Alpha-Glucosidase Inhibitors

ALPHA-GLUCOSIDASE INHIBITORS

Acarbose and miglitol are competitive inhibitors of the intestinalα-glucosidases and reduce postmeal glucose excursions by delay-ing the digestion and absorption of starch and disaccharides (Table 41–9). Only monosaccharides, such as glucose and fruc-tose, can be transported out of the intestinal lumen and into the bloodstream. Complex starches, oligosaccharides, and disaccha-rides must be broken down into individual monosaccharides before being absorbed in the duodenum and upper jejunum. This digestion is facilitated by enteric enzymes, including pancreatic α-amylase and α-glucosidases that are attached to the brush bor-der of the intestinal cells. Miglitol differs structurally from acar-bose and is six times more potent in inhibiting sucrase. Although the binding affinity of the two compounds differs, acarbose and miglitol both target the α-glucosidases: sucrase, maltase, glu-coamylase, and dextranase. Miglitol alone has effects on isomaltase and on β-glucosidases, which split β-linked sugars such as lactose. Acarbose alone has a small effect on α-amylase. The consequence of enzyme inhibition is to minimize upper intestinal digestion and defer digestion (and thus absorption) of the ingested starch and disaccharides to the distal small intestine, thereby lowering post-meal glycemic excursions as much as 45–60 mg/dL and creating an insulin-sparing effect.

Monotherapy with these drugs is associated with a modest drop (0.5–1%) in glycohemoglobin levels and a 20–25 mg/dL fall in fasting glucose levels. They are FDA-approved for persons with type 2 diabetes as monotherapy and in combination with sulfo-nylureas, in which the glycemic effect is additive. Both acarbose and miglitol are taken in doses of 25–100 mg just before ingesting the first portion of each meal; therapy should be initiated with the lowest dose and slowly titrated upward, and a similar amount of starch and disaccharides should be ingested at each meal.

Prominent adverse effects include flatulence, diarrhea, and abdominal pain and result from the appearance of undigested carbohydrate in the colon that is then fermented into short-chain fatty acids, releasing gas. These adverse effects tend to diminish with ongoing use because chronic exposure to carbohydrate induces the expression of α-glucosidase in the jejunum and ileum, increas-ing distal small intestine glucose absorption and minimizing the passage of carbohydrate into the colon. Although not a problem with monotherapy or combination therapy with a biguanide, hypoglycemia may occur with concurrent sulfonylurea treatment. Hypoglycemia should be treated with glucose (dextrose) and not sucrose, whose breakdown may be blocked. These drugs are con-traindicated in patients with inflammatory bowel disease or any intestinal condition that could be worsened by gas and distention. Because both miglitol and acarbose are excreted by the kidneys, these medications should not be prescribed in individuals with renal impairment. Acarbose has been associated with reversible hepatic enzyme elevation and should be used with caution in the presence of hepatic disease.

The STOP-NIDDM trial demonstrated that α-glucosidase therapy in prediabetic persons successfully prevented a significant number of new cases of type 2 diabetes and helped restore beta-cell function, in addition to reducing cardiovascular disease and hypertension. Intervention with acarbose also reduced cardiovas-cular events in persons with diabetes. Diabetes and cardiovascular disease prevention may become a further indication for this class of medications.

Alpha-glucosidase inhibitors are infrequently prescribed in the United States because of their prominent gastrointestinal adverse effects and relatively minor glucose-lowering benefit.