FDA HR Presentation in Defense of Avandia 07.14

8/9/2019 FDA HR Presentation in Defense of Avandia 07.14

1/42

1

In Defense of Avandia

(rosiglitazone)

Hal Roseman, MD, MPH, FACC, FACP


2/42

Hal M. Roseman, MD, MPH, FACC, FACP

B.A. (Social and Political Theory)- University ofPennsylvania

M.D.- University of Tennessee M.P.H. (Epidemiology of Cardiovascular Disease)- Yale

University

Cardiology Training: Brown University Affiliated Hospitals Massachusetts General Hospital

Specialist, American Society of Hypertension Fellow, National Lipid Association


3/42

Hal M. Roseman, MD, MPH, FACC, FACP

Conflict Declaration: Speaker Bureaus: GSK, Abbott, Novartis, Merck No stock ownership No advisory positions

This presentation represents my own opinions. I did notreceive financial support from GSK to make this

presentation.


4/42

http://www.time.com/time/health/article/0,8599,1623580,00.html?xid=feed-cnn-topics


5/42

No defining evidence to support a causal link betweenrosiglitazone and adverse cardiovascular events.

AHA/ACC Science Advisory1 (2010):

In summary, an association

between rosiglitazone and IHD

outcomes has not yet been firmlyestablished.

FDA2 (2007):

The available data on the riskof myocardial ischemia are

inconclusive.

1. Kaul S, et. al., Circulation. 2010;121:1868-18772.

FDA Issues Safety Alert on Avandia. www.fda.gov/bbs/topics/NEWS/2007/NEW01636.html


6/42

6

2009 AACE/ACE Glycemic Control Algorithm

American Association of Clinical Endocrinologists (AACE) and the AmericanCollege of Endocrinology (ACE) released a new algorithm for the treatment of

patients with type 2 diabetes in October 2009

AACE/ACE consensus panel has taken into consideration the results of several,large clinical trials, including RECORD, and continues to recommend the use of

AVANDIA (rosiglitazone maleate)

The authors state Although some studies have been controversial, recentclinical trials ADVANCE , VADT, and ACCORDshowed no increased risk of

mortality associated with rosiglitazone

The authors also discuss the known side-effect profile of the thiazolidinedione(TZD) class, including the risk of edema and congestive heart failure

AVANDIA continues to be included in the AACE/ACE algorithm

for appropriate patients with type 2 diabetes

Rodbard HW, et al . Endocrine Practice. 2009;15(6):540-559.


7/42

Top Five Reasons for KeepingAvandia on Open US Formulary.


8/42

5. Given the benefits of

durable glucose control inpreventing microvascular

disease, Avandias

demonstrated ability to

control blood sugar for fiveyears is unique among all

other diabetic medications.


9/42

9

ADOPT & RECORD:Similar Patterns of Durable A1c Control1-3

ADOPT

6.6

6.2

6.4

6.8

7.0

7.2

7.4

7.6

7.8

8.0

Time (years)0 1 2 3 4 5

AVANDIA

Sulfonylurea

Metformin

AVANDIA

7.2

7.4

7.6

7.8

8.0

Time (years)0 1 2 3 4 5

Metformin

6.8

7.0

7.2

7.4

7.6

7.8

8.0

Time (years)0 1 2 3 4 5

Sulfonylurea

RECORD*Background SU

AVANDIA

Background MET

1. Kahn SE et al. N Engl J Med. 2006;355:24272443. 2. Data on File, GlaxoSmithKline. 3. Home PD, et al. Lancet.2009;373:21252135.

*This study was not designed to show superiority in glycemic control.Model-adjusted mean A1c by background strata.


10/42

10

Longest Glycemic Control Monotherapy Trialwith Pioglitazone in Patients with T2DM*

FPG = fasting plasma glucose; T2DM = type 2 diabetes mellitus.*P


11/42

4. In terms of validityof data, randomizedclinical trials are thegold standard and

trumps that ofmetanalyses (e.g.,Steve Nissen) orobservational data

sets (e.g. Graham)


12/42

There is simply no serious scientific

alternative to the generation of large-scale randomized evidence.

Peto R et al. J Clin Epidemiol. 1995;48:2340.

R Peto

Professor of Medical Statistics and EpidemiologyUniversity of OxfordOxford, United Kingdom

Contributed to the developmentof the meta-analysis method

Peto R, Collins R, Gray R. J Clin Epidemiol 1995; 48: 23-40


13/42

13

Independent Diabetes Outcome Trials:Findings with Regard to AVANDIA

The investigators of VADT and ACCORD, 2 independent,long-term CV outcome studies involving more than 20,000

years of patient experience with rosiglitazone in a high-risk

population of patients with type 2 diabetes, reported that

AVANDIA was not related to an increased risk of mortality1,2

Although VADT and ACCORD were not prospectivelydesigned to assess the safety of AVANDIA, the mortality

results for AVANDIA are consistent with results from other

long-term studies (DREAM, ADOPT, RECORD) with

AVANDIA1-4

1. American Diabetes Association. http://www.diabetes.org/for-media/pr-intense-blood-glucose-control-yields-no-significant-effect-on-cvd-reduction.jsp. Accessed April 1, 2010.

2. ACCORD Study Group. N Engl J Med. 2008;358:25452559.3. Prescribing Information for AVANDIA.

4. Duckworth W et al. N Engl J Med. 2009;360(2):129139


14/42


15/42

Study Treatment No. of patientswith event

HR (95% CI)

ADOPT

RSG (N = 1456) 20 (1.4%)

vs MET (N = 1454) 17 (1.2%)

vs SU (N = 1441) 15 (1.0%)

DREAM

RSG (N = 1325) 5 (0.4%)

vs Placebo (N = 1321) 7 (0.5%)

RSG + Ramipril (N = 1310) 12 (0.9%)

vs Ramipril (N = 1313) 5 (0.4%)

No Significant Difference in Myocardial Infarction* inGSK Long-term Prospective Studies

*Adjudicated fatal and nonfatal myocardial infarction plus sudden death;Events were adjudicated during the study; Post-study adjudication.

Prescribing Information for AVANDIA.Data on file, GlaxoSmithKline.

1.0 5.00.5Favors RSG Favors control

1.21 (0.64, 2.32)

1.20 (0.62, 2.35)

0.71 (0.23, 2.24)

2.41 (0.85, 6.84)


16/42

Study TreatmentNo. of patients

with event HR (95% CI)

ADOPT

RSG (N = 1456) 35 (2.4%)

vs MET (N = 1454) 36 (2.5%)

vs SU (N = 1441) 28 (1.9%)

DREAM*

RSG (N = 1325) 15 (1.1%)

vs Placebo (N = 1321) 14 (1.1%)

RSG + Ramipril (N = 1310) 18 (1.4%)

vs Ramipril (N = 1313) 9 (0.7%)

No Significant Difference in MACE (CV Death, MI, Stroke)in GSK Long-term Prospective Studies

*Events were adjudicated during the study.Post-study adjudication for CV death and myocardial infarction; not adjudicated for stroke.

Prescribing Information for AVANDIA.

Data on file, GlaxoSmithKline.

1.0 5.00.5Favors RSG Favors control

1.00 (0.63, 1.59)

1.11 (0.67, 1.82)

1.07 (0.51, 2.21)

2.01 (0.90, 4.48)


17/42

No Significant Difference in Total Mortalityin GSK Long-term Prospective Studies

Prescribing Information for AVANDIA.Data on file, GlaxoSmithKline.

Study Treatment No. of patientswith event HR (95% CI)

ADOPT

RSG (N = 1456) 12 (0.8%)

vs MET (N = 1454) 15 (1.0%)

vs SU (N = 1441) 21 (1.5%)

DREAM

RSG (N = 1325) 15 (1.1%)

vs Placebo (N = 1321) 17 (1.3%)

RSG + Ramipril (N = 1310) 15 (1.1%)

vs Ramipril (N = 1313) 16 (1.2%)

0.5 1.0 5.00.2

Favors RSG Favors control

0.82 (0.39, 1.76)

0.51 (0.25, 1.04)

0.87 (0.44, 1.75)

0.94 (0.47, 1.90)


18/42

VADT: Rosiglitazone Use is notassociated with Increased CV Risk


19/42

VADT: Effect of Rosiglitazone dosageon Time to First Myocardial Infarction

Moritz T. Presentation at the 68th Scientific Sessions of the ADA: June 8, 2009 (San Francisco, CA)


20/42

VADT: Effect of Rosiglitazone dosageon Time to MACE

Baseline covariates: age, prior event, diabetes duration, baseline HbA1C, minority, SBP, total cholesterol, HDL** baseline and time dependent covariates: age, prior event, # of Insulin, diabetes duration, minority, total cholesterol, HDL, statins


21/42

BARI-2D: Rosiglitazone Effect onCardiovascular Events

Our observations from BARI 2D do not

suggest a significant cardiovascular hazard

and may suggest a potentially beneficial effect

on ischemic cardiovascular events associatedwith treatment with rosiglitazone among

patients with type 2 diabetes and established

coronary artery disease like those treated in

the trial"

Dr Bach, Presented at 70th Scientific Sessions of the

ADA ; June 2010 (Orlando, FL.)


22/42

BARI-2D SubAnalysis:Rosiglitazone vs. Non-TZD Treatment


23/42

BARI-2D Trial: CV Events during Treatmentwith Rosiglitazone Plus 3 Months vs. No TZD

Unadjusted Outcomes, Mean Follow-up 4.5 years


24/42

BARI-2D:Metabolic Benefits of Insulin Sensitization Treatment

In our study, plasma insulin levels were

consistently lower over time in patients in the

insulin sensitization groupMoreover, the

insulin-sensitization strategy was associated withfewer severe hypoglycemic episodes, less

weight gain, and higher HDL levels than those in

the insulin-provision strategy. These data may

suggest that insulin sensitization is preferable forpatients with type 2 diabetes and coronary

disease.

N Engl J Med 2009;360:2503-15.


25/42


26/42

Article published online on May 21, 2007

N Engl J Med 2007;356


27/42

Diamond GA, Bax L, Saul K. Ann Intern Med. 2007;147:578-581

Meta-analytic Odds Ratios for MyocardialInfarction and Cardiovascular Death


28/42

Uncertainty of Peto Method: Fixed vsRandom Effects


29/42


30/42

2. There has not been

put forth a convincinghypothesis why Avandiawould cause cardio-vascular harm, an

important omission.


31/42

Percentage of patients on lipid-lowering therapy at baseline (including statins) 26.0% AVANDIA, 25.9% MET, 25.7% SU1

Statin use at 4 years 51.5% AVANDIA, 43.5% MET, 40.2% SU1 Lab values assessed at 4 years (48 months)1

ADOPT: ADiabetes Outcome Progression TrialLong-term Lipid Data from ADOPT

Results shown are adjusted geometric mean change from baseline.*Percentage change calculated based on log transformed data.

1. Kahn SE et al. N Engl J Med. 2006;355:24272443. 2. Data on File, GlaxoSmithKline.

Baseline Lipids: LDL: 119-121 (98-144);

HDL: 46.5-47.3 (39.0-55); Trigs: 156-163 (112-233)


32/42

32

Baseline statin use 18.0% RSG vs 19.2% active control Statin use at 5 years 55.2% RSG vs 46.0% active control Lab values assessed at 5 years

RECORD: Rosiglitazone Evaluated forCardiacOutcomes and Regulation of glycemia in Diabetes

Lipid Data in Patients Taking AVANDIA

Results shown are mean results for lipid parameters.*Estimates of 5-year changes obtained with a baseline-adjusted repeated-measures model for all patient data (and Pvalues

for treatment difference).Lipids were not measured after initiation of any insulin therapy.

Home PD et al. Lancet. 2009;373:21252135.

TG 1.69 mmol/L = 150 mg/dL; HDL 1.03 mmol/L = 40 mg/dL; LDL 2.59 mmol/L = 100 mg/dL.


33/42

PROactive: PROspective pioglitAzoneClinical Trial In macroVascularEventsLipid Data in Patients Taking Pioglitazone

Baseline statin use 43% PIO vs 43% placebo Statin use at study end 55% PIO vs 56% placebo Lab values assessed at final visit, 34.5 months (2.9 years)

Results shown are median results for l ipid parameters.TG = triglycerides; HDL = high-density lipoprotein; LDL = low-density lipoprotein.

Dormandy JA et al. Lancet. 2005;366:12791289.

Baseline % Change

PIO placebo PIO placebo P

TG (mmol/L) 1.8 1.8 -11.4% +1.8%


34/42

Both Avandia and Actos have demonstratedsignificant effects on known cardiovascular surrogatemarkers

Carotid intima thickness regression Albumin reduction BP reduction


35/42

PPAR activation: Consistent reductionin carotid atherosclerosis

Study (year) TreatmentsPatients (n)

duration IMT (mm)Minamikawa

(1998)

Koshiyama(2001)

Sidhu

(2004)

Langenfeld

(2005)

Troglitazone 400 mg

Usual care

Type 2 diabetes

(n = 135)

6 mos

0.080, troglitazone

0.027, usual care

P < 0.001

Pioglitazone 30 mgUsual care

Type 2 diabetes(n = 106)

6 mos

0.084, troglitazone0.022, usual care

P < 0.001

Rosiglitazone 8 mg

Placebo

Stable CAD

(n = 92)

12 mos

0.012, rosiglitazone

0.0031, placebo

P = 0.03

Pioglitazone 45 mg

Glimepiride 2.7 mg

Type 2 diabetes

(n = 173)

6 mos

0.054, pioglitazone

0.011, glimepiride

P < 0.001

Minamikawa J et al. J Clin Endocrinol Metab. 1998;83:1818-20.

Koshiyama H et al. J Clin Endocrinol Metab. 2001;86;3452-6.

Sidhu JS et al.Arterioscler Thromb Vasc Biol. 2004;24:930-4.

Langenfeld MR et al. Circulation. 2005;111:2525-31.


36/42

Effects Of Rosiglitazone On CV BiomarkersIn Diabetics And Non-Diabetics

PAI-1*

Rosiglitazone

Insulin Resistance Glucose/HbA1c Insulin & Proinsulin CRP, IL-6 (?)* sCD40L* *ROS, MCP-1, P47phox* TNF* NFB*

PPAR Diastolic BP

Vascular Reactivity* Microalbuminuria* MMP-9* E-selectin* ADMA* NO In Human Skin*

sdLDL HDL2/ TC/HDL3

ImprovedLipid Profile ImprovedVascular Function* ReducedInflammation*ImprovedFibrinolytic Activity*

? CV and DM Outcomes, Atherosclerosis ?

Adiponectin*

* Freed et al. Diabetologia. 2000;43(suppl 1):1267. Data on file, GlaxoSmithKline. Mohanty et al. Diabetes. 2001;50(suppl 2):A68 (Abstract 276-OR). Stuhlinger et al. JAMA. 2002;287:1420-1426. Brunzell et al. Diabetes. 2001;

50(suppl 2):A141 (Abstract 567-8 and poster). Chu et al. Diabetes. 2002;51(suppl 1):(Abstract 553-P). Agrawal et al.Diabetes. 2002;51(suppl 1):A92 (Abstract 372P). Vinik et al. Diabetes. 2002;51(suppl 1):A82 (Abstract 333P).


37/42

LUMEN

INTIMA

MEDIA

Oxidization

of LDL

LDLEndothelial Injury

Monocyte

MacrophageFoam Cell

Transformation

CholesterolEfflux

ASMC

Migration

Adhesion Molecules

Colony

Stimulating

Factors

Cytokines

Mitotic Angiogenic

Factors: MMP

Growth

Factor:

PDGF

MCP-1

PAI-1

!!

Effect of Thiazolidinediones

on Atherosclerosis


38/42


39/42

PROactive: the only Long-Term Study withCardiovascular Safety Endpoints: Design and Results

Design

5238 patients 100% previous cardiovascular

disease

Average follow-up 2.9 years;15,060 patient-years

>30% insulin-treated at baseline

Pioglitazone + treatment vs placebo+ treatment design double blind

CHFnot included in primary andsecondary endpoints

Results

Failed to achieved primaryendpoint

Principal secondary endpoint(MACE*) 301 events PIO vs

358 events placebo

417 CHF events PIO vs 302events placebo (non-

adjudicated)

Paper did not report fatal andnon-fatal MI together

Dormandy JA et al. Lancet. 2005;366:12791289.

*For PROactive, MACE = all-cause death, non-fatal MI (excluding silent MI), and stroke.


40/42

According to the AHA and ACC, meta-analyses andobservational studies are not sufficient to evaluate clinical

differences between rosiglitazone and pioglitazone

Substantial differences between the pioglitazone and rosiglitazone meta-

analyses exist, eg, placebo-controlled versus active-controlled trials,

patient demographics, and treatment duration. Each of these factors

potentially can have a material impact on outcomes. This type of indirect

comparison is potentially misleading, may result in conflicting results

depending on the end points compared, and generally should beavoided. Healthcare databases used in observational studies are limited

by bias and confounding, and therefore, they are not particularly well

suited for drawing definitive conclusions to impact policy or clinical

practice recommendations.

Kaul S, et. al., Circulation. 2010;121:1868-1877.


41/42


42/42

END

FDA HR Presentation in Defense of Avandia 07.14

Documents

Transcript of FDA HR Presentation in Defense of Avandia 07.14