 35.7 mg/dL for glyburide and 21.2 mg/dL for metformin but was not statistically significantly different. These subjects were treatment naive with a mean baseline HbA1c of 8.14-8.23% and mean fasting plasma glucose of 175-179 mg/dL. Subjects were initiated on 2.5 mg of glyburide, 500 mg of metformin, and 1.25 mg/250 mg or 2.50 mg/500 mg of glyburide/metformin, and were titrated as needed to a maximum of four tablets daily. The mean final doses were 5.3 mg for glyburide, 1317 mg for metformin, 2.78 mg/557 mg and 4.1 mg/824 mg for the glyburide/metformin.
In a 16-week, double-blind, active-controlled, U.S. trial (n = 639), the combination of glyburide/metformin resulted in a reduction of HbA1c of 1.69-1.70% com- pared to glyburide (P < 0.001) and 1.90-1.91% com- pared to metformin (P < 0.001).
Fasting blood sugar was reduced 51.3 to 59.9 mg/dL compared to glyburide (P < 0.001) and 64.2-72.7 mg/dL compared to metformin (P < 0.001).1 These were subjects who were previously not adequately controlled on 10 mg of glyburide or 20 mg of glipizide. Mean baseline HbA1c ranged from 9.43-9.63% and fasting plasma glucose of 210-218 mg/dL. Subjects were initiated on 20 mg (fixed-dose) of glyburide, 500 mg of metformin, and 2.5 mg/500 mg or 5 mg/500 mg of glyburide/metformin.
Dose titration was allowed up to a maximum of four tablets daily for metformin and glyburide/metformin. The mean final doses were 20 mg (fixed dose) for glyburide, 1840 mg for metformin, 8.8 mg/1760 mg and 17 mg/1740 mg for glyburide/metformin. Glucovance is priced at $0.65/tablet for the 1.25 mg/250 mg strength tablet and $0.78 for the 2.5 mg/500 mg and 5 mg/500 mg strength tablets. These prices compare favorably to met- formin and glyburide prescribed separately and are not much different than metformin 500 mg alone—$0.69.
Clinical Implications
Most patients with type 2 diabetes have defects in insulin production as well as insulin resistance.2 Thus, combination therapy that addresses both of these problems seems logical. In addition, combination therapy gain additive benefits and may reduce side effects associated with higher doses of monotherapy. Proponents of early combination therapy at low dosages question the wisdom of titrating initial monotherapy to maximum dose before adding a second drug.2 Glucovance offers a fixed-dose combination alternative to initial monotherapy as well as second-line therapy if monotherapy has failed.
References
1. Glucovance Product Information. Bristol-Myers Squibb. July 2000.
2. Riddle M. Am J Med 2000;108:15S-22S.
3. Gregorio F, et al. Diabet Med 1999;16:1016-1024.
4. Erle G, et al. Acta Diabetol 1999;38:61-65.
5. Hermann LS, et al. Diabetes Care 1994;17:1100-1109.
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