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EDUCATIONAL SLIDE MODULES

Module C:
Evidence for effects of older
glucose-lowering agents on
CV risk
ACROSS T2D educational slide modules

Module A
• CV disease and T2D

Module B
• Approaches to managing CV risk in patients with T2D

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

Module D
• Evaluating CV safety and potential for CV risk reduction with newer T2D
agents

Module E
• EMPA-REG OUTCOME® results

2
Metformin

CVOT
interpretation SU

CV
safety

FDA
TZD
mandate

3
Metformin

CVOT
interpretation SU

CV
safety

FDA
TZD
mandate

4
Evolution of T2D agents
DPP4 SGLT2
inhibitors inhibitors

 Older T2D agents Newer T2D agents 

1950 1960 1970 1980 1990 2000 2010 2012 2013

GLP1 receptor
agonists
Lente class Recombinant Glimepiride: Insulin
of insulins human insulin 3rd generation SU degludec
produced produced

SUs first used 2nd generation


SUs available Insulin glargine
available2
Metformin
Metformin Three new classes introduced:
introduced -glucosidase inhibitors, meglitinides
introduced
and TZDs
in the UK
Adapted from 1. Kirby. Br J Diabetes Vasc Dis 2012;12:315–20. 2. Lantus® SPC.

5
Metformin: MOA
Metformin1

Intestine Liver Skeletal muscle

 Glucose utilisation  Gluconeogenesis  Insulin-mediated


 Glycogenolysis glucose uptake
 Fatty acid oxidation  Glycogenesis
 Fatty acid oxidation

 Hyperglycaemia

In addition to its glucose-lowering effects, metformin may have potential


effects on the CV system, e.g., improving plasma lipid profile 2

Adapted from 1. Bailey & Feher. Therapies for Diabetes 2004. 2. Batchuluun et al. J Endocrinol Diabetes Obes 2014;2:1035.

6
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 information3
• 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 alone1,4
– Metformin significantly reduced any diabetes-related complication, diabetes-related
and overall mortality, and absolute risk of MI vs diet alone after 10.7 years

1. 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.

7
UKPDS 34 provides some evidence for beneficial
CV effects of metformin in overweight patients
Risk of MI is 39% lower with metformin vs Significant reduction in MI maintained
conventional therapy in obese patients1,2 over 10 years’ follow-up3
Proportion of patients with events (%)

Myocardial infarction Overall values at study end in 1997


30 Conventional (n = 411; events = 73)
Annual values during 10-year post-trial monitoring period
Intensive (n = 951; events = 139)
Metformin (n = 342; events = 39) 1.4 RR 0.611 RR 0.67
p = 0.01 p = 0.005
1.2

HR (95% CI)
20
Metformin vs 1.0
conventional
p = 0.01 0.8
10
0.6
0.4
0.0 1997 1999 2001 2003 2005 2007
No. of events:
0 3 6 9 12 15
Conventional 73 83 92 106 118 126
Time from randomisation (years) therapy
Metformin 39 45 55 64 68 81

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.

8
UKPDS 34: CV effects of metformin added to SU

Metformin added to SU vs SU alone was associated with increased risk of diabetes-related


death and all-cause mortality
Relative risk
(95% CI)
Median follow up 6.6 years RR p-value
Any diabetes related endpoint 1.04 0.78
Diabetes-related deaths* 1.96 0.039
All-cause mortality* 1.60 0.041
Myocardial infarction* 1.09 0.73
Stroke* 1.21 0.61
Microvascular* 0.84 0.62

0.5 1.0 5
Favours Favours
added SU alone
metformin

*Interpret with caution in view of small event numbers.


UKPDS 34. Lancet 1998;352:854–65.

9
Section
recap CV safety of metformin

• Metformin is generally recommended as first-line therapy1,2


• Some evidence to suggest a CV benefit in overweight
patients1
• There remains a paucity of evidence from large, long-term,
placebo-controlled CV outcome trials3

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.

10
Metformin

CVOT
interpretation SU

CV
safety

FDA
TZD
mandate

11
Sulphonylureas: MOA

Reproduced from 1. Gore and McGuire. Eur Heart J 2011;32:1832–4.

12
Sulphonylureas and CV safety

• In the US, SUs carry a special warning around increased


risk of CV mortality1–3
– The warning is based on findings from the UGDP trial
that reported an excess of cardiac deaths in patients
receiving tolbutamide versus placebo4
• In the EU, the same SUs do not carry safety warnings
around increased CV mortality with SUs5–7

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
No deleterious CV effect of SUs vs insulin or
conventional therapy observed in UKPDS 331
0.4 Conventional (896)
Chlorpropamide (619)
Glibenclamide (615)
Insulin (911)
Patients with MI (%)

0.3

0.2

0.1 Conventional vs
glibenclamide vs insulin
p = 0.66

0.0
0 3 6 9 12 15
Years from randomisation
In addition, in the ADVANCE study, intensive glucose control involving

gliclazide was not associated with deleterious CV effects 2


1. UKPDS33. Lancet 1998;352:837–53. 2. Patel et al. N Engl J Med 2008;358:2560–72.

14
Meta-analysis of SU CV safety trials (≥ 6 months)
found no consistent association with MACE risk1
First author (year) MH-OR (95% CI)
Total # patients* Total # events*
Birkeland 1996 36 1
Chou 2008 452 3
Perriello 2006 283 9
Gerstein 2010 672 55
UKPDS 33 1998 3041 610
Hanefeld 2007 587 4
Seino 2010 400 4
Charbonnel 2005 630 14
Matthews 2005 1250 15
Rubin 2008 1805 46
Home 2009 2222 312
Arechavaleta 2011 1035 4
va der Laar 2004 96 2
Mazzone 2006 458 4
Riddle 1998 145 2
Giles 2010 300 26
Tolman 2009 2097 61
Kahn 2006 4351 72
Goke 2010 858 13
Garber 2009 495 13
Nissen 2008 543 24
Ristic 2007 262 5
Ferrannini 2009 2789 34
Bakris 2006 374 11
Gallwitz 2012 1551 38
Jain 2006 502 11
Johnston 1998 272 4
Nauck 2011 801 3
Seck 2010 1172 4
Overall 29,783 1495
0.01 0.1 1 10 100
Favours SUs Favours comparators

• 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)
1. Monami et al. Diabetes Obes Metab 2013;15:938–53.

15 *SU + comparator groups combined.


Section
recap 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 management2
• In ADVANCE, intensive glucose-lowering including gliclazide was not
associated with negative CV outcomes vs standard treatment3
• 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

‘CV safety of SUs cannot be considered established


unless evaluated in long-term CVOTs’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.

16
Metformin

CVOT
interpretation SU

CV
safety

FDA
TZD
mandate

17
Thiazolidinediones (TZD; PPAR-γ agonists): MOA
TZD

Skeletal muscle Adipose Liver


 Glucose uptake PPAR activation  Gluconeogenesis

Adipogenesis
 Fatty acid uptake
 Lipogenesis
 Glucose uptake

 Plasma FFA

 Hyperglycaemia

Adapted from Bailey & Feher. Therapies for Diabetes 2004.

18
In 2007, separate meta-analyses suggested
differing CV effects of drugs within the TZD class
Rosiglitazone meta-analysis1 Pioglitazone meta-analysis2

MI
MI
HR 0.81 (95% CI: 0.64‒1.02)
OR 1.43 (95% CI: 1.03‒1.98)
p = 0.08
p = 0.03

Death
CV death HR 0.92 (95% CI: 0.76‒1.11)
OR 1.64 (95% CI: 0.98‒2.74) p = 0.38
p = 0.06

0.5 1.0 2.0 0.5 1.0 2.0

Favours Favours control Favours Favours control


rosiglitazone pioglitazone

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

1. Nissen & Wolski. N Engl J Med 2007;356:2457–71. 2. Lincoff et al. JAMA 2007;298:1180–8.

19
Pioglitazone: PROactive trial design
Aim
Drug-specific trial to determine the impact of pioglitazone on macrovascular morbidity
and mortality in high-risk patients with T2D

Main inclusion criteria


1. Patients with T2D and evidence of macrovascular disease
2. Age 35–75 years
3. HbA1c > 6.5%

With or without background therapy


Pioglitazone versus Placebo
N = 5238; average follow-up 34.5 months

Primary endpoint: time to first occurrence of all-cause mortality, non-fatal MI, stroke,
ACS, endovascular/surgical intervention in coronary/leg arteries, amputation above ankle

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

Dormandy et al. Lancet 2005;366:1279–89.

20
PROactive: Pioglitazone was superior to placebo for
main secondary endpoint, but not for primary endpoint
Time to primary endpoint* Time to all-cause mortality, non-fatal MI, stroke

25 25
Pioglitazone (514 events) Pioglitazone (301 events)
Placebo (358 events)

Proportion of events (%)


Placebo (572 events)
Proportion of events (%)

20 20

15 15

10 10

5 5

0 0
0 6 12 18 24 30 36 0 6 12 18 24 30 36
Time from randomisation (months) Time from randomisation (months)

HR 0.90 (95% CI: 0.80–1.02) HR 0.84 (95% CI: 0.72–0.98)


p = 0.095 p = 0.027

Hospitalisation for Heart Failure:


6% (149 of 2605) in pioglitazone vs 4% (108 of 2633) in placebo; p = 0.007

*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.

21
Rosiglitazone: RECORD trial design
Aim
Drug-specific trial to compare macrovascular morbidity and mortality in patients with
T2D treated with rosiglitazone + metformin / SU

Main inclusion criteria


1. Patients with T2D on maximum tolerated doses of metformin or SU monotherapy
2. Age 40–75 years
3. BMI ≥ 25.0 kg/m2

OPEN-LABEL
versus OPEN-LABEL
Rosiglitazone + metformin or
Metformin + SU
Rosiglitazone + SU
N = 4447; follow-up 5–7 years

Primary endpoint:
Time to first occurrence of cardiovascular hospitalisation
CV hospitalisation or CV deathor cardiovascular death

Statistical analysis
• Non-inferiority margin of 1.20 for HR • 4000 participants followed for a
median of 6 years to give 99% power

Home et al. Lancet 2009;373:2125–35.

22
Rosiglitazone: RECORD trial results showed no increase
in CV death
CV outcomes for RECORD Rosiglitazone Active control
HR 95% CI
trial (original data)1,2 N = 2220 N = 2227
Primary endpoint
CV death or CV 321 323 0.99 0.85–1.16
hospitalisation
Secondary endpoint        
All-cause death 136 157 0.86 0.68–1.08
CV death 60 71 0.84 0.59–1.18
MI 64 56 1.14 0.80–1.63
Stroke 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

• In 2013, FDA panel voted to reduce safety restrictions on rosiglitazone3


• However, there are no long-term prospective data on CV safety, so
controversy remains4
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.

23
Section
recap 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 death1
• FDA reduced the safety restrictions on rosiglitazone imposed following
2007 meta-analysis3 but controversy over CV safety remains

‘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’4
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.

24
Metformin

CVOT
interpretation SU

CV
safety

FDA
TZD
mandate

25
Adverse CV events led the FDA to require demonstration
of CV safety for new glucose-lowering drugs

1961 UGDP trial: tolbutamide discontinued due to


increased CV mortality vs other treatment groups 1

Muraglitazar found to potentially increase CV • Sponsor withdrew


2005 application1
risk during FDA assessment2
Rosiglitazone associated with increased risk • Withdrawn in the EU1
2007
for MI and CV-related death3 • Use restricted in US1*
2008 ACCORD trial: intensive glucose lowering was *In 2013, FDA panel voted to reduce
associated with increased all-cause mortality 4 safety restrictions on rosiglitazone7

HR 1.22 (95% CI 1.01‒1.46); p = 0.04

2008 New FDA requirements5


2012 New EMA requirements6
New diabetes drugs should demonstrate CV safety
with meta-analysis and a CV outcome trial (CVOT)
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

26
Regulatory requirements for drug-specific CV
outcome data in T2D
FDA 2008 Guidance for Industry1 EMA 2012 Guideline2
‘To establish the safety of a new anti-
diabetes drug to treat T2D, sponsors ‘A fully powered CV safety assessment,
should demonstrate that the therapy will e.g., based on a dedicated CV outcome
not result in an unacceptable increase in study, should be submitted before
CV risk.’ marketing authorisation whenever a
• Important CV events should be safety concern is intrinsic in the
analysed molecule/MOA or has emerged from pre-
• High-risk population to be included clinical/clinical registration studies.’
• Long-term data required (≥ 2 years)
Two approaches are recommended:
• Prospective adjudication of CV events
• Meta-analysis of safety events
by an independent committee • Specific long-term controlled outcome
• Phase II and III trials designed and study with at least 18–24 months’
conducted to permit meta-analysis to follow-up
be performed at completion
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.

27
FDA guidance for CV outcome data: meta-analysis
limits and outcome trial requirements

Upper bound of 2-sided 95% CI

Post-marketing If overall risk–benefit Inadequate


CV trial(s) may analysis supports data to
not be approval, post- support
necessary marketing CV trial(s) approval
if < 1.3 needed to prove < 1.3

0.5 1.0 1.3 1.8 2.0


RR of incidence of CV events with
investigational agent vs control

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

28
Satisfying FDA requirements for CV safety
Number of CV events needed to satisfy 1.3 non-inferiority margin
1600 1507

1400

1200
Number of events

1126
1000 922

800 80% power


611
600 689 90% power
428
400 311 457
233
139 179 320
200 110 233
134 174
82 104
0
0.65 0.7 0.75 0.8 0.85 0.9 0.95 1 1.05 1.1 1.15
Assumed true relative risk
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 – 611 events for the 1.3 risk margin
Geiger et al. Ther Innovation Reg Science 2014;1–15.

29
Metformin

CVOT
interpretation SU

CV
safety

FDA
TZD
mandate

30
Contemporary CVOT trial design for T2D

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 T2D

Usual care – glucose lowering, BP lowering, lipid lowering etc.


Placebo Composite
High CV risk
Run-in R primary Statistics
patients
Drug X endpoint

Events

FDA
All
As
Run-inmandates
patients
adjustment
helps are
tothat
on
of CV
a safety
usual
background
establish betherapy
care
patient demonstrated
background
adherenceis in
encouraged,
to high CV
(tolong-term
control risk population
diabetes
CVOTs
treatmentand
not CVFU
designed
and
1
riskto
FDA recommends 3P-MACE as primary CV endpoint or expanded
factors);
assess investigators encouraged to adjust therapy following local guidelines
Trials impact
Sequential
4P-MACE of including
are(e.g.,
event adriven,
difference
statistical testing in than
HbA ofbetween
(superiority
hospitalisation
rather 1c tested
for
fixed study
only
unstable
duration ifarms
non-inferiority
angina pectoris)established)
1

Adapted from Geiger et al. Ther Innovation Reg Science 2014;1–15.


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

31
CVOTs designed to assess effects of a specific drug
or of a treatment strategy (e.g. glucose lowering)
Treatment strategy trials (intensive
Compound-specific trials
vs standard glucose lowering)
UKPDS1,2 FPG < 6 vs < 15 mmol/L Also assessed metformin vs SU +
insulin2
VADT3 HbA1c ≤ 6% vs 8–9%
ACCORD4 HbA1c < 6% vs 7–7.9%
ADVANCE5 HbA1c < 6.5% vs SOC Also assessed gliclazide + other
drugs in intensive arm vs standard
care arm
PROactive6 Pioglitazone vs placebo
RECORD7 Rosiglitazone + metformin or SU vs
metformin + SU
SAVOR-TIMI 538 Saxagliptin vs placebo
EXAMINE9 Alogliptin vs placebo
ELIXA10 Lixisenatide vs placebo
TECOS11 Sitagliptin vs placebo
EMPA-REG OUTCOME®12 Empagliflozin vs placebo
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.

32
Considerations for interpretation of contemporary
compound-specific CVOTs
Demonstration of CV safety is required by regulators for newer anti-hyperglycaemic
drugs as ‘class effects’ cannot be assumed based on drug-specific trials

Design features
• Most CVOTs employ hierarchical testing to test for superiority following
Power and
establishment of non-inferiority
duration
• CVOTs are typically event-driven; study duration can only be estimated 1
• Inclusion characteristics vary across trials (e.g., degree of pre-existing CV
Population risk or prior CVD, duration of T2D)
• This necessitates caution in comparing results across trials 1
• Trials performed on a usual care background (e.g., high antihypertensive and
Background
statin use) so CV risk factors (e.g. BP, LDL-C) are generally well controlled
therapy
• Investigators should adjust background therapy according to local guidelines 1

• Primary and secondary outcomes vary across trials (3P-MACE and


Outcomes
4P-MACE are common primary outcomes)2
1. Hirshberg & Katz. Diabetes Care 2013;36(suppl 2):S253–8.
2. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf.

33
Statistical considerations in CVOT interpretation
Power is the probability that the effect, if Sample size must be pre-planned
it exists, will be detected • Variables needed to calculate1,2:
• Power is usually set to 80% or 90% (i.e. 1. Assumed effect size (and accepted non-
the chance of demonstrating statistical inferiority margin)
significance if the true effect is at least as 2. Expected event rate in control group
pronounced as specified)1 3. Desired power
4. Significance level (incl. interim analyses)

Event rate Hierarchical testing for non-inferiority and


• 2008 FDA guidance highlights the need to then superiority is common among CVOTs,
conduct T2D trials that obtain sufficient e.g., in a recent protocol:4
end points 1. Primary analysis is non-inferiority for 3P-MACE
• Event rate varies according to baseline CV 2. If achieved, non-inferiority testing of 4P-MACE
risk of study population3 (key secondary outcome) will be conducted
Event rate (events / 1000 patient-years) 3. If achieved, superiority testing will follow of first
Baseline characteristics CV death 3P-MACE and, if positive, 4P-MACE
CVD 16.7
No CVD 3.6

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.

34
Overview of CVOTs of glucose-lowering drugs

SAVOR-TIMI 531 OMNEON13 CAROLINA®11


(n = 16,492) (n = 4000) (n = 6000)
1,222 3P-MACE 4P-MACE ≥ 631 4P-MACE
EXAMINE2 TECOS4 CARMELINA12
(n = 5380) (n = 14,724) (n = 8300)
621 3P-MACE ≥ 1300 4P-MACE 4P-MACE + renal

2013 2014 2015 2016 2017 2018 2019 2021

ELIXA3 EXSCEL14 REWIND16


(n = 6068) SUSTAIN-67
(n = 3297) (n = 14,000) (n = 9622)
≥ 844 4P-MACE ≥ 1591 3P-MACE ≥ 1067 3P-MACE
3P-MACE
ITCA CVOT9 DECLARE-TIMI 5815
(n = 4000) (n = 17,150)
LEADER6 4P-MACE ≥ 1390 3P-MACE
DPP4 inhibitor CVOTs (n = 9340) CREDENCE17
CANVAS10
≥ 611 3P-MACE (n = 4365) (n = 3700)
SGLT2 inhibitor ≥ 420 3P-MACE Renal + 5P-MACE
CVOTs EMPA-REG
OUTCOME®5 Ertugliflozin CVOT18
(n = 7034) CANVAS-R8
GLP1 CVOTs (n = 5700) (n = 3900)
≥ 691 3P-MACE HARMONY 3P-MACE
Albuminuria
Outcomes19
(n = 9400) 3P-MACE

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)

35
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 SUs2,3
– There is a need for evaluation of the CV safety of SUs in a long-term
dedicated CVOT
• The 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 safety4
• The 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 MACE6
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.
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