Pharmacology Update
Miglitol Tablets (Glyset-Pharmacia Upjohn)
By William T. Elliott, MD, FACP and James Chan, PharmD, PhD
Pharmacia upjohn recently began marketing the second alpha-glycosidase inhibitor, miglitol (Glyset), joining acarbose in this class. These drugs are not hypoglycemic agents; rather, they inhibit carbohydrate digestion in the brush border of the gut, delaying the absorption of glucose that attenuates postprandial hyperglycemia.1,2 Miglitol and acarbose were both developed by Bayer. Miglitol was approved by the FDA in 1996 and subsequently licensed to Pharmacia Upjohn.
Indications
Miglitol is indicated as monotherapy as adjunct to diet to improve glycemic control in patients with type 2 diabetes whose hyperglycemia is not adequately managed with diet alone. It is also indicated in combination with a sulfonylurea when diet plus a sulfonylurea or sulfonylurea alone does provide adequate glycemic control.
Dosage
The recommended starting dose is 25 mg three times daily with the first bite of each meal. Due to gastrointestinal side effects, some patients may start with 25 mg once daily and gradually increase to three times daily. The suggested titration regimen is 25 mg at the start of dinner for two weeks, 25 mg at breakfast and dinner for two weeks, then 25 mg three times a day at each meal. Patients should remain on 25 mg three times a day for 4-8 weeks. The dose should then be increased to 50 mg three times a day for about three months. Hemoglobin A1c should be measured periodically to assess the effectiveness of the drug. If the response is inadequate, a dose of 100 mg three times a day may be considered. If no improvement in glycosylated hemoglobin is observed, a reduction in the dose should be considered. The usual maintenance dose is 50 mg three times a day.1
Should a patient experience hypoglycemia (e.g., when miglitol is used with a sulfonylurea), glucose, not sucrose (table sugar), should be used to correct this condition since miglitol will inhibit the breakdown and absorption of sucrose.
Miglitol is supplied as 25 mg, 50 mg, and 100 mg tablets.
Potential Advantages
Similar to acarbose, miglitol does not cause hypoglycemia, hyperinsulinemia, or weight gain. When used with sulfonylureas, alpha-glycosidase inhibitors enhance glycemic control as well as attenuate sulfonylurea-associated weight gain and postprandial serum insulin concentrations.2 An unpublished 24-week study provided by the manufacturer suggests that miglitol is more potent than acarbose on a mg basis. Miglitol at 50 mg three times daily produces similar reduction in glycosylated hemoglobin as 100 mg three times daily of acarbose. An even greater reduction was achieved with miglitol 100 mg three times a day.1
Potential Disadvantages
Gastrointestinal side effects are common with alpha-glycosidase inhibitors. In U.S.-based placebo-controlled trials, the incidence of GI side effects compared to placebo were: flatulence (41.5% vs 12%), diarrhea (28.7% vs 10%), and abdominal pain (11.7% vs 4.7%). Flatulence is primarily caused by the gas production resulting from the metabolism of unabsorbed carbohydrates by the intestinal microflora. In these trials, the incidence of discontinuation due to adverse events was 12% compared to 7% for placebo. Low serum iron was reported in 4.3% of the patients treated with miglitol compared to 2.4% for placebo.2 In contrast to acarbose, miglitol is a smaller molecule (molecular weight of 207 vs 646) and shows dose-dependent systemic absorption. A 25 mg dose is completely absorbed while a 100 mg dose is 50-70% absorbed.2 The significance of this systemic absorption is not known. However, since miglitol is excreted primarily by the kidneys, its use in patients with renal impairment is not recommended. Miglitol is less effective than sulfonylureas in reducing glycosylated hemoglobulin. Reduction in glycosylated hemoglobulin is generally 25-50% less than that achieved with a sulfonylurea.3,4 Miglitol is contraindicated in patients with inflammatory bowel disease, colonic ulceration, predisposition to intestinal obstruction, and chronic intestinal disease associated with digestion or absorption disorder.1
Comments
Alpha glucosidase inhibitors, such as acarbose and miglitol, inhibit membrane-bounded intestinal brush border alpha glucoside hydrolase enzymes. This action inhibits the breakdown of dietary polysaccarides to absorbable monosaccarides resulting in a blunting of postprandial glucose excursion. Several placebo-controlled trials have demonstrated that miglitol significantly reduces glycosylated hemoglobin and one-hour postprandial glucose levels compared to placebo.1 The placebo-subtracted reduction of HbA1c ranged from 0.26% to 0.81% with doses of 25 mg to 100 mg three times a day with a study duration of three months to one year. One-hour, placebo-subtracted, postprandial glucose levels were reduced by 28 to 87 mg/dL. Compared to a sulfonyurea, miglitol was about 25-50% less effective in terms of reduction in HbA1c.3,4 The addition of miglitol to a sulfonylurea resulted in additional reduction of HbA1c by 0.30 to 0.82%.2 Two recently published one-year studies reported that miglitol was efficacious in Hispanics as well as African-Americans with type 2 diabetes.5,6 Gastrointestinal side effects and frequent dosing (with each meal) are potential limitations for adherence with dosing regimens. Efficacy has also been reported in the elderly and also in type 2 patients treated with insulin.4,7 The potential advantages of alpha glucosidase inhibitors are lack of hypoglycemia, hyperinsulinemia, and lack of weight gain. Unpublished data suggest that miglitol may be more potent than acarbose. The clinical relevance of significant systemic absorption of miglitol is not known.
The daily wholesale cost ranges from $1.50 to $2 per day and is similar to that of acarbose.
Clinical Implications
Miglitol provides another option for the management of diabetes mellitus. These drugs may be considered for monotherapy in newly diagnosed mild type 2 diabetics and as adjunctive therapy with oral agents or insulin in type 2 patients, especially where weight gain or hyperinsulinemia are problematic.
References
1. Glyset Product Information. Pharmacia Upjohn. October 1998.
2. Mooradian AD, et al. Drugs 1999;57(1):19-29.
3. Segal P, et al. Diabetes Care 1997;20:687-691.
4. Johnston PS, et al. J Clin Endocrinol Metab 1998:83(5):1515-1522.
5. Johnston PS, et al. Diabetes Care 1998;21(3):409-415.
6. Johnston PS, et al. Diabetes Care 1998;21(3):416-422.
7. Mitrakou A, et al. Diabet Med 1998;15(8):657-660.
Which is not true about miglitol?
a. It does not cause hypoglycemia when used as monotherapy.
b. If used in combination therapy, sucrose should not be used to treat hypoglycemia.
c. It does not need to be titrated.
d. It may attenuate sulfonylurea associated weight gain.
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