Diabetes: Alpha-glucosidase Inhibitors

CLINICAL PHARMACOLOGY
Acarbose is a complex oligosaccharide that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. As a consequence of plasma glucose reduction, acarbose reduces levels of glycosylated hemoglobin in patients with type 2 diabetes mellitus. Systemic non-enzymatic protein glycosylation, as reflected by levels of glycosylated hemoglobin, is a function of average blood glucose concentration over time.

Mechanism of Action: In contrast to sulfonylureas, acarbose does not enhance insulin secretion. The antihyperglycemic action of acarbose results from a competitive, reversible inhibition of pancreatic alpha-amylase and membrane-bound intestinal alpha-glucoside hydrolase enzymes. Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine, while the membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In diabetic patients, this enzyme inhibition results in a delayed glucose absorption and a lowering of postprandial hyperglycemia.

Because its mechanism of action is different, the effect of acarbose to enhance glycemic control is additive to that of sulfonylureas, insulin or metformin when used in combination. In addition, acarbose diminishes the insulinotropic and weight-increasing effects of sulfonylureas.

Acarbose has no inhibitory activity against lactase and consequently would not be expected to induce lactose intolerance.

INDICATIONS AND USAGE
Acarbose tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

CONTRAINDICATIONS
Acarbose is contraindicated in patients with known hypersensitivity to the drug and in patients with diabetic ketoacidosis or cirrhosis. acarbose is also contraindicated in patients with inflammatory bowel disease, colonic ulceration, partial intestinal obstruction or in patients predisposed to intestinal obstruction. In addition, acarbose is contraindicated in patients who have chronic intestinal diseases associated with marked disorders of digestion or absorption and in patients who have conditions that may deteriorate as a result of increased gas formation in the intestine.

Dosing:
Oral: - Adults: Dosage must be individualized on the basis of effectiveness and tolerance while not exceeding the maximum recommended dose

Initial dose: 25 mg 3 times/day with the first bite of each main meal.

Maintenance dose: Should be adjusted at 4- to 8-week intervals based on 1-hour postprandial glucose levels and tolerance. Dosage may be increased from 25 mg 3 times/day to 50 mg 3 times/day. Some patients may benefit from increasing the dose to 100 mg 3 times/day.

Maintenance dose ranges: 50-100 mg 3 times/day.

Maximum dose:

≤ 60 kg: 50 mg 3 times/day
>60 kg: 100 mg 3 times/day

Patients receiving sulfonylureas: Acarbose given in combination with a sulfonylurea will cause a further lowering of blood glucose and may increase the hypoglycemic potential of the sulfonylurea. If hypoglycemia occurs, appropriate adjustments in the dosage of these agents should be made.

Dosing adjustment in renal impairment:
Clcr <25 mL/minute: Plasma concentrations of acarbose in renally impaired volunteers were proportionally increased relative to the degree of renal dysfunction. Long-term clinical trials in diabetic patients with significant renal dysfunction (serum creatinine > 2 mg/dL) have not been conducted. Therefore, treatment of these patients with acarbose is not recommended.

Supplied
Tablet: 25 mg, 50 mg, 100 mg

Miglitol (glycet ®)

CLINICAL PHARMACOLOGY
Miglitol is a desoxynojirimycin derivative that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. As a consequence of plasma glucose reduction, GLYSET Tablets reduce levels of glycosylated hemoglobin in patients with Type II (non-insulin-dependent) diabetes mellitus. Systemic nonenzymatic protein glycosylation, as reflected by levels of glycosylated hemoglobin, is a function of average blood glucose concentration over time.

Mechanism of Action
In contrast to sulfonylureas, GLYSET does not enhance insulin secretion. The antihyperglycemic action of miglitol results from a reversible inhibition of membrane-bound intestinal α-glucoside hydrolase enzymes. Membrane-bound intestinal α-glucosidases hydrolyze oligosaccharides and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In diabetic patients, this enzyme inhibition results in delayed glucose absorption and lowering of postprandial hyperglycemia.

Because its mechanism of action is different, the effect of GLYSET to enhance glycemic control is additive to that of sulfonylureas when used in combination. In addition, GLYSET diminishes the insulinotropic and weight-increasing effects of sulfonylureas.

Miglitol has minor inhibitory activity against lactase and consequently, at the recommended doses, would not be expected to induce lactose intolerance.

INDICATIONS AND USAGE
GLYSET Tablets, as monotherapy, are indicated as an adjunct to diet to improve glycemic control in patients with non-insulin-dependent diabetes mellitus (NIDDM) whose hyperglycemia cannot be managed with diet alone. GLYSET may also be used in combination with a sulfonylurea when diet plus either GLYSET or a sulfonylurea alone do not result in adequate glycemic control. The effect of GLYSET to enhance glycemic control is additive to that of sulfonylureas when used in combination, presumably because its mechanism of action is different.

In initiating treatment for NIDDM, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling blood glucose and symptoms of hyperglycemia. The importance of regular physical activity when appropriate should also be stressed. If this treatment program fails to result in adequate glycemic control, the use of GLYSET should be considered. The use of GLYSET must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint.

CONTRAINDICATIONS
GLYSET Tablets are contraindicated in patients with:

-Diabetic ketoacidosis
-Inflammatory bowel disease, colonic ulceration, or partial intestinal obstruction, and in patients predisposed to intestinal obstruction
-Chronic intestinal diseases associated with marked disorders of digestion or absorption, or with conditions that may deteriorate as a result of increased gas formation in the intestine
-Hypersensitivity to the drug or any of its components.

Dosing
Adults: Oral: 25 mg 3 times/day with the first bite of food at each meal; the dose may be increased to 50 mg 3 times/day after 4-8 weeks; maximum recommended dose: 100 mg 3 times/day

Dosing adjustment in renal impairment :
Clcr<25 mL/minute: Plasma concentrations of GLYSET in renally impaired volunteers were proportionally increased relative to the degree of renal dysfunction. Long-term clinical trials in diabetic patients with significant renal dysfunction (serum creatinine >2.0 mg/dL) have not been conducted. Therefore, treatment of these patients with GLYSET is not recommended.

Supplied
Tablet: 25 mg, 50 mg, 100 mg

Background

Alpha-glucosidase inhibitors are oral anti-diabetic drugs used for diabetes mellitus type 2 that work by preventing the digestion of carbohydrates (such as starch and table sugar). Carbohydrates are normally converted into simple sugars (monosaccharides), which can be absorbed through the intestine. Hence, alpha-glucosidase inhibitors reduce the impact of carbohydrates on blood sugar.

Examples of alpha-glucosidase inhibitors include:
1. Acarbose- Precose
2. Miglitol - Glyset

Even though the drugs have a similar mechanism of action, there are subtle differences between acarbose and miglitol. Acarbose is an oligosaccharide, whereas miglitol resembles a monosaccharide. Miglitol is fairly well absorbed by the body, as opposed to acarbose. Moreover, acarbose inhibits pancreatic alpha-amylase in addition to alpha-glucosidase.

Role in clinical use [source]
Alpha-glucosidase inhibitors are used to establish greater glycemic control over hyperglycemia in diabetes mellitus type 2, particularly with regard to postprandial hyperglycemia. They may be used as monotherapy in conjunction with an appropriate diabetic diet and exercise, or they may be used in conjunction with other anti-diabetic drugs.

Alpha-glucosidase inhibitors may also be useful in patients with diabetes mellitus type 1; however, this use has not been officially approved by the Food and Drug Administration.

These medications are rarely used in the United States because of the severity of their side effects (flatulence and bloating). They are more commonly prescribed in Europe. They do have the potential to cause weight loss by lowering the amount of sugar metabolized.

Mechanism of action
Alpha-glucosidase inhibitors are saccharides that act as competitive inhibitors of enzymes needed to digest carbohydrates: specifically alpha-glucosidase enzymes in the brush border of the small intestines. The membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the small intestine.

Acarbose also blocks pancreatic alpha-amylase in addition to inhibiting membrane-bound alpha-glucosidases. Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine.

Inhibition of these enzyme systems reduces the rate of digestion of carbohydrates. Less glucose is absorbed because the carbohydrates are not broken down into glucose molecules. In diabetic patients, the short-term effect of these drugs therapies is to decrease current blood glucose levels: the long term effect is a small reduction in hemoglobin A1c level. [source]

Reference(s)

National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
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