EDUCATIONAL SLIDE MODULES - PowerPoint Presentation

Slide1

EDUCATIONAL SLIDE MODULES

Module C:

Evidence for effects of older glucose-lowering agents on CV risk

Slide2

ACROSS T2D educational slide modules

.

2

Slide3

3

CV safety

Metformin

SU

TZD

FDA mandate

CVOT interpretation

Slide4

4

CVOT interpretation

Slide5

Evolution of

T2D

agents

Adapted from 1. Kirby.

Br

J Diabetes

Vasc

Dis

 

2012;12:315–20

.

2. Lantus

® SPC.1950

196019701980

1990200020102012

2013Lente class of insulins producedSUs first usedMetformin introduced

Recombinant human insulin produced2nd generation SUs availableThree new classes introduced: -glucosidase inhibitors, meglitinides and TZDsGlimepiride: 3rd generation SU

DPP4 inhibitors

GLP1 receptor agonists

SGLT2 inhibitors

Insulin

degludec



Older T2D agents

Newer T2D agents



Insulin glargine available

2

5

Metformin introduced in the UK

Slide6

Metformin: MOA

Adapted from 1. Bailey &

Feher

. Therapies for Diabetes 2004. 2. Batchuluun et al. J Endocrinol Diabetes Obes 2014;2:1035.

In addition to

its glucose-lowering effects, metformin may have potential effects on the CV system, e.g., improving plasma lipid profile

2

6

Metformin

1

IntestineLiver

Skeletal muscle

 Glucose utilisation

 Gluconeogenesis Glycogenolysis Fatty acid oxidation Insulin-mediated glucose uptake Glycogenesis

 Fatty acid oxidation Hyperglycaemia

Slide7

Metformin is

recommended

as first-line therapy in T2D

Metformin is indicated for the treatment of T2D, and generally recommended as first-line therapy1,2

Evidence for effect on CV risk cited in international prescribing information differs for US vs EU

US prescribing information

3

States that there are no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin (or any other anti-diabetes drug)

EU prescribing information1 Cites UKPDS analysis from 342 overweight patients treated with metformin after failure of diet alone1,4Metformin significantly reduced any diabetes-related complication, diabetes-related and overall mortality, and absolute risk of MI vs diet alone after 10.7 years

71. http

://www.medicines.org.uk/emc/medicine/23244/SPC. 2. American Diabetes Association. Diabetes Care 2015;38(suppl. 1):S1–S94. 3

. http://www.drugs.com/pro/metformin.html 4. UKPDS 34. Lancet 1998;352:854–65.

Slide8

UKPDS 34 provides some evidence

for beneficial CV effects of

metformin in overweight patients

1. UKPDS 34. Lancet 1998;352:854–65. 2. http://

www.medicines.org.uk/emc/medicine/23244/SPC.

3. Holman

et al. N

Engl J Med 2008;359:1577–89.

Significant reduction in MI maintained over 10 years’ follow-up3

8

1997

1999

200120032005

2007No. of events:

Conventional therapy

738392106118

126Metformin394555

646881

Myocardial infarction

Metformin vs conventional

p = 0.01

Time from

randomisation

(years)

0

3

6

9

12

15

0.0

10

20

30

Proportion of patients with

event

s

(%)

Intensive (n = 951; events = 139)

Conventional (n = 411; events = 73)

Metformin

(n = 342; events = 39)

Risk of MI is 39% lower with metformin vs

conventional therapy in obese

patients

1,2

1.4

1.2

1.0

0.8

0.6

0.4

HR (95% CI)

RR 0.61

1

p = 0.01

RR 0.67

p

= 0.005

Overall values at study end in 1997

Annual values

during

10-year post-trial monitoring

period

0.4

Slide9

UKPDS 34: CV

effects of

metformin added to SU

9

*Interpret with caution in view of small event numbers.

UKPDS

34.

Lancet 1998;352:854–65.

Metformin added to SU vs SU alone was associated with increased risk of diabetes-related death and all-cause mortality

Median follow up 6.6 yearsRR

p-value

Any diabetes related endpoint

1.040.78Diabetes-related deaths*1.96

0.039All-cause mortality*1.600.041

Myocardial infarction*1.090.73

Stroke*1.210.61Microvascular*

0.840.62Relative risk (95% CI)

1.0Favours added metforminFavours SU alone

Slide10

CV safety of metformin

Metformin is generally recommended as first-line therapy

1,2

Some evidence to suggest a CV benefit in overweight patients1There remains a paucity of evidence from large, long-term, placebo-controlled CV outcome trials

3

10

Section recap

1. http://www.medicines.org.uk/emc/medicine/23244/SPC. 2.

American Diabetes Association. Diabetes Care 2015;38(suppl. 1):

S1–S94.

3.

Boussageaon

et al.

PLoS Med. 2012; 9:e1001204.

Slide11

11

CVOT interpretation

Slide12

Reproduced from 1. Gore

and

McGuire. Eur Heart J 2011;32:1832–4.

12

Sulphonylureas: MOA

Slide13

Sulphonylureas and

CV safety

In the US, SUs carry a special warning around increased risk of CV mortality

1–3The warning is based on findings from the UGDP trial that reported an excess of cardiac deaths in patients receiving tolbutamide versus placebo4In the EU, the same SUs do not carry safety warnings around increased CV mortality with SUs

5–7

1.

Glimepiride PI at http

://

www.accessdata.fda.gov/drugsatfda_docs/label/2009/020496s021lbl.pdf. 2. Tolbutamide PI at http://www.drugs.com/pro/tolbutamide.html. 3. Glipizide PI at http://www.drugs.com/pro/glipizide.html. 4.

Meinert et al. Diabetes 1970;19 (suppl):789–830. 5. Glimepiride EU SmPC at http://www.medicines.org.uk/emc/medicine/27033. 6. Tolbutamide EU SmPC at http://www.medicines.org.uk/emc/medicine/26366. 7. Glipizide EU

SmPC at http://www.medicines.org.uk/emc/medicine/9851.13

Slide14

No deleterious CV effect of SUs vs insulin or conventional therapy observed in UKPDS 33

1

14

1. UKPDS33. Lancet 1998;352:837–53. 2.

Patel

et al.

N

Engl J Med 2008;358:2560–72.

Conventional vs glibenclamide vs

insulin p = 0.66

Conventional (896)Chlorpropamide (619)Glibenclamide (615)Insulin (911)

Patients with MI (%)

0.4

0.3

0.2

0.1

0.0036

91512

Years from randomisation

In addition, in the ADVANCE study, intensive glucose control involving

gliclazide was not associated with deleterious CV effects

2

Slide15

Meta-analysis of SU CV safety

trials (≥ 6 months) found no consistent association with MACE risk

1

1. Monami et al. Diabetes

Obes

Metab

2013;15:938–53.

First author (year)

Birkeland 1996

Chou 2008

Perriello 2006

Gerstein 2010UKPDS 33 1998Hanefeld 2007Seino 2010Charbonnel 2005 Matthews 2005

Rubin 2008Home 2009Arechavaleta 2011va der Laar 2004

Mazzone 2006Riddle 1998Giles 2010Tolman 2009Kahn 2006

Goke 2010Garber 2009Nissen 2008Ristic 2007Ferrannini 2009

Bakris 2006 Gallwitz 2012 Jain 2006 Johnston 1998Nauck 2011

Seck 2010 OverallTotal # patients*

Total #

events*

36

1

452

3

283

9

672

55

3041

610

587

4

400

4

630

14

1250

15

1805

46

2222

312

1035

4

96

2

458

4

145

2

300

26

2097

61

4351

72

858

13

495

13

543

24

262

5

2789

34

374

11

1551

38

502

11

272

4

801

3

1172

4

29,783

1495

0.01

0.1

1

10

100

Favours SUs

Favours comparators

MH-OR (95% CI)

15

Overall MACE risk

estimate: MH-OR 1.08

(95% CI: 0.86–1.36);

p = 0.52

1

Mortality

was significantly

increased with

sulphonylureas

(MH-OR: 1.22 [1.01–1.49], p=0.047)

*SU + comparator groups combined.

Slide16

CV

safety of

SUs

The UGDP study raised safety concerns with tolbutamide (excess of cardiac deaths vs placebo)

1

UKPDS 33 demonstrated no deleterious effect of SUs on CV safety compared with insulin or conventional management

2

In ADVANCE, intensive glucose-lowering including gliclazide was not associated with negative CV outcomes vs standard treatment

3 In a meta-analysis of 115 RCTs, overall MACE risk estimate for SUs vs comparators was not statistically increased (OR 1.08, p = 0.52)

4

1. Meinert et al. Diabetes 1970;19(suppl):789–830. 2. UKPDS Group. Lancet 1998;352:837–53.

3. Patel et al. N Engl J Med 2008;358:2560–72. 4. 5.

Monami et al. Diabetes Obes Metab 2013;15:938–53. ‘CV safety of SUs cannot be considered established unless evaluated in long-term CVOTs’416

Section recap

Slide17

17

CVOT interpretation

Slide18

Thiazolidinediones (TZD;

PPAR-

γ

agonists): MOAAdapted from Bailey

& Feher. Therapies for Diabetes 2004.

18

TZD

Liver



Glucose uptake



Gluconeogenesis

Adipogenesis Fatty acid uptake Lipogenesis Glucose uptake

Hyperglycaemia

Adipose Plasma FFA

Skeletal muscle

PPAR activation

Slide19

In 2007,

separate meta-analyses

suggested differing CV effects of drugs within the TZD class

1. Nissen & Wolski. N Engl J Med

2007;356:2457–71. 2.

Lincoff

et al. JAMA 2007;298:1180–8.

Rosiglitazone meta-analysis

1

1.0

2.0

Favours rosiglitazoneFavours control

MIOR 1.43 (95% CI: 1.03‒1.98)p = 0.03CV death

OR 1.64 (95% CI: 0.98‒2.74)p = 0.06

Pioglitazone meta-analysis21.02.0

Favours pioglitazone

Favours control

MI

HR 0.81

(95%

CI: 0.64

‒

1.02)

p = 0.08

Death

HR 0.92

(95%

CI: 0.76

‒

1.11)

p = 0.38

19

No clinical trial directly compares the CV effects of pioglitazone and rosiglitazone

Slide20

Pioglitazone: PROactive trial design

Dormandy

et al. Lancet

2005;366:1279–89.

With or without background therapy

N = 5238

; average follow-up

34.5

months

Main inclusion

criteria1. Patients with T2D and evidence of macrovascular disease

2. Age 35–75 years

3. HbA1c > 6.5%Primary endpoint: time to first occurrence

of all-cause mortality, non-fatal MI, stroke, ACS, endovascular/surgical intervention in coronary/leg arteries, amputation above

anklePlaceboPioglitazone

versusAim Drug-specific trial to determine the impact of pioglitazone on macrovascular morbidity and mortality in high-risk patients with T2D

Secondary endpoint: time to first occurrence of all-cause mortality, non-fatal MI, stroke

Statistical analysis≥ 760 patients with ≥ 1 endpoint event

Last patient recruited followed up for 30 months

20

Slide21

PROactive: Pioglitazone was

superior

to placebo for main secondary endpoint, but not for primary

endpoint*Death from any cause, non-fatal MI (including silent MI), stroke, acute coronary syndrome, leg amputation, coronary revascularisation or revascularisation of the leg.

Dormandy

et

al. Lancet 2005;366:1279–89.

Time to primary endpoint*

Pioglitazone (514 events)

Placebo (572 events)

HR 0.90 (95% CI: 0.80–1.02)

p

= 0.095

Proportion of events (%)

Time from

randomisation

(months)

25

20

15

10

5

0

0

6

12

18

24

30

36

21

Time to a

ll-cause

mortality, non-fatal MI, stroke

Proportion of events (%)

Time from

randomisation

(months)

25

20

15

10

5

0

0

6

12

18

24

30

36

Pioglitazone (301 events)

Placebo (358 events)

HR 0.84

(95% CI: 0.72–0.98)

p

= 0.027

Hospitalisation for Heart Failure:

6

% (149 of

2605

)

in pioglitazone vs 4

% (108 of 2633)

in placebo; p = 0.007

Slide22

Rosiglitazone: RECORD trial design

Home et al. Lancet 2009;373:2125–35

.

Main inclusion

criteria

1.

Patients

with T2D

on maximum tolerated doses of metformin or SU monotherapy2

. Age 40–75 years3. BMI ≥ 25.0 kg/m2

N = 4447; follow-up 5–7 years

OPEN-LABEL

Metformin + SUOPEN-LABEL

Rosiglitazone + metformin or Rosiglitazone + SU

versusTime to first occurrence of CV hospitalisation or CV

deathAim Drug-specific trial to compare macrovascular morbidity and mortality in patients with T2D treated with rosiglitazone + metformin / SU22

Primary endpoint:Statistical analysis

Non-inferiority margin of 1.20 for HR

4000 participants followed for a median of 6 years to give 99% power

Time to first occurrence of cardiovascular

hospitalisation

or cardiovascular death

Slide23

Rosiglitazone: RECORD trial results showed no increase in CV death

1. AVANDIA US Prescribing information.

2. Home et al. Lancet 2009;373:2125–35

. 3.

FDA Safety Information.

4.

Rosenson et al. Am Heart J 2012;164:672–80.

Rosiglitazone

N = 2220

Active control N = 2227HR

95% CI

Primary endpointCV death or CV hospitalisation

3213230.990.85–1.16

Secondary endpoint    

All-cause death1361570.860.68–1.08CV death

60710.840.59–1.18MI

64561.140.80–1.63Stroke

46

63

0.72

0.49–1.06

CV death, MI or stroke

154

165

0.93

0.74–1.15

Heart failure

61

29

2.10

1.35–3.27

CV outcomes

for

RECORD

trial (original data)

1,2

23

In 2013, FDA panel voted to reduce safety restrictions on

rosiglitazone

3

However, there

are no long-term prospective data on CV safety,

so controversy remains

4

Slide24

CV safety of TZDs

TZDs cause

or

exacerbate heart failure in some patients1

CV meta-analyses in 2007 suggested differing effects on CV outcomes

Pioglitazone was associated with a significant 16% reduction in

3P-MACE (as a

secondary endpoint) vs placebo in PROactive2

Rosiglitazone open-label RECORD data showed no increase in CV death1FDA reduced the safety restrictions on rosiglitazone imposed following 2007 meta-analysis3 but controversy over CV safety remains

24

1

.

AVANDIA US Prescribing information. 2. Dormandy et al. Lancet 2005;366:1279–89. 3. FDA Safety Information. 4. Rosenson et al. Am Heart J. 2012;164:672–80.

‘Within the PPAR family, there is no “class effect” and each agent must be considered unique. The FDA has mandated that each agent within this class be evaluated individually in a variety of ways including clinical outcome studies’4Section recap

Slide25

25

CVOT interpretation

Slide26

Adverse CV events led the FDA to require

demonstration of CV safety for new glucose-lowering drugs

1. Nissen. Ann Intern Med 2012;157:671–2. 2. Nissen et al. JAMA 2005;294:2581–6. 3.

Nissen

et al. N

Engl

J Med 2007;356:2457–71. 4. ACCORD Study Group. N Engl J Med 2008;358:2545–59.

5. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/%20guidances/ucm071627.pdf 6. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf

7.http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm376683.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery

UGDP trial: tolbutamide discontinued due to increased CV mortality vs other treatment groups1

Sponsor withdrew

application1

Withdrawn in the EU1Use restricted in US1

**In 2013, FDA panel voted to reduce safety restrictions on rosiglitazone7

196120052007

2008

20082012

Muraglitazar

found to potentially increase CV risk during FDA assessment

2

Rosiglitazone associated with increased risk

for MI and CV-related death

3

ACCORD trial: intensive glucose lowering was

associated with increased all-cause mortality

4

HR 1.22 (95% CI 1.01

‒

1.46); p = 0.04

New FDA requirements

5

New EMA requirements

6

New diabetes drugs should demonstrate CV safety with meta-analysis and a CV outcome trial (CVOT)

26

Slide27

Regulatory requirements for drug-specific CV outcome data in T2D

1. http

://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf.

2. http

://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf.

FDA 2008 Guidance for Industry

1

‘To establish the safety of a new

anti-diabetes

drug to treat

T2D,

sponsors should demonstrate that the therapy will not result in an unacceptable increase in CV

risk.’

Important CV events should be analysed

High-risk population to be included

Long-term data required (≥ 2 years) Prospective adjudication of CV events by an independent committeePhase II and III trials designed and conducted to permit meta-analysis to be performed at completion

EMA 2012

Guideline2

‘A fully powered

CV

safety assessment,

e.g.,

based on a dedicated CV outcome study, should be submitted before marketing authorisation whenever a safety concern is intrinsic in the

molecule/MOA

or has emerged from

pre-clinical/clinical

registration

studies.’

Two approaches are recommended:

Meta-analysis of safety events

Specific long-term controlled outcome study with at least

18–24 months’

follow-up

27

Slide28

FDA guidance for CV outcome data: meta-analysis limits and outcome trial requirements

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf.

1.0

0.5

1.3

1.8

2.0

RR of incidence of CV events with investigational agent vs control

Upper bound of 2-sided 95% CI

Inadequate

data to

support approval

28

Post-marketing CV trial(s)

may not be necessary

if

< 1.3

If overall risk–benefit analysis supports approval, post-marketing CV trial(s) needed to prove

< 1.3

Slide29

Satisfying FDA requirements for CV safety

Number of

CV events

needed to satisfy 1.3 non-inferiority margin

29

Geiger et al.

Ther

Innovation

Reg

Science 2014;1–15

.

Assuming relative risk of 1.0 and 90% power, adjudicated CV events needed to satisfy the CI upper limits for non-inferiority

:122 events for the 1.8 risk margin

0.8

0.65

0.7

0.75

0.85

0.9

0.95

1

1.05

1.15

1.1

0

200

400

600

800

1000

1200

1400

1600

Number of events

Assumed true relative risk

80% power

90% power

110

139

179

233

311

428

611

1507

922

1126

689

457

233

320

134

174

104

82

–

611 events for the 1.3 risk margin

Slide30

30

CVOT interpretation

Slide31

Usual care

– glucose lowering, BP lowering, lipid lowering etc.

Contemporary CVOT trial design for T2D

31

Adapted from Geiger

et al.

Ther

Innovation

Reg

Science 2014;1–15. 1. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf.

Aim

Determine effect of Drug X compared with placebo/comparator on CV outcomes, on top of

glucose-lowering and CV therapies adjusted according to local guidelines, in patients with T2DPlaceboHigh CV risk patients

Compositeprimary endpointStatistics

R

Run-in

EventsDrug X

FDA mandates that CV safety be demonstrated in high CV risk population1Run-in helps to establish patient adherence to long-term treatment and FUAll patients are on a usual care background (to control diabetes and CV risk factors); investigators encouraged to adjust therapy following local guidelines

As adjustment of background therapy is encouraged, CVOTs not designed to assess impact of a difference in HbA

1c

between study arms

FDA recommends 3P-MACE as primary CV endpoint or expanded

4P-MACE (e.g., including hospitalisation for unstable angina

pectoris)

1

Sequential statistical testing (superiority tested only if non-inferiority established)

Trials are event driven, rather than of fixed duration

Slide32

CVOTs designed to assess effects of a specific drug or of a treatment strategy (e.g. glucose lowering)

1. UKPDS 33. Lancet

1998;352:837–53. 2. UKPDS 34. Lancet 1998;352:854–65. 3. Duckworth et al. N Engl J Med

2009;360:129–39.

4. ACCORD. N Engl J Med

2008;358:2545–59. 5. ADVANCE. N Engl J Med 2008;358:2560–72. 6. Dormandy et al. Lancet 2005;366:1279–89. 7.

Mahaffey et al. Am Heart J 2013;166:240–9.e1. 8. Scirica et al. N Engl J Med 2013;369:1317–26. 9. White et al. N Engl J Med 2013;369:1327–35. 10.

Bentley-Lewis et al. Am Heart J 2015;0:1–8.e7. 11. Bethel et al. Diabetes Obes Metab 2015;17:1395–402. 12. Zinman et al. Cardiovasc Diabetol

2014;13:102.

Treatment strategy trials (intensive vs standard glucose lowering)Compound-specific trialsUKPDS1,2FPG < 6 vs < 15 mmol/L

Also assessed metformin vs SU + insulin2VADT3HbA1c ≤ 6% vs 8–9%ACCORD4

HbA1c < 6% vs 7–7.9%ADVANCE5

HbA1c < 6.5% vs SOCAlso assessed gliclazide + other drugs in intensive arm vs standard care armPROactive6

Pioglitazone vs placeboRECORD7Rosiglitazone +

metformin or SU vs metformin + SU SAVOR-TIMI 538Saxagliptin vs placeboEXAMINE

9

Alogliptin vs placebo

ELIXA

10

Lixisenatide

vs placebo

TECOS

11

Sitagliptin

vs placebo

EMPA-REG OUTCOME

®

12

Empagliflozin vs placebo

32

Slide33

Considerations for interpretation of

contemporary compound-specific CVOTs

Design features

1.

Hirshberg

& Katz.

Diabetes

Care 2013;36(

suppl 2):S253–8. 2. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf

.

Most CVOTs employ hierarchical testing to test for superiority following establishment of non-inferiority

CVOTs are typically event-driven; study duration can only be estimated1

Power and durationPrimary and secondary outcomes vary across trials (3P-MACE and 4P-MACE are common primary outcomes)2Outcomes

Inclusion characteristics vary across trials (e.g., degree of pre-existing CV risk or prior CVD, duration of T2D)This necessitates caution in comparing results across trials1Population

Background therapyTrials performed on a usual care background (e.g., high antihypertensive and statin use) so CV risk factors (e.g. BP, LDL-C) are generally well controlledInvestigators should adjust background therapy according to local guidelines1

33Demonstration of CV safety is required by regulators for newer anti-hyperglycaemic drugs as ‘class effects’ cannot be assumed based on drug-specific trials

Slide34

Event rate

2008 FDA guidance highlights the need to conduct T2D trials that obtain sufficient end

points

Event rate varies according to baseline CV risk of study population

3

Statistical considerations in CVOT interpretation

34

1. Dell et al.

ILAR J. 2002;43:207–213. 2.

Eng. Radiology 2003;227:309–13. 3. Preiss et al. Am Heart J 2011;161:210-219.e1. 4. Zinman et al. Cardiovasc

Diabetol 2014;13:102.

Event rate (events

/ 1000 patient-years)Baseline characteristicsCV deathCVD16.7No CVD3.6

Power is the probability that the effect, if it exists, will be detectedPower is usually set to 80% or 90% (i.e. the chance of demonstrating statistical significance if the true effect is at least as pronounced as specified)1

Hierarchical testing for non-inferiority and then superiority is common among CVOTs, e.g., in a recent protocol:4Primary analysis is non-inferiority for 3P-MACE If achieved, non-inferiority testing of 4P-MACE (key secondary outcome) will be conductedIf achieved, superiority testing will follow of first 3P-MACE and, if positive, 4P-MACE

Sample size must be pre-plannedVariables needed to calculate1,2:Assumed effect size (and accepted non-inferiority margin)Expected event rate in control group

Desired power Significance level (incl. interim analyses)

Slide35

Overview of CVOTs of glucose-lowering

drugs

35

Timings represent estimated completion dates as per ClinicalTrials.gov.

Adapted from Johansen. World J Diabetes

2015;6:1092–96.(references 1–19

expanded in slide notes

)

CANVAS-R

8

(n = 5700)

Albuminuria

2013

2014

2015

20162017

20182019SAVOR-TIMI 53

1(n = 16,492)1,222 3P-MACEEXAMINE2

(n = 5380)

621 3P-MACE

TECOS

4

(n = 14,724)

≥ 1300 4P-MACE

LEADER

6

(n = 9340)

≥ 611 3P-MACE

SUSTAIN-6

7

(n = 3297)

3P-MACE

DECLARE-TIMI 58

15

(n = 17,150)

≥ 1390 3P-MACE

EMPA-REG OUTCOME®

5

(n = 7034)

≥

691 3P-MACE

CANVAS

10

(n = 4365)

≥ 420 3P-MACE

CREDENCE

17

(n = 3700)

Renal

+ 5P-MACE

CAROLINA

®

11

(n =

6000)

≥ 631 4P-MACE

ITCA CVOT

9

(n = 4000)

4P-MACE

EXSCEL

14

(n = 14,000)

≥ 1591 3P-MACE

DPP4 inhibitor CVOTs

SGLT2 inhibitor CVOTs

GLP1 CVOTs

Ertugliflozin

CVOT

18

(n = 3900)

3P-MACE

OMNEON

13

(n = 4000)

4P-MACE

CARMELINA

12

(n = 8300)

4P-MACE

+

renal

REWIND

16

(n = 9622)

≥ 1067 3P-MACE

2021

ELIXA

3

(n = 6068)

≥ 844 4P-MACE

HARMONY Outcomes

19

(n = 9400) 3P-MACE

Slide36

Module C: Summary

Metformin exerts various CV

effects

There is some evidence to suggest a CV benefit but there is a paucity of evidence from long-term CVOTs1

There is limited evidence evaluating the CV safety of profile of SUs

2,3

There is a need for evaluation of the CV safety of SUs in

a long-term

dedicated CVOTThe long-term CV safety profile of drugs within the TZD class remains controversial, emphasising the need for compounds within the same class to demonstrate CV safety

4The 2008 FDA guidance requires that new diabetes drugs demonstrate CV safety via meta-analysis and CVOT5

There are many considerations in interpreting the results of contemporary drug-specific CVOTs designed to assess the effect of a specific drug, added to background usual care, on MACE636

1. Boussageaon et al.

PLoS Med. 2012; 9:e1001204. 2. UKPDS 34. Lancet 1998;352::837–53. 3. ADVANCE. New Engl J Med 2008;358:2560–72. 4. Rosenson et al. Am Heart J. 2012;164:672–80. 5. FDA Guidance for Industry. 6. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf.

Slide37

Weight

Risk ratio (95% CI)

Risk ratio (95% CI)

Rosiglitazone trials

46.2%

2.41 (1.61–3.61)

Pioglitazone trials

53.8%

1.32

(1.04–1.68)

Total

100.0%

1.74 (0.97–3.14)

Test for overall

effect:

Z

= 1.85 (p = 0.07)

Meta-analysis showed increased risk for congestive heart failure with both pioglitazone and rosiglitazone

37

Lago et al. Lancet 2007;370:1129–36.

In a meta-analysis of 20,191 patients with pre-diabetes or T2D, the increased

risk for congestive heart failure with TZDs did not differ between

rosiglitazone and pioglitazone (p = 0.07)

Increased risk

Decreased risk

Comparison of risk of congestive heart failure

0.1

0.2

0.5

1

2

5

10

Slide38

Relative risk (95% credible interval)

Chlorpropamide

1.34 (0.98–1.86)

Tolbutamide

1.13 (0.90–1.42)

Glibenclamide (reference group)

Reference

Glipizide

0.98 (0.80–1.19)

Glimepiride

0.83 (0.68–1.00)

Gliclazide

0.65 (0.53–0.79)

Chlorpropamide

1.45 (0.88–2.44)

Tolbutamide

1.11 (0.79–1.55)Glibenclamide (reference group)

ReferenceGlipizide1.01 (0.72–1.43)

Glimepiride

0.79 (0.57–1.11)

Gliclazide

0.60 (0.45–0.84)

Network meta-analysis suggested possible variation

between

SUs

in effects on

mortality

Simpson et al. Lancet Diabetes

Endocrinol

2015;3:43–51.

38

All-cause

mortality

Cardiovascular

mortality

0.1

1.0

Lower risk than for reference group

Higher risk than for reference group

10.0

0.5

1.0

2.0