Prominent adverse effects of α-glucosidase inhibitors 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 expo sure to carbohydrate induces the expression of α-glucosidase in the jejunum and ileum, increasing distal small intestine glucose absorption and minimizing the passage of carbohydrate into the colon. Although not a problem with monotherapy or combina tion therapy with a biguanide, hypoglycemia may occur with con current sulfonylurea treatment. Hypoglycemia should be treated with glucose (dextrose) and not sucrose, whose breakdown may be blocked. An increase in hepatic aminotransferases has been noted in clinical trials with acarbose, especially with dosages greater than 300 mg/d. The abnormalities resolve on stopping the drug.
These drugs are infrequently prescribed in the United States because of their prominent gastrointestinal adverse effects and relatively modest glucose-lowering benefit.
An oral glucose load provokes a higher insulin response compared with an equivalent dose of glucose given intravenously. This is because the oral glucose causes a release of gut hormones (“incretins”), principally GLP-1 and glucose-dependent insulinotropic peptide (GIP), that amplify the glucose-induced insulin secretion. When GLP-1 is infused in patients with type 2 diabetes, it stimulates insulin release and lowers glucose levels. The GLP-1 effect is glucose dependent in that the insulin release is more pronounced when glucose levels are elevated but less so when glucose levels are normal. For this reason, GLP-1 has a lower risk for hypoglycemia than the sulfonylureas. In addition to its insulin stimulatory effect, GLP-1 has a number of other biologic effects. It suppresses glucagon secretion, delays gastric emptying, and reduces apoptosis of human islets in culture. In animals, GLP-1 inhibits feeding by a central nervous system mechanism. Type 2 diabetes patients on GLP-1 therapy are less hungry. It is unclear whether this is mainly related to the deceleration of gastric emptying or whether there is a central nervous system effect as well.
GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4) and by other enzymes such as endopeptidase 24.11 and is also cleared by the kidney. The native peptide therefore cannot be used therapeutically. One approach to this problem has been to develop metabolically stable analogs or derivatives of GLP-1 that are not subject to the same enzymatic degradation or renal clearance. Four such GLP-1 receptor agonists, exenatide, liraglutide, albiglutide, and dulaglutide are available for clinical use. The other approach has been to develop inhibitors of DPP-4 and prolong the action of endogenously released GLP-1 and GIP. Four oral DPP-4 inhibitors, sitagliptin, saxagliptin, linagliptin, and alogliptin, are available in the United States. An additional inhibitor, vildagliptin, is available in Europe.
Exenatide, a derivative of the exendin-4 peptide in Gila monster venom, has a 53% homology with native GLP-1 and a glycine substitution to reduce degradation by DPP-4. Exenatide is approved as an injectable, adjunctive therapy in persons with type 2 diabetes treated with metformin or metformin plus sulfonylureas who still have suboptimal glycemic control.