Increased resistance to insulin

Alpha glucosidase inhibitors as treatment options for diabetes mellitus type 2

Diabetes mellitus is generally known as type 2 diabetes and is characterized by an increased resistance to insulin. Type 2 diabetes is a multisystem disorder that requires multidisciplinary care, including education and ongoing counseling for effective patient self-management of the disease. This leads to a chronic state of hyperglycaemia in the affected patient, which should be treated as a serious problem, or else it can lead to various complications in the long term, such as cardiovascular diseases, nephropathy, etc.

The treatments of choice for diabetes type 2 are oral anti hyper-glycaemics, which can be of 5 classes. The reason why oral anti hyper-glycaemics are preferred are that these drugs affect the GIT absorption of glucose...Therefore they have better therapeutic effects, more rapid absorption and elimination from the body as compared to intravenous hypoglycaemics. Also, these drugs influence the GIT hormones, and this is best done when they themselves pass through the GIT. The newer oral drugs even have better bioavailability...e.g. Vildagliptin *(1,2). Another reason why use of oral therapeutic agents is much preferred as compared to IV drugs is that diabetes is a very widespread disease nowadays and long term regular use of oral drugs are easier and more cost-effective.

One of the classes of anti-hyperglycaemics used in the treatment of diabetes mellitus type 2, and even prediabetes is the alpha glucosidase inhibitors, e.g. ACARBOSE (Precose), MITLIGOL (Glyset) *(3), and Voglibose. These drugs are basically saccharides which act as competitive, reversible inhibitors of various enzymes which function in the digestion of complex sugars into glucose after ingestion of a meal.

There are certain enzymes, such as the membrane-bound alpha glucosidases which is present on the brush border of the cells of the small intestine, which breaks down oligosaccharides, disaccharides and trisaccharides into monosaccharides, especially glucose along with other sugars. The drugs in consideration inhibit those glucosidases, thereby preventing formation of excess glucose from the absorbed complex sugars, and thereby reducing the post-prandial spikes in blood glucose levels. They do not however affect either the production of insulin by the beta-cells of the pancreas, nor do they affect the action of insulin on the cells of the body...as a result, they do not induce hypoglycaemia in the individual when used as a monotherapy.

Apart from acting on alpha glucosidases, they even act on pancreatic alpha amylases, which physiologically hydrolyze complex starch to oligosaccharides within the intestinal lumen. Those are then hydrolyzed to glucose and other simpler sugars by the alpha glucosidases. The drugs in question also inhibit iarrhe, an enzyme which breaks down sucrose into glucose.

By inhibiting all the above mentioned enzymes, the drug helps in reducing the huge spike in blood glucose levels after a meal. These drugs should be taken at the start of meals, so that they can have an immediate effect on the bllod glucose levels, and keep them in control by inhibiting the enzymes and reducing the rate of digestion of complex sugars in the body.

Their dosage should be adjusted according to the meal times, e.g. if a meal is skipped, then they should be skipped too, etc. they are best suited for people who do not have blood glucose levels very high above the baseline levels, who have very high post-meal spikes in blood glucose levels and who have irregular meal schedules. However long term vascular benefits are not shown with their use, only with the use of sulfonylureas and metformin.*(4)

The major side effects of a-glucosidase inhibitors are GIT disturbances, such as flatulence, iarrhea, and abdominal cramping, which are thought to be due to the excessive unabsorbed fats present in the gastro-intestinal tract. These are however dose related and tolerance develops over time, so the initial dose should be small, and should then be suitably increased to treat the condition at hand. Patients with inflammatory bowel disease, intestinal obstruction, or colonic ulceration should not use these drugs, as they could aggravate the existing condition. Also, patients should not use metformin (a biguanide) and alpha glucosidases inhibitors concurrently, as these drugs decrease the bioavailability of metformin.

*Neither Glyset nor Precose are currently available in generic formulations *(5)

**Among the AGIs, acarbose has also been shown to decrease the risk of progressing to diabetes in subjects with impaired glucose tolerance (IGT). Studies have also suggested that acarbose could decrease the risk of cardiovascular disease, both in IGT and in diabetes. Furthermore, AGIs are very safe and are nontoxic drugs.(6)

***ACARBOSE has been shownto affect heart function positively *(6,7)

REFERENCES :

1. The Absolute Oral Bioavailability and Population-Based Pharmacokinetic Modelling of a Novel Dipeptidylpeptidase-IV Inhibitor, Vildagliptin, in Healthy Volunteers. Clinical Pharmacokinetics. 46(9):787-802, 2007. He, Yan-Ling 1; Sadler, Brian M 2; Sabo, Ron 3; Balez, Sebastien 4; Wang, Yibin 3; Campestrini, Joelle 4; Laurent, Aziz 5; Ligueros-Saylan, Monica 3; Howard, Dan 3
2. Clinical Pharmacokinetics of Nateglinide: A Rapidly-Absorbed, Short-Acting Insulinotropic Agent Clinical Pharmacokinetics. 43(2):97-120, 2004. McLeod, James F
3. Generic name...(brand name) www.drugdigest.org/DD/Comparison/NewComparison Long-term vascular risk reduction has been demonstrated only with sulfonylureas and metformin
4. Curr Diab Rep. 2007 Oct;7(5):333-9 Godbout A, Chiasson JL. Division of Endocrinology-Nutrition and Metabolism, Centre hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
5. Chiasson JL, Josse RG, Gomis R, et al. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance (The STOP-NIDDM Trial). JAMA. 2003;290(4):486-494.
6. Hanefeld M, Cagatay M, Petrowitsch T, Neuser D, Petzinna D, Rupp M. Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: meta-analysis of seven long-term studies. Eur Heart J. 2004;25(1):10-16.
7. Hanefeld M, Schaper F. Acarbose: oral anti-diabetes drug with additional cardiovascular benefits. Expert Rev Cardiovasc Ther. 2008 Feb;6(2):153-63. Review.