Rosiglitazone (Avandia) and Cardiovascular (CV) Risk - Controversies and related documents. www.RxFiles.ca: http://www.rxfiles.ca/rxfiles/uploads/documents/Rosiglitazone-CV-Controversy.htm

As always the challenge is to work through the controversy and subtleties for areas of uncertainty .   We want effectiveness and safety from the drugs we use to treat type 2 diabetes.  We have proven CV benefit with lifestyle, blood pressure agents, cholesterol agents, metformin and ASA.  With rosiglitazone, the controversy forms around potential adverse effects that are arround the same endpoints we are trying to achieve benefits in.

We have some cautionary signals of cardiovascular harm with rosiglitazone from RCTs prior to the meta-analysis, especially heart failure. The various meta-analysis have raised more questions. We have never seen CV outcome benefits in any rosiglitazone trial. Unfortunately we do not have the outcome trial we need to conclusively address the question of CV benefit or risk. The low numbers in the meta-analysis reflect the lower risk populations in early trials and the short term nature of the unpublished trials. Methodology is open to much criticism!   It will be interesting to see how things develop.  {Note: RECORD trial interim analysis discussed in NEJM June 5. 2007; GSKs own meta-analysis data suggest potential 30% increase in MI risk.}  An RxFiles preliminary summary of this area appears in the Q&A linked below.  You will also find the links/updates provide you with a chronology of how this issue has unfolded. We have attempted to provide balance and emphasize some of the more important considerations.  As always, this information needs to be interpreted and applied individually to the patient  "in your office".  "No one said it would be easy." 

Updated links below!

Original Q&A: Rosiglitazone AVANDIA and Cardiovascular Risk: To be concerned or not to be concerned (30May07)

Hypoglycemics Comparison Chart ; Landmark Trials Summary Chart

DREAM Trial Overview (May07): (Diabetes Reduction Assessment with Ramipril and/or Rosiglitazone Medication)

Related Links/Updates:

	21 Mar, 2011 Montori VM, Shah ND. What have we learnt from the rosiglitazone saga? BMJ. 2011 Mar 17;342:d1354. doi: 10.1136/bmj.d1354. PubMed PMID: 21415102. Accessed at: http://www.bmj.com/content/342/bmj.d1354.full 21 Nov, 2010 v Health Canada adds further restrictions on the use of rosiglitazone, essentially limiting its use to where there are no other options, and asking health professionals to review if existing patients should still be on, and get informed consent if continuing treatment. v http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2010/avandia_6_hpc-cps-eng.php 23 Sept, 2010 European Medicines Agency (EMA) suspends marketing authorization of rosiglitazone containing products. USA (FDA) sets further restrictions for use / labelling warnings for rosiglitazone. (Still available for old patients; unlikely to see too many new patients started.) http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm226994.htm Overall, lack evidence that benefits out-weight risks. Glaxo statement notes the company still believes the drug is important & is working to comply. http://www.gsk.com/media/pressreleases/2010/2010_pressrelease_10103.htm
	July 2010: The RECORD trial has come under increasing criticism since publication. o E.g. an FDA researcher “found at least a dozen instances in which patients taking Avandia suffered serious heart problems that were not counted in the trial’s tally of adverse events” ^NY Times – Accessed 12Jul10^http://www.nytimes.com/2010/07/13/health/policy/13avandia.html?_r=1 o This criticism is in the context of company data from 1999 showing signs of CV concerns relative to Pioglitazone; data that was not made public ^NY Times – Accessed 12Jul10^http://www.nytimes.com/2010/07/13/health/policy/13avandia.html?_r=1 o Additional information ^FDA review – 13Jul10 FDA Briefing: http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm218491.htm
	Rosiglitazone Meta-analysis (June 2010): Nissen & Wolski. Ann Int Med: Rosi increases risk of MI but not CV or all-cause mortality. http://archinte.ama-assn.org/cgi/content/full/2010.207
	Pio vs Rosi for CV - cohort (Aug 2009):  Juurlink et al.  Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study.  BMJ 2009;339:b2942 http://www.bmj.com/cgi/content/full/339/aug18_2/b2942
	RECORD trial: rosiglitazone (June 2009): n=4447, ~ 5.5yr; T2DM (A1C mean ~ 7.9%ð7.4-7.9%); non-inferiority trial; open label; funded by GSK Metformin or sulfonylurea (SU) + rosiglitazone vs metformin + SU. No difference in CV death, MI;  increase rate of HF & fracture. Suggests that CV outcomes for rosiglitazone are similar (e.g. no worse) to metformin + a SU over 5.5 yrs.  However limitations include open label design, more of the rosi group on statins & high rate of dropouts. Links: http://www.ncbi.nlm.nih.gov/pubmed/19501900 ; http://www.medscape.com/viewarticle/704038 Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, Jones NP, Komajda M, McMurray JJ; RECORD Study Team. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009 Jun 20;373(9681):2125-35.   See RxFiles Trial Summary: http://www.rxfiles.ca/rxfiles/uploads/documents/Diabetes-RECORD-Trial-Summary.pdf
	November 25, 2008 -- ADA News.  Doctors Claim Glaxo Dismissed Worries on Avandia. http://professional.diabetes.org/News_Display.aspx?TYP=9&CID=64642
	November 24, 2008 -- Older adults who take rosiglitazone appear to have a higher risk of death and heart failure than those taking pioglitazone (November 24 issue of Archives of Internal Medicine).  Medical claims data, 28,361 patients, age 65+,  who began taking either rosiglitazone or pioglitazone.  After an average of 380 days taking pioglitazone or 369 taking rosiglitazone, 1,869 patients died. After adjusting for other factors, individuals taking rosiglitazone had a 15% higher rate of death and a 13% greater risk of HF compared with those taking pioglitazone. No differences in heart attack or stroke risk between the 2 groups. http://archinte.ama-assn.org/cgi/reprint/168/21/2368
	APPROACH - Nov 13, 2008 -- Preliminary (unpublished): rosiglitazone does not increase atherosclerosis progression.  small trial n=672; short term 18months.  http://www.theheart.org/article/921219.do
	ADA & EASD - T2DM Update (Oct 2008): consensus group unanimously advised against using rosiglitazone. (Noted 'neutral to negative' outcomes with rosiglitazone compared to 'neutral to positive' outcomes for pioglitazone).  Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy : A consensus statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes. Diabetologia. 2008 Oct 22. http://care.diabetesjournals.org/misc/MedicalManagementofHyperglycemia.pdf
	CDA Diabetes Guidelines (Sep 2008): rank metformin as the first oral agent of choice; then may add an agent best suited to the individual based on advantages disadvantages.  Comments: re TZDs: "inconsistent data regarding CV outcomes"; Rosiglitazone: "suggestion of further risk of CV events with rosiglitazone awaits further study".  http://www.diabetes.ca/files/cpg2008/cpg-2008.pdf
	theheart.org: FDA reprimands GlaxoSmithKline over missing data on rosiglitazone (Apr 2008) "...company failed to report multiple postmarketing studies involving rosiglitazone....  In the FDA letter, dated March 25, 2008... nine studies were not disclosed until September 2007 and another 11 studies were not included in required annual reports, although some data were submitted to the agency in other reports or communications. " http://www.theheart.org/article/856275.do
	theheart.org: report on fall-out from reviewer S. Haffner leaking NEJM meta-analysis trial data to GSK (Jan31, 2008) http://www.theheart.org/article/841105.do
	Thiazolidinediones & CV Outcomes in Older Patients with Diabetes; JAMA Dec 12, 2007.  Population based, "case control" study in Ontario further suggests TZDs, primarily rosiglitazone áHF, MI, and mortality compared to other oral hypoglycemics. {n=159,026 diabetes patients; age 65+ (ave 74.7); 3.8yr; NNH=26 for AMI, 34 for CHF, 22 for death.} Article in Jama: http://jama.ama-assn.org/cgi/content/abstract/298/22/2634; theheart.org "heartwire": http://www.theheart.org/article/832915.do .  GSK responds: http://www.drugs.com/clinical_trials/glaxosmithkline-responds-jama-article-ices-thiazolidinediones-cardiovascular-outcomes-older-3007.html ;  Med Page Today: http://www.medpagetoday.com/Nephrology/Diabetes/tb/7615
	US Senate report on GSK intimidation of John Buse over rosiglitazone (Nov20, 2007). http://www.medscape.com/viewarticle/566298?src=mpnews
	Health Canada Advisory - Rosiglitazone AVANDIA (Nov 07):restrictions on approved indication in Canada.   http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2007/avandia_hpc-cps_5-eng.php
	FDA Advisory (Nov07): http://www.fda.gov/Cder/drug/InfoSheets/HCP/rosiglitazone200707HCP.htm
	Glitazone HF Meta-analysis: both rosiglitazone & pioglitazone increase risk of HF in prediabetes & type 2 diabetes; however no corresponding increase in CV death. ^19 (Lancet: Lago et al; pooled data) Lago RM, Singh PP, Nesto RW.  Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet. 2007 Sep 29;370(9593):1129-36.
	Medscape - Interview - theheart.org, Dr. Califf with Dr. Nissen. Aug07  http://www.medscape.com/viewarticle/561666?src=mp
	T2 Diabetes: Screening, Prevention, and TZDs.  Dalhousie AD Service. http://cme.medicine.dal.ca/files/Diabetes.pdf
	Gerrits CM, Bhattacharya M, Manthena S, Baran R, Perez A, Kupfer S.  Pharmacoepidemiol Drug Saf. 2007 Aug 3; [Epub ahead of print] A comparison of pioglitazone and rosiglitazone for hospitalization for acute myocardial infarction in type 2 diabetes.  "CONCLUSION: This retrospective cohort study showed that pioglitazone, in comparison with rosiglitazone, is associated with a 22% relative risk reduction of hospitalization for AMI in patients with type 2 diabetes."  PMID: 17674425
	The Rosiglitazone Story — Lessons from an FDA Advisory Committee Meeting.  NEJM (08Aug07): http://content.nejm.org/cgi/content/full/NEJMp078167
	Medscape: (08Aug07) http://www.medscape.com/viewarticle/561142
	Cochrane Review on Rosiglitazone (July07): http://www.cochrane.org/reviews/en/ab006063.html
	Medscape - Note on Cochrane Review of Rosiglitazone (18July07): http://www.medscape.com/viewarticle/559972?src=mp
	Medscape - Rosiglitazone: More Data, Continuing Concern (12June07):  http://www.medscape.com/viewarticle/559410_print
	Rosiglitazone Evaluated for Cardiovascular Outcomes (RECORD)— An Interim Analysis (05June07): http://content.nejm.org/cgi/reprint/NEJMoa073394v1.pdf {inconclusive findings; double the risk of heart failure; non-statistically significant increase in MI; study limitations: un-blinded, comparison to combo SU+MF, loss to follow-up}
	The Record on Rosiglitazone and the Risk of Myocardial Infarction (05June07): http://content.nejm.org/cgi/reprint/NEJMe078116v1.pdf
	Rosiglitazone — Continued Uncertainty about Safety (05June07): http://content.nejm.org/cgi/reprint/NEJMe078118v1.pdf
	Rosiglitazone and Cardiotoxicity — Weighing the Evidence (05June07):  http://content.nejm.org/cgi/reprint/NEJMe078117v1.pdf {DM Nathan; "unless further studies can provide convincing assurance that treatment with rosiglitazone does not increase the risk of CV disease, the largely circumstantial evidence of the meta-analyses and the nonsignificant trend in the current report from the RECORD trial must be taken seriously." }
	Health Canada Health Professional Advisory (Jun 1, 2007): Health Canada Endorsed Important Safety Information on ^PrAvandia^®, ^PrAvandamet^® and ^PrAvandaryl^TM ^http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2007/avandia_hpc-cps_4_e.html
	Health Canada Public Advisory (May 30, 2007) - Cardiac Safety of Avandia^® (rosiglitazone maleate)  http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/public/2007/avandia_pc-cp_3_e.html
	Note regarding Prescriber's Letter / Pharmacist's Letter on Avandia: http://www.emediawire.com/releases/2007/5/emw529558.htm
	FDA Alert (May 21, 2007)- Avandia: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01636.html
	GSK  - Position (May 30, 2007): http://www.gsk.com/media/press-kits/avandia-30may2007.pdf - GSK letter published in the Lancet  (May 30, 2007): http://multimedia.thelancet.com/pdf/rosiglitazone_response.pdf - Initial response (May 21, 2007): http://www.gsk.com/media/press-kits/avandia-21may2007.pdf

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