Diabetes Mellitus Treatment Regimens - Drugs for treating hyperglycemia

3. Drugs that affect absorption of glucose


α-Glucosidase inhibitors competitively inhibit the α-glucosidase enzymes in the gut that digest dietary starch and sucrose. Two of these drugs - acarbose and miglitol - are available for clinical use. Both are potent inhibitors of glucoamylase, α-amylase, and sucrase but have less effect on isomaltase and hardly any on trehalase and lactase. Acarbose binds 1000 times more avidly to the intestinal disaccharidases than do products of carbohydrate digestion or sucrose. A fundamental difference between acarbose and miglitol is in their absorption. Acarbose has the molecular mass and structural features of a tetrasaccharide, and very little (about 2%) crosses the microvillar membrane. Miglitol, however, has a structural similarity with glucose and is absorbable. Both drugs delay the absorption of carbohydrate and lower postprandial glycemic excursion.

a. Acarbose -  Acarbose is available as 50-mg and 100-mg tablets. The recommended starting dose of acarbose is 50 mg twice daily, gradually increasing to 100 mg three times daily. For maximal benefit on postprandial hyperglycemia, acarbose should be given with the first mouthful of food ingested. In diabetic patients, it reduces postprandial hyperglycemia by 30-50%, and its overall effect is to lower the HbA1c by 0.5-1%.

The principal adverse effect, seen in 20-30% of patients, is flatulence. This is caused by undigested carbohydrate reaching the lower bowel, where gases are produced by bacterial flora. In 3% of cases, troublesome diarrhea occurs. This gastrointestinal discomfort tends to discourage excessive carbohydrate consumption and promotes improved compliance of type 2 patients with their diet prescriptions. When acarbose is given alone, there is no risk of hypoglycemia. However, if combined with insulin or sulfonylureas, it might increase the risk of hypoglycemia from these agents. A slight rise in hepatic aminotransferases has been noted in clinical trials with acarbose (5% versus 2% in placebo controls, and particularly with doses > 300 mg/d). The levels generally return to normal on stopping the drug.

In the UKPDS, approximately 2000 patients on diet, sulfonylurea, metformin, or insulin therapy were randomized to acarbose or placebo therapy. By 3 years, 60% of the patients had discontinued the drug, mostly because of gastrointestinal symptoms. If one looked only at the 40% who remained on the drug, they had an 0.5% lower HbA1c compared with placebo.

b. Miglitol -  Miglitol is similar to acarbose in terms of its clinical effects. It is indicated for use in diet- or sulfonylurea-treated patients with type 2 diabetes. Therapy is initiated at the lowest effective dosage of 25 mg three times a day. The usual maintenance dose is 50 mg three times a day, although some patients may benefit from increasing the dose to 100 mg three times a day. Gastrointestinal side effects occur as with acarbose. The drug is not metabolized and is excreted unchanged by the kidney. Theoretically, absorbable α-glucosidase inhibitors could induce a deficiency of one or more of the α-glucosidases involved in cellular glycogen metabolism and biosynthesis of glycoproteins. This does not occur in practice because, unlike the intestinal mucosa, which sees a high concentration of the drug, the blood level is 200-fold to 1000-fold lower than the concentration needed to inhibit intracellular α-glucosidases. Miglitol should not be used in renal failure, when its clearance would be impaired.

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