2. 0
1
2
3
CV death All-cause mortality
Hazardratio(95%CI)(diabetes
vsnodiabetes)
Type 2 diabetes is increasingly
prevalent
• Globally, 387 million people
are living with diabetes1
• At least 68% of people >65 years with
diabetes die of heart disease2
This will rise to 592
million by 20351
1. IDF Diabetes Atlas 6th Edition 2014
http://www.idf.org/diabetesatlas;
2.Centers for Disease Control and
Prevention 2011; 3. Seshasai et al. N
Engl J Med 2011;364:829-41
Mortality risk associated with diabetes
(n=820,900)3
3. Life expectancy is reduced by ~12 years in
diabetes patients with previous CVD*
3
* male, 60 years of age with history of MI or stroke
The Emerging Risk Factors Collaboration. JAMA. 2015;314(1):52-60.
Modelling of Years of Life Lost by Disease Status of Participants at
Baseline Compared With Those Free of Diabetes, Stroke, and MI
4. 0.50 1.00 2.00
Number of events
More
intensive
Less
intensive
Difference in
HbA1c (%)
HR (95% CI)
All-cause mortality 980 884 -0.88 1.04 (0.90,1.20)
CV death 497 441 -0.88 1.10 (0.84,1.42)
Non-CV death 476 432 -0.88 1.02 (0.89,1.18)
Meta-analysis of intensive glucose control
in T2DM: mortality
4
Favours more intensive Favours less intensive
• Meta-analysis of 27,049 participants and 2370 major vascular events from
– ADVANCE
– UKPDS
– ACCORD
– VADT
5. CV effects of specific glucose
lowering drugs are controversial
5
UGDP: tolbutamide discontinued due to
increased CV mortality vs other treatment groups
• Sponsor withdrew
application1
• Withdrawn in the EU1
• Use restricted in US
*In 2013, FDA panel voted to reduce
safety restrictions on rosiglitazone7
1961
2005
2007
2008
2008
2012
Muraglitazar found to potentially increase CV risk
during FDA assessment
Rosiglitazone associated with increased risk
for MI and CV-related death
ACCORD study: intensive glucose lowering was
associated with increased all-cause mortality
HR 1.22 (95% CI 1.01‒1.46); p = 0.04
New FDA requirements
New EMA requirements
New diabetes drugs should demonstrate CV safety
with meta-analysis and a CVOT
6. REGULATORY REQUIREMENTS FOR DRUG-
SPECIFIC CV OUTCOME DATA IN T2DM
‘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 committee
• Phase II and III trials designed and
conducted to permit meta-analysis to
be performed at completion
FDA 2008 Guidance for Industry1 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
7. Majority of recent trials of newer glucose-lowering
agents have been neutral on the primary CV
outcome
SAVOR-TIMI 53
EXAMINE
HR: 1.0
(95% CI: 0.89, 1.12)
HR: 0.96
(95% CI: UL ≤1.16)
TECOS
HR: 0.98
(95% CI: 0.88, 1.09)
EMPA-REG OUTCOME
ELIXA
HR: 1.02
(95% CI: 0.89, 1.17)
Empagliflozin
DPP-4 inhibitors*
Lixisenatide
2013 2014 2015
SAXAGLIPTIN
ALOGLIPTIN
SITAGLIPTIN
HR: 0.86
(95% CI: 0.74, 0.99)
14. Objective
To examine the long-term effects of Liraglutide vs placebo, in
addition to standard of care, on CV morbidity and mortality in
patients with type 2 diabetes and at high risk of CV events
Aim
To fulfill regulatory requirements and to explore potential
benefits
15. Patients with type 2 diabetes who were at high risk for
cardiovascular disease were randomly assigned, in a 1:1
ratio, to receive liraglutide or placebo.
The minimum planned follow-up was 42 months, with
a maximum of 60 months of receiving the assigned
regimen and an additional 30 days of follow-up
afterward.
16. DESIGN FEATURES
• A steering committee oversaw the trial
• All CV events were adjudicated by independent, blinded,
clinical event committees
• An independent Data Safety Monitoring Board evaluated data
in a blinded fashion.
• Data were gathered by the site investigators, sponsor
performed site monitoring and data collection.
• The data were analysed by Statogen consulting and sponsor.
17. PATIENTS
• Patients with type 2 diabetes who had a
glycated hemoglobin level of 7.0% or more
were eligible if they either had not received
drugs for this condition previously or had
been treated with one or more oral
antihyperglycemic agents or insulin (human
neutral protamine Hagedorn, long-acting
analogue, or premixed) or a combination.
18. INCLUSION CRITERIA
• An age of 50 years or more with at least one cardiovascular
coexisting condition
– coronary heart disease
– cerebrovascular disease
– peripheral vascular disease
– chronic kidney disease of stage 3 or greater, or
– chronic heart failure of New York Heart Association class II or III
• An age of 60 years or more with at least one cardiovascular
risk factor, as determined by the investigator
– Microalbuminuria or proteinuria
– Hypertension and left ventricular hypertrophy,
– left ventricular systolic or diastolic dysfunction or
– an ankle–brachial index of less than 0.9
19. EXCLUSION CRITERIA
• Type 1 diabetes
• the use of GLP-1–receptor agonists, dipeptidyl peptidase 4 (DPP-
4) inhibitors, pramlintide, or rapid-acting insulin within three
months prior to screening
• a familial or personal history of multiple endocrine neoplasia
type 2 or medullary thyroid cancer;
• and the occurrence of an acute coronary or cerebrovascular
event within 14 days before screening and randomization.
• Chronic heart failure NYHA class IV
20. POPULATION
• ~64% males , 78% Caucasian, Black 8.3% Asian
10%, Hispanic 12%
• Age 64.3 +7.2 yrs
• Duration of diabetes ~12.8+8 yrs,
• HbA1c 8.7%+1.6
• BMI 32.5+6.3 kg/m2
• SBP 135.9+17.8 mmHg, DBP 77.1+10.2 mmHg
21. Comorbidity/risk factors:
MI ~30.7%, stroke or TIA ~16.1%,
revascularization ~39%
>50% stenosis (coronary, carotid, lower extremity
arteries) 25.4%
HF NYHA class II-III ~14%, CKD (eGFR <60
mL/min/1.73m2) ~24.7%, microalbuminuria or
proteinuria ~11.3%, HTN+LVH ~5.3%, ABI <0.9
2.4%.
22. Medications
92.3% on antihypertensives
(55.4% BB, 51% ACEI, 31.8% ARBs, 32% CCB [some
patients were on multiple agents ])
72% on statins
63% on ASA, 15.7% on other antiplatelet agent
76% on metformin, 51% on SU, 6.2% on TZD, and
44.5% on insulin
24. • If patient did not reach recommended target
for glycemic control (HgA1c ≤ 7% or
individualized target at investigator’s
discretion), addition of antihyperglycemics
(except GLP1-A DPP4-I, and pramlintide)
including insulin, were permitted.
25. TIMELINE
• September 2010: First patient entered
• April 2012 : Last patient entered
• August 2014 : Closeout (final visits) started
• December 2015: Last patient out
Median time follow up : 3.8 yrs
Efforts were made to track outcomes and vital
status for all patients, including those who
discontinued trial medication
35. Bottom line
Compared to standard care, for every 100
patients with T2DM and high CV disease risk,
treatment with liraglutide for ~4 years will
result in :
2 less CV events (composite endpoint of: CV death
(significant), nonfatal stroke (NS), nonfatal MI (NS))
2 less cases of nephropathy,
but 1 extra case of acute gallbladder disease, and
2 extra cases of discontinuation due to adverse events
such as nausea, vomiting and diarrhea.
36. Liraglutide resulted in an additional
~2.3kg weight loss over the placebo group
BP (SBP↓1.2 mmHg, DBP↑0.6 mmHg), and
heart rate (↑ 3 BPM).
Neither group achieved a mean A1C <7% at the end
of the trial. At 36 mnths, liraglutide gp – mean A1C
-0.40% lower than Placebo.
37. STRENGTHS
• Largest sample size of GLP1-A CV outcome
studies and longest duration of all published CV
outcome studies to date.
• Well-designed RCT
– (properly randomized [allocation concealment,
balanced baseline demographics]; registered;
appropriately powered;
– all CV outcomes were pre-specified & clinically
relevant; blinded, external adjudication of all
outcomes, ITT population used for superiority
analysis).
38. • International, multicentre design helps to
reveal potential environmental/geographical
confounding factors.
• 97% of the liraglutide group and 96.6% of the
placebo group completed the study; 0.2% loss
to follow up for both groups; and vital status
not confirmed for <0.05% of all participants
• Similar to other GLP1-A CV outcome study,
hospitalisation for HF was neutral.
39. LIMITATIONS
• Funded in part by Novo Nordisk, manufacturer
of Victoza. 4/15 steering committee members
were employees of Novo Nordisk.
• Subjects who completed or discontinued the
trial without having an outcome were
censored after their last visit, and events
occurring after that visit were not included,
meaning key events could have been missed.
40. • Study period was only 3.5-5 yrs, so safety and
efficacy data for long-term were not observed.
41. UNCERTAINITIES
• Applicability of observed benefits and risks to
groups with lower CV risk.
• Subgroup analysis for geographical region shows
no benefit (HR 1.01, 95% CI 0.84-1.22) for North
American patients (n=2847) in terms the primary
composite outcome.
• Effect of liraglutide on microvascular outcomes
(e.g., retinopathy, neuropathy, nephropathy) as
these may take 5-10+ years to develop and
median trial follow-up was only 3.8 years.
42. Unclear why this trial demonstrated positive CV
outcome results when many previous outcome
trials achieved only neutral results?
A neutral effect was also demonstrated in a post
hoc analysis of 15 phase 2 and 3 studies of
liraglutide versus control which included
approximately 4,000 patients and 39 adjudicated
major adverse CV events (incidence ratio 0.73, 95%
CI 0.38-1.41).
•
43. • Mechanism behind decreased CV death and
decreased all cause death not clear -
liraglutide does not cause a statistically
significant change in rates of nonfatal MI or
stroke.
• Similar to other positive CV outcome study,
EMPA-REG results of primary composite
endpoint were primarily driven by a reduction
in CV death, as other components were not
significantly different.
44. HOW DOES THIS TRIAL COMPARE TO
PREVIOUS OUTCOME TRIALS?
• EMPA-REG examined empagliflozin, a SGLT-2
inhibitor, which significantly decreased
primary composite endpoint (CV death,
nonfatal stroke and MI) in patients with T2DM
and high cardiovascular risk (ARR 1.6%)
(Primarily driven by decrease in CV death)
• Hospitalization for HF and all-cause mortality
were also significantly decreased.
45. Time to benefit occurred quicker in EMPA-REG
than LEADER
• Empaglifozin’s benefits may be related to
hemodynamic changes rather than modifying
the progression of atherosclerotic disease.
46. • ELIXA evaluated lixisenatide (Europe only),a
GLP1-A.
• However, in patients with T2DM and recent
acute coronary syndrome, adding lixisenatide
to current therapy did not show a definitive
CV benefit.
47. • TECOS examined sitagliptin, a DPP4-I, and its
effects on CV outcomes.
• No definitive CV benefit.
48. 1994
Simvastatin for 5.4 years
30
High CV risk
5% diabetes
26% hypertension
2000
Ramipril for 5 years
High CV risk
38% diabetes 46%
hypertension
56
Empagliflozin for 3 years
T2DM with high
CV risk
92% hypertension
39
3 years
T2DM with high
CV risk
92% hypertension
25
Empagliflozin for 5 years
+
Statin ACE-inh.
Number needed to treat(NNTs) to prevent one death
across land mark trials in patients with high CV risk
2015
48
49. Empagliflozin for 3 years
T2DM with high
CV risk
92% hypertension
39
3 years
T2DM with high
CV risk
77
Liraglutide for 4 years
LEADER
2016 (NNT)
50. INDIA
COST IS PROHIBITIVE
Dosage :
• 0.6 mg SC qDay for 1 week initially, then 1.2
mg qDay
Liraglutide for 1 year – Rs 1,80,000 !!!!
