Anti-diabetic drug
Anti-diabetic drugs treat diabetes mellitus by lowering glucose levels in the blood. With the exceptions of insulin, exenatide, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of anti-diabetic drugs, and their selection depends on the nature of the diabetes, age and situation of the person, as well as other factors.
Diabetes mellitus type 1 is a disease caused by the lack of insulin. Insulin must be used in Type I, which must be injected or inhaled.
Diabetes mellitus type 2 is a disease of insulin resistance by cells. Treatments include (1) agents which increase the amount of insulin secreted by the pancreas, (2) agents which increase the sensitivity of target organs to insulin, and (3) agents which decrease the rate at which glucose is absorbed from the gastrointestinal tract.
Several groups of drugs, mostly given by mouth, are effective in Type II, often in combination. The therapeutic combination in Type II may include insulin, not necessarily because oral agents have failed completely, but in search of a desired combination of effects. The great advantage of injected insulin in Type II is that a well-educated patient can adjust the dose, or even take additional doses, when blood glucose levels measured by the patient, usually with a simple meter, as needed by the measured amount of sugar in the blood.
| Diabetes mellitus
|
|---|
| Types of Diabetes |
| Diabetes mellitus type 1 Diabetes mellitus type 2 Gestational diabetes Pre-diabetes: |
| Disease Management |
| Diabetes management: •Diabetic diet •Anti-diabetic drugs •Conventional insulinotherapy •Intensive insulinotherapy |
| Other Concerns |
| Cardiovascular disease
Diabetic comas: Diabetic myonecrosis Diabetes and pregnancy |
| Blood tests |
| Blood sugar Fructosamine Glucose tolerance test Glycosylated hemoglobin |
Contents |
Insulin
Insulin is usually given subcutaneously, either by injections or by an insulin pump. Research is underway of other routes of administration. In acute care settings, insulin may also be given intravenously. There are several types of insulin, characterized by the rate which they are metabolized by the body.
Secretagogues
Sulfonylureas
Sulfonylureas were the first widely used oral hypoglycemic medications. They are insulin secretagogues, triggering insulin release by direct action on the KATP channel of the pancreatic beta cells. Eight types of these pills have been marketed in North America, but not all remain available. The "second-generation" drugs are now more commonly used. They are more effective than first-generation drugs and have fewer side effects. All may cause weight gain.
Sulfonylureas bind strongly to plasma proteins. Sulfonylureas are only useful in Type II diabetes, as they work by stimulating endogenous release of insulin. They work best with patients over 40 years old, who have had diabetes mellitus for under ten years. They can not be used with type I diabetes, or diabetes of pregnancy. They can be safely used with metformin or -glitazones. The primary side effect is hypoglycemia.
- First-generation agents
- tolbutamide (Orinase)
- acetohexamide (Dymelor)
- tolazamide (Tolinase)
- chlorpropamide (Diabinese)
- Second-generation agents
- glipizide (Glucotrol)
- glyburide (Diabeta, Micronase, Glynase)
- glimepiride (Amaryl)
- gliclazide (Diamicron)
Meglitinides
Meglitinides help the pancreas produce insulin and are often called "short-acting secretagogues." Their mode of action is original, affecting potassium channels.[1] By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, hence enhancing insulin secretion.[2]
They are taken with meals to boost the insulin response to each meal.
- repaglinide (Prandin) - The maximum dosage is 16 mg/day, taken 0 to 30 minutes before meals. If a meal is skipped, the medication is also skipped.
- nateglinide (Starlix) - The maximum dosage is 360 mg/day, usually 120 mg three times a day (TID). It also follows the same recommendations as repaglinide.
Adverse reactions include weight gain and hypoglycemia.
Sensitizers
Biguanides
Biguanides reduce hepatic glucose output and increase uptake of glucose by the periphery, including skeletal muscle. Although it must be used with caution in patients with impaired liver or kidney function, metformin has become the most commonly used agent for type 2 diabetes in children and teenagers. Amongst common diabetic drugs, metformin, a biguanide, is the only widely used oral drug that does not cause weight gain.
- metformin (Glucophage). Metformin may be the best choice for patients who also have heart failure.[3]
- phenformin (DBI): used from 1960s through 1980s, withdrawn due to lactic acidosis risk.
- buformin: also withdrawn due to lactic acidosis risk.
Metformin should be temporarily discontinued before any radiographic procedure involving intravenous iodinated contrast as patients are at an increased risk of lactic acidosis.
Metformin is usually the first-line medication used for treatment of type-2 diabetes. Initial dosing is 500 mg twice daily, but can be increased up to 1000 mg twice daily. It is also available in combination with other oral diabetic medications.
Thiazolidinediones
Thiazolidinediones (TZDs), also known as "glitazones," bind to PPARγ, a type of nuclear regulatory proteins involved in transcription of genes regulating glucose and fat metabolism. These PPARs act on Peroxysome Proliferator Responsive Elements (PPRE [1]). The PPREs influence insulin sensitive genes, which enhance production of mRNAs of insulin dependent enzymes. The final result is better use of glucose by the cells.
- rosiglitazone (Avandia)
- pioglitazone (Actos)
- troglitazone (Rezulin): used in 1990s, withdrawn due to hepatitis and liver damage risk.
As a result of multiple retrospective studies, there is a concern about rosiglitazone's safety, although it is established that the group, as a whole, has beneficial effects on diabetes. The greatest concern is an increase in the number of severe cardiac events in patients taking it. The ADOPT study showed that initial therapy with drugs of this type may prevent the progression of disease,[4] as did the DREAM trial.[5]
Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in the New England Journal of Medicine.[6] There have been a significant number of publications since then, and a Food and Drug Administration panel[7] voted, with some controversy, 20:3 that available studies "supported a signal of harm," but voted 22:1 to keep the drug on the market. The meta-analysis was not supported by an interim analysis of the trial designed to evaluate the issue, and several other reports have failed to conclude the controversy. This weak evidence for adverse effects has reduced the use of rosiglitazone, despite its important and sustained effects on glycemic control.[8] Safety studies are continuing.
In contrast, at least one large prospective study, PROactive 05, has shown that pioglitazone may decrease the overall incidence of cardiac events in people with type II diabetes who have already had a heart attack.[9]
Alpha-glucosidase inhibitors
Alpha-glucosidase inhibitors are "diabetes pills" but not technically hypoglycemic agents because they do not have a direct effect on insulin secretion or sensitivity. These agents slow the digestion of starch in the small intestine, so that glucose from the starch of a meal enters the bloodstream more slowly, and can be matched more effectively by an impaired insulin response or sensitivity. These agents are effective by themselves only in the earliest stages of impaired glucose tolerance, but can be helpful in combination with other agents in type 2 diabetes.
- miglitol (Glyset)
- acarbose (Precose/Glucobay)
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.
Peptide analogs
Incretin mimetics
Incretins are insulin secretagogues. The two main candidate molecules that fulfill criteria for being an incretin are Glucagon-like peptide-1 (GLP-1) and Gastric inhibitory peptide (aka glucose-dependent Insulinotropic peptide or GIP). Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).
Glucagon-like peptide (GLP) analogs and agonists
GLP agonists bind to a membrane GLP receptor.[2] As a consequence of this, insulin release from the pancreatic beta cells is increased. Endogenous GLP has a half life of only a few minutes; thus an analogue of GLP would not be practical.
- Exenatide (also Exendin-4, marketed as Byetta) is the first GLP-1 agonist approved for the treatment of type 2 diabetes. Exenatide is not an analogue of GLP, but rather a GLP agonist.[10][11] Exenatide has only 53% homology with GLP, which increases its resistance to degradation by DPP-4 and extends its half-life.[12]
- Liraglutide, a once daily human analogue (97% homology), is being developed by Novo Nordisk. As of 2007[update], it is in phase III clinical trials.[13]
These agents may also cause a decrease in gastric motility, responsible for the common side effect of nausea, and is probably the mechanism by which weight loss occurs.
Gastric inhibitory peptide (GIP) analogs
- None are FDA approved
DPP-4 inhibitors
Dipeptidyl peptidase-4 (DPP-4) inhibitors increase blood concentration of the incretin GLP-1 (glucagon-like peptide-1) by inhibiting its degradation by dipeptidyl peptidase-4 (DPP-4). Examples are:
- vildagliptin
- sitagliptin
Amylin analogues
Amylin agonist analogues slow gastric emptying and suppress glucagon. They have all the incretins actions except stimulation of insulin secretion. As of 2007[update], pramlintide is the only clinically available amylin analogue. Like insulin, it is administered by subcutaneous injection. The most frequent and severe adverse effect of pramlintide is nausea, which occurs mostly at the beginning of treatment and gradually reduces.
Experimental agents
Many other potential drugs are currently in investigation by pharmaceutical companies. Some of these are simply newer members of one of the above classes, but some work by novel mechanisms. For example, at least one compound that enhances the sensitivity of glucokinase to rising glucose is in the stage of animal research. Others are undergoing phase I/II studies.
- PPARα/γ ligands (muraglitazar and tesaglitazar - development stopped due to adverse risk profile, aleglitazar - under clinical development)
- SGLT (sodium-dependent glucose transporter 1) inhibitors increase urinary glucose.
- FBPase (fructose 1,6-bisphosphatase) inhibitors decrease gluconeogenesis in the liver.
Herbal extracts
A recent review article presents the profiles of plants with hypoglycaemic properties, reported in the literature from 1990 to 2000 and states that "Medical plants play an important role in the management of diabetes mellitus especially in developing countries where resources are meager."[14] Animal studies have found that walnut leaf[15] and garlic can significantly reduce fasting blood glucose levels in rats with alloxan-induced diabetes.[16]
- Myrcia
The first registered use of anti-diabetic drugs was as herbal extracts used by Indians in the Amazon Basin for the treatment of type 2 diabetes, and today promoted as vegetable insulin although not formally an insulin analog.[17] The major recent development was done in Brazil around Myrcia sphaerocarpa and other Myrcia species.
"Many countries, especially in the developing world, have a long history of the use of herbal remedies in diabetes (...) STZ diabetic rats were also used to test Myrcia Uniflora extracts (...) ".[18]
The usual treatment is with concentrated (root) Myrcia extracts, commercialized in a 4 US dollar per kilogram packed rocks (~100 times cheaper than equivalent artificial drugs), named "Pedra hume de kaá". Phytochemical analysis of the Myrcia extracts reported kinds of flavanone glucosides (myrciacitrins) and acetophenone glucosides (myrciaphenones), and inhibitory activities on aldose reductase and alpha-glucosidase.[19]
- Cinnamon
At least two studies have shown that cinnamon can act significantly reducing some effects of diabetes. One study on people used fine ground cinnamon (Cinnamomum cassia) for oral consumption. Another study used an extract (MHCP) on laboratory rats.
The study on people published in 2003 conducted in the Department of Human Nutrition, NWFP Agricultural University, Peshawar, Pakistan concluded "that the inclusion of cinnamon in the diet of people with type 2 diabetes will reduce risk factors associated with diabetes and cardiovascular diseases."[20] The study on laboratory rats at Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University published in 2001 used purified hydroxychalcone (MHCP) from cinnamon. Part of the study's conclusion stated that "the MHCP is fully capable of mimicking insulin" and recommended further studies.[21] [22] The Food and Drug Administration has not yet evaluated the use of cinnamon for the management of diabetes.
Notes
- ↑ Rendell M (2004). "Advances in diabetes for the millennium: drug therapy of type 2 diabetes". MedGenMed 6 (3 Suppl): 9. PMID 15647714. Free full text with registration at Medscape. Full text at PMC: 1474831
- ↑ 2.0 2.1 "Helping the pancreas produce insulin". HealthValue. Retrieved on 2007-09-21.
- ↑ Eurich DT, McAlister FA, Blackburn DF, et al (2007). "Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review". BMJ 335 (7618): 497. doi:. PMID 17761999.
- ↑ Haffner, Steven M. (2007). "Expert Column - A Diabetes Outcome Progression Trial (ADOPT)". Medscape. Retrieved on 2007-09-21.
- ↑ Gagnon, Louise (2007). "DREAM: Rosiglitazone Effective in Preventing Diabetes". Medscape. Retrieved on 2007-09-21.
- ↑ Nissen SE, Wolski K (2007). "Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes". N Engl J Med 356 (24): 2457–71. doi:. PMID 17517853. http://content.nejm.org/cgi/content/full/356/24/2457. Lay summary – Associated Press (2007-05-21).
- ↑ Wood, Shelley (2007-07-31). "FDA Advisory Panels Acknowledge Signal of Risk With Rosiglitazone, but Stop Short of Recommending Its Withdrawal". Heartwire. Retrieved on 2007-09-21.
- ↑ Ajjan RA, Grant PJ (2008). "The cardiovascular safety of rosiglitazone". Expert Opin Drug Saf 7 (4): 367–76. doi:. PMID 18613801.
- ↑ Erdman, Erland; Dormandy, JA; Charbonnel, B; Massi-Benedetti, M;Moules, IK;Skene,AM (2007). "The Effect of Pioglitazone on Recurrent Myocardial Infarction in 2,445 Patients With Type 2 Diabetes and Previous Myocardial Infarction. Results From PROactive (PROactive 05)". J Am Coll Cardiol 49 (17): 1772–1780. doi:. PMID 17466227. http://www.medscape.com/viewarticle/554997. Retrieved on 2007-05-21.
- ↑ Briones M, Bajaj M (June 2006). "Exenatide: a GLP-1 receptor agonist as novel therapy for Type 2 diabetes mellitus". Expert Opin Pharmacother 7 (8): 1055–64. doi:. PMID 16722815.
- ↑ Gallwitz B (December 2006). "Exenatide in type 2 diabetes: treatment effects in clinical studies and animal study data". Int J Clin Pract 60 (12): 1654–61. doi:. PMID 17109672.
- ↑ Cvetković RS, Plosker GL (2007). "Exenatide: a review of its use in patients with type 2 diabetes mellitus (as an adjunct to metformin and/or a sulfonylurea)". Drugs 67 (6): 935–54. PMID 17428109.
- ↑ "Novo Nordisk A/S - R&D Pipeline: Liraglutide (NN2211)". Novo Nordisk (2007). Retrieved on 2007-09-30.
- ↑ Bnouham M et al (2006). "Medicinal plants with potential antidiabetic activity - A review of ten years of herbal medicine research (1990-2000)" (PDF). Int J Diabetes & Metabolism 14: 1–25. http://ijod.uaeu.ac.ae/iss_1401/a.pdf.
- ↑ Jelodar G, Mohsen M, Shahram S (2007). "Effect of Walnut leaf, coriander and pomegranate on blood glucose and histopathology of pancreas of alloxan induced diabetic rats". African Journal of Traditional, Complimentary and Alternative Medicines 4 (3): 299–305. http://www.bioline.org.br/request?tc07044. Retrieved on 2008-05-10.
- ↑ Jelodar GA, Maleki M, Motadayen MH, Sirus S (February 2005). "Effect of fenugreek, onion and garlic on blood glucose and histopathology of pancreas of alloxan-induced diabetic rats". Indian J Med Sci 59 (2): 64–9. PMID 15738612. http://www.indianjmedsci.org/article.asp?issn=0019-5359;year=2005;volume=59;issue=2;spage=64;epage=69;aulast=Jelodar.
- ↑ Soumyanath, Amala(ed.) (2005-11-01). Traditional Medicines for Modern Times (1st Edition ed.). Taylor & Francis. ISBN 0-415-33464-0.
- ↑ McNeill, John H. (1999-02-01). Experimental Models of Diabetes (1st Edition ed.). CRC Press. pp. 208. ISBN 0-8493-1667-7.
- ↑ Matsuda, H; Nishida N, Yoshikawa M. (March 2002). "Antidiabetic principles of natural medicines. V. Aldose reductase inhibitors from Myrcia multiflora DC. (2): Structures of myrciacitrins III, IV, and V". Chem Pharm Bull (Tokyo) 50(3): 429–31. doi:.
- ↑ Alam Khan, MS, PHD, Mahpara Safdar, MS, Mohammad Muzaffar Ali Khan, MS, PHD, Khan Nawaz Khattak, MS and Richard A. Anderson, PHD, Cinnamon Improves Glucose and Lipids of People With Type 2 Diabetes, DIABETES CARE, Vol. 26, Numbr 12, December 2003, retrieved August 4 2008
- ↑ Karalee J. Jarvill-Taylor, PhD, Richard A. Anderson, PhD and Donald J. Graves, PhD A Hydroxychalcone Derived from Cinnamon Functions as a Mimetic for Insulin in 3T3-L1 Adipocytes Journal of the American College of Nutrition Vol. 20, No. 4, 327-336 (2001), retrieved August 4 2008
- ↑ Richard A. Anderson, Ph.D., CNS, Cinnamon, Glucose Tolerance and Diabetes, www.ars.usda.gov, August 23 2005, retrieved August 4 2008
References
- Lebovitz, Harold E. (2004). Therapy For Diabetes Mellitus and Related Disorders (4th ed. ed.). Alexandria, VA: American Diabetes Association. ISBN 1-58040-187-2.
- Adams, Michael Ian; Holland, Norman Norwood (2003). Core Concepts in Pharmacology. Englewood Cliffs, NJ: Prentice Hall. ISBN 0-13-089329-3.
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