1. No category

15.10-15.25:
Post EASD: EMPA-REG OUTCOME®
Odd Erik Johansen, lege, PhD
Medisinsk direktør,
Boehringer Ingelheim Norge KS
1
Interessekonflikt
•  Jeg er ansatt i Boehringer Ingelheim
2
Life expectancy is reduced by ~12 years in
diabetes patients with previous CVD*
Modelling of Years of Life Lost by Disease Status of Participants at
Baseline Compared With Those Free of Diabetes, Stroke, and MI
* male, 60 years of age with history of MI or stroke
The Emerging Risk Factors Collaboration. JAMA. 2015;314(1):52-60.
3
Meta-analysis of intensive glucose control in
T2DM: mortality
Number of events
More
Less
intensive
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)
0,50 1,00 Favours more intensive
2,00 Favours less intensive
•  Meta-analysis of 27,049 participants and 2370 major vascular events from
–  ADVANCE
–  UKPDS
–  ACCORD
–  VADT
HR, hazard ratio; CV, cardiovascular
Turnbull FM et al. Diabetologia 2009;52:2288–2298
4
CV effects of specific glucose lowering drugs are
controversial
1961
UGDP: tolbutamide discontinued due to
increased CV mortality vs other treatment groups1
2005
Muraglitazar found to potentially increase CV risk
during FDA assessment2
2007
Rosiglitazone associated with increased risk
for MI and CV-related death3
2008
ACCORD study: intensive glucose lowering was
associated with increased all-cause mortality4
•  Sponsor withdrew
application1
•  Withdrawn in the EU1
•  Use restricted in US1*
HR 1.22 (95% CI 1.01‒1.46); p = 0.04
2008
2012
*In 2013, FDA panel voted to reduce
safety restrictions on rosiglitazone7
New FDA requirements5
New EMA requirements6
New diabetes drugs should demonstrate CV safety
with meta-analysis and a 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.
5
4. ACCORD
Study Group. N Engl J Med 2008;358:2545–59. 5. FDA Guidance for
Industry. 6. EMA Guidelines. 7. FDA Safety Information.
5
Regulatory requirements for drug-specific CV
outcome data in T2D
FDA 2008 Guidance for Industry1
‘To establish the safety of a new antidiabetes 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
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
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.
6
FDA guidance for industry to evaluate CV risk with
new glucose-lowering therapies to treat T2DM
*If overall benefit-risk analysis of the drug supports approval.
Abbreviations: RR, relative risk
Bailey CJ. Interpreting Adverse Signals in Diabetes Drug Development Programs.
Diabetes Care 2013; DOI: 10.2337/dc13-0182
Recent trials of newer glucose-lowering agents
have been neutral on the primary CV outcome
HR: 1.0
(95% CI: 0.89, 1.12)
SAVOR-TIMI 53
HR: 0.96
(95% CI: UL ≤1.16)
EXAMINE
2013
HR: 0.98
(95% CI: 0.88, 1.09)
TECOS
2014
HR: 1.02
(95% CI: 0.89, 1.17)
2015
ELIXA
DPP-4 inhibitors*
Lixisenatide
EMPA-REG OUTCOME®
Empagliflozin
CV, cardiovascular; HR, hazard ratio; DPP-4, dipeptidyl peptidase-4
*Saxagliptin, alogliptin, sitagliptin
Adapted from Johansen OE. World J Diabetes 2015;6:1092-96
8
Empagliflozin
•  Empagliflozin is a highly selective inhibitor of the sodium
glucose cotransporter 2 (SGLT2) in the kidney
~30% active parent drug present in the tubular system1
•  Glucose reduction occurs by reducing renal glucose
reabsorption and thus increasing urinary glucose
excretion
•  In patients with type 2 diabetes, empagliflozin leads to:2
–  Significant reductions in HbA1c
–  Weight loss
–  Reductions in blood pressure
1. Chen LZ, et al. Xenobiotica 2015; 45: 520-29.
2. Liakos A et al. Diabetes Obes Metab 2014;16:984-93.
9
Indikasjon
Til voksne med diabetes mellitus type 2, for å bedre glykemisk
kontroll.
•  Gis som monoterapi når diett og fysisk aktivitet alene ikke gir adekvat
glykemisk kontroll, og metformin er uegnet pga. intoleranse.
•  Gis i kombinasjon med andre glukosesenkende legemidler inkl. insulin, når
disse, sammen med diett og fysisk aktivitet, ikke gir adekvat glykemisk kontroll.
Sikkerhetsinformasjon
•  JARDIANCE® er ikke anbefalt for pasienter med moderat til alvorlig nedsatt
nyrefunksjon, nyresvikt, og/eller leversvikt. Skal ikke initieres ved eGFR<60 ml/
min, og skal seponeres når eGFR faller til <45 ml/min.
•  Legemiddelet er heller ikke anbefalt for pasienter over 85 år, for gravide eller
ammende, for pasienter med type 1-diabetes, eller til behandling av
ketoacidose.
•  Bivirkninger: Svært vanlige (≥1/10): hypoglykemi ved kombinasjon med SU
eller insulin; Vanlige (≥1/100 til < 1/100): Pruritus, vaginal monilasis,
vulvovaginitt, balanitt og andre genitale infeksjoner, urinveisinfeksjon. Økt
urinering; Mindre vanlige (≥1/1000 til < 1/100): volumdeplesjon, dysuri.
10
Refusjon
Refusjonsberettiget bruk:
Til behandling av type-2 diabetes mellitus i kombinasjon med
metformin og/eller sulfonylurea
Refusjonskode:
•  ICPC: T90 Diabetes type 2
•  ICD: E11 Diabetes mellitus type 2
Vilkår 198:
Refusjon ytes kun til pasienter som ikke oppnår tilstrekkelig
sykdomskontroll på høyeste tolererte dose med:
•  kombinasjonen av metformin og sulfonylurea, eller
•  metformin alene dersom det er tungtveiende medisinske grunner for
ikke å bruke sulfonylurea, eller
•  sulfonylurea alene dersom det er tungtveiende medisinske grunner
for ikke å bruke metformin
11
Empagliflozin modulates several factors related
to CV risk
CV, cardiovascular
Inzucchi SE,Zinman, B, Wanner, C et al. Diab Vasc Dis Res 2015;12:90-100
12
EMPA-REG OUTCOME®
•  Randomised, double-blind, placebo-controlled CV
outcomes trial
•  Objective
To examine the long-term effects of empagliflozin versus
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
CV, cardiovascular
13
Participating countries
590 sites in 42 countries
Asia
North America, Australia, New Zealand
Latin America
Europe
Africa
14
Trial design
Screening
(n=11531)
Placebo
(n=2333)
Randomised
and treated
(n=7020)
Empagliflozin 10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342)
•  Study medication was given in addition to standard of care
–  Glucose-lowering therapy was to remain unchanged for first 12 weeks
•  Primary outcome: 3-point MACE
–  Time to first occurrence of CV death, non-fatal MI or non-fatal stroke
•  Key secondary outcome: 4-point MACE
–  Time to first occurrence of CV death, non-fatal MI, non-fatal stroke or
hospitalisation for unstable angina
•  Further presepecified outcomes
–  Hospitalisation for heart failure, Overall mortality
15
Design features
•  A steering committee oversaw the trial
•  All CV and neurological events were adjudicated by
independent, blinded, clinical event committees
•  The trial was to continue until at least 691 patients experienced an adjudicated primary
outcome event
•  An independent Data Safety Monitoring Board evaluated
data in a blinded fashion (met 3-4 x/year)
Francine K. Welty, Beth Israel Deaconess Medical Center, Boston, USA; Klaus G. Parhofer, University of Munich,
Munich, Germany; Terje R. Pedersen, Oslo University Hospital, Oslo, Norway; Kennedy R. Lees, University of
Glasgow, Glasgow, UK; Tim Clayton, London School of Hygiene and Tropical Medicine, UK; Stuart Pocock,
London School of Hygiene and Tropical Medicine, UK; Mike Palmer, N Zero 1 Ltd, Wilmslow, UK
•  The CV outcome analyses were independently validated by
statisticians at the University of Freiburg, Germany
16
Timeline
•  September 15th 2010: First patient entered
•  April 13th 2013: Last patient entered
•  December 15th 2014: Closeout (final visits) started
•  April 13th 2015: Last patient out
•  Efforts were made to track outcomes and vital status for all
patients, including those who discontinued trial medication
17
Patient disposition
Placebo
Empagliflozin
10 mg
Empagliflozin
25 mg
N (%)
Intent-to-treat population
2333 (100)
2345 (100)
2342 (100)
Discontinued study drug
prematurely
683 (29.3)
555 (23.7)
542 (23.1)
Completed study or died
2266 (97.1)
2264 (96.5)
2264 (96.5)
Vital status available
2316 (99.3)
2324 (99.1)
2327 (99.4)
18
Baseline characteristics:
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
8.08 (0.84)
8.07 (0.86)
8.06 (0.84)
1339 (57.4)
1354 (57.7)
1318 (56.3)
Metformin
1734 (74.3)
1729 (73.7)
1730 (73.9)
Sulphonylurea
992 (42.5)
985 (42.0)
1029 (43.9)
Insulin
1135 (48.6)
1132 (48.3)
1120 (47.8)
65 (50.6)
65 (47.9)
66 (48.9)
30.7 (5.2)
30.6 (5.2)
30.6 (5.3)
Systolic blood pressure, mmHg
135.8 (17.2)
134.9 (16.8)
135.6 (17.0)
Diastolic blood pressure, mmHg
76.8 (10.1)
76.6 (9.8)
76.6 (9.7)
HbA1c, %
Time since diagnosis of type 2 diabetes, years
>10
Glucose-lowering medication*
Mean daily dose, U**
Body mass index, kg/m2
Data are n (%) or mean (SD) in patients treated with ≥1 dose of study drug
*Medication taken alone or in combination
**Placebo, n=1135; empagliflozin 10 mg, n=1132; empagliflozin 25 mg, n=1120
19
Baseline characteristics:
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
LDL cholesterol, mg/dL
84.9 (35.3)
86.3 (36.7)
85.5 (35.2)
HDL cholesterol, mg/dL
44.0 (11.3)
44.7 (12.0)
44.5 (11.8)
eGFR, mL/min/1.73m2 (MDRD)
73.8 (21.1)
74.3 (21.8)
74.0 (21.4)
≥90 mL/min/1.73m2
488 (20.9%)
519 (22.1%)
531 (22.7%)
60 to <90 mL/min/1.73m2
1238 (53.1%)
1221 (52.1%)
1204 (51.4%)
<60 mL/min/1.73m2
607 (26.0%)
605 (25.8%)
607 (25.9%)
2307 (98.9%)
2333 (99.5%)
2324 (99.2%)
Coronary artery disease
1763 (75.6%)
1782 (76.0%)
1763 (75.3%)
History of MI
1083 (46.4%)
1107 (47.2%)
1083 (46.2%)
Cardiac failure*
244 (10.5%)
240 (10.2%)
222 (9.5%)
Any CV risk factor
Data are n (%) in patients treated with ≥1 dose of study drug
*Based on narrow standardised MedDRA query “cardiac failure”
20
Baseline characteristics: CV medication
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
Any anti-hypertensive
therapy
2221 (95.2%)
2227 (95.0%)
2219 (94.7%)
ACE inhibitors/ARBs
1868 (80.1%)
1896 (80.9%)
1902 (81.2%)
Beta-blockers
1498 (64.2%)
1530 (65.2%)
1526 (65.2%)
Diuretics
988 (42.3%)
1036 (44.2%)
1011 (43.2%)
Statins
1773 (76.0%)
1827 (77.9%)
1803 (77.0%)
Fibrates
199 (8.5%)
1927 (82.6%)
214 (9.1%)
1939 (82.7%)
217 (9.3%)
1937 (82.7%)
Acetylsalicylic acid
Data are n (%) in patients treated with ≥1 dose of study drug
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers
21
Primary outcome:
3-point MACE
10.5% vs 12.1% i empa
(10+25mg) vs placebo,
ARR: 1.6%
HR 0.86
(95.02% CI 0.74, 0.99)
p=0.0382*
Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio.
* Two-sided tests for superiority were conducted (statistical significance was indicated if p≤0.0498)
22
CV død: 3.7 vs 5.9% (empa vs
placebo)
ARR= 2.2%
CV death
HR 0.62
(95% CI 0.49, 0.77)
p<0.0001
Cumulative incidence function. HR, hazard ratio
23
CV death, MI and stroke
Patients with event/analysed
Empagliflozin
Placebo
HR
(95% CI)
p-value
3-point MACE
490/4687 282/2333 0.86 (0.74, 0.99)*
0.0382
CV death
172/4687
137/2333 0.62 (0.49, 0.77)
<0.0001
Non-fatal MI
213/4687
121/2333 0.87 (0.70, 1.09)
0.2189
Non-fatal stroke
150/4687
60/2333
0.1638
1.24 (0.92, 1.67)
0,25
0,50
Favours empagliflozin
1,00
2,00
Favours placebo
Cox regression analysis. MACE, Major Adverse Cardiovascular Event;
HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction
*95.02% CI
24
3-point MACE and 4-point MACE
Patients with event/analysed
Empagliflozin
Placebo
HR
(95% CI)
p-value
3-point MACE
490/4687 282/2333 0.86 (0.74, 0.99)*
CV death
172/4687
137/2333 0.62 (0.49, 0.77)
<0.0001
Non-fatal MI
213/4687
121/2333 0.87 (0.70, 1.09)
0.2189
Non-fatal stroke
150/4687
60/2333
1.24 (0.92, 1.67)
0.1638
4-point MACE
599/4687
333/2333 0.89 (0.78, 1.01)*
0.0795
0,25
0,50
Favours empagliflozin
0.0382
1,00
2,00
Favours placebo
Cox regression analysis. MACE, Major Adverse Cardiovascular Event;
HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction
*95.02% CI
25
Hospitalisation for heart failure
Hospitalisering for hjertesvikt: 2.7 vs
4.1%, ARR 1.4%
HR 0.65
(95% CI 0.50, 0.85)
p=0.0017
Cumulative incidence function. HR, hazard ratio
26
All-cause mortality
All-cause mortality: 5.7% vs
8.3%, ARR 2.6%
HR 0.68
(95% CI 0.57, 0.82)
p<0.0001
Kaplan-Meier estimate. HR, hazard ratio
27
Adverse events consistent with urinary tract
infection
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
n (%)
Rate
n (%)
Rate
n (%)
Rate
423
(18.1%)
8.21
426
(18.2%)
8.02
416
(17.8%)
7.75
10
(0.4%)
0.17
22
(0.9%)
0.37
19
(0.8%)
0.31
Male
158
(9.4%)
3.96
180
(10.9%)
4.49
170
(10.1%)
4.09
Female
265
(40.6%)
22.81
246
(35.5%)
18.83
246
(37.3%)
20.38
Events consistent with UTI
Events leading to
discontinuation
By sex
Rate = per100 patient-years
Patients treated with ≥1 dose of study drug
Based on 79 MedDRA preferred terms
28
Adverse events consistent with genital infection
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
n (%)
Rate
n (%)
Rate
n (%)
Rate
Events consistent with
genital infection
42
(1.8%)
0.73
153
(6.5%)
2.66
148
(6.3%)
2.55
Events leading to
discontinuation
2
(0.1%)
0.03
19
(0.8%)
0.32
14
(0.6%)
0.23
Male
25
(1.5%)
0.60
89
(5.4%)
2.16
77
(4.6%)
1.78
Female
17
(2.6%)
1.09
64
(9.2%)
3.93
71
(10.8%)
4.81
By sex
Rate = per100 patient-years
Patients treated with ≥1 dose of study drug
Based on 88 MedDRA preferred terms
29
Confirmed hypoglycaemic adverse events
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
n (%)
Confirmed hypoglycaemic
adverse events
Events requiring
assistance
650 (27.9%)
656 (28.0%)
647 (27.6%)
36 (1.5%)
33 (1.4%)
30 (1.3%)
483 (42.6%)
494 (43.6%)
464 (41.4%)
28 (2.5%)
27 (2.4%)
25 (2.2%)
Patients taking insulin at
baseline
Total
Events requiring
assistance
Patients treated with ≥1 dose of study drug
Plasma glucose <3.9 mmol/L (70 mg/dL) and/or requiring assistance
30
Other adverse events (1)
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
n (%)
Rate
n (%)
Rate
n (%)
Rate
Diabetic ketoacidosis*
1
(<0.1%)
0.02
3
(0.1%)
0.05
1
(<0.1%)
0.02
Events consistent with
volume depletion§
115
(4.9%)
2.04
115
(4.9%)
1.97
124
(5.3%)
2.11
Serious events
24
(1.0%)
0.42
19
(0.8%)
0.32
26
(1.1%)
0.43
Events leading to
discontinuation
7
(0.3%)
0.12
1
(<0.1%)
0.02
4
(0.2%)
0.07
91
(3.9%)
1.61
92
(3.9%)
1.57
87
(3.7%)
1.46
Bone fractures†
Rate = per100 patient-years
Patients treated with ≥1 dose of study drug
*Based on 4 MedDRA preferred terms. †Based on 1 standardised MedDRA query
§Based on 8 MedDRA preferred terms. **Based on 1 standardised MedDRA query
31
EMPA-REG OUTCOME®: oppsummering
•  Jardiance®
–  Reduserte risikoen for 3P MACE med 14%
–  Var assosiert med en reduksjon i HbA1c, vekt og
blodtrykk, uten økning i hypoglykemi.
–  Var assosiert med en liten økning i LDL og HDL-kolesterol.
–  Var assosiert med økt forekomst av genitalinfeksjoner,
men forøvrig godt tolerert.
MACE, Major Adverse Cardiovascular Event; HDL, high density lipoprotein; LDL, low density lipoprotein
32
EMPA-REG OUTCOME®: Summary
•  Jardiance®
–  Reduserte kardiovaskulær død med 32%
–  Reduserte død av alle årsaker med 38%
–  Reduserte hospitalisering for hjertesvikt med 35%
CV, cardiovascular
33
Number needed to treat(NNTs) to prevent one death
across land mark trials in patients with high CV risk
2015
39
25
1994
30
T2DM with high
CV risk
92% hypertension
years
Empagliflozin for 35 years
High CV risk
5% diabetes
26% hypertension
Statin
Simvastatin1for 5.4 years
2000
High CV risk
56
+
38% diabetes 46%
hypertension
ACE-inh.
Ramipril2 for 5 years
1:4S investigator. Lancet 1994; 344: 1383-89 , http://www.trialresultscenter.org/study2590-4S.htm
2: HOPE investigator N Engl J Med 2000;342:145-53, EBM2000;5 :47 http://www.trialresultscenter.org/study2606-HOPE.htm
34
Takk for oppmerksomheten
35