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{{SI}}
{{Diabetes mellitus }}
{{CMG}}
{{CMG}}; '''Associate Editor(s)-In-Chief:''' [[Priyamvada Singh|Priyamvada Singh, M.D.]] [mailto:psingh13579@gmail.com]


==Overview==
==Overview==
'''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.
'''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.


== Overview ==
In 2008, the U.S. [[Food and Drug Administration]] announced that "manufacturers developing new drugs and biologics for type 2 diabetes provide evidence that the therapy will not increase the risk of such cardiovascular events as a heart attack.".<ref>Anonymous (2008). [http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116994.htm FDA Announces New Recommendations on Evaluating Cardiovascular Risk in Drugs Intended to Treat Type 2 Diabetes]</ref>


[[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.
==Oral hypoglycemic agents==


[[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.
Comparative effectiveness of oral agents have been studied with network-[[meta-analysis]].<ref name="pmid26104021">{{cite journal| author=Mearns ES, Saulsberry WJ, White CM, Kohn CG, Lemieux S, Sihabout A et al.| title=Efficacy and safety of antihyperglycaemic drug regimens added to metformin and sulphonylurea therapy in Type 2 diabetes: a network meta-analysis. | journal=Diabet Med | year= 2015 | volume= 32 | issue= 12 | pages= 1530-40 | pmid=26104021 | doi=10.1111/dme.12837 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26104021  }} </ref>


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.
:{| class="wikitable" border="1"
 
|+
{{Diabetes}}
! Drug !! Class !!  Mechanism of action  !! Dosage !! Side effects
|-
| Tolbutamide (Ornase) Tolazamide (Tolinase), Chlorpropamide (Diabenese) || Sulfonylureas (1st generation) || Increases insulin production in the pancreas || Tolbutamide: 0.25–2.0 g/day in divided doses; maximum, 3 g/day, Tolazamide: 100–1,000 mg/day in divided doses; maximum, 1 g/day, Chlorpropamide: 100–500 mg/day BID; maximum, 750 mg/day || Hypoglycemia, weight gain, hyperinsulinemia, Disulfiram reaction with alcohol, long acting extreme caution with elderly or patients with hepatic or renal dysfunction, periodic evaluation of liver function is suggested
|-
| Glyburide (Micronase, Diabeta,Glynase), Glipizide (Glucotrol, Glucotrol XL), Glimepiride (Amaryl) || Sulfonylureas (2nd generation) || Increases insulin production in the pancreas || Glyburide: 1.25–5 mg/once or twice a day; maximum, 20 mg/day, Glynase: 0.75–12.0 mg/day; maximum 12 mg/day, Glipizide: 2.5–20.0 mg/OD or BID; maximum, 40 mg/day; or XL 2.5–10.0 mg/OD or BID; maximum, 20 mg/day, Glimepiride: 1–8 mg/day; maximum, 8 mg/day || Hypoglycemia, weight gain,hyperinsulinemia, caution in patients with hepatic or renal impairment, Glipizide preferred in renal impairment, Glimepiride indicated for use with insulin, Shown to have some insulin-sensitizing effect
|-
|Repaglinide (Prandin) || Meglitinide || Increases insulin release from pancreas || New diagnosis or A1C <8%, 0.5 mg; A1C >8%, 1–2 mg, 15–30 min before each meal; increase weekly until results are obtained; maximum, 16 mg/day || Hypoglycemia, weight gain,hyperinsulinemia
caution on patient with hepatic or renal impairment, medication no more than 30 minutes prior to a meal. If meals are skipped or added, the medication should be skipped or added as well. Approved for use as monotherapy or in combinatin with TZD or metformin.
|-
|Nateglinide (Starlix) || Phenylalanine derivative || Increases insulin release from pancreas || 60–120 mg before each meal || Minimal risk of hypoglycemia, use with caution in moderate to severe hepatic disease, approved as monotherapy or in combination with metformin or TZD, 2-hour duration of action
|-
|[[Metformin]] (Fortamet,Glumetza, Glucophage) || Biguanide || Decreases hepatic glucose production, minor increase in muscle glucose uptake which may improve insulin resistance || 500 mg/day BID with meals, increase by 500 mg every 1–3 wk, BID or TID; usually most effective at 2,000 mg/day; maximum, 2,550 mg/day Long acting form Glucophage XR: 500mg OD, max dose 2000 mg OD || Nausea, diarrhea, metallic taste, lactic acidosis, cautious in alcohol abuse, liver or kidney disease, CHF, contraindicated if serum creatinine is: >1.5 mg/dL in men or >1.4 mg/dL women, monitor hematological and renal function annually, discontinue for 48 hr after contrast dye procedures, beneficial in obese patients as help in weight loss, improved lipid profile, and lack of potential for hypoglycemia
|-
|Rosiglitazone (Avandia) || Thiazolidinedione || Decreases insulin resistance, increasing glucose uptake, fat redistribution; minor decrease in hepatic glucose output; preserves cell function; decreases vascular inflammation || Initially 4 mg/day in single or divided doses, increase to 8 mg/day in 12 wk, if needed;<br/>Maximum, 8 mg/day with or without food || Minor weight increase of 3–6 lbs.,
edema, contraindicated in CHF or hepatic disease, avoid initiation if ALT >2.5X upper limit of normal, approved for use as monotherapy and in combination with metformin, sulfonylureas, or insulin, Less interactions associated with CYP-450
|-
|Pioglitazone (Actos) || Thiazolidinedione || Same as rosiglitazone || Initially 15 or 30 mg/day;<br/>Maximum with or without food 45 mg for monotherapy,30 mg for combination therapy || Weight gain
|-
|[[Alogliptin]] || [[Dipeptidyl peptidase-4 inhibitor]] (gliptin)|| Blocks [[dipeptidyl peptidase-4]] || 25 mg/day orally;
|| heart failure and pancreatic cancer(disputed)
|-
|Empagliflozin || [[SGLT2|Sodium-glucose transport proteins]] inhibitor|| Decrease renal glucose reabsorption || 10 or 25 mg/day;
|| Genital infections
|}


== Insulin ==
== 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.
 
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 ==
== 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.
[[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.
* The "second-generation" drugs are now more commonly used.  They are more effective than first-generation drugs and have fewer side effects.
 
* Sulfonylureas bind strongly to [[plasma protein]]s. Sulfonylureas are only useful in Type II diabetes, as they work by stimulating endogenous release of insulin.  
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]].
* 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.
 
== Meglitinides ==
* First-generation agents
* [[Meglitinide]]s help the pancreas produce insulin and are often called "short-acting secretagogues."
** [[tolbutamide]] (Orinase)
* 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>
** [[acetohexamide]] (Dymelor)
* They are taken with meals to boost the insulin response to each meal.
** [[tolazamide]] (Tolinase)
** [[chlorpropamide]] (Diabinese)
* Second-generation agents
** [[glipizide]] (Glucotrol)
** [[glyburide]] (Diabeta, Micronase, Glynase)
** [[glimepiride]] (Amaryl)
** [[gliclazide]] (Diamicron)
 
== Biguanides ==
== Biguanides ==
{{main|Biguanide}}
* [[Biguanide]]s reduce [[liver|hepatic]] glucose output and increase uptake of glucose by the periphery, including skeletal muscle.  
[[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 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]] (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 ==
== Thiazolidinediones ==
{{main|Thiazolidinedione}}
* [[Thiazolidinedione]]s ([[TZD]]s), also known as "glitazones," bind to [[Peroxisome proliferator-activated receptors|PPARγ]], a type of nuclear regulatory proteins involved in transcription of genes regulating glucose and fat metabolism.
[[Thiazolidinedione]]s ([[TZD]]s), also known as "glitazones," bind to [[Peroxisome proliferator-activated receptors|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.
* 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.
 
* 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
*[[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
   | last = Haffner
   | first = Steven M.
   | first = Steven M.
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   | accessdate =  2007-09-21}}</ref>  
   | 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
* 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
   | last = Nissen
   | first = Steven E.
   | first = Steven E.
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   | url = http://www.medscape.com/viewarticle/560709
   | 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.
   | 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
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
   | last = Erdman
   | first = Erland
   | first = Erland
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== Peptide analogs ==
== Peptide analogs ==
[[Image:Incretins and DPP 4 inhibitors.svg|thumb|300px|right|Overview of insulin secretion]]
[[Image:Incretins and DPP 4 inhibitors.svg|thumb|300px|right|Overview of insulin secretion]]
Hormones that affect glucose homeostasis and can be pharmacologically manipulated are either produced in the pancreas or gastrointestinal tract
Pancreatic hormones
** Insulin, produced by beta cells
** Amylin, produced by beta cells;
** Glucagon, produced by alpha cells
Gastrointestinal peptides are incretin mimetics
* Glucagon-like peptide-1 (GLP-1)
* Glucose-dependent insulinotropic polypeptide or gastric inhibitory polypeptide (GIP)


===Incretin mimetics===
===Incretin mimetics===
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==== Glucagon-like peptide (GLP) analogs ====
==== 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.
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.
All are injectable only and include:
* Short acting exenatide and lixisenatide.
* Long actiing analogues (more resistant to [[dipeptidyl peptidase 4]] (DPP-4)) and include liraglutide, taspoglutide, extended release exenatide, albiglutide, and dulaglutide.
* [[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>
* [[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>
* [[Liraglutide]]- a once daily human analogue (97% homology) was developed by [[Novo Nordisk]]. [[Liraglutide]] may delay death and major cardiovascular events.<ref name="pmid27295427">{{cite journal| author=Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA et al.| title=Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. | journal=N Engl J Med | year= 2016 | volume=  | issue=  | pages=  | pmid=27295427 | doi=10.1056/NEJMoa1603827 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27295427  }} </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.
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.
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{{main|Dipeptidyl peptidase-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:
[[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:
* [[Alogliptin]]
* [[vildagliptin]]
* [[vildagliptin]]
* [[sitagliptin]]
* [[sitagliptin]]


===Amylin analogues===
====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.
[[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.
 
====Sodium-glucose transport proteins inhibitor====
Sodium-glucose transport proteins ([[SGLT2]]) inhibitor decrease renal glucose reabsorption.
 
[[Empagliflozin]] may reduce cardiac events. <ref name="pmid27376831">{{cite journal| author=Salsali A, Kim G, Woerle HJ, Broedl UC, Hantel S| title=Cardiovascular safety of empagliflozin in patients with type 2 diabetes: a meta-analysis of data from randomized placebo-controlled trials. | journal=Diabetes Obes Metab | year= 2016 | volume=  | issue=  | pages=  | pmid=27376831 | doi=10.1111/dom.12734 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27376831  }} </ref>
 
[[SGLT2]] inhibitors may cause [[necrotizing fasciitis]] of the perineum, or [[Fournier's gangrene]] <ref>Anonymous (2018).  [https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm618908.htm SGLT2(sodium-glucose cotransporter-2) Inhibitors for Diabetes: Drug Safety Communication - Regarding Rare Occurrences of a Serious Infection of the Genital Area]. [[Food and Drug Administration]]</ref>.


==Experimental agents==
==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.
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
*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.
*FBPase (fructose 1,6-bisphosphatase) inhibitors decrease gluconeogenesis in the liver.


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== References ==
== References ==
=== Notes ===
{{Reflist|2}}
{{Reflist|2}}
 
==External links==
[http://ndep.nih.gov/media/Drug_tables_supplement.pdf ndep.nih.gov drug tables]
=== Sources ===
=== Sources ===
* {{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=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=}}
* {{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}}
{{SIB}}
[[Category:Anti-diabetic drugs]]
[[Category:Anti-diabetic drugs]]
[[Category:Endocrinology]]
[[Category:Endocrinology]]
[[ar:مضادات السكري]]
[[ar:مضادات السكري]]
[[ca:Antidiabètic]]
[[ca:Antidiabètic]]
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Latest revision as of 00:35, 5 September 2018

Diabetes mellitus Main page

Patient Information

Type 1
Type 2

Overview

Classification

Diabetes mellitus type 1
Diabetes mellitus type 2
Gestational diabetes

Differential Diagnosis

Complications

Screening

Diagnosis

Prevention

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.D. [2]

Overview

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.

In 2008, the U.S. Food and Drug Administration announced that "manufacturers developing new drugs and biologics for type 2 diabetes provide evidence that the therapy will not increase the risk of such cardiovascular events as a heart attack.".[1]

Oral hypoglycemic agents

Comparative effectiveness of oral agents have been studied with network-meta-analysis.[2]

Drug Class Mechanism of action Dosage Side effects
Tolbutamide (Ornase) Tolazamide (Tolinase), Chlorpropamide (Diabenese) Sulfonylureas (1st generation) Increases insulin production in the pancreas Tolbutamide: 0.25–2.0 g/day in divided doses; maximum, 3 g/day, Tolazamide: 100–1,000 mg/day in divided doses; maximum, 1 g/day, Chlorpropamide: 100–500 mg/day BID; maximum, 750 mg/day Hypoglycemia, weight gain, hyperinsulinemia, Disulfiram reaction with alcohol, long acting extreme caution with elderly or patients with hepatic or renal dysfunction, periodic evaluation of liver function is suggested
Glyburide (Micronase, Diabeta,Glynase), Glipizide (Glucotrol, Glucotrol XL), Glimepiride (Amaryl) Sulfonylureas (2nd generation) Increases insulin production in the pancreas Glyburide: 1.25–5 mg/once or twice a day; maximum, 20 mg/day, Glynase: 0.75–12.0 mg/day; maximum 12 mg/day, Glipizide: 2.5–20.0 mg/OD or BID; maximum, 40 mg/day; or XL 2.5–10.0 mg/OD or BID; maximum, 20 mg/day, Glimepiride: 1–8 mg/day; maximum, 8 mg/day Hypoglycemia, weight gain,hyperinsulinemia, caution in patients with hepatic or renal impairment, Glipizide preferred in renal impairment, Glimepiride indicated for use with insulin, Shown to have some insulin-sensitizing effect
Repaglinide (Prandin) Meglitinide Increases insulin release from pancreas New diagnosis or A1C <8%, 0.5 mg; A1C >8%, 1–2 mg, 15–30 min before each meal; increase weekly until results are obtained; maximum, 16 mg/day Hypoglycemia, weight gain,hyperinsulinemia

caution on patient with hepatic or renal impairment, medication no more than 30 minutes prior to a meal. If meals are skipped or added, the medication should be skipped or added as well. Approved for use as monotherapy or in combinatin with TZD or metformin.

Nateglinide (Starlix) Phenylalanine derivative Increases insulin release from pancreas 60–120 mg before each meal Minimal risk of hypoglycemia, use with caution in moderate to severe hepatic disease, approved as monotherapy or in combination with metformin or TZD, 2-hour duration of action
Metformin (Fortamet,Glumetza, Glucophage) Biguanide Decreases hepatic glucose production, minor increase in muscle glucose uptake which may improve insulin resistance 500 mg/day BID with meals, increase by 500 mg every 1–3 wk, BID or TID; usually most effective at 2,000 mg/day; maximum, 2,550 mg/day Long acting form Glucophage XR: 500mg OD, max dose 2000 mg OD Nausea, diarrhea, metallic taste, lactic acidosis, cautious in alcohol abuse, liver or kidney disease, CHF, contraindicated if serum creatinine is: >1.5 mg/dL in men or >1.4 mg/dL women, monitor hematological and renal function annually, discontinue for 48 hr after contrast dye procedures, beneficial in obese patients as help in weight loss, improved lipid profile, and lack of potential for hypoglycemia
Rosiglitazone (Avandia) Thiazolidinedione Decreases insulin resistance, increasing glucose uptake, fat redistribution; minor decrease in hepatic glucose output; preserves cell function; decreases vascular inflammation Initially 4 mg/day in single or divided doses, increase to 8 mg/day in 12 wk, if needed;
Maximum, 8 mg/day with or without food		 Minor weight increase of 3–6 lbs.,

edema, contraindicated in CHF or hepatic disease, avoid initiation if ALT >2.5X upper limit of normal, approved for use as monotherapy and in combination with metformin, sulfonylureas, or insulin, Less interactions associated with CYP-450

Pioglitazone (Actos) Thiazolidinedione Same as rosiglitazone Initially 15 or 30 mg/day;
Maximum with or without food 45 mg for monotherapy,30 mg for combination therapy		 Weight gain
Alogliptin Dipeptidyl peptidase-4 inhibitor (gliptin) Blocks dipeptidyl peptidase-4 25 mg/day orally; heart failure and pancreatic cancer(disputed)
Empagliflozin Sodium-glucose transport proteins inhibitor Decrease renal glucose reabsorption 10 or 25 mg/day; Genital infections

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

  • 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.
  • The "second-generation" drugs are now more commonly used. They are more effective than first-generation drugs and have fewer side effects.
  • 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.

Meglitinides

  • Meglitinides help the pancreas produce insulin and are often called "short-acting secretagogues."
  • Their mode of action is original, affecting potassium channels.[3] By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, hence enhancing insulin secretion.[4]
  • They are taken with meals to boost the insulin response to each meal.

Biguanides

  • Biguanides reduce hepatic glucose output and increase uptake of glucose by the periphery, including skeletal muscle.
  • Metformin should be temporarily discontinued before any radiographic procedure involving intravenous iodinated contrast as patients are at an increased risk of lactic acidosis.

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 [3]). 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.
  • 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,[5] as did the DREAM trial.[6]
  • Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in the New England Journal of Medicine.[7] There have been a significant number of publications since then, and a Food and Drug Administration panel[8] 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.[9]

Alpha-glucosidase inhibitors

Main article: Alpha-glucosidase inhibitor

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.

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

File:Incretins and DPP 4 inhibitors.svg
Overview of insulin secretion

Hormones that affect glucose homeostasis and can be pharmacologically manipulated are either produced in the pancreas or gastrointestinal tract

Pancreatic hormones

    • Insulin, produced by beta cells
    • Amylin, produced by beta cells;
    • Glucagon, produced by alpha cells

Gastrointestinal peptides are incretin mimetics

  • Glucagon-like peptide-1 (GLP-1)
  • Glucose-dependent insulinotropic polypeptide or gastric inhibitory polypeptide (GIP)

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

GLP agonists bind to a membrane GLP receptor.[4] 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.

All are injectable only and include:

  • Short acting exenatide and lixisenatide.
  • Long actiing analogues (more resistant to dipeptidyl peptidase 4 (DPP-4)) and include liraglutide, taspoglutide, extended release exenatide, albiglutide, and dulaglutide.
  • Exenatide (also Exendin-4, marketed as Byetta) is the first GLP agonist approved for the treatment of type 2 diabetes. Exenatide is not an analogue of GLP, but rather a GLP agonist.[citation needed] Exenatide has only 53% homology with GLP, which increases its resistance to degradation by DPP-4 and extends its half-life.[10]
  • Liraglutide- a once daily human analogue (97% homology) was developed by Novo Nordisk. Liraglutide may delay death and major cardiovascular events.[11]

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 article: 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:

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.

Sodium-glucose transport proteins inhibitor

Sodium-glucose transport proteins (SGLT2) inhibitor decrease renal glucose reabsorption.

Empagliflozin may reduce cardiac events. [12]

SGLT2 inhibitors may cause necrotizing fasciitis of the perineum, or Fournier's gangrene [13].

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
  • 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.[14] 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 (...) ".[15]

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.[16]

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."[17]

References

  1. ↑ Anonymous (2008). FDA Announces New Recommendations on Evaluating Cardiovascular Risk in Drugs Intended to Treat Type 2 Diabetes
  2. ↑ Mearns ES, Saulsberry WJ, White CM, Kohn CG, Lemieux S, Sihabout A; et al. (2015). "Efficacy and safety of antihyperglycaemic drug regimens added to metformin and sulphonylurea therapy in Type 2 diabetes: a network meta-analysis". Diabet Med. 32 (12): 1530–40. doi:10.1111/dme.12837. PMID 26104021.
  3. ↑ 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. PMC 1474831
  4. ↑ 4.0 4.1 "Helping the pancreas produce insulin". HealthValue. Retrieved 2007-09-21.
  5. ↑ Haffner, Steven M. (2007). "Expert Column - A Diabetes Outcome Progression Trial (ADOPT)". Medscape. Retrieved 2007-09-21.
  6. ↑ Gagnon, Louise (2007). "DREAM: Rosiglitazone Effective in Preventing Diabetes". Medscape. Retrieved 2007-09-21.
  7. ↑ Nissen, Steven E. (2007-06-14). "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes (early web release)". N Engl J Med. 356 (24): 2457–2471. doi:10.1056/NEJMoa072761. PMID 17517853. Unknown parameter |coauthors= ignored (help); line feed character in |title= at position 61 (help); |access-date= requires |url= (help)
  8. ↑ Wood, Shelley (2007-07-31). "FDA Advisory Panels Acknowledge Signal of Risk With Rosiglitazone, but Stop Short of Recommending Its Withdrawal". Heartwire. Retrieved 2007-09-21.
  9. ↑ Erdman, Erland (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:10.1016/j.jacc.2006.12.048. PMID 17466227. Retrieved 2007-05-21. Unknown parameter |coauthors= ignored (help)
  10. ↑ 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.
  11. ↑ Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA; et al. (2016). "Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes". N Engl J Med. doi:10.1056/NEJMoa1603827. PMID 27295427.
  12. ↑ Salsali A, Kim G, Woerle HJ, Broedl UC, Hantel S (2016). "Cardiovascular safety of empagliflozin in patients with type 2 diabetes: a meta-analysis of data from randomized placebo-controlled trials". Diabetes Obes Metab. doi:10.1111/dom.12734. PMID 27376831.
  13. ↑ Anonymous (2018). SGLT2(sodium-glucose cotransporter-2) Inhibitors for Diabetes: Drug Safety Communication - Regarding Rare Occurrences of a Serious Infection of the Genital Area. Food and Drug Administration
  14. ↑ Soumyanath, Amala(ed.) (2005-11-01). Traditional Medicines for Modern Times (1st Edition ed.). Taylor & Francis. ISBN 0-415-33464-0.
  15. ↑ McNeill, John H. (1999-02-01). Experimental Models of Diabetes (1st Edition ed.). CRC Press. p. 208. ISBN 0-8493-1667-7.
  16. ↑ Matsuda, H (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. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  17. ↑ 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.

External links

ndep.nih.gov drug tables

Sources

  • 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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