Anti-diabetic drug 253721 222460579 2008-06-29T13:21:12Z DOI bot 6652755 Citation maintenance. Formatted: title. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. '''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}} == Insulin == {{main|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. == Sulfonylureas == {{main|Sulfonylurea}} [[Sulfonylurea]]s were the first widely used oral hypoglycemic medications. They are ''insulin [[secretagogue]]s'', triggering insulin release by direct action on the K<sub>ATP</sub> channel of the pancreatic [[beta cell]]s. 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 protein]]s. 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) == Biguanides == {{main|Biguanide}} [[Biguanide]]s reduce [[liver|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]].<ref name="pmid17761999">{{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}}</ref> * [[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 [[iodine|iodinated]] [[radiocontrast|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. == Meglitinides == {{main|Meglitinide}} [[Meglitinide]]s help the pancreas produce insulin and are often called "short-acting secretagogues." Their mode of action is original, affecting [[potassium channel]]s.<ref>{{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}}</ref> By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, hence enhancing insulin secretion.<ref name=diabetespancreasbeta>{{cite web | url = http://www.healthvalue.net/diabetespancreasbeta.html | title = Helping the pancreas produce insulin | accessdate = 2007-09-21 | publisher = HealthValue}}</ref> They are taken with meals to boost the insulin response to each meal. * [[repaglinide]] (Prandin) - The maximum dosage is 16&nbsp;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&nbsp;mg/day, usually 120&nbsp;mg three times a day (TID). It also follows the same recommendations as repaglinide. Adverse reactions include weight gain and hypoglycemia. == Thiazolidinediones == {{main|Thiazolidinedione}} [[Thiazolidinedione]]s ([[TZD]]s), also known as "glitazones," bind to [[Peroxisome proliferator-activated receptor gamma|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,<ref>{{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}} </ref> as did the DREAM trial.<ref>{{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}}</ref> Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in the ''New England Journal of Medicine''.<ref>{{cite journal | last = Nissen | first = Steven E. | authorlink = | coauthors = Wolksi, K | title = Effect of Rosiglitazone on the Risk of Myocardial Infarction and 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 }}</ref> There have been a significant number of publications since then, and a [[Food and Drug Administration]] panel<ref>{{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 }}</ref> 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.<ref>{{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 }}</ref> == Alpha-glucosidase inhibitors == {{main|Alpha-glucosidase inhibitor}} [[Alpha-glucosidase inhibitor]]s 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 == [[Image:Incretins and DPP 4 inhibitors.svg|thumb|300px|right|Overview of insulin secretion]] ===Incretin mimetics=== [[Incretin]]s are insulin [[secretagogue]]s. 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 ==== GLP agonists bind to a membrane GLP receptor.<ref name=diabetespancreasbeta/> 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 [[glucagon-like peptide-1|GLP]] agonist approved for the treatment of [[type 2 diabetes]]. Exenatide is not an analogue of GLP, but rather a GLP agonist.{{Fact|date=August 2007}} Exenatide has only 53% homology with GLP, which increases its resistance to degradation by DPP-4 and extends its half-life.<ref name="pmid17428109">{{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=}}</ref> * [[Liraglutide]]- a once daily human analogue (97% homology) is being developed by [[Novo Nordisk]]. [[As of 2007]], it is in [[Clinical trial#Phase III|phase III clinical trials]].<ref>{{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]]}}</ref> 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=== {{main|Dipeptidyl peptidase-4 inhibitors}} [[Dipeptidyl peptidase-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 *SGLT (sodium-dependent glucose transporter 1) inhibitors increase urinary glucose. *FBPase (fructose 1,6-bisphosphatase) inhibitors decrease gluconeogenesis in the liver. ==Herbal extracts == 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]].<ref>{{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= |language=english |id=ISBN 0-415-33464-0 |doi=}}</ref> The major recent development was done in [[Brazil]] around ''[[Myrcia sphaerocarpa]]'' and other ''[[Myrcia]]'' species. <blockquote>"Many countries, especially in the developing world, have a long history of the use of herbal remedies in diabetes (...) [[Streptozotocin|STZ]] diabetic rats were also used to test ''Myrcia Uniflora'' extracts (...) ".<ref>{{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= |language=english |id=ISBN 0-8493-1667-7 |doi=}}</ref></blockquote> 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.<!-- --><ref>{{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}}</ref> 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."''<ref>{{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}}</ref> Animal studies on the possible role of walnut leaf, coriander and pomegranate preparations found supportive evidence only for the former {{unclear}} of these,<ref>{{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}}</ref> while on testing fenugreek, onion and garlic only for the latter {{unclear}}.<ref name="pmid15738612">{{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}}</ref> == Notes == {{Reflist|2}} == References == * {{cite book |author=Lebovitz, Harold E. |title=Therapy For Diabetes Mellitus and Related Disorders |publisher=[[American Diabetes Association]] |location=Alexandria, VA |year=2004 |edition=4<sup>th</sup> ed. |pages= |isbn=1-58040-187-2 |oclc= |doi=}} * {{cite book |author=Adams, Michael Ian; Holland, Norman Norwood |title=Core Concepts in Pharmacology |publisher=Prentice Hall |location=Englewood Cliffs, NJ |year=2003 |pages= |isbn=0-13-089329-3 |oclc= |doi=}} {{-}} {{Oral hypoglycemics}} {{Major Drug Groups}} [[Category:Anti-diabetic drugs]] [[ar:مضادات السكري]] [[ca:Antidiabètic]] [[de:Antidiabetikum]] [[fr:Antidiabétique]] [[ja:経口血糖降下薬]] [[sk:Antidiabetikum]]