Drugs that affect absorption of glucose − Rakyat Biologi

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 HbA_1c 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 HbA_1c 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.

4. Drug combinations

A glyburide and metformin combination (Glucovance) is available in dose forms of 1.25 mg/250 mg, 2.5 mg/500 mg, and 5 mg/500 mg. A rosiglitazone and metformin combination (Avandamet) is available in dose forms of 1 mg/500 mg, 2 mg/500 mg, and 4 mg/500 mg. These drug combinations, however, limit the clinician's ability to optimally adjust dosage of the individual drugs and for that reason are of questionable usefulness.

5. Safety of the oral hypoglycemic agents

The UKPDS has put to rest previous concerns regarding the safety of sulfonylureas. It did not confirm any cardiovascular hazard among over 1500 patients treated intensively with sulfonylureas for over 10 years, compared with a comparable number who received either insulin or diet therapy. Analysis of a subgroup of obese patients receiving metformin also showed no hazard and even a slight reduction in cardiovascular deaths compared with conventional therapy.

The currently available thiazolidinediones have not to date exhibited the idiosyncratic hepatotoxicity seen with troglitazone. However, these drugs can precipitate congestive heart failure and should not be used in patients with New York Heart Association class III and IV cardiac status. Lactic acidosis from metformin (see above) is quite rare and probably not a major problem with its use in the absence of major risk factors such as impaired renal or hepatic disease or conditions predisposing to hypoxia.

C. Incretins

Oral glucose provokes a threefold to fourfold higher insulin response than an equivalent dose of glucose given intravenously because the oral glucose causes a release of gut hormones, principally glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP1), which amplify the glucose-induced insulin release. This "incretin effect" has been reported to be impaired in patients with type 2 diabetes. GLP-1, when infused in patients with type 2 diabetes, stimulates insulin secretion and lowers glucose levels. GLP-1, however, is rapidly proteolysed by dipeptidyl peptidase-IV (DPP IV) and is not a practical therapeutic agent. Exenatide is a GLP-1 analog that is more resistant to DPP IV action, and it lowers blood glucose and HbA_1c levels when given subcutaneously twice a day to patients with type 2 diabetes. Oral DPP IV inhibitors, which work by prolonging the action of endogenously released GLP-1, are also in clinical trials for use in type 2 diabetes.

D. Insulin

Insulin is indicated for type 1 diabetes as well as for type 2 diabetic patients with insulinopenia whose hyperglycemia does not respond to diet therapy either alone or combined with oral hypoglycemic drugs.

With the development of highly purified human insulin preparations, immunogenicity has been markedly reduced, thereby decreasing the incidence of therapeutic complications such as insulin allergy, immune insulin resistance, and localized lipoatrophy at the injection site. However, the problem of achieving optimal insulin delivery remains unsolved with the present state of technology. It has not been possible to reproduce the physiologic patterns of intraportal insulin secretion with subcutaneous injections of soluble or longer-acting insulin suspensions. Even so, with the help of appropriate modifications of diet and exercise and careful monitoring of capillary blood glucose levels at home, it has often been possible to achieve acceptable control of blood glucose by using various mixtures of short- and longer-acting insulins injected at least twice daily or portable insulin infusion pumps.