View
218
Download
0
Category
Preview:
Citation preview
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
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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.
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
4/42
http://www.time.com/time/health/article/0,8599,1623580,00.html?xid=feed-cnn-topics
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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.
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
7/42
Top Five Reasons for KeepingAvandia on Open US Formulary.
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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.
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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.
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
10/42
10
Longest Glycemic Control Monotherapy Trialwith Pioglitazone in Patients with T2DM*
FPG = fasting plasma glucose; T2DM = type 2 diabetes mellitus.*P
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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)
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
14/42
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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)
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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)
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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)
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
18/42
VADT: Rosiglitazone Use is notassociated with Increased CV Risk
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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)
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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.)
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
22/42
BARI-2D SubAnalysis:Rosiglitazone vs. Non-TZD Treatment
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
23/42
BARI-2D Trial: CV Events during Treatmentwith Rosiglitazone Plus 3 Months vs. No TZD
Unadjusted Outcomes, Mean Follow-up 4.5 years
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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.
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
25/42
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
26/42
Article published online on May 21, 2007
N Engl J Med 2007;356
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
27/42
Diamond GA, Bax L, Saul K. Ann Intern Med. 2007;147:578-581
Meta-analytic Odds Ratios for MyocardialInfarction and Cardiovascular Death
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
28/42
Uncertainty of Peto Method: Fixed vsRandom Effects
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
29/42
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
30/42
2. There has not been
put forth a convincinghypothesis why Avandiawould cause cardio-vascular harm, an
important omission.
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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)
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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.
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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%
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
34/42
Both Avandia and Actos have demonstratedsignificant effects on known cardiovascular surrogatemarkers
Carotid intima thickness regression Albumin reduction BP reduction
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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.
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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).
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
38/42
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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.
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
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.
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
41/42
8/9/2019 FDA HR Presentation in Defense of Avandia 07.14
42/42
END
Recommended