-Glucosidase inhibitors

-Glucosidase inhibitors reduce intestinal absorption of starch, dextrin, and disaccharides by inhibiting the action of -glucosidase in the intestinal brush border. Inhibition of this enzyme slows the absorption of carbohydrates; the postprandial rise in plasma glucose is blunted in both normal and diabetic subjects.

 -Glucosidase inhibitors do not stimulate insulin release and therefore do not result in hypoglycemia. These agents may be considered as monotherapy in elderly patients or in patients with predominantly postprandial hyperglycemia. -Glucosidase inhibitors typically are used in combination with other oral antidiabetic agents and/or insulin. The drugs should be administered at the start of a meal. They are poorly absorbed.

 Acarbose (PRECOSE), an oligosaccharide of microbial origin, and miglitol (GLYSET), a desoxynojirimycin derivative, also competitively inhibit glucoamylase and sucrase but have weak effects on pancreatic a-amylase. They reduce postprandial plasma glucose levels in type 1 and type 2 DM subjects. -Glucosidase inhibitors can significantly improve hemoglobin A1c levels in severely hyperglycemic type 2 DM patients. However, in patients with mild-to-moderate hyperglycemia, the glucose-lowering potential of a-glucosidase inhibitors (assessed by hemoglobin A1c levels) is about 30% to 50% of that of other oral antidiabetic agents.

 a-Glucosidase inhibitors cause dose-related malabsorption, flatulence, diarrhea, and abdominal bloating. Titrating the dose of drug slowly (25 mg at the start of a meal for 4 to 8 weeks, followed by increases at 4- to 8-week intervals to a maximum of 75 mg before each meal) reduces gastrointestinal side effects. Smaller doses are given with snacks. Acarbose is most effective when given with a starchy, high-fiber diet with restricted amounts of glucose and sucrose. If hypoglycemia occurs when a-glucosidase inhibitors are used with insulin or an insulin secretagogue, glucose rather than sucrose, starch, or maltose should be administered.

 These agents block the enzyme responsible for the breakdown of complex carbohydrates in the gut and can effectively reduce the increase in blood glucose after a meal. Acarbose acts in this way and can be used alone or in combination with other oral hypoglycaemic agents. Its hypoglycaemic effect is relatively small and the severe flatulence which develops (to some extent avoidable by starting with small amounts) deters many patients from using it.

Mechanism and Effects

Acarbose and miglitol are carbohydrate analogs that act within the intestine to inhibit -glucosidase, an enzyme necessary for the conversion of complex starches, oligosaccharides, and disaccharides to the monosaccharides that can be transported out of the intestinal lumen and into the bloodstream. As a result of slowed absorption, postprandial hyperglycemia is reduced. These drugs lack an effect on fasting blood sugar. Both drugs can be used as monotherapy or in combination with other antidiabetic drugs. They are taken just before a meal. Like metformin and the thiazolidinediones, the -glucosidase inhibitors have been shown to prevent type 2 diabetes in prediabetic persons.

Toxicities

The primary adverse effects of the -glucosidase inhibitors include flatulence, diarrhea, and abdominal pain resulting from increased fermentation of unabsorbed carbohydrate by bacteria in the colon. Patients taking an -glucosidase inhibitor who experience hypoglycemia should be treated with oral glucose (dextrose) and not sucrose, because the absorption of sucrose will be delayed.

Alpha-Glucosidase Inhibitors

Acarbose and miglitol are competitive inhibitors of the intestinal -glucosidases and reduce post-meal glucose excursions by delaying the digestion and absorption of starch and disaccharides . Only monosaccharides, such as glucose and fructose, can be transported out of the intestinal lumen and into the bloodstream. Complex starches, oligosaccharides, and disaccharides 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 -amylase and glucosidases that are attached to the brush border of the intestinal cells. Miglitol differs structurally from acarbose and is six times more potent in inhibiting sucrase. Although the binding affinity of the two compounds differs, acarbose and miglitol both target the -glucosidases: sucrase, maltase, glucoamylase, and dextranase. Miglitol alone has effects on isomaltase and on -glucosidases, which split -linked sugars such as lactose. Acarbose alone has a small effect on -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 postmeal glycemic excursions as much as 4560 mg/dL and creating an insulin-sparing effect.

 Monotherapy with these drugs is associated with a modest drop (0.51%) in glycohemoglobin levels and a 2025 mg/dL fall in fasting glucose levels. They are FDA-approved for persons with type 2 diabetes as monotherapy and in combination with sulfonylureas, in which the glycemic effect is additive. Both acarbose and miglitol are taken in doses of 25100 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 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 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 contraindicated 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 -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 cardiovascular 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.

Drug combinations

Sulphonylurea (or metaglitidine analogue) with metformin Sulphonylurea (or metaglinide analogue) with thiazolidinedione (if metformin is contraindicated or not tolerated) Metformin with thiazolidinedione Nateglinide with metformin Metformin with insulin (for overweight patients) Acarbose can be used in association with any of the above

 A trial with acarbose was conducted in middle-aged men (STOPNIDDM) Interestingly, a secondary analysis of this trial suggested that those on active treatment to reduce or delay type 2 diabetes were also protected from cardiovascular events. The latter account for most of the reduced life expectancy of people with type 2 diabetes.

 Lifestyle changes, use of metformin, acarbose and orlistat are partially effective to prevent or slow the development of diabetes.

BENEFITS OF PHARMACOLOGICAL TREATMENT IN THE PRIMARY PREVENTION OF DIABETES AND IN SECONDARY PREVENTION OF CHRONIC VASCULAR COMPLICATIONS

In primary prevention, weight reduction may reduce the risk of developing diabetes in subjects with IGT, as shown by lifestyle interventions , and by use of drugs such as metformin, acarbose and orlistat

 The Study TO Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM), a double-blind, placebo-controlled, randomized trial, assessed the effects of acarbose in 1429 overweight and obese subjects with IGT. Acarbose was associated with a mean weight loss of1.15 kg compared with 0.26 kg weight gain in the placebo group at 3 years. Acarbose significantly reduced weight, waist circumference, body mass index (BMI), systolic and diastolic blood pressure, 2-h plasma glucose levels and triglycerides compared with placebo. Acarbose treatment was associated with a 36% reduction in the incidence of type 2 diabetes and a 49% relative risk reduction in the development of cardiovascular events

 Acarbose significantly reduced weight, waist circumference, BMI, systolic and diastolic blood pressure, 2-h plasma glucose levels and triglycerides compared with placebo. Acarbose treatment was associated with a 34% relative risk reduction in the incidence of hypertension, and a 49% relative risk reduction in the development of cardiovascular events

 A meta-analysis of seven long-term studies of acarbose in type 2 diabetes found that treatment with acarbose led to a small but significant weight loss (1.1 kg) compared with placebo, improvements in glycaemic control, triglyceride levels, and systolic blood pressure

 In addition, a 64% relative risk reduction for myocardial infarction was achieved with acarbose use . When one realizes that CVD is the leading cause of mortality among patients with type 2 diabetes, accounting for 4050% of all deaths, and that the mortality risk for cardio- and cerebrovascular disease is 2- to 10-fold higher than in the non-diabetic population, the above-mentioned findings are very important.

 Side-effects reported with the use of acarbose include flatulence, diarrhoea and abdominal pain. Acarbose is poorly absorbed into the bloodstream, and has a low systemic availability of less than 2%. As a result, the risk of any toxic reaction is very low.

 Acarbose is an L-glucosidase inhibitor, an antihyperglycaemic agent that reduces postprandial glucose excursions by delaying and reducing carbohydrate absorption. Acarbose binds with high affinity and specificity to Lglucosidases found in the brush border of the small intestine. These enzymes are responsible for the hydrolysis of complex carbohydrates (starch and oligosaccharides) to absorbable simple sugars (monosaccharides such as glucose). Acarbose may also increase GLP-1 levels

 Alpha-glucosidase inhibitors can be combined with metformin (and any other antidiabetic treatment option). In clinical studies, an additional HbA1c reduction of 0.650.8% was observed in patients receiving acarbose additional to ongoing metformin therapy. The results of the acarbose arm of the UKPDS showed that the additional therapy with acarbose in previously drug-treated patients with type 2 diabetes led to a 0.5% reduction in HbA1c in the group of patients receiving the drug over 3 years (39% of patients in the acarbose arm). The total acarbose cohort had an HbA1 reduction of 0.2% . A multicentre observational study carried out in Germany showed an efficacy of acarbose to lower HbA1c by 1.82.4% in an outpatient and general practice setting

 Acarbose specifically acts on post-meal hyperglycaemia, is weight-neutral and has lowered cardiovascular events in a prospective, randomized double-blind clinical trial in subjects with IGT. In type 2 diabetic patients, a meta-analysis also showed a reduction of cardiovascular events in patients treated with acarbose. Gastrointestinal side-effects and costs, however, are a barrier to broad use of this compound

 Mechanism and Efficacy The anti-hyperglycemic effect of acarbose results from inhibition of disaccharide cleavage in the small intestine, which delays carbohydrate absorption. This effect results in a decrease in postprandial hyperglycemia. A typical AC reduction with acarbose is 0.51%. It is important to note that the mechanism of acarbose is uniquely effective for patients who are eating and will not lower glucose levels in patients who are fasting. Its efficacy is also related to the amount of carbohydrate in the diet.

 Safety The most common adverse effects with acarbose are gastrointestinal: diarrhea, flatulence, and abdominal discomfort. These may decrease in severity over weeks of treatment. However, because of these actions, this drug is contraindicated in patients with chronic intestinal diseases. Also, there have been reports of patients with elevated transaminases while taking acarbose, and its use is not recommended in patients with cirrhosis. Acarbose does not cause hypoglycemia as mono-therapy. Because acarbose inhibits disaccharide cleavage, orally administered disaccharides such as sucrose can not be used to treat hypoglycemia when acarbose has been administered. Orally administered glucose tablets or glucose gel, as well as other non-oral methods of hypoglycemia treatment, should be effective.

 Inpatient Considerations As above, acarbose is uniquely effective in patients who are eating regular meals with significant portions of carbohydrate. For this reason, it is infrequently used in the inpatient setting, given the propensity for missed meals.