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.

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 K_ATP 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. [cite journal |author=Rendell M |title=Advances in diabetes for the millennium: drug therapy of type 2 diabetes |journal=MedGenMed |volume=6 |issue=3 Suppl |pages=9 |year=2004 |pmid=15647714 |doi= [http://www.medscape.com/viewarticle/488273 Free full text with registration at Medscape] . PMC|1474831] By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, hence enhancing insulin secretion.cite web | url = http://www.healthvalue.net/diabetespancreasbeta.html | title = Helping the pancreas produce insulin | accessdate = 2007-09-21 | publisher = HealthValue]

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.cite journal |author=Eurich DT, McAlister FA, Blackburn DF, "et al" |title=Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review |journal=BMJ |volume=335 |issue=7618 |pages=497 |year=2007 |pmid=17761999 |doi=10.1136/bmj.39314.620174.80]
* 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 [http://www.healthvalue.net/diabetesinsulinPPAR.html] ). 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, [cite web
last = Haffner
first = Steven M.
title = Expert Column - A Diabetes Outcome Progression Trial (ADOPT)
work =
publisher = Medscape
date = 2007
url = http://www.medscape.com/viewarticle/552484
format =
doi =
accessdate = 2007-09-21] as did the DREAM trial. [cite web
last = Gagnon
first = Louise
title = DREAM: Rosiglitazone Effective in Preventing Diabetes
publisher = Medscape
date = 2007
url = http://www.medscape.com/viewarticle/546503
accessdate = 2007-09-21]

Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in the "New England Journal of Medicine". [cite journal
last = Nissen
first = Steven E.
authorlink =
coauthors = Wolksi, K
title = Effect of Rosiglitazone on the Risk of Myocardial Infarctionand Death from Cardiovascular Causes (early web release)
journal = N Engl J Med
volume = 356
issue = 24
pages = 2457–2471
date = 2007-06-14
url =
doi = 10.1056/NEJMoa072761
pmid = 17517853
accessdate = 2007-05-21 ] There have been a significant number of publications since then, and a Food and Drug Administration panel [cite web
last = Wood
first = Shelley
title = FDA Advisory Panels Acknowledge Signal of Risk With Rosiglitazone, but Stop Short of Recommending Its Withdrawal
publisher = Heartwire
date = 2007-07-31
url = http://www.medscape.com/viewarticle/560709
accessdate = 2007-09-21 ] 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. 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. [cite journal
last = Erdman
first = Erland
coauthors = Dormandy, JA; Charbonnel, B; Massi-Benedetti, M;Moules, IK;Skene,AM
title = 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)
journal = J Am Coll Cardiol
volume = 49
issue = 17
pages = 1772–1780
date = 2007
url = http://www.medscape.com/viewarticle/554997
pmid = 17466227
doi = 10.1016/j.jacc.2006.12.048
accessdate = 2007-05-21 ]

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. 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. [cite journal |author=Briones M, Bajaj M |title=Exenatide: a GLP-1 receptor agonist as novel therapy for Type 2 diabetes mellitus |journal=Expert Opin Pharmacother |volume=7 |issue=8 |pages=1055–64 |year=2006 |month=June |pmid=16722815 |doi=10.1517/14656566.7.8.1055] [cite journal |author=Gallwitz B |title=Exenatide in type 2 diabetes: treatment effects in clinical studies and animal study data |journal=Int J Clin Pract |volume=60 |issue=12 |pages=1654–61 |year=2006 |month=December |pmid=17109672 |doi=10.1111/j.1742-1241.2006.01196.x] Exenatide has only 53% homology with GLP, which increases its resistance to degradation by DPP-4 and extends its half-life.cite journal |author=Cvetković RS, Plosker GL |title=Exenatide: a review of its use in patients with type 2 diabetes mellitus (as an adjunct to metformin and/or a sulfonylurea) |journal=Drugs |volume=67 |issue=6 |pages=935–54 |year=2007 |pmid=17428109 |doi=]
* Liraglutide, a once daily human analogue (97% homology), is being developed by Novo Nordisk. As of 2007, it is in phase III clinical trials. [cite web | url = http://www.novonordisk.com/investors/rd_pipeline/rd_pipeline.asp?showid=4 | title = Novo Nordisk A/S - R&D Pipeline: Liraglutide (NN2211) | year = 2007 | accessdate = 2007-09-30 | publisher = Novo Nordisk]

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. As of 2007, 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." [cite journal | author = Bnouham M et al | title=Medicinal plants with potential antidiabetic activity - A review of ten years of herbal medicine research (1990-2000) | journal=Int J Diabetes & Metabolism | volume=14 | pages=1–25 | date=2006| url=http://ijod.uaeu.ac.ae/iss_1401/a.pdf] Animal studies have found that walnut leaf [cite journal |author=Jelodar G, Mohsen M, Shahram S |title=Effect of Walnut leaf, coriander and pomegranate on blood glucose and histopathology of pancreas of alloxan induced diabetic rats |journal=African Journal of Traditional, Complimentary and Alternative Medicines |year=2007 |volume=4 |issue=3 |pages=299–305 |url=http://www.bioline.org.br/request?tc07044 |accessdate=2008-05-10] and garlic can significantly reduce fasting blood glucose levels in rats with alloxan-induced diabetes.cite journal |author=Jelodar GA, Maleki M, Motadayen MH, Sirus S |title=Effect of fenugreek, onion and garlic on blood glucose and histopathology of pancreas of alloxan-induced diabetic rats |journal=Indian J Med Sci |volume=59 |issue=2 |pages=64–9 |year=2005 |month=February |pmid=15738612 |doi= |url=http://www.indianjmedsci.org/article.asp?issn=0019-5359;year=2005;volume=59;issue=2;spage=64;epage=69;aulast=Jelodar]

;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. [cite book |last = Soumyanath | first=Amala(ed.) | coauthors = |title=Traditional Medicines for Modern Times |url= |format= |accessdate= |accessyear= |accessmonth= |edition=1st Edition |date=2005-11-01 |publisher=Taylor & Francis |location= |id=ISBN 0-415-33464-0 |doi=] 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 (...) ". [cite book |last = McNeill | pages=208| first=John H. | coauthors = |title=Experimental Models of Diabetes |url= |format= |accessdate= |accessyear= |accessmonth= |edition=1st Edition |date=1999-02-01 |publisher=CRC Press |location= |id=ISBN 0-8493-1667-7 |doi=]

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. [cite journal | last = Matsuda | first=H | coauthors = Nishida N, Yoshikawa M. | title=Antidiabetic principles of natural medicines. V. Aldose reductase inhibitors from Myrcia multiflora DC. (2): Structures of myrciacitrins III, IV, and V | volume=50(3) | pages=429–31 | year=2002 | month=Mar | journal=Chem Pharm Bull (Tokyo) | doi=10.1248/cpb.50.429]

;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." [Alam Khan, MS, PHD, Mahpara Safdar, MS, Mohammad Muzaffar Ali Khan, MS, PHD, Khan Nawaz Khattak, MS and Richard A. Anderson, PHD, [http://care.diabetesjournals.org/cgi/content/abstract/26/12/3215 Cinnamon Improves Glucose and Lipids of People With Type 2 Diabetes] , "DIABETES CARE", Vol. 26, Numbr 12, December 2003, retrieved August 4 2008] 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. [Karalee J. Jarvill-Taylor, PhD, Richard A. Anderson, PhD and Donald J. Graves, PhD [http://www.jacn.org/cgi/content/full/20/4/327 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, [http://www.ars.usda.gov/Research/docs.htm?docid=8877 Cinnamon, Glucose Tolerance and Diabetes] , "www.ars.usda.gov", August 23 2005, retrieved August 4 2008] The Food and Drug Administration has not yet evaluated the use of cinnamon for the management of diabetes.

Notes

References

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