Diabetes medication: Difference between revisions
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{{Short description|Drugs that lower blood glucose levels to treat diabetes}} |
{{Short description|Drugs that lower blood glucose levels to treat diabetes}} |
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{{About|treatment of diabetes mellitus|treatment of diabetes insipidus|Diabetes insipidus}} |
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{{Use mdy dates|date=September 2011}} |
{{Use mdy dates|date=September 2011}} |
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'''Drugs used in diabetes''' treat [[diabetes mellitus]] by |
'''Drugs used in diabetes''' treat [[diabetes mellitus]] by altering the [[blood sugar level|glucose level in the blood]]. With the exceptions of [[Insulin (medication)|insulin]], most [[Glucagon-like peptide-1 receptor agonist|GLP receptor agonists]] ([[liraglutide]], [[exenatide]], and others), 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. |
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[[Diabetes mellitus type 1]] is a disease caused by the lack of insulin. |
[[Diabetes mellitus type 1]] is a disease caused by the lack of insulin. Insulin must be used in type 1, which must be injected. |
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[[Diabetes mellitus type 2]] is a disease of insulin resistance by cells. Type 2 diabetes mellitus is the most common type of diabetes. Treatments include agents that (1) increase the amount of insulin secreted by the pancreas, (2) increase the sensitivity of target organs to insulin, (3) decrease the rate at which glucose is absorbed from the gastrointestinal tract, and (4) increase |
[[Diabetes mellitus type 2]] is a disease of insulin resistance by cells. Type 2 diabetes mellitus is the most common type of diabetes. Treatments include agents that (1) increase the amount of insulin secreted by the pancreas, (2) increase the sensitivity of target organs to insulin, (3) decrease the rate at which glucose is absorbed from the gastrointestinal tract, and (4) increase loss of glucose through urination. |
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Several groups of drugs, mostly given by mouth, are effective in type 2, often in combination. The therapeutic combination in type 2 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 2 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. |
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Several drug classes are indicated for use in type 2 diabetes and are often used in combination. Therapeutic combinations may include several [[Insulin (medication)|insulin]] isoforms or varying classes of oral antihyperglycemic agents. As of 2020, 23 unique antihyperglycemic drug combinations were approved by the [[Food and Drug Administration|FDA]].<ref name="pmid35126141">{{cite journal | vauthors = Dahlén AD, Dashi G, Maslov I, Attwood MM, Jonsson J, Trukhan V, Schiöth HB | title = Trends in Antidiabetic Drug Discovery: FDA Approved Drugs, New Drugs in Clinical Trials and Global Sales| journal = Front Pharmacol | volume = 12 | issue = | pages = 4119 | date = January 2022 | pmid = 35126141 | pmc = 8807560 | doi = 10.3389/fphar.2021.807548 | doi-access = free}}</ref> [[Dapagliflozin/saxagliptin/metformin|The first triple combination]] of oral anti-diabetics was approved in 2019, consisting of [[metformin]], [[saxagliptin]], and [[dapagliflozin]]. [[Empagliflozin/linagliptin/metformin|Another triple combination]] approval for [[metformin]], [[linagliptin]], and [[empagliflozin]] followed in 2020.<ref name="pmid35126141"/> |
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[[Exenatide]] ([[Exenatide|Byetta]]) is a long-acting analogue of the hormone [[Glucagon-like peptide-1|GLP-1]], which the intestines secrete in response to the presence of food. Among other effects, GLP-1 delays stomach emptying and promotes a feeling of fullness after eating. Some obese people are deficient in GLP-1, and dieting reduces GLP-1 further. Byetta in Payless Online Pharmacy is currently available as a treatment for [[Type 2 diabetes|Diabetes mellitus type 2]]. Some, but not all, patients find that they lose substantial weight when taking Byetta. Drawbacks of Byetta include that it must be injected subcutaneously twice daily, and that it causes severe nausea in some patients, especially when therapy is initiated. Byetta is recommended only for patients with Type 2 Diabetes. |
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==Mechanisms of action== |
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Diabetes medications have four main mechanisms of action:{{citation needed|date=January 2024}} |
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* [[#Sensitizers|Insulin sensitization]]: Increased sensitivity of insulin receptors on cells leading to decreased [[insulin resistance]], and higher effects of insulin on blood glucose levels. |
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* [[#Secretagogues|Stimulation of beta cells]]: This stimulation increases insulin secretion from [[beta cell]]s of [[pancreas]]. |
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* [[#Alpha-glucosidase inhibitors|Alpha-glucosidase inhibition]]: Inhibition of the [[alpha-glucosidase]] enzyme decreases the rate at which glucose is absorbed from the gastrointestinal tract. |
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* [[#SGLT2 inhibitors|SGLT2 inhibition]]: Inhibition of [[SGLT2 inhibitor|sodium-glucose transport protein 2]] (SGLT2) decreases glucose reabsorption in the renal tubules of nephrons, thus increasing the amount of glucose excreted in urine. |
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==Insulin== |
==Insulin== |
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{{Main|Insulin (medication)}} |
{{Main|Insulin (medication)}} |
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Insulin is usually given [[Subcutaneous tissue|subcutaneously]], either by injections or by an [[insulin pump]]. In acute care settings, insulin may also be given intravenously. Insulins are typically characterized by the rate at which they are metabolized by the body, yielding different peak times and durations of action.<ref>{{cite book | vauthors = Powers AC | veditors = Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J |editor2-link=Anthony Fauci |title=[[Harrison's Principles of Internal Medicine]] |date=2011 |publisher=McGraw-Hill |isbn=978-0071748896 |edition=18th |chapter=Diabetes Mellitus}}</ref> Faster-acting insulins peak quickly and are subsequently metabolized, while longer-acting insulins tend to have extended peak times and remain active in the body for more significant periods.<ref name=":0">{{cite book | vauthors = Donner T, Sarkar S | chapter = Insulin – Pharmacology, Therapeutic Regimens, and Principles of Intensive Insulin Therapy |date=2000 | chapter-url= http://www.ncbi.nlm.nih.gov/books/NBK278938/ | title =Endotext |veditors = Feingold KR, Anawalt B, Boyce A, Chrousos G |publisher=MDText.com, Inc. |pmid=25905175 |access-date=2019-11-16 }}</ref> |
Insulin is usually given [[Subcutaneous tissue|subcutaneously]], either by injections or by an [[insulin pump]]. In acute care settings, insulin may also be given intravenously. Insulins are typically characterized by the rate at which they are metabolized by the body, yielding different peak times and durations of action.<ref>{{cite book | vauthors = Powers AC | veditors = Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J |editor2-link=Anthony Fauci |title=[[Harrison's Principles of Internal Medicine]] |date=2011 |publisher=McGraw-Hill |isbn=978-0071748896 |edition=18th |chapter=Diabetes Mellitus}}</ref> Faster-acting insulins peak quickly and are subsequently metabolized, while longer-acting insulins tend to have extended peak times and remain active in the body for more significant periods.<ref name=":0">{{cite book | vauthors = Donner T, Sarkar S | chapter = Insulin – Pharmacology, Therapeutic Regimens, and Principles of Intensive Insulin Therapy |date=2000 | chapter-url= http://www.ncbi.nlm.nih.gov/books/NBK278938/ | title =Endotext |veditors = Feingold KR, Anawalt B, Boyce A, Chrousos G |publisher=MDText.com, Inc. |pmid=25905175 |access-date=2019-11-16 }}</ref> |
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Examples of rapid-acting insulins (peak at ~1 hour) are: |
Examples of rapid-acting insulins (peak at ~1 hour) are: |
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* Insulin degludec (Tresiba) |
* Insulin degludec (Tresiba) |
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Insulin degludec is sometimes classed separately as an "ultra-long" acting insulin due to its duration of action of about 42 hours, compared with 24 hours for most other long |
Insulin degludec is sometimes classed separately as an "ultra-long" acting insulin due to its duration of action of about 42 hours, compared with 24 hours for most other long acting insulin preparations.<ref name=":0" /> |
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As |
As systematic review of studies comparing insulin detemir, insulin glargine, insulin degludec and NPH insulin did not show any clear benefits or serious [[Side effect|adverse effects]] for any particular form of insulin for nocturnal [[hypoglycemia]], severe hypoglycemia, [[glycated hemoglobin]] A1c, non-fatal [[myocardial infarction]]/[[stroke]], [[Quality of life (healthcare)|health-related quality of life]] or [[all-cause mortality]].<ref name=":2">{{cite journal | vauthors = Hemmingsen B, Metzendorf MI, Richter B | title = (Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus | journal = The Cochrane Database of Systematic Reviews | volume = 3 | issue = 4 | pages = CD013498 | date = March 2021 | pmid = 33662147 | pmc = 8094220 | doi = 10.1002/14651858.cd013498.pub2 }}</ref> The same review did not find any differences in effects of using these insulin analogues between adults and children.<ref name=":2" /> |
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Most oral anti-diabetic agents are contraindicated in pregnancy, in which |
Most oral anti-diabetic agents are contraindicated in pregnancy, in which insulin is preferred.<ref name="agabegi2nd-185" /> |
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Insulin is not administered by other routes, although this has been studied. An inhaled form was briefly licensed but was subsequently withdrawn.{{citation needed |date=April 2021}} |
Insulin is not administered by other routes, although this has been studied. An inhaled form was briefly licensed but was subsequently withdrawn.{{citation needed |date=April 2021}} |
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===Biguanides=== |
===Biguanides=== |
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{{Main|Biguanide}} |
{{Main|Biguanide}} |
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[[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, [[ |
[[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]], a biguanide, has become the most commonly used agent for type 2 diabetes in children and teenagers. Among common diabetic drugs, metformin is the only widely used oral drug that does not cause weight gain. |
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Typical reduction in [[glycated hemoglobin]] (A1C) values for |
Typical reduction in [[glycated hemoglobin]] (A1C) values for metformin is 1.5–2.0% |
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* |
*[[Metformin]] (Glucophage) may be the best choice for patients who also have heart failure,<ref name="pmid17761999">{{cite journal | vauthors = Eurich DT, McAlister FA, Blackburn DF, Majumdar SR, Tsuyuki RT, Varney J, Johnson JA | title = Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review | journal = BMJ | volume = 335 | issue = 7618 | pages = 497 | date = September 2007 | pmid = 17761999 | pmc = 1971204 | doi = 10.1136/bmj.39314.620174.80 }}</ref> but it should be temporarily discontinued before any radiographic procedure involving intravenous [[iodine|iodinated]] [[radiocontrast|contrast]], as patients are at an increased risk of [[lactic acidosis]]. |
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* [[Phenformin]] (DBI) was used from 1960s through 1980s, but was withdrawn due to lactic acidosis risk.<ref name="pmid16567854">{{cite journal | vauthors = Fimognari FL, Pastorelli R, Incalzi RA | title = Phenformin-induced lactic acidosis in an older diabetic patient: a recurrent drama (phenformin and lactic acidosis) | journal = Diabetes Care | volume = 29 | issue = 4 | pages = 950–951 | date = April 2006 | pmid = 16567854 | doi = 10.2337/diacare.29.04.06.dc06-0012 | url = http://care.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=16567854 | url-status = live | doi-access = free | df = mdy-all | archive-url = https://archive.today/20121209052027/http://care.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=16567854 | archive-date = December 9, 2012 }}</ref> |
* [[Phenformin]] (DBI) was used from 1960s through 1980s, but was withdrawn due to lactic acidosis risk.<ref name="pmid16567854">{{cite journal | vauthors = Fimognari FL, Pastorelli R, Incalzi RA | title = Phenformin-induced lactic acidosis in an older diabetic patient: a recurrent drama (phenformin and lactic acidosis) | journal = Diabetes Care | volume = 29 | issue = 4 | pages = 950–951 | date = April 2006 | pmid = 16567854 | doi = 10.2337/diacare.29.04.06.dc06-0012 | url = http://care.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=16567854 | url-status = live | doi-access = free | df = mdy-all | archive-url = https://archive.today/20121209052027/http://care.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=16567854 | archive-date = December 9, 2012 }}</ref> |
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* [[Buformin]] also was withdrawn due to lactic acidosis risk.<ref name="Verdonck">{{cite journal | vauthors = Verdonck LF, Sangster B, van Heijst AN, de Groot G, Maes RA | title = Buformin concentrations in a case of fatal lactic acidosis | journal = Diabetologia | volume = 20 | issue = 1 | pages = 45–46 | year = 1981 | pmid = 7202882 | doi = 10.1007/BF01789112 | doi-access = free }}</ref> |
* [[Buformin]] also was withdrawn due to lactic acidosis risk.<ref name="Verdonck">{{cite journal | vauthors = Verdonck LF, Sangster B, van Heijst AN, de Groot G, Maes RA | title = Buformin concentrations in a case of fatal lactic acidosis | journal = Diabetologia | volume = 20 | issue = 1 | pages = 45–46 | year = 1981 | pmid = 7202882 | doi = 10.1007/BF01789112 | doi-access = free }}</ref> |
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Metformin is |
Metformin is usually the first-line medication used for treatment of type 2 diabetes. In general, it is prescribed at initial diagnosis in conjunction with exercise and weight loss, as opposed to in the past, where it was prescribed after diet and exercise had failed. There is an immediate release as well as an extended-release formulation, typically reserved for patients experiencing [[gastrointestinal]] side-effects. It is also available in combination with other oral diabetic medications. |
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===Thiazolidinediones=== |
===Thiazolidinediones=== |
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{{Main|Thiazolidinedione}} |
{{Main|Thiazolidinedione}} |
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[[Thiazolidinedione]]s ([[TZD]]s), also known as "glitazones," bind to [[Peroxisome proliferator-activated receptor gamma|PPARγ]], |
[[Thiazolidinedione]]s ([[TZD]]s), also known as "glitazones," bind to [[Peroxisome proliferator-activated receptor gamma|PPARγ]], peroxysome proliferator activated receptor [[Peroxisome proliferator-activated receptor gamma|γ]], a type of nuclear regulatory protein involved in transcription of genes regulating glucose and fat metabolism. These PPARs act on peroxysome proliferator responsive elements (PPRE).<ref>{{Cite web |url=http://www.healthvalue.net/diabetesinsulinPPAR.html |title=diabetesinsulinPPAR |website=www.healthvalue.net |url-status=live |archive-url=https://web.archive.org/web/20160303204348/http://www.healthvalue.net/diabetesinsulinPPAR.html |archive-date=March 3, 2016 |access-date=May 6, 2018 |df=mdy-all}}</ref> 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 drugs also enhance PPAR-α activity and hence lead to a rise in HDL and some larger components of LDL. |
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* [[Rosiglitazone]] (Avandia): the [[European Medicines Agency]] recommended in September 2010 that it be suspended from the EU market due to elevated cardiovascular risks.<ref>European Medicines Agency, [http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2010/09/news_detail_001119.jsp&mid=WC0b01ac058004d5c1&jsenabled=true "European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim"] {{webarchive|url=https://web.archive.org/web/20140203052646/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fnews_and_events%2Fnews%2F2010%2F09%2Fnews_detail_001119.jsp&mid=WC0b01ac058004d5c1&jsenabled=true |date=February 3, 2014 }}, ''EMA'', 23 September 2009</ref> |
* [[Rosiglitazone]] (Avandia): the [[European Medicines Agency]] recommended in September 2010 that it be suspended from the EU market due to elevated cardiovascular risks.<ref>European Medicines Agency, [http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2010/09/news_detail_001119.jsp&mid=WC0b01ac058004d5c1&jsenabled=true "European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim"] {{webarchive|url=https://web.archive.org/web/20140203052646/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fnews_and_events%2Fnews%2F2010%2F09%2Fnews_detail_001119.jsp&mid=WC0b01ac058004d5c1&jsenabled=true |date=February 3, 2014 }}, ''EMA'', 23 September 2009</ref> |
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* [[Pioglitazone]] (Actos): remains on the market but has also been associated with increased cardiovascular risks.<ref name="pmid17848652">{{cite journal | vauthors = Lincoff AM, Wolski K, Nicholls SJ, Nissen SE | title = Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials | journal = JAMA | volume = 298 | issue = 10 | pages = 1180–1188 | date = September 2007 | pmid = 17848652 | doi = 10.1001/jama.298.10.1180 }}</ref> |
* [[Pioglitazone]] (Actos): remains on the market but has also been associated with increased cardiovascular risks.<ref name="pmid17848652">{{cite journal | vauthors = Lincoff AM, Wolski K, Nicholls SJ, Nissen SE | title = Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials | journal = JAMA | volume = 298 | issue = 10 | pages = 1180–1188 | date = September 2007 | pmid = 17848652 | doi = 10.1001/jama.298.10.1180 }}</ref> |
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Multiple retrospective studies have resulted in 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 |url=http://www.medscape.com/viewarticle/552484 |title=Expert Column – A Diabetes Outcome Progression Trial (ADOPT) | vauthors = Haffner SM |year=2007 |publisher=Medscape |access-date=2007-09-21}}</ref> as did the DREAM trial.<ref>{{Cite web |url= http://www.medscape.com/viewarticle/546503 |title=DREAM: Rosiglitazone Effective in Preventing Diabetes | vauthors = Gagnon L |date=24 October 2006 |publisher=Medscape |url-status=live |archive-url= https://web.archive.org/web/20081202225351/http://www.medscape.com/viewarticle/546503 |archive-date=December 2, 2008 |access-date=2007-09-21 |df=mdy-all}}</ref> The [[American Association of Clinical Endocrinologists]] (AACE), which provides clinical practice guidelines for management of diabetes, retains thiazolidinediones as recommended first, second, or third line agents for type 2 diabetes mellitus, as of their 2019 executive summary, over sulfonylureas and α-glucosidase inhibitors. However, they are less preferred than GLP-1 agonists or SGLT2 inhibitors, especially in patients with cardiovascular disease (which [[liraglutide]], [[empagliflozin]], and [[canagliflozin]] are all FDA approved to treat).<ref name=":1">{{cite journal | vauthors = Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, Dagogo-Jack S, DeFronzo RA, Einhorn D, Fonseca VA, Garber JR, Garvey WT, Grunberger G, Handelsman Y, Hirsch IB, Jellinger PS, McGill JB, Mechanick JI, Rosenblit PD, Umpierrez GE | display-authors = 6 | title = Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 2019 Executive Summary | journal = Endocrine Practice | volume = 25 | issue = 1 | pages = 69–100 | date = January 2019 | pmid = 30742570 | doi = 10.4158/cs-2018-0535 | doi-access = free }}</ref> |
Multiple retrospective studies have resulted in 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 |url=http://www.medscape.com/viewarticle/552484 |title=Expert Column – A Diabetes Outcome Progression Trial (ADOPT) | vauthors = Haffner SM |year=2007 |publisher=Medscape |access-date=2007-09-21}}</ref> as did the DREAM trial.<ref>{{Cite web |url= http://www.medscape.com/viewarticle/546503 |title=DREAM: Rosiglitazone Effective in Preventing Diabetes | vauthors = Gagnon L |date=24 October 2006 |publisher=Medscape |url-status=live |archive-url= https://web.archive.org/web/20081202225351/http://www.medscape.com/viewarticle/546503 |archive-date=December 2, 2008 |access-date=2007-09-21 |df=mdy-all}}</ref> The [[American Association of Clinical Endocrinologists]] (AACE), which provides clinical practice guidelines for management of diabetes, retains thiazolidinediones as recommended first, second, or third line agents for type 2 diabetes mellitus, as of their 2019 executive summary, over sulfonylureas and α-glucosidase inhibitors. However, they are less preferred than GLP-1 agonists or SGLT2 inhibitors, especially in patients with cardiovascular disease (which [[liraglutide]], [[empagliflozin]], and [[canagliflozin]] are all FDA approved to treat).<ref name=":1">{{cite journal | vauthors = Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, Dagogo-Jack S, DeFronzo RA, Einhorn D, Fonseca VA, Garber JR, Garvey WT, Grunberger G, Handelsman Y, Hirsch IB, Jellinger PS, McGill JB, Mechanick JI, Rosenblit PD, Umpierrez GE | display-authors = 6 | title = Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 2019 Executive Summary | journal = Endocrine Practice | volume = 25 | issue = 1 | pages = 69–100 | date = January 2019 | pmid = 30742570 | doi = 10.4158/cs-2018-0535 | doi-access = free }}</ref> |
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Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in [[the New England Journal of Medicine]].<ref>{{cite journal | vauthors = Nissen SE, Wolski K | title = Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes | journal = The New England Journal of Medicine | volume = 356 | issue = 24 | pages = 2457–2471 | date = June 2007 | pmid = 17517853 | doi = 10.1056/NEJMoa072761 | |
Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in [[the New England Journal of Medicine]].<ref>{{cite journal | vauthors = Nissen SE, Wolski K | title = Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes | journal = The New England Journal of Medicine | volume = 356 | issue = 24 | pages = 2457–2471 | date = June 2007 | pmid = 17517853 | doi = 10.1056/NEJMoa072761 | lay-url = http://www.nbcnews.com/id/18783816 | lay-date = May 21, 2007 | lay-source = [[Associated Press]] }}</ref> There have been a significant number of publications since then, and a [[Food and Drug Administration]] panel<ref>{{cite web | vauthors = Wood S | 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 | access-date = 2007-09-21 | url-status = live | archive-url = https://web.archive.org/web/20140318013618/http://www.medscape.com/viewarticle/560709 | archive-date = March 18, 2014 | df = mdy-all }}</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. 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]].<ref name=Ajjan>{{cite journal | vauthors = Ajjan RA, Grant PJ | title = The cardiovascular safety of rosiglitazone | journal = Expert Opinion on Drug Safety | volume = 7 | issue = 4 | pages = 367–376 | date = July 2008 | pmid = 18613801 | doi = 10.1517/14740338.7.4.367 | s2cid = 73109231 }}</ref> Safety studies are continuing. |
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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 2 diabetes who have already had a heart attack.<ref>{{cite journal | vauthors = Erdmann E, 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 the PROactive (PROactive 05) Study | journal = Journal of the American College of Cardiology | volume = 49 | issue = 17 | pages = 1772–1780 | date = May 2007 | pmid = 17466227 | doi = 10.1016/j.jacc.2006.12.048 | doi-access = free }}</ref> |
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 2 diabetes who have already had a heart attack.<ref>{{cite journal | vauthors = Erdmann E, 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 the PROactive (PROactive 05) Study | journal = Journal of the American College of Cardiology | volume = 49 | issue = 17 | pages = 1772–1780 | date = May 2007 | pmid = 17466227 | doi = 10.1016/j.jacc.2006.12.048 | doi-access = free }}</ref> |
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===Lyn kinase activators=== |
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The [[LYN]] kinase activator [[ |
The [[LYN]] kinase activator [[tolimidone]] has been reported to potentiate insulin signaling in a manner that is distinct from the glitazones.<ref name="Müller2000a">{{cite journal | vauthors = Müller G, Wied S, Frick W | title = Cross talk of pp125(FAK) and pp59(Lyn) non-receptor tyrosine kinases to insulin-mimetic signaling in adipocytes | journal = Molecular and Cellular Biology | volume = 20 | issue = 13 | pages = 4708–4723 | date = July 2000 | pmid = 10848597 | pmc = 85892 | doi = 10.1128/mcb.20.13.4708-4723.2000 }}</ref> The compound has demonstrated positive results in a Phase 2a clinical study involving 130 diabetic subjects.<ref>{{cite web|url=http://www.businesswire.com/news/home/20160613005028/en/Melior-Pharmaceuticals-Announces-Positive-Phase-2A-Results|title=Melior Pharmaceuticals Announces Positive Phase 2A Results in Type 2 Diabetes Study|website=businesswire.com|date=June 13, 2016|access-date=May 6, 2018|url-status=live|archive-url=https://web.archive.org/web/20170812162052/http://www.businesswire.com/news/home/20160613005028/en/Melior-Pharmaceuticals-Announces-Positive-Phase-2A-Results|archive-date=August 12, 2017|df=mdy-all}}</ref> |
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==Secretagogues== |
==Secretagogues== |
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{{unreferenced section|date=January 2016}} |
{{unreferenced section|date=January 2016}} |
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{{Main|Sulfonylurea}} |
{{Main|Sulfonylurea}} |
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[[Sulfonylurea]]s were the first widely used oral anti-hyperglycemic medications. They are ''insulin secretagogues'', triggering insulin release by inhibiting the [[ATP-sensitive potassium channel|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" |
[[Sulfonylurea]]s were the first widely used oral anti-hyperglycemic medications. They are ''insulin secretagogues'', triggering insulin release by inhibiting the [[ATP-sensitive potassium channel|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. |
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Current clinical practice guidelines from the [[American Association of Clinical Endocrinologists|AACE]] rate sulfonylureas (as well as glinides) below all other classes of antidiabetic drugs in terms of suggested use as first, second, or third line agents - this includes [[ |
Current clinical practice guidelines from the [[American Association of Clinical Endocrinologists|AACE]] rate sulfonylureas (as well as glinides) below all other classes of antidiabetic drugs in terms of suggested use as first, second, or third line agents - this includes [[bromocriptine]], the bile acid sequestrant [[colesevelam]], [[Alpha-glucosidase inhibitor|α-glucosidase inhibitors]], [[Thiazolidinedione|TZDs]] (glitazones), and [[Dipeptidyl peptidase-4 inhibitor|DPP-4 inhibitors]] (gliptins).<ref name=":1" /> The low cost of most sulfonylureas, however, especially when considering their significant efficacy in blood glucose reduction, tends to keep them as a more feasible option in many patients - neither SGLT2 inhibitors nor GLP-1 agonists, the classes most favored by the AACE guidelines after metformin, are currently available as generics. |
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Sulfonylureas bind strongly to [[plasma protein]]s. Sulfonylureas are useful only in type 2 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 cannot be used with type 1 diabetes, or diabetes of pregnancy. They can be safely used with metformin or glitazones. The primary side-effect is [[hypoglycemia]], which appears to happen more commonly with sulfonylureas than with other treatments.<ref name=":3">{{cite journal | vauthors = Shyangdan DS, Royle P, Clar C, Sharma P, Waugh N, Snaith A | title = Glucagon-like peptide analogues for type 2 diabetes mellitus | journal = The Cochrane Database of Systematic Reviews | issue = 10 | pages = CD006423 | date = October |
Sulfonylureas bind strongly to [[plasma protein]]s. Sulfonylureas are useful only in type 2 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 cannot be used with type 1 diabetes, or diabetes of pregnancy. They can be safely used with metformin or glitazones. The primary side-effect is [[hypoglycemia]], which appears to happen more commonly with sulfonylureas than with other treatments.<ref name=":3">{{cite journal | vauthors = Shyangdan DS, Royle P, Clar C, Sharma P, Waugh N, Snaith A | title = Glucagon-like peptide analogues for type 2 diabetes mellitus | journal = The Cochrane Database of Systematic Reviews | issue = 10 | pages = CD006423 | date = October 2011 | pmid = 21975753 | pmc = 6486297 | doi = 10.1002/14651858.cd006423.pub2 }}</ref> |
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A [[Cochrane (organisation)|Cochrane]] [[systematic review]] from 2011 showed that treatment with [[Sulfonylurea]] |
A [[Cochrane (organisation)|Cochrane]] [[systematic review]] from 2011 showed that treatment with [[Sulfonylurea|Sulphonylurea]] did not improve control of glucose levels more than insulin at 3 nor 12 months of treatment.<ref name=":4">{{cite journal | vauthors = Brophy S, Davies H, Mannan S, Brunt H, Williams R | title = Interventions for latent autoimmune diabetes (LADA) in adults | journal = The Cochrane Database of Systematic Reviews | issue = 9 | pages = CD006165 | date = September 2011 | pmid = 21901702 | pmc = 6486159 | doi = 10.1002/14651858.cd006165.pub3 }}</ref> This same review actually found evidence that treatment with Sulphonylurea could lead to earlier insulin dependence, with 30% of cases requiring insulin at 2 years.<ref name=":4" /> When studies measured fasting [[C-peptide]], no intervention influenced its concentration, but insulin maintained concentration better compared to Sulphonylurea.<ref name=":4" /> Still, it is important to highlight that the studies available to be included in this review presented considerable flaws in quality and design.<ref name=":4" /> |
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Typical reductions in [[glycated hemoglobin]] (A1C) values for second-generation sulfonylureas are 1.0–2.0%. |
Typical reductions in [[glycated hemoglobin]] (A1C) values for second-generation sulfonylureas are 1.0–2.0%. |
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* First-generation agents |
* First-generation agents |
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** [[tolbutamide]] |
** [[tolbutamide]] |
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** [[acetohexamide]] |
** [[acetohexamide]] |
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** [[tolazamide]] |
** [[tolazamide]] |
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** [[chlorpropamide]] |
** [[chlorpropamide]] |
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* Second-generation agents |
* Second-generation agents |
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** [[glipizide]] |
** [[glipizide]] |
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** glyburide or [[glibenclamide]] |
** glyburide or [[glibenclamide]] |
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** [[glimepiride]] |
** [[glimepiride]] |
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** [[gliclazide]] |
** [[gliclazide]] |
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** [[glyclopyramide]] |
** [[glyclopyramide]] |
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** [[gliquidone]] |
** [[gliquidone]] |
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===Nonsulfonylurea secretagogues=== |
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===Meglitinides=== |
====Meglitinides==== |
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{{Main|Meglitinide}} |
{{Main|Meglitinide}} |
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[[Meglitinide]]s help the pancreas produce insulin and are often called "short-acting secretagogues." They act on the same potassium channels as sulfonylureas, but at a different binding site.<ref>{{cite journal | vauthors = Rendell M | title = Advances in diabetes for the millennium: drug therapy of type 2 diabetes | journal = MedGenMed | volume = 6 | issue = 3 Suppl | pages = 9 | date = September 2004 | pmid = 15647714 | pmc = 1474831 }}</ref> By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, thereby enhancing insulin secretion.<ref name=diabetespancreasbeta>{{cite web | url = http://www.healthvalue.net/diabetespancreasbeta.html | title = Helping the pancreas produce insulin | access-date = 2007-09-21 | publisher=HealthValue| archive-url= https://web.archive.org/web/20070927043729/http://www.healthvalue.net/diabetespancreasbeta.html| archive-date= September 27, 2007 | url-status= live}}</ref> |
[[Meglitinide]]s help the pancreas produce insulin and are often called "short-acting secretagogues." They act on the same potassium channels as sulfonylureas, but at a different binding site.<ref>{{cite journal | vauthors = Rendell M | title = Advances in diabetes for the millennium: drug therapy of type 2 diabetes | journal = MedGenMed | volume = 6 | issue = 3 Suppl | pages = 9 | date = September 2004 | pmid = 15647714 | pmc = 1474831 }}</ref> By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, thereby enhancing insulin secretion.<ref name=diabetespancreasbeta>{{cite web | url = http://www.healthvalue.net/diabetespancreasbeta.html | title = Helping the pancreas produce insulin | access-date = 2007-09-21 | publisher=HealthValue| archive-url= https://web.archive.org/web/20070927043729/http://www.healthvalue.net/diabetespancreasbeta.html| archive-date= September 27, 2007 | url-status= live}}</ref> |
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Typical reductions in [[glycated hemoglobin]] (A1C) values are 0.5–1.0%. |
Typical reductions in [[glycated hemoglobin]] (A1C) values are 0.5–1.0%. |
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* [[repaglinide]] |
* [[repaglinide]] |
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* [[nateglinide]] |
* [[nateglinide]] |
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{{unreferenced section|date=January 2016}} |
{{unreferenced section|date=January 2016}} |
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{{Main|Alpha-glucosidase inhibitor}} |
{{Main|Alpha-glucosidase inhibitor}} |
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[[Alpha-glucosidase inhibitor]]s are |
[[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]]. |
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Typical reductions in [[glycated hemoglobin]] (A1C) values are 0.5–1.0%. |
Typical reductions in [[glycated hemoglobin]] (A1C) values are 0.5–1.0%. |
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* [[miglitol]] |
* [[miglitol]] |
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* [[acarbose]] |
* [[acarbose]] |
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* [[voglibose]] |
* [[voglibose]] |
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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. |
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. |
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==Peptide analogs== |
==Peptide analogs== |
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[[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]] |
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===Injectable incretin mimetics=== |
===Injectable incretin mimetics === |
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[[Incretin]]s are |
[[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]] (glucose-dependent insulinotropic peptide, GIP). Both GLP-1 and GIP are rapidly inactivated by the enzyme [[dipeptidyl peptidase-4]] (DPP-4). |
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====Injectable glucagon-like peptide analogs and agonists==== |
====Injectable glucagon-like peptide analogs and agonists==== |
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Glucagon-like peptide (GLP) agonists bind to a membrane GLP receptor.<ref name=diabetespancreasbeta/> As a consequence, 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. As of 2019, the [[American Association of Clinical Endocrinologists|AACE]] lists GLP-1 agonists, along with SGLT2 inhibitors, as the most preferred anti-diabetic agents after metformin. [[Liraglutide]] in particular may be considered first-line in diabetic patients with cardiovascular disease, as it has received FDA approval for reduction of risk of major adverse cardiovascular events in patients with type 2 diabetes.<ref name=":1" /><ref>{{Cite web|url=https://www.drugs.com/newdrugs/victoza-liraglutide-approved-reduce-risk-three-major-adverse-cardiovascular-events-type-2-diabetes-4582.html|title=Victoza (liraglutide) is Approved to Reduce the Risk of Three Major Adverse Cardiovascular Events in Type 2 Diabetes Patients|website=Drugs.com|language=en|access-date=2019-11-16}}</ref> In a 2011 [[Cochrane (organisation)|Cochrane]] [[Systematic review|review]], GLP-1 agonists showed approximately a 1% reduction in HbA1c when compared to placebo.<ref name=":3" /> GLP-1 agonists also show improvement of [[Beta cell|beta-cell]] function, but this effect does not last after treatment is stopped.<ref name=":3" /> Due to shorter duration of studies, this review did not allow for long-term positiver or negative effects to be assessed.<ref name=":3" /> |
Glucagon-like peptide (GLP) agonists bind to a membrane GLP receptor.<ref name=diabetespancreasbeta/> As a consequence, 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. As of 2019, the [[American Association of Clinical Endocrinologists|AACE]] lists GLP-1 agonists, along with SGLT2 inhibitors, as the most preferred anti-diabetic agents after metformin. [[Liraglutide]] in particular may be considered first-line in diabetic patients with cardiovascular disease, as it has received FDA approval for reduction of risk of major adverse cardiovascular events in patients with type 2 diabetes.<ref name=":1" /><ref>{{Cite web|url=https://www.drugs.com/newdrugs/victoza-liraglutide-approved-reduce-risk-three-major-adverse-cardiovascular-events-type-2-diabetes-4582.html|title=Victoza (liraglutide) is Approved to Reduce the Risk of Three Major Adverse Cardiovascular Events in Type 2 Diabetes Patients|website=Drugs.com|language=en|access-date=2019-11-16}}</ref> In a 2011 [[Cochrane (organisation)|Cochrane]] [[Systematic review|review]], GLP-1 agonists showed approximately a 1% reduction in HbA1c when compared to placebo.<ref name=":3" /> GLP-1 agonists also show improvement of [[Beta cell|beta-cell]] function, but this effect does not last after treatment is stopped.<ref name=":3" /> Due to shorter duration of studies, this review did not allow for long-term positiver or negative effects to be assessed.<ref name=":3" /> |
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* [[Exenatide]] (also Exendin-4, marketed as Byetta) is the first [[glucagon-like peptide-1|GLP-1]] agonist approved for the treatment of [[type 2 diabetes]]. Exenatide is not an analogue of GLP but rather a GLP agonist.<ref>{{cite journal | vauthors = Briones M, Bajaj M | title = Exenatide: a GLP-1 receptor agonist as novel therapy for Type 2 diabetes mellitus | journal = Expert Opinion on Pharmacotherapy | volume = 7 | issue = 8 | pages = 1055–1064 | date = June 2006 | pmid = 16722815 | doi = 10.1517/14656566.7.8.1055 | s2cid = 43740629 }}</ref><ref>{{cite journal | vauthors = Gallwitz B | title = Exenatide in type 2 diabetes: treatment effects in clinical studies and animal study data | journal = International Journal of Clinical Practice | volume = 60 | issue = 12 | pages = 1654–1661 | date = December 2006 | pmid = 17109672 | doi = 10.1111/j.1742-1241.2006.01196.x | s2cid = 8800490 | doi-access = free }}</ref> 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 | vauthors = 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 = 935–954 | year = 2007 | pmid = 17428109 | doi = 10.2165/00003495-200767060-00008 | s2cid = 195691202 }}</ref> A 2011 Cochrane review showed a HbA1c reduction of 0.20% more with Exenatide 2 mg compared to insulin glargine, exenatide 10 µg twice daily, sitagliptin and pioglitazone.<ref name=":3" /> Exenatide, together with liraglutide, led to greater weight loss than glucagon-like peptide analogues.<ref name=":3" /> |
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* [[Liraglutide]], a once-daily human analogue (97% homology), has been developed by [[Novo Nordisk]] under the brand name [[Victoza]]. The product was approved by the [[European Medicines Agency]] (EMEA) on July 3, 2009, and by the [[U.S. Food and Drug Administration]] (FDA) on January 25, 2010.<ref>{{cite web |url=https://www.drugs.com/nda/liraglutide_080530.html |title=Novo Nordisk Files for Regulatory Approval of Liraglutide in Both the US and Europe |access-date=2018-01-23 |url-status=live |archive-url=https://web.archive.org/web/20171215054200/https://www.drugs.com/nda/liraglutide_080530.html |archive-date=December 15, 2017 |df=mdy-all }} May 2008</ref><ref>{{cite web |url=http://www.medicalnewstoday.com/articles/74913.php |title=Liraglutide Provides Significantly Better Glucose Control Than Insulin Glargine in Phase 3 Study |access-date=2010-02-09 |url-status=live |archive-url=https://web.archive.org/web/20100723042509/http://www.medicalnewstoday.com/articles/74913.php |archive-date=July 23, 2010 |df=mdy-all }} "Liraglutide Provides Significantly Better Glucose Control Than Insulin Glargine In Phase 3 Study" June 2007</ref><ref>{{cite web |url=http://www.medicalnewstoday.com/articles/110349.php |title=Clinical Study Shows Liraglutide Reduced Blood Sugar, Weight, and Blood Pressure in Patients with Type 2 Diabetes |access-date=2010-02-09 |url-status=live |archive-url=https://web.archive.org/web/20090205233559/http://www.medicalnewstoday.com/articles/110349.php |archive-date=February 5, 2009 |df=mdy-all }} "Clinical Study Shows Liraglutide Reduced Blood Sugar, Weight, And Blood Pressure In Patients With Type 2 Diabetes" June 2008</ref><ref>{{cite web |url=http://www.drugdevelopment-technology.com/projects/liraglutide/ |title=Liraglutide – Next-Generation Antidiabetic Medication |access-date=2010-02-09 |url-status=live |archive-url=https://web.archive.org/web/20100618110150/http://www.drugdevelopment-technology.com/projects/liraglutide/ |archive-date=June 18, 2010 |df=mdy-all }}</ref><ref>{{cite web|url=http://www.novonordisk.com/science/about_rd/quarterly_rd_update.asp |title=Quarterly R&D; Update - Novo Nordisk A/S |access-date=2010-02-09 |url-status=dead |archive-url=https://web.archive.org/web/20100109101501/http://www.novonordisk.com/science/about_rd/quarterly_rd_update.asp |archive-date=January 9, 2010 }} Oct 2008 Inc results of LEAD 6 extension</ref><ref>{{cite web |url=https://money.cnn.com/news/newsfeeds/articles/marketwire/0580389.htm |title=Novo Nordisk Receives US Approval for Victoza(R) (Liraglutide) for the Treatment of Type 2 Diabetes |access-date=2010-02-09 |url-status=live |archive-url=https://web.archive.org/web/20100129215943/https://money.cnn.com/news/newsfeeds/articles/marketwire/0580389.htm |archive-date=January 29, 2010 |df=mdy-all }} January 2009</ref> A 2011 Cochrane review showed a HbA1c reduction of 0.24% more with liraglutide 1.8 mg compared to insulin glargine, 0.33% more than exenatide 10 µg twice daily, sitagliptin and rosiglitazone.<ref name=":3" /> Liraglutide, together with exenatide, led to greater weight loss than glucagon-like peptide analogues.<ref name=":3" /> |
*[[Exenatide]] (also Exendin-4, marketed as Byetta) is the first [[glucagon-like peptide-1|GLP-1]] agonist approved for the treatment of [[type 2 diabetes]]. Exenatide is not an analogue of GLP but rather a GLP agonist.<ref>{{cite journal | vauthors = Briones M, Bajaj M | title = Exenatide: a GLP-1 receptor agonist as novel therapy for Type 2 diabetes mellitus | journal = Expert Opinion on Pharmacotherapy | volume = 7 | issue = 8 | pages = 1055–1064 | date = June 2006 | pmid = 16722815 | doi = 10.1517/14656566.7.8.1055 | s2cid = 43740629 }}</ref><ref>{{cite journal | vauthors = Gallwitz B | title = Exenatide in type 2 diabetes: treatment effects in clinical studies and animal study data | journal = International Journal of Clinical Practice | volume = 60 | issue = 12 | pages = 1654–1661 | date = December 2006 | pmid = 17109672 | doi = 10.1111/j.1742-1241.2006.01196.x | s2cid = 8800490 }}</ref> 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 | vauthors = 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 = 935–954 | year = 2007 | pmid = 17428109 | doi = 10.2165/00003495-200767060-00008 }}</ref> A 2011 Cochrane review showed a HbA1c reduction of 0.20% more with Exenatide 2 mg compared to insulin glargine, exenatide 10 µg twice daily, sitagliptin and pioglitazone.<ref name=":3" /> Exenatide, together with liraglutide, led to greater weight loss than glucagon-like peptide analogues.<ref name=":3" /> |
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*[[Liraglutide]], a once-daily human analogue (97% homology), has been developed by [[Novo Nordisk]] under the brand name [[Victoza]]. The product was approved by the [[European Medicines Agency]] (EMEA) on July 3, 2009, and by the [[U.S. Food and Drug Administration]] (FDA) on January 25, 2010.<ref>{{cite web |url=https://www.drugs.com/nda/liraglutide_080530.html |title=Novo Nordisk Files for Regulatory Approval of Liraglutide in Both the US and Europe |access-date=2018-01-23 |url-status=live |archive-url=https://web.archive.org/web/20171215054200/https://www.drugs.com/nda/liraglutide_080530.html |archive-date=December 15, 2017 |df=mdy-all }} May 2008</ref><ref>{{cite web |url=http://www.medicalnewstoday.com/articles/74913.php |title=Liraglutide Provides Significantly Better Glucose Control Than Insulin Glargine in Phase 3 Study |access-date=2010-02-09 |url-status=live |archive-url=https://web.archive.org/web/20100723042509/http://www.medicalnewstoday.com/articles/74913.php |archive-date=July 23, 2010 |df=mdy-all }} "Liraglutide Provides Significantly Better Glucose Control Than Insulin Glargine In Phase 3 Study" June 2007</ref><ref>{{cite web |url=http://www.medicalnewstoday.com/articles/110349.php |title=Clinical Study Shows Liraglutide Reduced Blood Sugar, Weight, and Blood Pressure in Patients with Type 2 Diabetes |access-date=2010-02-09 |url-status=live |archive-url=https://web.archive.org/web/20090205233559/http://www.medicalnewstoday.com/articles/110349.php |archive-date=February 5, 2009 |df=mdy-all }} "Clinical Study Shows Liraglutide Reduced Blood Sugar, Weight, And Blood Pressure In Patients With Type 2 Diabetes" June 2008</ref><ref>{{cite web |url=http://www.drugdevelopment-technology.com/projects/liraglutide/ |title=Liraglutide – Next-Generation Antidiabetic Medication |access-date=2010-02-09 |url-status=live |archive-url=https://web.archive.org/web/20100618110150/http://www.drugdevelopment-technology.com/projects/liraglutide/ |archive-date=June 18, 2010 |df=mdy-all }}</ref><ref>{{cite web|url=http://www.novonordisk.com/science/about_rd/quarterly_rd_update.asp |title=Quarterly R&D; Update - Novo Nordisk A/S |access-date=2010-02-09 |url-status=dead |archive-url=https://web.archive.org/web/20100109101501/http://www.novonordisk.com/science/about_rd/quarterly_rd_update.asp |archive-date=January 9, 2010 }} Oct 2008 Inc results of LEAD 6 extension</ref><ref>{{cite web |url=https://money.cnn.com/news/newsfeeds/articles/marketwire/0580389.htm |title=Novo Nordisk Receives US Approval for Victoza(R) (Liraglutide) for the Treatment of Type 2 Diabetes |access-date=2010-02-09 |url-status=live |archive-url=https://web.archive.org/web/20100129215943/https://money.cnn.com/news/newsfeeds/articles/marketwire/0580389.htm |archive-date=January 29, 2010 |df=mdy-all }} January 2009</ref> A 2011 Cochrane review showed a HbA1c reduction of 0.24% more with liraglutide 1.8 mg compared to insulin glargine, 0.33% more than exenatide 10 µg twice daily, sitagliptin and rosiglitazone.<ref name=":3" /> Liraglutide, together with exenatide, led to greater weight loss than glucagon-like peptide analogues.<ref name=":3" /> |
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* |
*[[Taspoglutide]] is presently in Phase III clinical trials with [[Hoffman-La Roche]]. |
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* Lixisenatide (Lyxumia) Sanofi Aventis |
* Lixisenatide (Lyxumia) Sanofi Aventis |
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* |
*[[Semaglutide]] (Ozempic) (oral version is Rybelsus) |
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* |
*[[Dulaglutide]] ([[Trulicity]]) - once weekly |
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* |
*[[Albiglutide]] (Tanzeum) - once weekly |
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These agents may also cause a decrease in gastric motility, responsible for the common side-effect of nausea, which tends to subside with time.<ref name=":3" /> |
These agents may also cause a decrease in gastric motility, responsible for the common side-effect of nausea, which tends to subside with time.<ref name=":3" /> |
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====Dipeptidyl peptidase-4 inhibitors==== |
====Dipeptidyl peptidase-4 inhibitors==== |
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{{Main|Dipeptidyl peptidase-4 inhibitor}} |
{{Main|Dipeptidyl peptidase-4 inhibitor}} |
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GLP-1 analogs resulted in weight loss and had more gastrointestinal side-effects, while in general [[dipeptidyl peptidase-4]] (DPP-4) inhibitors were weight-neutral and |
GLP-1 analogs resulted in weight loss and had more gastrointestinal side-effects, while in general [[dipeptidyl peptidase-4]] (DPP-4) inhibitors were weight-neutral and increased risk for infection and headache, but both classes appear to present an alternative to other antidiabetic drugs. However, weight gain and/or hypoglycemia have been observed when [[dipeptidyl peptidase-4 inhibitor]]s were used with sulfonylureas; effects on long-term health and morbidity rates are still unknown.<ref name=nps01>{{Cite journal |author=National Prescribing Service |journal=RADAR |title=Dipeptidyl peptidase-4 inhibitors ('gliptins') for type 2 diabetes mellitus |date=1 August 2010 |url=https://www.nps.org.au/radar/articles/dipeptidyl-peptidase-4-inhibitors-gliptins-for-type-2-diabetes-mellitus |access-date=7 March 2021}}</ref> |
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DPP-4 inhibitors increase blood concentration of the [[incretin]] GLP-1 by inhibiting its degradation by DPP-4. |
DPP-4 inhibitors increase blood concentration of the [[incretin]] GLP-1 by inhibiting its degradation by DPP-4. |
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DPP-4 inhibitors lowered hemoglobin [[Glycated hemoglobin|A1C]] values by 0.74%, comparable to other antidiabetic drugs.<ref>{{cite journal | vauthors = Amori RE, Lau J, Pittas AG | title = Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis | journal = JAMA | volume = 298 | issue = 2 | pages = 194–206 | date = July 2007 | pmid = 17622601 | doi = 10.1001/jama.298.2.194 }}</ref> |
DPP-4 inhibitors lowered hemoglobin [[Glycated hemoglobin|A1C]] values by 0.74%, comparable to other antidiabetic drugs.<ref>{{cite journal | vauthors = Amori RE, Lau J, Pittas AG | title = Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis | journal = JAMA | volume = 298 | issue = 2 | pages = 194–206 | date = July 2007 | pmid = 17622601 | doi = 10.1001/jama.298.2.194 }}</ref> |
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A result in one RCT comprising 206 patients aged 65 or older (mean baseline HgbA1c of 7.8%) receiving either 50 or 100 mg/d of [[sitagliptin]] was shown to reduce HbA1c by 0.7% (combined result of both doses).<ref>{{cite journal| vauthors = Barzilei N, Mahoney EM, Guo H |title=Sitagliptin is well tolerated and leads to rapid improvement in blood glucose in the first days of monotherapy in patients aged 65 years and older with T2DM|journal=Diabetes|year=2009|volume=58|pages=587}}</ref> A combined result of 5 RCTs enlisting a total of 279 patients aged 65 or older (mean baseline HbA1c of 8%) receiving 5 mg/d of [[saxagliptin]] was shown to reduce HbA1c by 0.73%.<ref>{{cite journal | vauthors = Doucet J, Chacra A, Maheux P, Lu J, Harris S, Rosenstock J | title = Efficacy and safety of saxagliptin in older patients with type 2 diabetes mellitus | journal = Current Medical Research and Opinion | volume = 27 | issue = 4 | pages = 863–869 | date = April 2011 | pmid = 21323504 | doi = 10.1185/03007995.2011.554532 | s2cid = 206965817 }}</ref> A combined result of 5 RCTs enlisting a total of 238 patients aged 65 or older (mean baseline HbA1c of 8.6%) receiving 100 mg/d of [[vildagliptin]] was shown to reduce HbA1c by 1.2%.<ref>{{cite journal | vauthors = Pratley RE, Rosenstock J, Pi-Sunyer FX, Banerji MA, Schweizer A, Couturier A, Dejager S | title = Management of type 2 diabetes in treatment-naive elderly patients: benefits and risks of vildagliptin monotherapy | journal = Diabetes Care | volume = 30 | issue = 12 | pages = 3017–3022 | date = December 2007 | pmid = 17878242 | doi = 10.2337/dc07-1188 | doi-access = free }}</ref> Another set of 6 combined RCTs involving [[alogliptin]] (approved by FDA in 2013) was shown to reduce HbA1c by 0.73% in 455 patients aged 65 or older who received 12.5 or 25 mg/d of the medication.<ref>{{cite journal | vauthors = Pratley RE, McCall T, Fleck PR, Wilson CA, Mekki Q | title = Alogliptin use in elderly people: a pooled analysis from phase 2 and 3 studies | journal = Journal of the American Geriatrics Society | volume = 57 | issue = 11 | pages = 2011–2019 | date = November 2009 | pmid = 19793357 | doi = 10.1111/j.1532-5415.2009.02484.x | s2cid = 28683917 }}</ref> |
A result in one RCT comprising 206 patients aged 65 or older (mean baseline HgbA1c of 7.8%) receiving either 50 or 100 mg/d of [[sitagliptin]] was shown to reduce HbA1c by 0.7% (combined result of both doses).<ref>{{cite journal| vauthors = Barzilei N, Mahoney EM, Guo H |title=Sitagliptin is well tolerated and leads to rapid improvement in blood glucose in the first days of monotherapy in patients aged 65 years and older with T2DM|journal=Diabetes|year=2009|volume=58|pages=587}}</ref> A combined result of 5 RCTs enlisting a total of 279 patients aged 65 or older (mean baseline HbA1c of 8%) receiving 5 mg/d of [[saxagliptin]] was shown to reduce HbA1c by 0.73%.<ref>{{cite journal | vauthors = Doucet J, Chacra A, Maheux P, Lu J, Harris S, Rosenstock J | title = Efficacy and safety of saxagliptin in older patients with type 2 diabetes mellitus | journal = Current Medical Research and Opinion | volume = 27 | issue = 4 | pages = 863–869 | date = April 2011 | pmid = 21323504 | doi = 10.1185/03007995.2011.554532 | s2cid = 206965817 }}</ref> A combined result of 5 RCTs enlisting a total of 238 patients aged 65 or older (mean baseline HbA1c of 8.6%) receiving 100 mg/d of [[vildagliptin]] was shown to reduce HbA1c by 1.2%.<ref>{{cite journal | vauthors = Pratley RE, Rosenstock J, Pi-Sunyer FX, Banerji MA, Schweizer A, Couturier A, Dejager S | title = Management of type 2 diabetes in treatment-naive elderly patients: benefits and risks of vildagliptin monotherapy | journal = Diabetes Care | volume = 30 | issue = 12 | pages = 3017–3022 | date = December 2007 | pmid = 17878242 | doi = 10.2337/dc07-1188 | doi-access = free }}</ref> Another set of 6 combined RCTs involving [[alogliptin]] (approved by FDA in 2013) was shown to reduce HbA1c by 0.73% in 455 patients aged 65 or older who received 12.5 or 25 mg/d of the medication.<ref>{{cite journal | vauthors = Pratley RE, McCall T, Fleck PR, Wilson CA, Mekki Q | title = Alogliptin use in elderly people: a pooled analysis from phase 2 and 3 studies | journal = Journal of the American Geriatrics Society | volume = 57 | issue = 11 | pages = 2011–2019 | date = November 2009 | pmid = 19793357 | doi = 10.1111/j.1532-5415.2009.02484.x | s2cid = 28683917 }}</ref> |
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===Injectable amylin analogues=== |
===Injectable amylin analogues=== |
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{{unreferenced section|date=January 2016}} |
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⚫ | [[Amylin]] agonist analogues slow gastric emptying and suppress [[glucagon]]. They have all the incretins actions except stimulation of insulin secretion. {{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. Typical reductions in A1C values are 0.5–1.0%. |
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==Glycosurics== |
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⚫ | [[Amylin]] agonist analogues slow gastric emptying and suppress [[glucagon]]. They have all the incretins actions except stimulation of insulin secretion. {{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. Typical reductions in A1C values are 0.5–1.0%. |
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==SGLT2 inhibitors== |
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{{Main|Gliflozin}} |
{{Main|Gliflozin}} |
||
[[ |
[[SLC5A2|SGLT-2 inhibitors]] block the re-uptake of glucose in the renal tubules, promoting loss of glucose in the urine. This causes both mild weight loss, and a mild reduction in blood sugar levels with little risk of hypoglycemia.<ref>{{cite journal | vauthors = Dietrich E, Powell J, Taylor JR | title = Canagliflozin: a novel treatment option for type 2 diabetes | journal = Drug Design, Development and Therapy | volume = 7 | pages = 1399–1408 | date = November 2013 | pmid = 24285921 | pmc = 3840773 | doi = 10.2147/DDDT.S48937 }}</ref> Oral preparations may be available alone or in combination with other agents.<ref>{{Cite web|url=https://www.fda.gov/Drugs/DrugSafety/ucm446852.htm|title=Drug Safety and Availability - Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors | author = Center for Drug Evaluation and Research|website=www.fda.gov|language=en|access-date=2017-08-26|url-status=live|archive-url=https://web.archive.org/web/20161129094121/http://www.fda.gov/Drugs/DrugSafety/ucm446852.htm|archive-date=November 29, 2016|df=mdy-all}}</ref> Along with GLP-1 agonists, they are considered preferred second or third agents for type 2 diabetics sub-optimally controlled with metformin alone, according to most recent clinical practice guidelines.<ref name=":1" /> Because they are taken by mouth, rather than injected (like GLP-1 agonists), patients who are [[Fear of needles|injection-averse]] may prefer these agents over the former. They may be considered first line in diabetic patients with cardiovascular disease, especially [[heart failure]], as these medications have been shown to reduce the risk of hospitalization in patients with such comorbidities.<ref>{{Cite web|url=https://www.uptodate.com/contents/sodium-glucose-co-transporter-2-inhibitors-for-the-treatment-of-hyperglycemia-in-type-2-diabetes-mellitus?search=sglt2%20inhibitors&source=search_result&selectedTitle=2~69&usage_type=default&display_rank=1#H3506386806|title=UpToDate|website=www.uptodate.com|access-date=2019-11-16}}</ref> Because they are not available as generic medications, however, cost may limit their feasibility for many patients. Furthermore, there has been growing evidence that the effectiveness and safety of this drug class could depend on genetic variability of the patients.<ref>[https://www.bjbms.org/ojs/index.php/bjbms/article/view/5646 Imamovic Kadric S, Kulo Cesic A, Dujic T. Pharmacogenetics of new classes of antidiabetic drugs. Bosn J of Basic Med Sci. 2021.] DOI: https://doi.org/10.17305/bjbms.2021.5646</ref> |
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Examples include: |
Examples include: |
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* [[Dapagliflozin]] |
* [[Dapagliflozin]] |
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* [[Canagliflozin]] |
* [[Canagliflozin]] |
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* [[Empagliflozin]] |
* [[Empagliflozin]] |
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* |
*[[Remogliflozin]] |
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The side effects of |
The side effects of SGLT-2 inhibitors are derived directly from their mechanism of action; these include an increased risk of: [[ketoacidosis]], [[urinary tract infection]]s, [[Vaginal yeast infection|candidal vulvovaginitis]], and [[hypoglycemia]].<ref>{{Cite news|url=http://www.diabetes.co.uk/diabetes-medication/sglt2-inhibitors.html|title=SGLT2 Inhibitors (Gliflozins) – Drugs, Suitability, Benefits & Side Effects|access-date=2017-08-26|url-status=live|archive-url=https://web.archive.org/web/20170827050028/http://www.diabetes.co.uk/diabetes-medication/sglt2-inhibitors.html|archive-date=August 27, 2017|df=mdy-all}}</ref> |
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==Comparison== |
==Comparison== |
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! colspan="5" style="background-color: #CCEEEE;" | Comparison of anti-diabetic medication<ref>{{cite journal | vauthors = Cambon-Thomsen A, Rial-Sebbag E, Knoppers BM | title = Trends in ethical and legal frameworks for the use of human biobanks | journal = The European Respiratory Journal | volume = 30 | issue = 2 | pages = 373–382 | date = August 2007 | pmid = 17666560 | doi = 10.1183/09031936.00165006 | doi-access = free }} adapted from table 2, which includes a list of issues</ref><ref name="BBDdiabetesM2">{{Cite journal |author1 = Consumer Reports Health Best Buy Drugs |author1-link = Consumer Reports |title = The Oral Diabetes Drugs: Treating Type 2 Diabetes |publisher = [[Consumer Reports]] |journal = Best Buy Drugs |page = 20 |url = http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/DiabetesUpdate-FINAL-Feb09.pdf |access-date = September 18, 2012 |url-status = live |archive-url = https://web.archive.org/web/20130227145458/http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/DiabetesUpdate-FINAL-Feb09.pdf |archive-date = February 27, 2013 |df = mdy-all }}, which is citing |
! colspan="5" style="background-color: #CCEEEE;" | Comparison of anti-diabetic medication<ref>{{cite journal | vauthors = Cambon-Thomsen A, Rial-Sebbag E, Knoppers BM | title = Trends in ethical and legal frameworks for the use of human biobanks | journal = The European Respiratory Journal | volume = 30 | issue = 2 | pages = 373–382 | date = August 2007 | pmid = 17666560 | doi = 10.1183/09031936.00165006 | doi-access = free }} adapted from table 2, which includes a list of issues</ref><ref name="BBDdiabetesM2">{{Cite journal |author1 = Consumer Reports Health Best Buy Drugs |author1-link = Consumer Reports |title = The Oral Diabetes Drugs: Treating Type 2 Diabetes |publisher = [[Consumer Reports]] |journal = Best Buy Drugs |page = 20 |url = http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/DiabetesUpdate-FINAL-Feb09.pdf |access-date = September 18, 2012 |url-status = live |archive-url = https://web.archive.org/web/20130227145458/http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/DiabetesUpdate-FINAL-Feb09.pdf |archive-date = February 27, 2013 |df = mdy-all }}, which is citing |
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* {{cite journal|title=Oral Diabetes Medications for Adults With Type 2 Diabetes. An Update|journal=Comparative Effectiveness Review|date=March 2011| |
* {{cite journal|title=Oral Diabetes Medications for Adults With Type 2 Diabetes. An Update|journal=Comparative Effectiveness Review|date=March 2011|volume=number 27|issue=AHRQ Pub. No. 11–EHC038–1|url=http://effectivehealthcare.ahrq.gov/ehc/products/155/645/Oral%20Diabetes_ExSumm%20%282%29.pdf|access-date=28 November 2012|author=Agency for Healthcare Research and Quality|author-link=Agency for Healthcare Research and Quality|url-status=dead|archive-url=https://web.archive.org/web/20130927121129/http://effectivehealthcare.ahrq.gov/ehc/products/155/645/Oral%20Diabetes_ExSumm%20%282%29.pdf|archive-date=September 27, 2013|df=mdy-all}} |
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* {{cite journal | vauthors = Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R, Marinopoulos SS, Puhan MA, Ranasinghe P, Block L, Nicholson WK, Hutfless S, Bass EB, Bolen S | display-authors = 6 | title = Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations | journal = Annals of Internal Medicine | volume = 154 | issue = 9 | pages = 602–613 | date = May 2011 | pmid = 21403054 | pmc = 3733115 | doi = 10.7326/0003-4819-154-9-201105030-00336 }} |
* {{cite journal | vauthors = Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R, Marinopoulos SS, Puhan MA, Ranasinghe P, Block L, Nicholson WK, Hutfless S, Bass EB, Bolen S | display-authors = 6 | title = Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations | journal = Annals of Internal Medicine | volume = 154 | issue = 9 | pages = 602–613 | date = May 2011 | pmid = 21403054 | pmc = 3733115 | doi = 10.7326/0003-4819-154-9-201105030-00336 }} |
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</ref> |
</ref> |
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|- |
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| [[Sulfonylurea]]s ([[glyburide]], [[glimepiride]], [[glipizide]]) |
| [[Sulfonylurea]]s ([[glyburide]], [[glimepiride]], [[glipizide]]) |
||
| Stimulating insulin release by pancreatic [[beta cell]]s by inhibiting the [[ATP-sensitive potassium channel|K<sub>ATP</sub> channel]] |
| Stimulating insulin release by pancreatic [[beta cell]]s by inhibiting the [[ATP-sensitive potassium channel|K<sub>ATP</sub> channel]] |
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| |
| |
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* |
*Inexpensive |
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* |
*Fast onset of action |
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* |
*No effect on [[blood pressure]] |
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* |
*No detrimental effect on [[low-density lipoprotein]] |
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* |
*Lower risk of [[Human gastrointestinal tract|gastrointestinal]] side effects than metformin |
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* |
*Convenient dosing |
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| |
| |
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* |
*Cause an average of 5–10 pounds [[weight gain]] |
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* |
*Increase the risk of hypoglycemia |
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* |
*Glyburide increases risk of [[hypoglycemia]] slightly more compared to glimepiride and glipizide |
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|- |
|- |
||
| [[Metformin]] |
| [[Metformin]] |
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| Acts on the liver to reduce gluconeogenesis and causes a decrease in [[insulin resistance]] via increasing [[AMPK]] signalling. |
| Acts on the liver to reduce gluconeogenesis and causes a decrease in [[insulin resistance]] via increasing [[AMPK]] signalling. |
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| |
| |
||
* |
*Associated with weight loss |
||
* |
*Lower risk of hypoglycemia compared to other antidiabetics |
||
* |
*Decreases [[low-density lipoprotein]] |
||
* |
*Decreases [[triglycerides]] |
||
* |
*No effect on blood pressure |
||
* |
*Lowered all-cause mortality in diabetics |
||
* |
*Inexpensive |
||
| |
| |
||
* |
*Higher risk of [[Human gastrointestinal tract|gastrointestinal]] side effects |
||
* |
*Due to the risk of potentially fatal [[lactic acidosis]], contraindicated in people with [[shock (circulatory)|shock]]; with acute or chronic, moderate or severe [[kidney disease]] or at risk for impaired kidney function from [[Radiocontrast agent|intravenous dye]]; and with acute or chronic [[metabolic acidosis]] |
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* |
*Risk of lactic acidosis also is increased for people with unstable or acute [[heart failure]], [[liver disease]], or [[alcoholism]], or who are recovering from major [[surgery]] |
||
* |
*Increased risk of [[vitamin B12 deficiency]]<ref name=agabegi2nd-185/> |
||
* |
*[[Metallic taste]]<ref name=agabegi2nd-185/> |
||
|- |
|- |
||
| [[Alpha-glucosidase inhibitor]]s ([[acarbose]], [[miglitol]], [[voglibose]]) |
| [[Alpha-glucosidase inhibitor]]s ([[acarbose]], [[miglitol]], [[voglibose]]) |
||
| Inhibit carbohydrate digestion in the small intestine by inhibiting enzymes that break down polysaccharides |
| Inhibit carbohydrate digestion in the small intestine by inhibiting enzymes that break down polysaccharides |
||
| |
| |
||
* |
*Slightly lower risk of hypoglycemia compared to sulfonylureas |
||
* |
*Associated with modest weight loss |
||
* |
*Decreases triglycerides |
||
* |
*No detrimental effect on cholesterol |
||
| |
| |
||
* |
*Less effective than most other diabetes pills in lowering [[glycated hemoglobin]] |
||
* |
*Increased risk of GI side effects than other diabetes pills except metformin |
||
* |
*Inconvenient dosing |
||
|- |
|- |
||
| [[Thiazolidinediones]] ([[Pioglitazone]], [[Rosiglitazone]]) |
| [[Thiazolidinediones]] ([[Pioglitazone]], [[Rosiglitazone]]) |
||
| Reduce insulin resistance by activating [[Peroxisome proliferator-activated receptor gamma|PPAR-γ]] in fat and muscle |
| Reduce insulin resistance by activating [[Peroxisome proliferator-activated receptor gamma|PPAR-γ]] in fat and muscle |
||
| |
| |
||
* |
*Lower the risk of hypoglycemia |
||
* |
*May slightly increase [[high-density lipoprotein]] |
||
* |
*Rosiglitazone linked to decreased triglycerides |
||
* |
*Convenient dosing |
||
| |
| |
||
* |
*Increase the risk of [[heart failure]] |
||
* |
*Cause an average of 5–10 pounds [[weight gain]] |
||
* |
*Are associated with a higher risk of edema, anemia and bone fractures |
||
* |
*Can increase low-density lipoprotein |
||
* |
*Rosiglitazone has been linked to increased triglycerides and an increased risk of a heart attack |
||
* |
*Pioglitazone has been linked to an increased risk of bladder cancer |
||
* |
*Have a slower onset of action |
||
* |
*Require monitoring for [[hepatotoxicity]] |
||
* |
*Expensive |
||
|- |
|- |
||
|[[SGLT2 inhibitors]] |
|[[SGLT2 inhibitors]] |
||
|} |
|} |
||
== |
==Generic== |
||
Many anti-diabetes drugs are available as generics. These include:<ref>{{cite web |url=http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/DiabetesUpdate-FINAL-Feb09.pdf |title=The Oral Diabetes Drugs Treating Type 2 Diabetes Comparing Effectiveness, Safety, and Price |access-date=July 17, 2013 |url-status=live |archive-url=https://web.archive.org/web/20130615083100/http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/DiabetesUpdate-FINAL-Feb09.pdf |archive-date=June 15, 2013 |df=mdy-all }}</ref> |
Many anti-diabetes drugs are available as generics. These include:<ref>{{cite web |url=http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/DiabetesUpdate-FINAL-Feb09.pdf |title=The Oral Diabetes Drugs Treating Type 2 Diabetes Comparing Effectiveness, Safety, and Price |access-date=July 17, 2013 |url-status=live |archive-url=https://web.archive.org/web/20130615083100/http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/DiabetesUpdate-FINAL-Feb09.pdf |archive-date=June 15, 2013 |df=mdy-all }}</ref> |
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* [[Sulfonylureas]] – glimepiride, glipizide, glyburide |
* [[Sulfonylureas]] – glimepiride, glipizide, glyburide |
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Line 278: | Line 279: | ||
* [[Meglitinide]]s – nateglinide |
* [[Meglitinide]]s – nateglinide |
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* Combination of sulfonylureas plus metformin – known by generic names of the two drugs |
* Combination of sulfonylureas plus metformin – known by generic names of the two drugs |
||
No generics are available for [[dipeptidyl peptidase-4 inhibitor]]s (Onglyza), the glifozins, the incretins and various combinations |
No generics are available for [[dipeptidyl peptidase-4 inhibitor]]s (Januvia, Onglyza), the glifozins, the incretins and various combinations. |
||
== Alternative Medicine == |
== Alternative Medicine == |
||
The effect of [[Ayurveda|Ayurvedic]] treatments has been researched, however due to methodological flaws of |
The effect of [[Ayurveda|Ayurvedic]] treatments has been researched, however due to methodological flaws of studies it has not been possible to draw conclusion regarding efficacy of these treatments and there is insufficient evidence to recommend them.<ref>{{cite journal | vauthors = Sridharan K, Mohan R, Ramaratnam S, Panneerselvam D | title = Ayurvedic treatments for diabetes mellitus | journal = The Cochrane Database of Systematic Reviews | issue = 12 | pages = CD008288 | date = December 2011 | pmid = 22161426 | pmc = 3718571 | doi = 10.1002/14651858.CD008288.pub2 | collaboration = Cochrane Metabolic and Endocrine Disorders Group }}</ref> |
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== References == |
== References == |
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Line 293: | Line 294: | ||
{{Major Drug Groups}} |
{{Major Drug Groups}} |
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{{Diabetes}} |
{{Diabetes}} |
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{{Authority control}} |
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{{DEFAULTSORT:Anti-Diabetic Drug}} |
{{DEFAULTSORT:Anti-Diabetic Drug}} |
Revision as of 03:01, 3 May 2024
Drugs used in diabetes treat diabetes mellitus by altering the glucose level in the blood. With the exceptions of insulin, most GLP receptor agonists (liraglutide, exenatide, and others), 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 1, which must be injected.
Diabetes mellitus type 2 is a disease of insulin resistance by cells. Type 2 diabetes mellitus is the most common type of diabetes. Treatments include agents that (1) increase the amount of insulin secreted by the pancreas, (2) increase the sensitivity of target organs to insulin, (3) decrease the rate at which glucose is absorbed from the gastrointestinal tract, and (4) increase loss of glucose through urination.
Several groups of drugs, mostly given by mouth, are effective in type 2, often in combination. The therapeutic combination in type 2 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 2 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.
Exenatide (Byetta) is a long-acting analogue of the hormone GLP-1, which the intestines secrete in response to the presence of food. Among other effects, GLP-1 delays stomach emptying and promotes a feeling of fullness after eating. Some obese people are deficient in GLP-1, and dieting reduces GLP-1 further. Byetta in Payless Online Pharmacy is currently available as a treatment for Diabetes mellitus type 2. Some, but not all, patients find that they lose substantial weight when taking Byetta. Drawbacks of Byetta include that it must be injected subcutaneously twice daily, and that it causes severe nausea in some patients, especially when therapy is initiated. Byetta is recommended only for patients with Type 2 Diabetes.
Insulin
Insulin is usually given subcutaneously, either by injections or by an insulin pump. In acute care settings, insulin may also be given intravenously. Insulins are typically characterized by the rate at which they are metabolized by the body, yielding different peak times and durations of action.[1] Faster-acting insulins peak quickly and are subsequently metabolized, while longer-acting insulins tend to have extended peak times and remain active in the body for more significant periods.[2]
Examples of rapid-acting insulins (peak at ~1 hour) are:
- Insulin lispro (Humalog)
- Insulin aspart (Novolog)
- Insulin glulisine (Apidra)
Examples of short-acting insulins (peak 2–4 hours) are:
- Regular insulin (Humulin R, Novolin R)
- Prompt insulin zinc (Semilente)
Examples of intermediate-acting insulins (peak 4–10 hours) are:
- Isophane insulin, neutral protamine Hagedorn (NPH) (Humulin N, Novolin N)
- Insulin zinc (Lente)
Examples of long-acting insulins (duration 24 hours, often without peak) are:
- Extended insulin zinc insulin (Ultralente)
- Insulin glargine (Lantus)
- Insulin detemir (Levemir)
- Insulin degludec (Tresiba)
Insulin degludec is sometimes classed separately as an "ultra-long" acting insulin due to its duration of action of about 42 hours, compared with 24 hours for most other long acting insulin preparations.[2]
As systematic review of studies comparing insulin detemir, insulin glargine, insulin degludec and NPH insulin did not show any clear benefits or serious adverse effects for any particular form of insulin for nocturnal hypoglycemia, severe hypoglycemia, glycated hemoglobin A1c, non-fatal myocardial infarction/stroke, health-related quality of life or all-cause mortality.[3] The same review did not find any differences in effects of using these insulin analogues between adults and children.[3]
Most oral anti-diabetic agents are contraindicated in pregnancy, in which insulin is preferred.[4]
Insulin is not administered by other routes, although this has been studied. An inhaled form was briefly licensed but was subsequently withdrawn.[citation needed]
Sensitizers
Insulin sensitizers address the core problem in type 2 diabetes – insulin resistance.
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, a biguanide, has become the most commonly used agent for type 2 diabetes in children and teenagers. Among common diabetic drugs, metformin is the only widely used oral drug that does not cause weight gain.
Typical reduction in glycated hemoglobin (A1C) values for metformin is 1.5–2.0%
- Metformin (Glucophage) may be the best choice for patients who also have heart failure,[5] but it should be temporarily discontinued before any radiographic procedure involving intravenous iodinated contrast, as patients are at an increased risk of lactic acidosis.
- Phenformin (DBI) was used from 1960s through 1980s, but was withdrawn due to lactic acidosis risk.[6]
- Buformin also was withdrawn due to lactic acidosis risk.[7]
Metformin is usually the first-line medication used for treatment of type 2 diabetes. In general, it is prescribed at initial diagnosis in conjunction with exercise and weight loss, as opposed to in the past, where it was prescribed after diet and exercise had failed. There is an immediate release as well as an extended-release formulation, typically reserved for patients experiencing gastrointestinal side-effects. It is also available in combination with other oral diabetic medications.
Thiazolidinediones
Thiazolidinediones (TZDs), also known as "glitazones," bind to PPARγ, peroxysome proliferator activated receptor γ, a type of nuclear regulatory protein involved in transcription of genes regulating glucose and fat metabolism. These PPARs act on peroxysome proliferator responsive elements (PPRE).[8] 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 drugs also enhance PPAR-α activity and hence lead to a rise in HDL and some larger components of LDL.
Typical reductions in glycated hemoglobin (A1C) values are 1.5–2.0%. Some examples are:
- Rosiglitazone (Avandia): the European Medicines Agency recommended in September 2010 that it be suspended from the EU market due to elevated cardiovascular risks.[9]
- Pioglitazone (Actos): remains on the market but has also been associated with increased cardiovascular risks.[10]
- Troglitazone (Rezulin): used in 1990s, withdrawn due to hepatitis and liver damage risk.[11]
Multiple retrospective studies have resulted in 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,[12] as did the DREAM trial.[13] The American Association of Clinical Endocrinologists (AACE), which provides clinical practice guidelines for management of diabetes, retains thiazolidinediones as recommended first, second, or third line agents for type 2 diabetes mellitus, as of their 2019 executive summary, over sulfonylureas and α-glucosidase inhibitors. However, they are less preferred than GLP-1 agonists or SGLT2 inhibitors, especially in patients with cardiovascular disease (which liraglutide, empagliflozin, and canagliflozin are all FDA approved to treat).[14]
Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in the New England Journal of Medicine.[15] There have been a significant number of publications since then, and a Food and Drug Administration panel[16] 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.[17] 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 2 diabetes who have already had a heart attack.[18]
Lyn kinase activators
The LYN kinase activator tolimidone has been reported to potentiate insulin signaling in a manner that is distinct from the glitazones.[19] The compound has demonstrated positive results in a Phase 2a clinical study involving 130 diabetic subjects.[20]
Secretagogues
Secretagogues are drugs that increase output from a gland, in the case of insulin from the pancreas.
Sulfonylureas
Sulfonylureas were the first widely used oral anti-hyperglycemic medications. They are insulin secretagogues, triggering insulin release by inhibiting 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.
Current clinical practice guidelines from the AACE rate sulfonylureas (as well as glinides) below all other classes of antidiabetic drugs in terms of suggested use as first, second, or third line agents - this includes bromocriptine, the bile acid sequestrant colesevelam, α-glucosidase inhibitors, TZDs (glitazones), and DPP-4 inhibitors (gliptins).[14] The low cost of most sulfonylureas, however, especially when considering their significant efficacy in blood glucose reduction, tends to keep them as a more feasible option in many patients - neither SGLT2 inhibitors nor GLP-1 agonists, the classes most favored by the AACE guidelines after metformin, are currently available as generics.
Sulfonylureas bind strongly to plasma proteins. Sulfonylureas are useful only in type 2 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 cannot be used with type 1 diabetes, or diabetes of pregnancy. They can be safely used with metformin or glitazones. The primary side-effect is hypoglycemia, which appears to happen more commonly with sulfonylureas than with other treatments.[21]
A Cochrane systematic review from 2011 showed that treatment with Sulphonylurea did not improve control of glucose levels more than insulin at 3 nor 12 months of treatment.[22] This same review actually found evidence that treatment with Sulphonylurea could lead to earlier insulin dependence, with 30% of cases requiring insulin at 2 years.[22] When studies measured fasting C-peptide, no intervention influenced its concentration, but insulin maintained concentration better compared to Sulphonylurea.[22] Still, it is important to highlight that the studies available to be included in this review presented considerable flaws in quality and design.[22]
Typical reductions in glycated hemoglobin (A1C) values for second-generation sulfonylureas are 1.0–2.0%.
- First-generation agents
- Second-generation agents
- glipizide
- glyburide or glibenclamide
- glimepiride
- gliclazide
- glyclopyramide
- gliquidone
Nonsulfonylurea secretagogues
Meglitinides
Meglitinides help the pancreas produce insulin and are often called "short-acting secretagogues." They act on the same potassium channels as sulfonylureas, but at a different binding site.[23] By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, thereby enhancing insulin secretion.[24]
They are taken with or shortly before meals to boost the insulin response to each meal. If a meal is skipped, the medication is also skipped.
Typical reductions in glycated hemoglobin (A1C) values are 0.5–1.0%.
Adverse reactions include weight gain and hypoglycemia.
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.
Typical reductions in glycated hemoglobin (A1C) values are 0.5–1.0%.
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
This section needs additional citations for verification. (January 2016) |

Injectable 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 (glucose-dependent insulinotropic peptide, GIP). Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).
Injectable glucagon-like peptide analogs and agonists
Glucagon-like peptide (GLP) agonists bind to a membrane GLP receptor.[24] As a consequence, 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. As of 2019, the AACE lists GLP-1 agonists, along with SGLT2 inhibitors, as the most preferred anti-diabetic agents after metformin. Liraglutide in particular may be considered first-line in diabetic patients with cardiovascular disease, as it has received FDA approval for reduction of risk of major adverse cardiovascular events in patients with type 2 diabetes.[14][25] In a 2011 Cochrane review, GLP-1 agonists showed approximately a 1% reduction in HbA1c when compared to placebo.[21] GLP-1 agonists also show improvement of beta-cell function, but this effect does not last after treatment is stopped.[21] Due to shorter duration of studies, this review did not allow for long-term positiver or negative effects to be assessed.[21]
- 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.[26][27] Exenatide has only 53% homology with GLP, which increases its resistance to degradation by DPP-4 and extends its half-life.[28] A 2011 Cochrane review showed a HbA1c reduction of 0.20% more with Exenatide 2 mg compared to insulin glargine, exenatide 10 µg twice daily, sitagliptin and pioglitazone.[21] Exenatide, together with liraglutide, led to greater weight loss than glucagon-like peptide analogues.[21]
- Liraglutide, a once-daily human analogue (97% homology), has been developed by Novo Nordisk under the brand name Victoza. The product was approved by the European Medicines Agency (EMEA) on July 3, 2009, and by the U.S. Food and Drug Administration (FDA) on January 25, 2010.[29][30][31][32][33][34] A 2011 Cochrane review showed a HbA1c reduction of 0.24% more with liraglutide 1.8 mg compared to insulin glargine, 0.33% more than exenatide 10 µg twice daily, sitagliptin and rosiglitazone.[21] Liraglutide, together with exenatide, led to greater weight loss than glucagon-like peptide analogues.[21]
- Taspoglutide is presently in Phase III clinical trials with Hoffman-La Roche.
- Lixisenatide (Lyxumia) Sanofi Aventis
- Semaglutide (Ozempic) (oral version is Rybelsus)
- Dulaglutide (Trulicity) - once weekly
- Albiglutide (Tanzeum) - once weekly
These agents may also cause a decrease in gastric motility, responsible for the common side-effect of nausea, which tends to subside with time.[21]
Gastric inhibitory peptide analogs
Dipeptidyl peptidase-4 inhibitors
GLP-1 analogs resulted in weight loss and had more gastrointestinal side-effects, while in general dipeptidyl peptidase-4 (DPP-4) inhibitors were weight-neutral and increased risk for infection and headache, but both classes appear to present an alternative to other antidiabetic drugs. However, weight gain and/or hypoglycemia have been observed when dipeptidyl peptidase-4 inhibitors were used with sulfonylureas; effects on long-term health and morbidity rates are still unknown.[35]
DPP-4 inhibitors increase blood concentration of the incretin GLP-1 by inhibiting its degradation by DPP-4.
Examples are:
- vildagliptin (Galvus) EU Approved 2008
- sitagliptin (Januvia) FDA approved Oct 2006
- saxagliptin (Onglyza) FDA Approved July 2009
- linagliptin (Tradjenta) FDA Approved May 2, 2011
- alogliptin
- septagliptin
- teneligliptin
- gemigliptin (Zemiglo)
DPP-4 inhibitors lowered hemoglobin A1C values by 0.74%, comparable to other antidiabetic drugs.[36]
A result in one RCT comprising 206 patients aged 65 or older (mean baseline HgbA1c of 7.8%) receiving either 50 or 100 mg/d of sitagliptin was shown to reduce HbA1c by 0.7% (combined result of both doses).[37] A combined result of 5 RCTs enlisting a total of 279 patients aged 65 or older (mean baseline HbA1c of 8%) receiving 5 mg/d of saxagliptin was shown to reduce HbA1c by 0.73%.[38] A combined result of 5 RCTs enlisting a total of 238 patients aged 65 or older (mean baseline HbA1c of 8.6%) receiving 100 mg/d of vildagliptin was shown to reduce HbA1c by 1.2%.[39] Another set of 6 combined RCTs involving alogliptin (approved by FDA in 2013) was shown to reduce HbA1c by 0.73% in 455 patients aged 65 or older who received 12.5 or 25 mg/d of the medication.[40]
Injectable 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. Typical reductions in A1C values are 0.5–1.0%.
Glycosurics
SGLT-2 inhibitors block the re-uptake of glucose in the renal tubules, promoting loss of glucose in the urine. This causes both mild weight loss, and a mild reduction in blood sugar levels with little risk of hypoglycemia.[41] Oral preparations may be available alone or in combination with other agents.[42] Along with GLP-1 agonists, they are considered preferred second or third agents for type 2 diabetics sub-optimally controlled with metformin alone, according to most recent clinical practice guidelines.[14] Because they are taken by mouth, rather than injected (like GLP-1 agonists), patients who are injection-averse may prefer these agents over the former. They may be considered first line in diabetic patients with cardiovascular disease, especially heart failure, as these medications have been shown to reduce the risk of hospitalization in patients with such comorbidities.[43] Because they are not available as generic medications, however, cost may limit their feasibility for many patients. Furthermore, there has been growing evidence that the effectiveness and safety of this drug class could depend on genetic variability of the patients.[44]
Examples include:
The side effects of SGLT-2 inhibitors are derived directly from their mechanism of action; these include an increased risk of: ketoacidosis, urinary tract infections, candidal vulvovaginitis, and hypoglycemia.[45]
Comparison
The following table compares some common anti-diabetic agents, generalizing classes, although there may be substantial variation in individual drugs of each class. When the table makes a comparison such as "lower risk" or "more convenient" the comparison is with the other drugs on the table.
Comparison of anti-diabetic medication[46][47] | ||||
---|---|---|---|---|
Drug class[47] | Mechanism of action[4] | Advantages[47] | Disadvantages[47] | |
Sulfonylureas (glyburide, glimepiride, glipizide) | Stimulating insulin release by pancreatic beta cells by inhibiting the KATP channel |
|
| |
Metformin | Acts on the liver to reduce gluconeogenesis and causes a decrease in insulin resistance via increasing AMPK signalling. |
|
| |
Alpha-glucosidase inhibitors (acarbose, miglitol, voglibose) | Inhibit carbohydrate digestion in the small intestine by inhibiting enzymes that break down polysaccharides |
|
| |
Thiazolidinediones (Pioglitazone, Rosiglitazone) | Reduce insulin resistance by activating PPAR-γ in fat and muscle |
|
| |
SGLT2 inhibitors |
Generic
Many anti-diabetes drugs are available as generics. These include:[48]
- Sulfonylureas – glimepiride, glipizide, glyburide
- Biguanides – metformin
- Thiazolidinediones (Tzd) – pioglitazone, Actos generic
- Alpha-glucosidase inhibitors – Acarbose
- Meglitinides – nateglinide
- Combination of sulfonylureas plus metformin – known by generic names of the two drugs
No generics are available for dipeptidyl peptidase-4 inhibitors (Januvia, Onglyza), the glifozins, the incretins and various combinations.
Alternative Medicine
The effect of Ayurvedic treatments has been researched, however due to methodological flaws of studies it has not been possible to draw conclusion regarding efficacy of these treatments and there is insufficient evidence to recommend them.[49]
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Further reading
- Lebovitz, Harold E. (2004). Therapy For Diabetes Mellitus and Related Disorders (4th ed.). Alexandria, VA: American Diabetes Association. ISBN 978-1-58040-187-6.
- Adams, Michael Ian; Holland, Norman Norwood (2003). Core Concepts in Pharmacology. Englewood Cliffs, NJ: Prentice Hall. ISBN 978-0-13-089329-1.