Rosiglitazone: Difference between revisions

{{Short description|Chemical compound}}

| Verifiedfields = changed

| verifiedrevid = 458777178

| IUPAC_name = (''RS'')-5-[4-(2-[methyl(pyridin-2-yl)amino]ethoxy)benzyl]thiazolidine-2,4-dione

| image = rosiglitazone.svg

| width = 232

| chirality = [[Racemic mixture]]

| image2 = Rosiglitazone ball-and-stick.png

| tradename = Avandia

| Drugs.com = {{drugs.com|monograph|avandia}}

| MedlinePlus = a699023

| licence_EU = yes

| licence_US = Rosiglitazone

| pregnancy_AU = B3

| pregnancy_US = C

| legal_UK = POM

| legal_US = Rx-only

| routes_of_administration = By mouth

| bioavailability = 99%

| protein_bound = 99.8%

| metabolism = [[Liver]] ([[CYP2C8]]-mediated)

| elimination_half-life = 3–4 hours

| excretion = [[Kidney]] (64%) and fecal (23%)

| CAS_number_Ref = {{cascite|correct|??}}

| ATC_prefix = A10

| ATC_suffix = BG02

| PubChem = 77999

| IUPHAR_ligand = 1056

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB00412

| ChemSpiderID = 70383

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 05V02F2KDG

| KEGG_Ref = {{keggcite|changed|kegg}}

| KEGG = D08491

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 50122

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 121

| PDB_ligand = RGZ

<!--Chemical data-->

| smiles = O=C1NC(=O)SC1Cc3ccc(OCCN(c2ncccc2)C)cc3

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C18H19N3O3S/c1-21(16-4-2-3-9-19-16)10-11-24-14-7-5-13(6-8-14)12-15-17(22)20-18(23)25-15/h2-9,15H,10-12H2,1H3,(H,20,22,23)

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = YASAKCUCGLMORW-UHFFFAOYSA-N

| melting_point = 122

| melting_high = 123

'''Rosiglitazone''' (trade name '''Avandia''') is an [[antidiabetic drug]] in the [[thiazolidinedione]] class. It works as an [[insulin]] sensitizer, by binding to the [[PPAR]] in fat cells and making the cells more responsive to insulin. It is marketed by the pharmaceutical company GlaxoSmithKline (GSK) as a stand-alone drug or for use in combination with [[metformin]] or with [[glimepiride]]. First released in 1999, annual sales peaked at approximately $2.5-billion in 2006; however, following a [[meta-analysis]] in 2007 that linked the drug's use to an increased risk of [[Myocardial infarction|heart attack]],<ref name="pmid17517853">{{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 | s2cid = 46431986 | doi-access = free }}</ref> sales plummeted to just $9.5-million in 2012. The drug's patent expired in 2012.<ref>{{cite patent|country=US|number=5002953|title=Novel compounds|pubdate=1991-03-26|inventor = Hindley RM |assign=[[Beecham Group|Beecham Group plc]]}}</ref>

It was patented in 1987 and approved for medical use in 1999.<ref>{{Cite book | vauthors = Fischer J, Ganellin CR |url= https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA450 |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=450 |language=en}}</ref> Despite rosiglitazone's effectiveness at decreasing blood sugar in [[type 2 diabetes mellitus]], its use decreased dramatically as studies showed apparent associations with increased risks of heart attacks and death.<ref name="Chen2012">{{cite journal | vauthors = Chen X, Yang L, Zhai SD | title = Risk of cardiovascular disease and all-cause mortality among diabetic patients prescribed rosiglitazone or pioglitazone: a meta-analysis of retrospective cohort studies | journal = Chinese Medical Journal | volume = 125 | issue = 23 | pages = 4301–4306 | date = December 2012 | pmid = 23217404 }}</ref> Adverse effects alleged to be caused by rosiglitazone were the subject of over 13,000 lawsuits against GSK;<ref name="bloomberg.com">{{Cite news |url=https://www.bloomberg.com/news/2010-07-09/glaxo-withheld-avandia-study-former-fda-manager-said-to-testify-in-suit.html |title=Glaxo Withheld Avandia Study, Ex-Regulator Said to Testify |publisher=Bloomberg}}</ref> as of July 2010, GSK had agreed to settlements on more than 11,500 of these suits.

Some reviewers recommended rosiglitazone be taken off the market, but an [[Food and Drug Administration|FDA]] panel disagreed, and it remains available in the U.S.<ref>{{Cite news | vauthors = Harris G |url=https://www.nytimes.com/2010/02/20/health/policy/20avandia.html |title=Controversial Diabetes Drug Harms Heart, U.S. Concludes |date=February 19, 2010 |work=New York Times}}</ref> From November 2011 until November 2013, the federal government did not allow Avandia to be sold without a prescription from a certified doctor; moreover, patients were required to be informed of the risks associated with its use, and the drug had to be purchased by mail order through specified pharmacies.<ref>{{Cite news |url=http://yourlife.usatoday.com/health/medical/heartdisease/story/2011/05/Diabetes-drug-Avandia-to-be-pulled-from-retail-shelves/47316450/1?csp=34news |title=Most Popular E-mail Newsletter |date=2011-05-24 |work=USA Today |access-date=2011-05-19 |archive-date=2018-07-20 |archive-url=https://web.archive.org/web/20180720171305/https://www.usatoday.com/topic/D2591A44-DFD9-4D0D-AF7A-CC0B3B92CBB0/health-wellness/ |url-status=dead }}</ref> In 2013, the FDA lifted its earlier restrictions on rosiglitazone after reviewing the results of a 2009 trial which failed to show increased heart attack risk.<ref name="urlGlaxo's Avandia Cleared From Sales Restrictions by FDA - Bloomberg">{{Cite news |url=https://www.bloomberg.com/news/2013-11-25/glaxo-s-avandia-cleared-from-sales-restrictions-by-fda.html |title=Glaxo's Avandia Cleared From Sales Restrictions by FDA |publisher=Bloomberg}}</ref><ref>{{Cite news |last=U.S. Food and Drug Administration |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm376516.htm |title=FDA requires removal of certain restrictions on the diabetes drug Avandia |date=November 25, 2013 |author-link=Food and Drug Administration}}</ref>

In Europe, the [[European Medicines Agency]] (EMA) recommended in September 2010 that the drug be suspended because the benefits no longer outweighed the risks.<ref name="ema_recommend_suspend">{{cite web | url = http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2010/09/news_detail_001119.jsp&murl=menus/news_and_events/news_and_events.jsp&mid=WC0b01ac058004d5c1&jsenabled=false | publisher = European Medicines Agency | work = News and Events | title = European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim | date = 2018-09-17 }}</ref><ref name="bbc_ema_suspension">{{cite news | url = https://www.bbc.co.uk/news/health-11397645 | publisher = BBC News | title = Call to 'suspend' diabetes drug | date=2010-09-23}}</ref> It was withdrawn from the market in the UK, Spain and India in 2010,<ref name=ban>{{cite web | url = http://cdsco.nic.in/html/drugsbanned.html | title = Drugs banned in India | publisher = Central Drugs Standard Control Organization, Dte.GHS, Ministry of Health and Family Welfare, Government of India | access-date = 2013-09-17 | url-status = dead | archive-url = https://web.archive.org/web/20150221053621/http://cdsco.nic.in/html/drugsbanned.html | archive-date = 2015-02-21 }}</ref> and in New Zealand and South Africa in 2011.<ref name="Stuff.co.nz_4669573">{{cite news |url=http://www.stuff.co.nz/4669573 |archive-url=https://web.archive.org/web/20131013121141/http://www.stuff.co.nz/4669573 |url-status=dead |archive-date=13 October 2013 |title=Diabetes drug withdrawn |date=17 February 2011 |agency=[[NZPA]] |work=[[Stuff.co.nz]] |access-date=5 November 2011 }}</ref>

{{TOC limit|3}}

==Medical uses==

Rosiglitazone was approved for glycemic control in people with [[type 2 diabetes]], as measured by [[glycated haemoglobin]] A1c (HbA1c) as a surrogate endpoint, similar to that of other oral antidiabetic drugs.<ref name="pmid17636824">{{cite journal | vauthors = Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH | title = Rosiglitazone for type 2 diabetes mellitus | journal = The Cochrane Database of Systematic Reviews | volume = 2007 | issue = 3 | pages = CD006063 | date = July 2007 | pmid = 17636824 | pmc = 7389529 | doi = 10.1002/14651858.CD006063.pub2 }}</ref><ref name="pmid18955635">{{cite journal | vauthors = Selvin E, Bolen S, Yeh HC, Wiley C, Wilson LM, Marinopoulos SS, Feldman L, Vassy J, Wilson R, Bass EB, Brancati FL | display-authors = 6 | title = Cardiovascular outcomes in trials of oral diabetes medications: a systematic review | journal = Archives of Internal Medicine | volume = 168 | issue = 19 | pages = 2070–2080 | date = October 2008 | pmid = 18955635 | pmc = 2765722 | doi = 10.1001/archinte.168.19.2070 }}</ref> The controversy over adverse effects has dramatically reduced the use of rosiglitazone.<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>

Published studies did not provide evidence that outcomes like mortality, morbidity, adverse effects, costs and health-related quality of life are positively influenced by rosiglitazone.<ref name=pmid17636824 />

===Heart failure===

One of the safety concerns identified before approval was fluid retention. Moreover, the combination of rosiglitazone with insulin resulted in a higher rate of congestive heart failure. In Europe there were contraindications for use in heart failure and combination with insulin.<ref name="pmid21153629">{{cite journal | vauthors = Blind E, Dunder K, de Graeff PA, Abadie E | title = Rosiglitazone: a European regulatory perspective | journal = Diabetologia | volume = 54 | issue = 2 | pages = 213–218 | date = February 2011 | pmid = 21153629 | doi = 10.1007/s00125-010-1992-5 | s2cid = 33360502 | doi-access = free }}</ref>

A meta analysis of all trials from 2010 and 2019 confirmed a higher risk of heart failure and a double risk when rosiglitazone was administered as add-on therapy to insulin.<ref name="pmid19328563">{{cite journal | vauthors = Mannucci E, Monami M, Di Bari M, Lamanna C, Gori F, Gensini GF, Marchionni N | title = Cardiac safety profile of rosiglitazone: a comprehensive meta-analysis of randomized clinical trials | journal = International Journal of Cardiology | volume = 143 | issue = 2 | pages = 135–140 | date = August 2010 | pmid = 19328563 | doi = 10.1016/j.ijcard.2009.01.064 }}</ref><ref>{{cite journal | vauthors = Wallach JD, Wang K, Zhang AD, Cheng D, Grossetta Nardini HK, Lin H, Bracken MB, Desai M, Krumholz HM, Ross JS | display-authors = 6 | title = Updating insights into rosiglitazone and cardiovascular risk through shared data: individual patient and summary level meta-analyses | journal = BMJ | volume = 368 | pages = l7078 | date = February 2020 | pmid = 32024657 | pmc = 7190063 | doi = 10.1136/bmj.l7078 | doi-access = free }}</ref> Two meta-analyses of real life cohort studies found a higher risk of heart failure compared to pioglitazone.<ref name=Chen2012 /><ref name="pmid21415101" /> There were 649 excess cases of heart failure every 100,000 patients who received rosiglitazone rather than pioglitazone.

===Heart attacks===

The relative risk of ischemic cardiac events seen in pre-approval trials of rosiglitazone was similar to that of comparable drugs, but there was increased LDL cholesterol, LDL/HDL cholesterol ratio, triglycerides and weight.<ref>{{cite web| vauthors = Nissen S |title= Rosiglitazone a critical overview. Presentation to FDA Advisory Committee |website=[[Food and Drug Administration]]|url=https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM224741.pdf |access-date=30 March 2014}}</ref><ref>{{cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21071_Avandia_medr.pdf |title=Medical Officer's Review of New Drug Application 21-071: Rosiglitazone (Avandia) |date=April 19, 1999 |access-date=May 26, 2014}}</ref>

In 2005, at the insistence of the World Health Organization, GSK performed a meta-analysis of all 37 trials involving use of rosiglitazone, finding a hazard ratio of 1.29 (0.99 to 1.89).

In 2006 the GSK updated the analysis, now including 42 trials and showing a hazard ratio of 1.31 (1.01 to 1.70). A large observational study comparing patients treated with rosiglitizone with patients treated with other diabetes therapies was performed at the same time and found a relative risk of 0.93 (95% C.I. 0.8 to 1.1) for those treated with rosiglitazone. The information was passed to the FDA and posted on the company website, but not otherwise published. GSK provided these analyses to the FDA, but neither the company nor the FDA warned prescribers or patients of the hazard.<ref name="Nissen">{{cite journal | vauthors = Nissen SE | title = Rosiglitazone: a case of regulatory hubris | journal = BMJ | volume = 347 | pages = f7428 | date = December 2013 | pmid = 24335808 | doi = 10.1136/bmj.f7428 | s2cid = 42125428 }}</ref> According to the FDA, the Agency did not issue a safety bulletin because the results of the meta analysis conflicted with those of the observational study and with the results of the ADOPT trial.<ref>{{cite web |url=https://www.fda.gov/NewsEvents/Testimony/ucm153838.htm |title=Safety of Rosiglitazone Maleate (Avandia) |website=[[Food and Drug Administration]] }}</ref>

A [[meta-analysis]] in May 2007 reported the use of rosiglitazone was associated with a 1.4 fold increased risk of [[myocardial infarction|heart attack]] and a numerically higher (but non-significant) increase in risk of death from all cardiovascular diseases against control. It contained 42 trials of which 27 were unpublished.<ref name="pmid17517853" /> Another meta analysis of 4 trials with follow-up longer than 1 year found similar results.<ref name="Singh 1189–95">{{cite journal | vauthors = Singh S, Loke YK, Furberg CD | title = Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis | journal = JAMA | volume = 298 | issue = 10 | pages = 1189–1195 | date = September 2007 | pmid = 17848653 | doi = 10.1001/jama.298.10.1189 | s2cid = 41755937 }}</ref> Nissen's meta analysis was criticized in a 2007 article by George Diamond ''et al.'' in the [[Annals of Internal Medicine]]. The authors concluded that Nissens' analysis had excluded trials with important data on the cardiovascular profile of rosiglitazone, had inappropriately combined trials of greatly differing design, and had inappropriately excluded trials with no cardiovascular events. The authors concluded that no firm conclusion could be drawn regarding whether rosiglitazone increased or decreased cardiovascular risk.<ref>{{cite journal | vauthors = Diamond GA, Bax L, Kaul S | title = Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death | journal = Annals of Internal Medicine | volume = 147 | issue = 8 | pages = 578–581 | date = October 2007 | pmid = 17679700 | doi = 10.7326/0003-4819-147-8-200710160-00182 | doi-access = }}</ref> Investigators from the [[Cochrane Collaboration]] published a meta-analysis of their own on the use of rosiglitazone in Type II diabetes, concluding there was not sufficient evidence to show any health benefit for rosiglitazone. Noting the recent publication by Nissen, they repeated their meta analysis including only the trials included in the Nissen study that dealt with Type II diabetics. (The Nissen study included some trials in people with other disorders.) They did not find a statistically significant increase in cardiovascular events, but noted that all of the cardiovascular endpoints they analyzed showed a non-significant trend toward worse outcomes in the rosiglitazone arms.<ref>{{cite journal | vauthors = Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH | title = Rosiglitazone for type 2 diabetes mellitus | journal = The Cochrane Database of Systematic Reviews | volume = 2007 | issue = 3 | pages = CD006063 | date = July 2007 | pmid = 17636824 | pmc = 7389529 | doi = 10.1002/14651858.CD006063.pub2 }}</ref>

In July 2007 the FDA held a joint meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. FDA scientist Joy Mele presented a meta analysis examining the cardiovascular risk of rosiglitazone in completed clinical trials. The study found an overall 1.4 fold increase in risk of cardiovascular ischemic events relative to the control arms. The results were heterogenous, with clear evidence of increased risk relative to placebo but not relative to other diabetes treatments and higher risk associated with combinations of rosiglitazone with insulin or metformin.<ref>{{cite web |url=https://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4308s1-00-index.htm |title=Dockets |website=[[Food and Drug Administration]] }}</ref> Based on the 1.4 fold increased risk relative to control groups, FDA scientist David Graham presented an analysis suggesting that rosiglitazone had caused 83,000 excess heart attacks between 1999 and 2007.<ref name=Senatereport>{{cite web | url = http://www.finance.senate.gov/newsroom/chairman/download/?id=9e4b091f-de21-4df1-b65e-b227d74bec12 | title = Staff report on GlaxoSmithKline and the diabetes drug Avandia | work = Committee on Finance | publisher = United States Senate | date = January 2010 }}</ref>{{rp|4}}<ref name=Graham>{{cite web | author-link1 = David Graham (epidemiologist) | vauthors = Graham | url = https://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4308s1-08-fda-graham_files/frame.htm | title = Assessment of the cardiovascular risks and health benefits of rosiglitazone | work = Office of Surveillance and Epidemiology | publisher = U.S. Food and Drug Administration | date = 30 July 2007 }}</ref> The advisory panel voted 20 : 3 that the evidence available indicated that rosiglitazone increased the risk of cardiovascular events and 22 : 1 that the overall risk:benefit ratio of rosiglitazone justified its continued marketing in the United States. The FDA placed restrictions on the drug, including adding a [[boxed warning]] about heart attacks, but did not withdraw it.<ref>{{cite web | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109026.htm | title = FDA Adds Boxed Warning for Heart-related Risks to Anti-Diabetes Drug Avandia. Agency says drug to remain on market, while safety assessment continues | publisher = U.S. Food and Drug Administration | date = 14 November 2007 }}</ref>

In 2000 a study to address the concerns regarding cardiovascular safety was requested by the [[European Medicines Agency]] (EMA). GSK agreed to perform post-marketing a long-term cardiovascular morbidity/mortality study in patients on rosiglitazone in combination with a sulfonylurea or metformin: the RECORD study. The results as published in 2009 showed that rosiglitazone was non-inferior to treatment with metformin or a sulfonylurea with respect to the rate of cardiovascular events and cardiovascular death. European regulators concluded that due in part to design limitations, the results neither proved nor eliminated concerns of excess cardiovascular risk.<ref name=pmid21153629 />

In February 2010, the FDA's associate director of drug safety, recommended rosiglitazone be taken off the market. In June 2010, they published a retrospective study comparing roziglitazone to pioglitazone, the other thiazolidinedione marketed in the United States and concluded rosiglitazone was associated with "an increased risk of stroke, heart failure, and all-cause mortality and an increased risk of the composite of AMI, stroke, heart failure, or all-cause mortality in patients 65 years or older".<ref name="pmid20584880">{{cite journal | vauthors = Graham DJ, Ouellet-Hellstrom R, MaCurdy TE, Ali F, Sholley C, Worrall C, Kelman JA | title = Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone | journal = JAMA | volume = 304 | issue = 4 | pages = 411–418 | date = July 2010 | pmid = 20584880 | doi = 10.1001/jama.2010.920 | doi-access = }}</ref> The [[number needed to harm]] with roziglitazone was sixty. Graham argued rosiglitazone caused 500 more heart attacks and 300 more heart failures than its main competitor.

Two meta analyses released in 2010, one incorporating 56 trials and a second incorporating 164 trials reached conflicting conclusions. Nissen et al. found again an increased risk for heart infarction against control, but no increased risk for cardiovascular death.<ref name="pmid20656674">{{cite journal | vauthors = Nissen SE, Wolski K | title = Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality | journal = Archives of Internal Medicine | volume = 170 | issue = 14 | pages = 1191–1201 | date = July 2010 | pmid = 20656674 | doi = 10.1001/archinternmed.2010.207 | doi-access = }}</ref> Mannucci et al. found no statistically significant increase in cardiac events but a significant increase in heart failure.<ref>{{cite journal | vauthors = Mannucci E, Monami M, Di Bari M, Lamanna C, Gori F, Gensini GF, Marchionni N | title = Cardiac safety profile of rosiglitazone: a comprehensive meta-analysis of randomized clinical trials | journal = International Journal of Cardiology | volume = 143 | issue = 2 | pages = 135–140 | date = August 2010 | pmid = 19328563 | doi = 10.1016/j.ijcard.2009.01.064 }}</ref> A 2011 drug class review found an increased risk of cardiovascular adverse events.<ref name="drug class review" />

A meta-analysis of 16 observational studies released in March, 2011, compared rosiglitazone to pioglitazone, finding support for greater cardiovascular safety for pioglitazone. The meta-analysis involved 810 000 patients taking rosiglitazone or [[pioglitazone]]. The study suggests 170 excess myocardial infarctions, 649 excess cases of heart failure, and 431 excess deaths for every 100 000 patients who receive rosiglitazone rather than pioglitazone.<ref name="pmid21415101">{{cite journal | vauthors = Loke YK, Kwok CS, Singh S | title = Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies | journal = BMJ | volume = 342 | pages = d1309 | date = March 2011 | pmid = 21415101 | pmc = 3230110 | doi = 10.1136/bmj.d1309 }}</ref><ref>{{cite web| author = Hughes S | title = More damning data on rosiglitazone | url = http://www.theheart.org/article/1199863.do | publisher = theheart.org | access-date = 6 April 2011 | date = 27 March 2011 }}</ref> This was confirmed by another meta-analysis involving 945 286 patients in 8 retrospective cohort studies, most in the US.<ref name=Chen2012/>

In 2012, the U.S. Justice Department announced GlaxoSmithKline had agreed to plead guilty and pay a $3 billion fine, in part for withholding the results of two studies of the cardiovascular safety of Avandia between 2001 and 2007.<ref name="nytimes.com">{{cite news|title=Glaxo Agrees to Pay $3 Billion in Fraud Settlement|newspaper=The New York Times|date=July 2, 2012|url=https://www.nytimes.com/2012/07/03/business/glaxosmithkline-agrees-to-pay-3-billion-in-fraud-settlement.html| vauthors = Thomas K, Schmidt MS }}</ref>

===Death===

There was no difference in all cause and vascular death in a meta-analysis of 4 trials against controls.<ref name="drug class review" /><ref name="Singh 1189–95"/> Two meta-analyses of cohort studies found excess deaths against pioglitazone.<ref name=Chen2012/><ref name=pmid21415101 />

An retrospective observational study performed using Medicare data found that patients treated with rosiglitazone had a 27% higher risk of stroke compared to those treated with pioglitazone.<ref>{{cite journal | vauthors = Graham DJ, Ouellet-Hellstrom R, MaCurdy TE, Ali F, Sholley C, Worrall C, Kelman JA | title = Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone | journal = JAMA | volume = 304 | issue = 4 | pages = 411–418 | date = July 2010 | pmid = 20584880 | doi = 10.1001/jama.2010.920 | doi-access = }}</ref>

GlaxoSmithKline reported a greater incidence of [[fracture]]s of the upper arms, hands and feet in female diabetics given rosiglitazone compared with those given metformin or [[glyburide]].<ref>Cobitz, Alexander R (February 2007). {{cite web|url= https://www.fda.gov/medwatch/safety/2007/Avandia_GSK_Ltr.pdf |title=Clinical Trial Observation of an Increased Incidence of Fractures in Female Patients Who Received Long-Term Treatment with Avandia (rosiglitazone maleate) Tablets for Type 2 Diabetes Mellitus |website=[[Food and Drug Administration]] }}&nbsp;{{small|(49.9&nbsp;[[Kibibyte|KiB]])}}. [[GlaxoSmithKline]]. Retrieved on 10 April 2007.</ref>

The information was based on data from the ADOPT trial<ref name="pmid17145742">{{cite journal | vauthors = [[Steven Kahn (endocrinologist)|Kahn SE]], Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O'Neill MC, Zinman B, Viberti G | display-authors = 6 | title = Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy | journal = The New England Journal of Medicine | volume = 355 | issue = 23 | pages = 2427–2443 | date = December 2006 | pmid = 17145742 | doi = 10.1056/NEJMoa066224 | s2cid = 30076668 | doi-access = free }}</ref> The same increase has been found with pioglitazone (Actos), another [[thiazolidinedione]].

A meta-analysis of 10 RCTs, involving 13,715 patients and including both rosiglitazone- and pioglitazone-treated patients, showed an overall 45% increased risk of fracture with thiazolidone use compared with placebo or active comparator. It doubled the risk of fractures among women with type 2 diabetes, without a significant increase in risk of fractures among men with type 2 diabetes.<ref name="Loke metaanalysis">{{cite journal | vauthors = Loke YK, Singh S, Furberg CD | title = Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis | journal = CMAJ | volume = 180 | issue = 1 | pages = 32–39 | date = January 2009 | pmid = 19073651 | pmc = 2612065 | doi = 10.1503/cmaj.080486 }}</ref>

===Hypoglycaemia===

The risk of hypoglycaemia is reduced with [[thiazolidinedione]]s when compared with [[sulfonylureas]]; the risk is similar to the risk with metformin (high strength of evidence).<ref name="drug class review">{{cite web| vauthors = Jonas D, Van Scoyoc E, Gerrald K, Wines R, Amick H, Triplette M, Runge T |title=Drug Class Review: Newer Diabetes Medications, TZDs, and Combinations Final Original Report Drug Class Reviews |year=2011 |url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0009777/ | location = Portland (OR) |publisher=Oregon Health & Science University|pmid=21595121 |access-date=1 April 2014}}</ref>

===Weight gain===

Both [[thiazolidinedione]]s cause a similar degree of weight gain to that caused by sulfonylureas (moderate strength of evidence).<ref name="drug class review" />

Both rosiglitazone and pioglitazone have been suspected of causing [[macular edema]], which damages the retina of the eye and causes partial blindness. Blindness is also a possible effect of diabetes, which rosiglitazone is intended to treat. One report<ref name="pmid16467508">{{cite journal | vauthors = Kendall C, Wooltorton E | title = Rosiglitazone (Avandia) and macular edema | journal = CMAJ | volume = 174 | issue = 5 | pages = 623 | date = February 2006 | pmid = 16467508 | pmc = 1389823 | doi = 10.1503/cmaj.060074 }}</ref> documented several occurrences and recommended discontinuation at the first sign of vision problems. A retrospective cohort study showed an association between the use of [[thiazolidinedione]]s and the incidence of diabetic macular edema (DME). Both use was associated with a 2,3 higher risk at 1 year and at 10 year follow-up, rising to 3 if associated with insulin.<ref name="drug class review" />

Moderate to severe acute hepatitis has occurred in several adults who had been taking the drug at the recommended dose for two to four weeks. Plasma rosiglitazone concentrations may be increased in people with existing liver problems.<ref>R. Baselt, ''Disposition of Toxic Drugs and Chemicals in Man'', 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1399-1400.</ref>

===Contraindications===

Both rosiglitazone and pioglitazone are contraindicated in people with [[NYHA classification|NYHA Class]] III and IV heart failure. They are not recommended for use in heart failure.<ref>{{cite web|title=rosiglitazone|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ef14122b-7fff-45fa-b13b-0ea9e48bd57d|publisher=DailyMed The National Library of Medicine}}</ref>

In Europe rosiglitazone was contraindicated for heart failure or history of heart failure with regard to all NYHA stages, for combined use with insulin and for acute coronary syndrome.<ref name=pmid21153629 /> The European Medicines Agency recommended on 23 September 2010 that Avandia be suspended from the European market.<ref name="ema_recommend_suspend" /><ref name="bbc_ema_suspension"/>

==Pharmacology==

[[File:Avandia 2mg oral tablet.jpg|thumb|Two Avandia 2 mg oral tablets]]

Rosiglitazone is a member of the thiazolidinedione class of drugs. Thiazolidinediones act as insulin sensitizers. They reduce glucose, fatty acid, and insulin blood concentrations. They work by binding to the [[peroxisome proliferator-activated receptor]]s (PPARs). PPARs are transcription factors that reside in the nucleus and become activated by ligands such as thiazolidinediones. Thiazolidinediones enter the cell, bind to the nuclear receptors, and alter the expression of genes. The several PPARs include PPARα, PPARβ/δ, and PPARγ. Thiazolidinediones bind to [[Peroxisome proliferator-activated receptor gamma|PPARγ]].

PPARs are expressed in fat cells, cells of the liver, muscle, heart, and inner wall (endothelium) and smooth muscle of blood vessels. PPARγ is expressed mainly in fat tissue, where it regulates genes involved in fat cell (adipocyte) differentiation, fatty acid uptake and storage, and glucose uptake. It is also found in pancreatic beta cells, vascular endothelium, and macrophages<ref name="pmid15356308">{{cite journal | vauthors = Yki-Järvinen H | title = Thiazolidinediones | journal = The New England Journal of Medicine | volume = 351 | issue = 11 | pages = 1106–1118 | date = September 2004 | pmid = 15356308 | doi = 10.1056/NEJMra041001 }}</ref> Rosiglitazone is a selective ligand of PPARγ and has no PPARα-binding action. Other drugs bind to PPARα.

Rosiglitazone also appears to have an anti-[[inflammation|inflammatory]] effect in addition to its effect on [[insulin resistance]]. Nuclear factor kappa-B ([[NF-κB]]), a signaling molecule, stimulates the inflammatory pathways. NF-κB inhibitor (IκB) downregulates the inflammatory pathways. When patients take rosiglitazone, NF-κB levels fall and IκB levels increase.<ref name="pmid15181049">{{cite journal | vauthors = Mohanty P, Aljada A, Ghanim H, Hofmeyer D, Tripathy D, Syed T, Al-Haddad W, Dhindsa S, Dandona P | display-authors = 6 | title = Evidence for a potent antiinflammatory effect of rosiglitazone | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 89 | issue = 6 | pages = 2728–2735 | date = June 2004 | pmid = 15181049 | doi = 10.1210/jc.2003-032103 | doi-access = free }}</ref>

==History==

Rosiglitazone was approved by the US FDA in 1999 and by the EMA in 2000; the EMA however required two postmarketing studies on longterm adverse effects, one for chronic heart failure and the other for cardiovascular effects.<ref name="ema_recommend_suspend"/>

US sales of the drug were of $2.2 billion in 2006.<ref>{{cite web | url = http://www.mmm-online.com/FDA-toughens-Avandia-warnings/article/96354/ | title = FDA toughens Avandia warnings | publisher = Medical Marketing and Media | date = 2007-11-14 }}</ref> Sales in 2Q 2007 down 22% compared to 2006.<ref>{{cite news| url=https://www.usatoday.com/news/health/2007-07-25-avandia-fda_N.htm | work=USA Today | title=FDA panels to weigh Avandia heart risks | vauthors = Rubin R | date=2007-07-26 | access-date=2010-05-22}}</ref> 4Q 2007 sales down to $252 million.<ref>{{cite news| url=https://www.bloomberg.com/apps/news?pid=20601087&sid=aHobgoX8jyfg | work=Bloomberg | title=Glaxo Fourth-Quarter Profit Fell 10% on Avandia Sales (Update6) | date=2008-02-07}}</ref>

Though sales have gone down since 2007 due to safety concerns, Avandia sales for 2009 totalled $1.2 billion worldwide.<ref name=fallout>{{cite news|url=http://www.newsobserver.com/2010/02/23/353164/avandia-fallout-could-hit-triangle.html?storylink=misearch |title=Avandia fallout could hit Triangle | vauthors = Ranii D |work=[[News & Observer]] |date=2010-02-23 |access-date=2010-03-05 |url-status=dead |archive-url=https://web.archive.org/web/20110304230627/http://www.newsobserver.com/2010/02/23/353164/avandia-fallout-could-hit-triangle.html?storylink=misearch |archive-date=2011-03-04 }}</ref>

According to analysts from UBS, 13,000 suits had been filed by March 2010.<ref>{{cite news|url=http://www.newsobserver.com/2010/03/05/371760/avandia-could-cost-gsk-billions.html?storylink=misearch |title=Avandia could cost GSK billions | vauthors = Ranii D |work=[[News & Observer]] |date=2010-03-05 |access-date=2010-03-05 |url-status=dead |archive-url=https://web.archive.org/web/20121002035320/http://www.newsobserver.com/2010/03/05/371760/avandia-could-cost-gsk-billions.html?storylink=misearch |archive-date=2012-10-02 }}</ref> Included among those suing: [[Santa Clara County, California]], which claims to have spent $2 million on rosiglitazone between 1999 and 2007 at its public hospital and is asking for "triple damages".<ref>{{cite news|url=http://www.boston.com/business/healthcare/articles/2010/03/01/california_county_sues_glaxo_over_diabetes_drug/ |title=California county sues Glaxo over diabetes drug |work=[[Boston Globe]] |date=2010-03-01 |access-date=2013-02-25 |url-status=dead |archive-url=https://web.archive.org/web/20150505203624/http://www.boston.com/business/healthcare/articles/2010/03/01/california_county_sues_glaxo_over_diabetes_drug/ |archive-date=May 5, 2015 }}</ref>

In May 2010, GlaxoSmithKline (GSK) reached settlement agreements for some of the cases against the company, agreeing to pay $60 million to resolve 700 suits.<ref>{{cite news| url=https://www.bloomberg.com/news/2010-05-10/glaxo-said-to-pay-about-60-million-in-first-settlement-of-avandia-drug.html | publisher = Bloomberg |vauthors=Feeley J, Kelley T | title = Glaxo Said to Pay About $60 Million in First Avandia Heart-Risk Settlement | date=2010-05-11}}</ref> In July 2010, GSK reached settlement agreements to close another 10,000 of the lawsuits against it, agreeing to pay about $460 million to settle these suits.<ref>{{cite news|url=http://noir.bloomberg.com/apps/news?pid=newsarchive&sid=aP.inHBfGVcU |archive-url=https://archive.today/20120713023558/http://noir.bloomberg.com/apps/news?pid=newsarchive&sid=aP.inHBfGVcU |url-status=dead |archive-date=2012-07-13 |publisher=Bloomberg |vauthors=Feeley J, Kelley T |title=Glaxo Said to Pay $460 Million to Settle Avandia Damage Suits |date=2010-07-13 }}</ref><ref>{{cite news| url=https://www.independent.co.uk/news/business/news/gsk-settles-avandia-claims-on-first-day-of-safety-hearing-2025957.html | location=London | work=The Independent | title=GSK 'settles Avandia claims' on first day of safety hearing | vauthors = Dawber A | date=2010-07-14}}</ref>

<ref name="urlGSK settles bulk of Avandia suits for $460M - FiercePharma">{{cite web | url = http://www.fiercepharma.com/story/gsk-settles-bulk-avandia-suits-460m/2010-07-14 | title = GSK settles bulk of Avandia suits for $460M | publisher = FiercePharma }}</ref>

In 2012, the U.S. Justice Department announced GlaxoSmithKline had agreed to plead guilty and pay a $3 billion fine, in part for withholding the results of two studies of the cardiovascular safety of Avandia between 2001 and 2007. The settlement stems from claims made by four employees of GlaxoSmithKline, including a former senior marketing development manager for the company and a regional vice president, who tipped off the government about a range of improper practices from the late 1990s to the mid-2000s.<ref name="nytimes.com"/>

GlaxoSmithKline was being investigated by the FDA and the US Congress regarding Avandia.

Senators Democrat [[Max Baucus]] and Republican [[Charles Grassley]] filed a report urging GSK to withdraw Avandia in 2008 due to the side effects. The report noted the drug caused 500 avoidable heart attacks a month, and Glaxo officials sought to intimidate doctors who criticized the drug. It also said GSK continued to sell and promote the drug despite knowing the increased risk of heart attacks and stroke.<ref name="urlInteractive: Timeline: The story of Avandia | Need to Know | PBS">{{cite web | url = https://www.pbs.org/wnet/need-to-know/health/timeline-history-of-avandia/2314/ | title = Interactive: Timeline: The story of Avandia &#124; Need to Know | publisher = PBS | date = 16 July 2010 }}</ref>

The [[Senate Finance Committee]], in a panel investigation, revealed emails from GSK company officials that suggest the company downplayed scientific findings about safety risks dating back to 2000. It was also alleged by the committee that the company initiated a "ghostwriting campaign", whereby GSK sought outside companies to write positive articles about Avandia to submit to medical journals.<ref name="urlAvandias Fate May be Sealed Today">{{cite web | url = http://www.portfolio.com/views/blogs/heavy-doses/2010/07/14/medical-experts-vote-on-whether-to-pull-avandia-from-market#ixzz0tgGHXXRG | title = Avandia's Fate May be Sealed Today }}</ref> GSK defended itself by presenting data that its own tests found Avandia to be safe, although an FDA staff report showed the conclusions were flawed.<ref name="urlAvandia Safety Questioned Again">{{cite web | url = http://www.portfolio.com/views/blogs/heavy-doses/2010/07/09/avandia-safety-questioned-again-before-a-government-panel-review | title = Avandia Safety Questioned Again }}</ref>

On July 14, 2010, after two days of extensive deliberations, the FDA panel investigating Avandia came to a mixed vote. Twelve members of the panel voted to take the drug off the market, 17 recommended to leave it on but with a more revised warning label, and three voted to keep it on the market with the current warning label.<ref name="url12 panel members recommend Avandia withdrawal - FiercePharma">{{cite web | url = http://www.fiercepharma.com/story/breaking-news-12-panel-members-recommend-avandia-withdrawal/2010-07-14 | title = 12 panel members recommend Avandia withdrawal | publisher = FiercePharma }}</ref><ref name="urlWhat is the meaning of the Avandia vote? - FiercePharma">{{cite web | url = http://www.fiercepharma.com/story/what-does-avandia-vote-mean/2010-07-14 | title = What is the meaning of the Avandia vote? | publisher = FiercePharma }}</ref> The panel has come to some controversy, however; on July 20, 2010, one of the panelists was discovered to have been a paid speaker for GlaxoSmithKline, arousing questions of a conflict of interest. This panel member was one of the three who voted to keep Avandia on the market with no additional warning labels.<ref>{{cite news | url = https://www.wsj.com/articles/SB10001424052748704720004575377552600421936 | work=The Wall Street Journal | title=Panelist Who Backed Avandia Gets Fees From Glaxo | author = Mundy A | date=2010-07-20}}</ref><ref>{{cite news| url=http://triangle.bizjournals.com/triangle/stories/2010/07/19/daily18.html | vauthors = Gallagher J | title=Report: Avandia panelist paid by GSK | date=2010-07-20}}</ref>

In 2011 the FDA has decided on revising its prescribing information and medication guides for all rosilitazone containing medicines. The US label for rosiglitazone ([[Avandia]], [[GlaxoSmithKline]]) and all rosiglitazone-containing medications ([[Avandamet]] and [[Avandaryl]]) now include the additional safety information and restrictions.<ref name="pmid22232110">{{cite journal | vauthors = Ross JS, Jackevicius C, Krumholz HM, Ridgeway J, Montori VM, Alexander GC, Zerzan J, Fan J, Shah ND | display-authors = 6 | title = State Medicaid programs did not make use of prior authorization to promote safer prescribing after rosiglitazone warning | journal = Health Affairs | volume = 31 | issue = 1 | pages = 188–198 | date = January 2012 | pmid = 22232110 | pmc = 3319744 | doi = 10.1377/hlthaff.2011.1068 }}</ref><ref>{{cite web| author = O'Riordan M | title = New rosiglitazone label includes restrictions on use | url = http://www.theheart.org/article/1182011.do | publisher = theheart.org | access-date = 1 April 2011 }}</ref> The revised labels restrict use to patients already taking a rosiglitazone-containing medicine or to new patients who are unable to achieve adequate glycemic control on other diabetes medications and to those, who in consultation with their healthcare provider, have decided not to take Actos ([[pioglitazone]]) or other pioglitazone-containing medicines for medical reasons.<ref>{{cite web |title=GSK revises US Avandia label to include new restrictions on use |url=http://www.gsk.com/media/pressreleases/2011/2011_pressrelease_10024.htm |publisher=GlaxoSmithKline |access-date=1 April 2011 |url-status=dead |archive-url=https://web.archive.org/web/20110217063445/http://www.gsk.com/media/pressreleases/2011/2011_pressrelease_10024.htm |archive-date=17 February 2011 }}</ref>

In June 2013 an FDA Advisory Committee reviewed all available data, including a re-adjudicated RECORD trial, found no evidence of increased cardiovascular risk with Avandia, and voted to remove the restrictions on Avandia marketing in the United States. In November 2013, the US FDA removed these marketing restrictions on the product.<ref>{{cite web | title = Rosiglitazone-containing Diabetes Medicines: Drug Safety Communication – Removal of Some Prescribing and Dispensing Restrictions | url = https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm376683.htm | publisher = U.S. Food and Drug Administration }}</ref> Under the FDA's instruction, Avandia's maker, GlaxoSmithKline, had funded the Duke Clinical Research Institute to re-analyze the raw data from the study. At the 2010 panel, three panelists voted that the existing warnings were good enough; two were back in 2013. Seven voted to make those warnings more onerous, and five of them returned. But of the 10 who voted to restrict Avandia's use, only four returned. And of the 12 who voted in 2010 to withdraw Avandia from the market, only three came back.<ref>{{cite news| vauthors = Herper M |title=Avandia Vote Ends An Era Of Drug Safety Scandals |url= https://www.forbes.com/sites/matthewherper/2013/06/06/what-the-fdas-avandia-decision-means-for-the-future/ |access-date=31 March 2014|newspaper=Forbes|date=2013-06-06}}</ref>

In 2000 a study to address the concerns regarding cardiovascular safety was requested by the EMA, and the makers agreed to perform post-marketing a long-term cardiovascular morbidity/mortality study in patients on rosiglitazone in combination with a sulfonylurea or metformin: the RECORD study. The results as published in 2009 showed non-inferiority with regard to cardiovascular events and cardiovascular death when the treatment with rosiglitazone was compared with metformin or a sulfonylurea. For myocardial infarction, there was a non-statistically significant increase in risk. In their assessment, the European regulators acknowledged weaknesses of the study, such as an unexpectedly low rate of cardiovascular events and the [[Open-label trial|open-label]] design, which may lead to reporting bias. They found that the results were inconclusive.<ref name=pmid21153629 /> The European Medicines Agency recommended on 23 September 2010 that Avandia be suspended from the European market.<ref name="ema_recommend_suspend"/><ref name="bbc_ema_suspension"/>

According to a probe by the ''[[British Medical Journal]]'' in September 2010, the United Kingdom's Commission on Human Medicines recommended to the Medicines and Healthcare Products Regulatory Agency (MHRA) back in July 2010, to withdraw Avandia sale because its "risks outweigh its benefits". Additionally, the probe revealed that in 2000, members of the European panel in charge of reviewing Avandia prior to its approval had concerns about the long-term risks of the drug.<ref>{{cite news| url=https://www.wsj.com/articles/SB10001424052748703713504575475884140520538?mod=googlenews_wsj | work=The Wall Street Journal | title=U.K. Medical Journal Questions Avandia License | vauthors = Douglas J | date=2010-09-06}}</ref><ref name="urlU.K. watchdogs vote for Avandia withdrawal – FiercePharma">{{cite web | url = http://www.fiercepharma.com/story/u-k-watchdogs-vote-avandia-withdrawal/2010-09-07 | title = U.K. watchdogs vote for Avandia withdrawal | publisher = FiercePharma }}</ref>

Rosiglitazone was withdrawn from the New Zealand market April 2011 because [[Medsafe]] concluded the suspected cardiovascular risks of the medicine for patients with type 2 diabetes outweigh its benefits.<ref>{{cite news| url = http://www.nzherald.co.nz/nz/news/article.cfm?c_id=1&objectid=10706910 | title = Diabetes drug to be withdrawn over heart risk fears | date = Feb 17, 2011 | publisher = New Zealand Herald}}</ref>

====South Africa====

A notice issued by the Medicines Control Council of South Africa on July 5, 2011, stated that it had resolved on July 3, 2011, to withdraw all rosiglitazone-containing medicines from the South African market due to safety risks. It disallowed all new prescriptions of Avandia.<ref name=MCC>{{cite web| work = Medicines Control Council |title=Withdrawal of rosiglitazone-containing medicines from SA market |url=http://www.doh.gov.za/show.php?id=2788 |publisher=Department of Health, Republic of South Africa |access-date=25 November 2012 |url-status=dead |archive-url=https://web.archive.org/web/20111105104135/http://doh.gov.za/show.php?id=2788 |archive-date=5 November 2011 }}</ref>

===Controversy and response===

Following the reports in 2007 that Avandia can significantly increase the risk of heart attacks, the drug has been controversial. A 2010 article in ''Time'' uses the Avandia case as evidence of a broken FDA regulatory system that "may prove criminal as well as fatal". It details the disclosure failures, adding, "Congressional reports revealed that GSK sat on early evidence of the heart risks of its drug, and that the FDA knew of the dangers months before it informed the public." It reports, "the FDA is investigating whether GSK broke the law by failing to fully inform the agency of Avandia's heart risks", according to deputy FDA commissioner Dr. Joshua Sharfstein. GSK threatened academics who reported adverse research results, and received multiple warning letters from the FDA for deceptive marketing and failure to report clinical data.<ref name="urlTIME">{{cite magazine | url = http://www.time.com/time/health/article/0,8599,2010028,00.html | archive-url = https://web.archive.org/web/20100815112413/http://www.time.com/time/health/article/0,8599,2010028,00.html | url-status = dead | archive-date = August 15, 2010 | title = After Avandia: Does the FDA Have a Drug Problem? | date = Aug 12, 2010 | magazine = Time}}</ref> The maker of the drug, GlaxoSmithKline, has dealt with serious backlash against the company for the drug's controversy.<ref name="urlWill Avandia Be Yanked Off the Market? - US News">{{cite web | url = http://health.usnews.com/health-news/managing-your-healthcare/diabetes/articles/2010/07/09/will-avandia-be-yanked-off-the-market.html | title = Will Avandia Be Yanked Off the Market? | publisher = US News }}</ref> Sales on the drug dropped significantly after the story first broke in 2007, dropping from $2.5 billion in 2006 to less than $408 million in 2009 in the US.<ref name="urlExclusive: Takeda launches Actos DTC campaign today – Medical Marketing and Media">{{cite web | url = http://www.mmm-online.com/exclusive-takeda-launches-actos-dtc-campaign-today/article/174652/ | title = Exclusive: Takeda launches Actos DTC campaign today | publisher = Medical Marketing and Media | date = 2010-07-15 }}</ref>

In response to the rise in risk of heart attacks, the Indian government ordered GSK to suspend its research study, called TIDE, in 2010.<ref name="urlwww.pharmalot.com">{{cite web | url = http://www.pharmalot.com/2010/07/an-undisclosed-conflict-on-the-fda-avandia-panel/ | archive-url = https://web.archive.org/web/20100723144438/http://www.pharmalot.com/2010/07/an-undisclosed-conflict-on-the-fda-avandia-panel/ | url-status = dead | archive-date = 2010-07-23 | title = An Undisclosed Conflict On The FDA Avandia Panel? | author = Silverman E | publisher = Pharmalot | date = 2010-07-20 }}</ref><ref name="urlAvandia Drug Trials Shut Down In India « CBS Detroit">{{cite web | url = http://wwj.cbslocal.com/2010/07/14/avandia-drug-trials-shut-down-in-india/ | title = Avandia Drug Trials Shut Down In India | publisher = CBS Detroit | date = 2010-07-14 }}</ref> The FDA also halted the TIDE study in the United States.<ref name="foodconsumer.org">{{cite web | url = http://www.foodconsumer.org/newsite/Non-food/Drug/fda_orders_glaxo_to_stop_an_avandia_trial_2307100700.html | publisher = foodconsumer.org | title = FDA Orders Glaxo to Stop an Avandia Trial | url-status = dead | archive-url = https://web.archive.org/web/20141109090036/http://www.foodconsumer.org/newsite/Non-food/Drug/fda_orders_glaxo_to_stop_an_avandia_trial_2307100700.html | archive-date = 2014-11-09 }}</ref>

Three doctors' groups, the [[Endocrine Society]], the [[American Diabetes Association]] and the [[American Association of Clinical Endocrinologists]], urged patients to continue to take the drug as it would be much worse to stop all treatment, despite any associated risk, but that patients could consult their doctors and begin a switch to a different drug if they or their doctors find concern.<ref>{{cite news| url=https://www.reuters.com/article/idUSN1521260120100715 | work=Reuters | title=Don't dump Avandia, diabetes groups urge patients | date=2010-07-15}}</ref><ref>{{cite news| url=https://www.latimes.com/archives/la-xpm-2010-jul-15-la-heb-avandia-20100715-story.html | work=The Los Angeles Times | title=Patients taking Avandia should keep on doing so, doctor groups say | vauthors = Maugh II TH | date=2010-07-15}}</ref><ref>{{cite news| url=http://www.cbsnews.com/8301-504763_162-20010767-10391704.html | work=CBS News | title=Avandia News: What You Need to Know | vauthors = Katz N | date=2010-07-16}}</ref> The [[American Heart Association]] said in a statement in June 2010: " ...the reports deserves serious consideration, and patients with diabetes who are 65 years of age or older and being treated with rosiglitazone should discuss the findings with their prescribing physician....".

"For patients with diabetes, the most serious consequences are heart disease and stroke, and the risk of suffering from them is significantly increased when diabetes is present. As in most situations, patients should not change or stop medications without consulting their healthcare provider."<ref>{{cite news| url=http://latimesblogs.latimes.com/booster_shots/2010/06/avandia-rosiglitazone-heart-attack.html | work=The Los Angeles Times | title=Booster Shots | date=2010-06-29}}</ref><ref name="urlAmerican Heart Association Comment: Advisory Committee Recommends that U.S. Food and Drug Administration Keep Rosiglitazone (Avandia) on the Market, Continue Clinical Trial of Safety and Efficacy – Health News – redOrbit">{{cite web | url = http://www.redorbit.com/news/health/1892007/american_heart_association_comment_advisory_committee_recommends_that_us_food/index.html | title = American Heart Association Comment: Advisory Committee Recommends that U.S. Food and Drug Administration Keep Rosiglitazone (Avandia) on the Market, Continue Clinical Trial of Safety and Efficacy | work = Health News | publisher = redOrbit }}{{Dead link|date=March 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>

As a result of the Avandia Affair, FDA required that cardiac safety be demonstrated for new drugs to treat type 2 diabetes. This process is described by Dr Robert Misbin in INSULIN-History from an FDA Insider, published June 1, 2020 on Amazon. Dr Misbin was the first FDA reviewer for rosiglitazone (Avandia) and cautioned about its potential to increase the risk of cardiovascular disease.

==Research==

Rosiglitazone was thought to be able to benefit patients with [[Alzheimer's disease]] who do not express the [[Apolipoprotein E|ApoE4]] [[allele]],<ref name="pmid16446752">{{cite journal | vauthors = Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM, Zvartau-Hind ME, Hosford DA, Roses AD | display-authors = 6 | title = Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease | journal = The Pharmacogenomics Journal | volume = 6 | issue = 4 | pages = 246–254 | year = 2006 | pmid = 16446752 | doi = 10.1038/sj.tpj.6500369 | doi-access = }}</ref> but the phase III trial designed to test this showed that rosiglitazone was ineffective in all patients, including [[Apolipoprotein E|ApoE4]]-negative patients.<ref name="pmid20733306">{{cite journal | vauthors = Gold M, Alderton C, Zvartau-Hind M, Egginton S, Saunders AM, Irizarry M, Craft S, Landreth G, Linnamägi U, Sawchak S | display-authors = 6 | title = Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study | journal = Dementia and Geriatric Cognitive Disorders | volume = 30 | issue = 2 | pages = 131–146 | year = 2010 | pmid = 20733306 | pmc = 3214882 | doi = 10.1159/000318845 }}</ref>

Rosiglitazone may also treat mild to moderate [[ulcerative colitis]], due to its anti-inflammatory properties as a PPAR ligand.<ref name="pmid18471502">{{cite journal | vauthors = Lewis JD | title = Will 2008 mark the start of a new clinical trial era in gastroenterology? | journal = Gastroenterology | volume = 134 | issue = 5 | pages = 1289 | date = May 2008 | pmid = 18471502 | doi = 10.1053/j.gastro.2008.03.030 | doi-access = free }}</ref>

Rosiglitazone has been investigated as an agent that may expedite body fat redistribution into [[Gynoid fat distribution|a more feminine shape]] in trans women who have had little [[Feminizing hormone therapy#Fat changes|fat redistribution from hormone replacement therapy]], due to thiozolidinediones' effects on body fat metabolism.<ref>{{Cite journal | vauthors = Malik I, Barrett J, Seal L |date= March 2009 |title=Thiazolindinediones are useful in achieving female type fat distribution in male to female transsexuals |url=https://www.endocrine-abstracts.org/ea/0019/ea0019p74 |journal=Endocrine Abstracts |language=en |volume=19 |issn=1470-3947}}</ref>

==Synthesis==

[[File:Rosiglitazone synthesis.png|thumb|center|800px|Rosiglitazone synthesis:<ref>{{cite journal | vauthors = Cantello BC, Cawthorne MA, Haigh D, Hindley RM, Smith SA, Thurlby PL | title = The synthesis of BRL 49653-a novel and potent antihyperglycaemic agent. | journal = Bioorganic & Medicinal Chemistry Letters | date = May 1994 | volume = 4 | issue = 10 | pages = 1181–1184 | doi = 10.1016/S0960-894X(01)80325-5 }}</ref><ref>{{cite book | chapter = The Synthesis of Rosiglitazone | title = The Art of Drug Synthesis | veditors = Johnson DS, Li JJ | pages = 121–122 }}</ref> {{US patent|5646169}}]]

== References ==

* {{cite web | title = Rosiglitazone | url = https://www.nlm.nih.gov/medlineplus/druginfo/meds/a699023.html | work = MedlinePlus | publisher = U.S. National Library of Medicine }}

* {{cite web | title = Rosiglitazone May Improve Function in Patients With Mild Alzheimer's Disease | vauthors = Peck P | date = 20 July 2004 | url = http://www.medscape.com/viewarticle/483837 | work = Medscape }}

* {{cite web | url = http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Rosiglitazone | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Rosiglitazone }}

{{PPAR modulators}}

[[Category:3β-Hydroxysteroid dehydrogenase inhibitors]]

[[Category:CYP17A1 inhibitors]]

[[Category:Hepatotoxins]]

[[Category:2-Aminopyridines]]

[[Category:Withdrawn drugs]]

[[Category:Drugs developed by GSK plc]]

[[Category:Ethanolamines]]

[[Category:Tertiary amines]]