Empagliflozin as Adjunct to Insulin in Patients with Type 1 Diabetes - Endocrinologic and Metabolic Drugs Advisory Committee - FDA
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Empagliflozin as Adjunct to Insulin in Patients
with Type 1 Diabetes
Endocrinologic and Metabolic Drugs Advisory Committee
November 13, 2019
CC-1
Introduction
Dr. Jyothis George, MBBS, PhD, FRCP, FACE
Head of Medicine – Empagliflozin, Boehringer Ingelheim
Associate Clinical Professor – University of Warwick
CC-2
Addressing an Unmet Need in Type 1 Diabetes
• Improve glycemic control without weight gain,
and without increasing risk of hypoglycemia
• Type 1 diabetes is distinct from other types of diabetes
with patients being dependent on insulin for survival
– Adjunct therapies need to complement insulin
– We propose an adjunct therapy to insulin that is specific
to Type 1 diabetes
CC-3
Glucometabolic Effects of SGLT2 Inhibition
• Four SGLT2 inhibitors are approved in the US
in Type 2 diabetes including empagliflozin
Glucose excretion HbA1c
without increasing hypo risk
SGLT2 Diuresis
Inhibitor Weight
Sodium excretion
Blood Pressure
CC-4
SGLT Inhibition in Type 1 Diabetes
Opportunity and Challenge
Insulin dose
Glucose excretion HbA1c reduction
without increasing hypo risk Increased Risk
SGLT2 Diuresis of Diabetic
Inhibitor Weight Ketoacidosis
Sodium excretion (DKA)
Blood Pressure Ketogenesis
Improving efficacy can also increase risk
CC-5
SGLT Inhibitors in Type 1 Diabetes:
Meaningful Efficacy With Associated Risk
Metabolic Efficacy1 Risk of Diabetic Ketoacidosis2
Reduction Odds Ratio
(95% CI) Study or Subgroup M-H, Random, 95% CI
Sotagliflozin
-0.39
HbA1c (%) InTandem1 (Sota 200 mg and 400 mg)
(-0.43, -0.36)
InTandem2 (Sota 200 mg and 400 mg)
-3.47 InTandem3 (Sota 200 mg and 400 mg)
Body weight (%)
(-3.78, -3.16) Dapagliflozin
DEPICT-1 (Dapa 5 mg and 10 mg)
DEPICT-2 (Dapa 5 mg and 10 mg)
Empagliflozin
EASE-2/3 (Empa 10 mg and 25 mg)
EASE-3 (Empa 2.5 mg)
0.10 1.00 10.00 100.00
Favors SGLT Inhibitor Favors Placebo
1. Lu J, et al. Diabetes Metab Res Rev. 2019 Apr 11:e3169. doi: 10.1002/dmrr.3169.
2. Adpated from: Goldenberg RM, et al. Diabetes Obes Metab. 2019 doi: 10.1111/dom.13811 CC-6
Type 1 Diabetes Specific Dose Provides
a Favorable Balance Between Efficacy and Safety
Empagliflozin (Effect vs. Placebo)
2.5 mg 10 mg* 25 mg*
Glycemic improvement (HbA1c), % -0.3 -0.5 -0.5
Weight loss, kg -1.8 -2.9 -3.4
Hypoglycemia Not increased Not increased Not increased
Insulin dose reduction, % -6 -11 -13
Diabetic ketoacidosis (DKA) Not increased Increased Increased
Empagliflozin 2.5 mg provides a favorable balance between benefit and risk
*Pooled data; up to week 26 for HbA1c, weight and insulin dose: up to 52 weeks for hypoglycemia and DKA CC-7
Balancing Efficacy and Safety in Type 1 Diabetes
Insulin SGLT2 Inhibition
Risk for Hypoglycemia
Risk for DKA
T1D-specific Dose
Efficacy Efficacy
CC-8
Empagliflozin Clinical Development
in Type 1 Diabetes
2013 2014 2015 2016 2017 2018
EASE-1 Planning J-EASE-1
n=75 Phase 3 n=48 M-EASE
4 weeks based on: 4 weeks
2.5, 10 and Positive 2.5, 10 and
results for 10 2.5 mg
25 mg 25 mg
and 25 mg
EASE-2
n=730; 52 weeks
FDA mentioned
10 and 25 mg
exploration of
lower dose EASE-3
n=975; 26 weeks
2.5, 10 and 25 mg
Initial aim was to register the same doses in T1D as approved in T2D
CC-9Evidence Supporting Empagliflozin 2.5 mg
EASE-3 Substantial Evidence1 Consistent Efficacy
• Multi-center design with high • Across randomized
retention, low missing data controlled trials
– EASE-3
• Consistency across endpoints
– EASE-1
and subgroups
– J-EASE-1
• Persuasive statistical evidence
• Confirmed by exposure-response
• Effect in related disease (T2DM) simulation studies
• Pharmacologic evidence – M-EASE
on clinical effects
• Findings in similar population
1. FDA Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products, 1998 CC-10Proposed Indication For a Type 1 Diabetes
Specific Dose
Proposed indication for empagliflozin 2.5 mg:
Adjunct to insulin therapy to improve glycemic control
in adults with Type 1 diabetes
We propose a dedicated brand for Type 1 diabetes with
• Type 1 specific prescribing information
• Professional and patient education
CC-11Patient and Professional Education
Type 1 Diabetes Specific Brand and Dose
FOR PATIENTS FOR PRESCRIBERS
Education on Safe Use Education on Safe use
• Avoidance of risk factors • Appropriate patients
• Cautious insulin dose adjustment • Cautious insulin dose adjustment
• Ketone monitoring • Ketone monitoring
POST AUTHORIZATION REAL-WORLD EVIDENCE
will be implemented in partnership with patients, physicians and regulators
CC-12Agenda
Introduction Jyothis George, MBBS, PhD, FRCP, FACE
Head of Medicine – Empagliflozin, Boehringer Ingelheim
Unmet Need Jennifer Green, MD
Duke University Medical Center, Durham
Efficacy Jan Marquard, MD
Clinical Development Lead – Empagliflozin, Boehringer Ingelheim
Ona Kinduryte Schorling, MD, MSc
Safety Head of Drug Safety – Metabolism, Boehringer Ingelheim
Clinical Implications Bruce Perkins, MD
Leadership Sinai Centre for Diabetes, Toronto
Closing Remarks Jyothis George, MBBS, PhD, FRCP
CC-13Unmet Medical Need in People Living
With Type 1 Diabetes
Jennifer Green, MD
Professor of Medicine
Duke University Medical Center, Division of Endocrinology
Duke Clinical Research Institute, Durham, NC
CC-14Type 1 Diabetes
• Type 1 diabetes is an autoimmune condition which destroys
the insulin-producing beta cells of the pancreas
• Insulin treatment essential to reduce risk of:
– Symptomatic hyperglycemia
– Life-threatening, acute complications such as diabetic ketoacidosis (DKA)
– Chronic complications
• Microvascular complications
– Diabetic kidney disease, eye disease, neuropathy
• Cardiovascular complications
• Type 1 diabetes reduces life expectancy by ~11 to 13 years
• With 1.25 million Americans affected, this is a major public health issue
https://www.diabetes.org/resources/statistics/statistics-about-diabetes; Atkinson MA et al. Lancet 2014;
Livingstone SJ et al. JAMA. 2015; Costacou,T et al. Cardiovascular Endo & Metab 2019 CC-15Type 1 Diabetes and Its Challenges
• Management of Type 1 diabetes is highly complex1
– Intensive insulin therapy
• Multiple daily injections
• Inhalations
• Insulin pump
– Frequent glucose testing
• Fingersticks
• Glucose sensor
– One non-insulin therapeutic option approved
(the amylin analogue pramlintide)2
• Often very difficult to find a balance between hyper and
hypoglycemia
1. Atkinson MA et al. Lancet 2014. 2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021332s007_S016.pdf CC-16DKA is An Inherent Risk in Type 1 Diabetes
• DKA is an acute complication inherent to Type 1 diabetes
– Current annualized rates of DKA are 2-6/100 patient years
– Current US case fatality rate is ~0.4% of patients with DKA
• DKA prevention is an integral part of Type 1 diabetes
management
– Patients educated on precipitating factors
– ADA statement recommends ongoing sick day management education
and use of ketone monitoring for early recognition of DKA
Vellanki and Umpeirrez Diabetes Care 2018, Benoit et al. MMWR Morb Mortal Wkly Rep 2018, Kitabchi et al. Diabetes Care 2009 CC-17Intensive Glycemic Control Reduces
Risk for Complications in Type 1 Diabetes
• Diabetes Control and Complications Trial (DCCT) and
• Epidemiology of Diabetes Interventions and Complications
(EDIC)
– Studied effects of intensive vs conventional glycemic management
in type 1 diabetes
– 35-90% reduced risks of retinopathy, nephropathy, and neuropathy1
– 57% reduced risk for CV complications after a mean of 17 years
of follow-up2
HbA1c lowering is an accepted surrogate
for reducing risk of complications
1. DCCT. N Engl J Med 1993, 2. Nathan DM, et al. N Engl J Med 2005 CC-18All Reduction in HbA1c is Meaningful
Renal and eye complications
70
-0.25% HbA1c reduction
Cumulative Incidence Over 50 Years (%)
translates into a projected:
60
~8% reduction in risk for
retinopathy, and ~5% for
50
microalbuminuria
40 Diabetic retinopathy
30
Severe vision loss
20
Microalbuminuria
End stage renal disease
10
0
0.0 -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8
HbA1c Reduction from 7.9% at Baseline
Simulated cohorts based on data from the Swedish National Diabetes Register (NDR)
Jendle J et al. Diabetes Ther 2018 CC-19Despite Known Benefits, Glycemic Control
is Suboptimal
• Mean HbA1c in US Type 1 diabetes patients is 8.4%, despite
– Innovations in insulin formulations and delivery
– Use of glucose sensors
– Improvements in diabetes education
– Use of team approach to diabetes management
• Common barriers to glycemic control
– Hypoglycemia
– Weight gain
– Regimen complexity
Foster et al. Diabetes Technol Ther 2019 CC-20Tighter Glycemic Control Increases
Risk of Hypoglycemia
120
Rate of Severe Hypoglycemia
100
(per 100 patient-years)
80
60
40
20
0
5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5
HbA1c (%)
DCCT. N Engl J Med. 1993 CC-21Tighter Glycemic Control Increases
Risk of Weight Gain
Conventionally Treated Intensively Treated
40 40
Adult Men Adult Women
30 30
% Patients
% Patients
20 20
10 10
0 0
1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9
Follow Up (in years) Follow Up (in years)
Russel-Jones and Khan Diabetes Obes Metab 2007 CC-22Patient Priorities in Type 1 Diabetes
Unmet Need Scores
(≥10 indicate important need not being met effectively or at all)
Simple and predictable diabetes management 13.6
HbA1c reduced or maintained at target 13.5
Daytime blood glucose 70-180 mg/dL (3.9-10 mmol/L) 13.2
Reduced mental effort needed to manage diabetes 13.2
Patient
Overnight blood glucose 70-130mg/dL (3.9-7.2 mmol/L) 12.8
Perspective1 Prevention of weight gain 12.7
Fasting blood glucose 70-180 mg/dL (3.9-10 mmol/L) 12.5
Flexibility with diet and exercise 12.5
Postprandial glucoseWhat is the Unmet Need?
More options to improve glycemic control
without weight gain and without increasing
risk of hypoglycemia
CC-24Limited Choice of Adjunct Medicines
for Type 1 Diabetes
• Pramlintide: the only FDA approved adjunct to insulin therapy1
– HbA1c reduction: ~0.3%
– Weight reduction: ~1.0 kg
– Increased risk of severe hypoglycemia
• Not widely used since approval in 2004
– 1.6% pramlintide users of 7,384 age ≥26 years in a recent Type 1 diabetes
registry report2
• T1D Exchange Data reports use of therapies not approved
by FDA for treatment of T1D
– Metformin (6%)
– GLP-1 Agonist (3.6%)
– SGLT2 Inhibitor (3%)
1: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021332s007_S016.pdf; 2: Foster et al. Diabetes Technol Ther 2019 CC-25What is Critical to Address the Unmet Need?
“How do we make life better,
Safety Simplicity
not just longer, for people
with diabetes?”
- Dr. Robert Ratner
Glycemic
Control
DiaTribe transcript, Public Workshop: Diabetes Outcome Measures Beyond Hemoglobin A1c (HbA1c); August 29, 2016. Fda.gov/drugs/news-events-human-drugs/public-workshop-
diabetes-outcome-measures-beyond-hemoglobin-a1c-hba1c CC-26What is Critical to Address the Unmet Need?
More options to improve glycemic control without
weight gain and without increasing risk hypoglycemia
Reductions in cardiovascular risk factors (e.g., blood pressure
and weight) would be an added advantage
These options should be convenient for patients
and regulated by FDA
CC-27EASE Phase 3 Program and Efficacy Results
Dr. Jan Marquard, MD
Clinical Development Lead Empagliflozin in T1D
Boehringer Ingelheim
CC-28Efficacy Data Package for Empagliflozin 2.5 mg
EASE Phase 3 Program
Phase Study Duration Empagliflozin Doses
EASE-3 26 weeks 2.5 – 10 – 25 mg
Phase 3
EASE-2 52 weeks 10 – 25 mg
EASE-1 4 weeks 2.5 – 10 – 25 mg
Phase 2
J-EASE-1 4 weeks 2.5 – 10 – 25 mg
Exposure-response EASE-2
52 weeks 2.5 mg
simulation study simulation
CC-29EASE Phase 3 Program and Efficacy Results
CC-30EASE Phase 3 Program Trial Design
EASE-3 26 weeks 3 weeks
1 week 6 weeks 2 weeks
Placebo
T1D therapy Placebo Empagliflozin 2.5 mg
Screening
intensification run-in
R Follow-up
Empagliflozin 10 mg
Empagliflozin 25 mg
CGM CGM CGM
substudy substudy substudy
26 weeks
EASE-2 (primary endpoint)
52 weeks 3 weeks
1 week 6 weeks 2 weeks
Placebo
T1D therapy Placebo
Screening
intensification run-in
R Empagliflozin 10 mg Follow-up
Empagliflozin 25 mg
CGM CGM CGM
Exposure-response Simulated Empagliflozin 2.5 mg
simulation study
T1D=Type 1 diabetes; CGM=Continuous glucose monitoring CC-31Efficacy Assessments – Based on FDA Guidance1
• Primary efficacy outcome
– Change from baseline in HbA1c at week 26
• Key secondary efficacy outcomes
– Change from baseline at week 26 in:
• Symptomatic hypoglycemic adverse events with blood glucose
(BG)Statistical Testing Hierarchy (Alpha Protected Endpoints)
EASE Phase 3 Program
Full Analysis Set (FAS)
10 mg and 25 mg
all treated patients with a baseline
HbA1c (efficacy) and ≥1 on-treatment A1c
Primary
10 mg and 25 mg Modified Intention-To-Treat set (mITT)
Endpoint all treated patients with a baseline
(HbA1c) HbA1c (effectiveness) and ≥1 post randomization A1c,
including on- and off-treatment values
2.5 mg (efficacy)1
10 mg and 25 mg
Key Secondary
Weight,
Endpoints CGM2, Hypoglycemia
Insulin
1. EASE-3 only; 2. EASE-2 only Blood pressure
HbA1c=Glycated hemoglobin; CGM=Continuous glucose monitoring CC-33Key Inclusion and Exclusion Criteria
EASE Phase 3 Program
Key inclusion criteria
• Adults with Type 1 diabetes for at least 12 months
• Understanding of disease and how to manage it/willing and capable
to comply with study requirements
• On multiple daily insulin injections or insulin pump
• HbA1c between 7.5 and 10.0% after insulin intensification
• Body mass index (BMI) of ≥ 18.5 kg/m2
• Estimated glomerular filtration rate (eGFR) of at least 30 ml/min/1.73m2
Key exclusion criteria
• DKA and/or severe hypoglycemia 3 months before screening and until
randomization
• Eating disorders
DKA=Diabetic ketoacidosis CC-34Demographics Balanced Between Groups/Trials and Representative
of Patients With Type 1 Diabetes
EASE Phase 3 Program
Main baseline parameter EASE-3 EASE-2
Sex, female 51% 53%
Main regions
Europe 63% 54%
North America 25% 39%
Race, Caucasian 95% 94%
Mean age, years 43 years 45 years
Mean blood pressure, SBP/DB 124/76 mmHg 125/76 mmHg
Mean body mass index 28 kg/m2 29 kg/m2
Mean eGFR, CKD-EPI creatinine 97 ml/min/1.73m2 95 ml/min/1.73m2
Time since diagnosis of T1D 21 years 23 years
Mean HbA1c 8.2% 8.1%
Mean total insulin dose (range) 0.70 (0.2–1.7) U/kg 0.71 (0.1–1.9) U/kg
Insulin therapy
Multiple daily insulin injections 66% 59%
Insulin pump 34% 41%
Based on Full Analysis Set
CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration; eGFR=Estimated glomerular filtration rate; HbA1c=Glycated hemoglobin CC-35High Completion Rate
EASE Phase 3 Program
EASE-3 EASE-2
(Week 26)
Screened (N=1751) Screened (N=1338)
Randomized (N=977) Randomized (N=730)
Treated (N=975) Treated (N=730)
Empagliflozin Empagliflozin Empagliflozin Empagliflozin Empagliflozin
Placebo Placebo
2.5 mg 10 mg 25 mg 10 mg 25 mg
(n=241) (n=243)
(n=241) (n=248) (n=245) (n=243) (n=244)
217 completed 225 completed 223 completed 223 completed 212 completed 228 completed 229 completed
treatment treatment treatment treatment treatment treatment treatment
(90.0%) (93.4%) (89.9%) (91.0%) (87.2.%) (93.8%) (93.9%)
224 completed 232 completed 235 completed 233 completed 233 completed 241 completed 241 completed
trial (92.9%) trial (96.3%) trial (94.8%) trial (95.1%) trial (95.9%) trial (99.2%) trial (98.8%)
CC-36HbA1c Reduction With Empagliflozin Over Time
EASE-3
Placebo Empagliflozin 2.5 mg Empagliflozin 10 mg Empagliflozin 25 mg
8.9
8.7
Mean (SE) HbA1c (%)
8.5
8.3
6-week intensification
8.1
2-week run-in
7.9
7.7
7.5
Screening 0 4 12 18 26
Week
HbA1c=Glycated hemoglobin
Confirmatory analyses; MMRM, FAS CC-37HbA1c Reduction With Empagliflozin 2.5 mg Consistent
Across Analyses Sets
EASE-3
Empagliflozin Adjusted Mean Change from
Placebo 2.5 mg Baseline in HbA1c at Week 26
N N (95% CI)
Primary efficacy
238 237 -0.28 (-0.42, -0.15)
MMRM, FAS (on-treatment only)
Effectiveness
239 239 -0.27 (-0.40, -0.14)
MMRM, mITT (on- and off-treatment)
Multiple imputation
241 241 -0.25 (-0.38, -0.11)
Treated Set (on- and off-treatment)
Pattern mixture model
241 241 -0.25 (-0.39, -0.12)
Jump to reference, TS (on- and off-treatment)
“Wash-out” analysis
241 241 -0.26 (-0.39, -0.12)
Treated set (on- and off-treatment)
-0.6 -0.4 -0.2 0.0
Favors Empagliflozin Favors Placebo
HbA1c=Glycated hemoglobin CC-38HbA1c Reduction With Empagliflozin 10 mg and 25 mg Consistent
Across Analyses Sets
EASE-3
Adjusted Mean Change
from Baseline in HbA1c
Placebo Empagliflozin at Week 26
N N (95% CI)
Empagliflozin 10 mg vs placebo
Primary efficacy
238 244 -0.45 (-0.58, -0.32)
MMRM, FAS (on-treatment only)
Effectiveness
239 246 -0.44 (-0.57, -0.30)
MMRM, mITT (on- and off-treatment)
Empagliflozin 25 mg vs placebo
Primary efficacy
238 242 -0.52 (-0.66, -0.39)
MMRM, FAS (on-treatment only)
Effectiveness
239 245 -0.50 (-0.64, -0.37)
MMRM, mITT (on- and off-treatment)
-0.8 -0.6 -0.4 -0.2 0.0
Favors Empagliflozin Favors Placebo
HbA1c=Glycated hemoglobin CC-39HbA1c Reduction With Empagliflozin 2.5 mg Generally Consistent
Across Subgroups – Region, Sex, Age, and BMI
EASE-3
n Analyzed
Empa 2.5 mg/Placebo Difference (95% CI)
Empagliflozin 2.5 mg vs placebo 225/217 -0.28 (-0.42, -0.15)
US 40/36 -0.32 (-0.63, -0.01)
Region
Non-US 185/181 -0.28 (-0.42, -0.13)
Female 114/115 -0.17 (-0.35, 0.01)
Sex
Male 111/102 -0.41 (-0.60, -0.22)HbA1c Reduction With Empagliflozin 2.5 mg Generally Consistent
Across Additional Subgroups
EASE-3
n Analyzed
Empa 2.5 mg/Placebo Difference (95% CI)
Empagliflozin 2.5 mg vs placebo 225/217 -0.28 (-0.42, -0.15)
≤5 years 14/11 -0.81 (-1.36, -0.26)
Time since >5-10 years 23/30 -0.26 (-0.64, 0.12)
diagnosis >10-25 years 106/91 -0.30 (-0.50, -0.10)
>25 years 82/85 -0.19 (-0.41, 0.03)
Insulin Multiple daily injections 148/141 -0.32 (-0.49, -0.16)
administration Insulin pump 77/76 -0.21 (-0.43, 0.02)
0.8 U/kg 50/64 -0.43 (-0.69, -0.17)
≥90 ml/min 152/154 -0.28 (-0.44, -0.12)
eGFR 60-Body Weight Reduction With All Three Doses
EASE-3
Placebo Empagliflozin 2.5 mg Empagliflozin 10 mg Empagliflozin 25 mg
1.0
from Baseline in Weight (kg)
Adjusted Mean (SE) Change
0.0 -1.8
(95% CI:-2.3, -1.2)
pEarly and Sustained Insulin Dose Reduction
EASE-3
Placebo Empagliflozin 2.5 mg Empagliflozin 10 mg Empagliflozin 25 mg
0.02
Total Daily Insulin Dose (U/kg)
0.00
Change from Baseline in
-0.05 (-6%)
Adjusted Mean (SE)
-0.02 (95% CI:-0.07, -0.03)
pMeaningful Reduction in Blood Pressure With Empagliflozin 2.5 mg
EASE-3
Empagliflozin 2.5 mg Empagliflozin 10 mg Empagliflozin 25 mg
(n=236) (n=240) (n=238)
vs Placebo in Change from Baseline
0
Adjusted Mean (95% CI) Difference
-1
in SBP (mmHG)
-2
-3
-4
-2.1
-5 *
-6 -3.7
-3.9
** **
SBP=Systolic blood pressure
*pEmpagliflozin 2.5 mg Increased Time in Target Glucose Range
by ~1 Hour Per Day
EASE-3
Glucose ≤70 mg/dl Glucose >70–≤180 mg/dl Glucose >180 mg/dl
Baseline Week 26
43% 46% % Difference vs
Placebo
(n=26)
5% 5% Placebo (95% CI)
52% 49%
49% 54% +4.3%
Empagliflozin 2.5 mg
6% 6% (-0.9, 9.5) + 1 hour/day
(n=36) 40% p=0.1063
45%
43% 54% +10.7%
Empagliflozin 10 mg
6% 6% (5.6, 15.7) +2.6 hour/day
(n=41) 51% 39% pResults Summary: Efficacy Sustained Over 52 Weeks
EASE-2
26 Weeks 52 Weeks
Mean difference vs. placebo
change from baseline Empa 10 mg Empa 25 mg Empa 10 mg Empa 25 mg
-0.54***1 -0.53***1
HbA1c, % -0.39*** -0.45***
-0.53***2 -0.51***2
Body weight, kg -2.7*** -3.3*** -3.2*** -3.6***
CGM time in range, % 11.9*** 12.9*** 12.2*** 12.5***
Total daily insulin dose, % -13.3*** -12.6*** -12.0*** -12.9***
SBP, mmHg -2.1* -3.7** -3.4* -4.7***
DBP, mmHg -1.3* -2.3** -1.7* -1.5*
1. FAS; 2. mITT
Confirmatory analyses; ***pHypoglycemia Reporting
EASE Phase 3 Program
Hypoglycemia with blood Severe
glucoseHypoglycemia Results Empagliflozin 2.5 mg
EASE Phase 3 Program
Empagliflozin Placebo
Events, Events, Rate Ratio
Week 1-26
N n N n (95% CI) p-value
Key secondary hypoglycemia endpoint1
Empagliflozin 2.5 mg 237 976 238 1339 0.93 (0.68, 1.27) 0.6587
Severe hypoglycemia Patients/ Patients/
Events Events
Empagliflozin 2.5 mg 241 3/92 241 6/6 0.18 (0.03, 1.15) 0.0698
Patient-reported3 hypos with BGHypoglycemia Results Empagliflozin 10 and 25 mg
EASE Phase 3 Program
Empagliflozin Placebo
Events, Events, Rate Ratio
N n N n (95% CI) p-value
EASE-3 (week 1–26)
Empagliflozin 10 mg 244 1423 238 1339 1.26 (0.93, 1.71) 0.1438
Key secondary1
hypoglycemia Empagliflozin 25 mg 242 1216 238 1339 1.05 (0.77, 1.43) 0.7543
endpoint EASE-2 (week 1–26)
(week 1-26)
Empagliflozin 10 mg 243 1327 239 1870 0.77 (0.57, 1.05) 0.0972
Empagliflozin 25 mg 241 1333 239 1870 0.78 (0.58, 1.06) 0.1180
EASE-2 and EASE-3 pooled (week 1–52/1–26)
Severe
hypoglycemia Empagliflozin 10 mg 491 20/332 484 15/212 1.47 (0.70, 3.10) 0.3095
(week 1-26)
Empagliflozin 25 mg 489 13/142 484 15/212 0.55 (0.23, 1.29) 0.1695
EASE-2 and EASE-3 pooled (week 1–52/1–26)
Patient-reported3
hypoglycemia Empagliflozin 10 mg 491 9133 484 11446 0.81 (0.70, 0.94) 0.0043
with BGDiabetes Treatment Satisfaction Questionnaire (DTSQ)
Showed Significant Improvement in Treatment Satisfaction
EASE-3 Fast-acting Long-acting
Insulin Analog1 Insulin Analog2
3 ** **
3 3
1.8
*
2.0 **
Change from Baseline
2 1.9
Adjusted Mean (SE)
1.2 2 2 **
1.3
1
1 0.6 1
-0.2
0 0 0
-1 -1 -1 -0.6
-2 -2 -2
Placebo Empa Empa Empa Human insulin Insulin aspart NPH Insulin
(n=213) 2.5 mg 10 mg 25 mg (n=358) (n=707) (isophane) glargine
(n=214) (n=213) (n=218) (n=256) (n=261)
DTSQ mean
29.6 29.2 28.8 29.1 29.9 30.1 28.1 27.8
BL total score
Exploratory analyses; **pSupportive Clinical Data from Phase 2 Studies
CC-51Phase 2 Study Design
EASE-1
1 week 2 weeks 4 weeks 1 week
Placebo
Placebo Empagliflozin 2.5 mg
Screening
run-in R Follow-up
Empagliflozin 10 mg
Empagliflozin 25 mg
CGM CGM CGM
• All patients Caucasian Europeans
• 70% male, 30% female
• Mean age 41 years, BMI 26 kg/m2
• Mean HbA1c at baseline 8.2%
BMI=Body mass index; HbA1c=Glycated hemoglobin CC-52Empagliflozin 2.5 mg Provides 70% of the Urinary Glucose
Excretion (UGE) Effect of the Higher Doses
EASE-1
140 103.1 101.5
Mean (SD) Change from
Baseline in UGE (g/24h)
120 72.8
100
80
60
40
-3.3
20
0
-20
-40
Placebo Empagliflozin 2.5 mg Empagliflozin 10 mg Empagliflozin 25 mg
(n=19) (n=19) (n=19) (n=18)
BL Mean 20.3 21.4 14.0 13.4
CC-53Evidence for an Effective Disease Specific Dose
EASE-1
Empagliflozin Empagliflozin Empagliflozin
2.5 mg 10 mg 25 mg
n=19 n=19 n=18
Main efficacy
HbA1c at day 28 (%) -0.35* -0.36* -0.49*
Weight at day 28 (kg) -1.5** -1.8** -1.9**
Time in rangea, week 4 (hour/day) +1.3 +1.5 +3.0*
Main safety
General safety Comparable to Type 2 diabetes
DKA No reported cases
Severe hypoglycemia One case on placebo
Genital infections No reported cases
Empagliflozin improved glycemic control with weight loss and
without increased hypoglycemia in short-term Phase 2 trials
**pResults Exposure-response Simulation Studies
CC-55General Concept of Exposure-response Study
Exposure Response
Concentration vs. Time Concentration vs. Effect
Concentration
Effect
Time Concentration
Exposure-response Simulation Study
Effect vs. Time
Effect
Time CC-56
Adapted from Mehrotra et al. Int J Impot Res 2007Exposure-response Simulation Study –
Model Development
Development Independent of Description of EASE-2 Data
EASE-3 Observed Simulated median with 95% CI
0.4
0.2
Data from
Placebo
796 Patients 0
Change from Baseline HbA1c (%)
EASE-1 and EASE-2 -0.2
• HbA1c 0
• Empagliflozin -0.2
exposure Empagliflozin
-0.4 10 mg
Previous -0.6
Knowledge 0
Exposure-response -0.2
Empagliflozin
data across all available -0.4 25 mg
patient populations
-0.6
0 4 12 18 26 43 52
Time (Weeks)
HbA1c=Glycated hemoglobin CC-57Exposure-response Simulation Study –
Validation
• Validation: Replication of HbA1c lowering in EASE-3
after 26 weeks of treatment
Observed in EASE-3 Simulated for validation
Dose group Mean ± SE Mean ± SE
Empagliflozin
-0.28 ± 0.07 -0.29 ± 0.05
2.5 mg
Empagliflozin
-0.45 ± 0.07 -0.47 ± 0.05
10 mg
Empagliflozin
-0.52 ± 0.07 -0.53 ± 0.04
25 mg
• Model validation demonstrates suitability of the model
to investigate untested scenarios with clinical trial simulations
HbA1c=Glycated hemoglobin CC-58Exposure-response Simulation Study –
Results
• HbA1c lowering for a 2.5 mg empagliflozin dose was simulated
in EASE-2 population:
– Number of patients: 239
– Number of replicated trials: 500
• Simulated placebo corrected HbA1c change from baseline
after 26 weeks was -0.29 (95% CI -0.38, -0.20)
• Simulated effect (HbA1c reduction) was sustained over 52 weeks
HbA1c=Glycated hemoglobin CC-59Totality of Data Provides Evidence of Efficacy
for Empagliflozin 2.5 mg
• Meaningful HbA1c reduction with empagliflozin 2.5 mg consistent
across studies
Phase 3 Phase 2 Exposure-response Simulation Study
EASE-3 EASE-1 EASE-2 Simulation
26 weeks 4 weeks 26 weeks 52 weeks
Placebo–corrected
-0.28 -0.35 -0.29 -0.29
change in HbA1c (%)
• Empagliflozin 2.5 mg benefits beyond HbA1c reduction
– Body weight reduction (-1.8 kg)
– Reduction in systolic blood pressure (-2.1 mmHg)
– Increased treatment satisfaction
– No increased risk of hypoglycemia
HbA1c=Glycated hemoglobin CC-60Safety and DKA Risk Mitigation
Dr. Ona Kinduryte Schorling, MD, MSc
Head of Drug Safety, Metabolism
Boehringer Ingelheim
CC-61Safety Analysis
EASE Phase 3 Program
Empagliflozin 2.5 mg Empagliflozin 10 and 25 mg
• Studied in EASE-3 only • Data from higher doses serve as
the upper bound for general safety
EASE-2 (52 weeks)
EASE-3 (26 weeks) EASE-3 (26 weeks)
Placebo
Placebo
Placebo
Empagliflozin 2.5 mg Empagliflozin 10 mg
Empagliflozin 10 mg
Empagliflozin 25 mg
Empagliflozin 25 mg
CC-62General Safety: Summary
EASE-3 and EASE-2 and EASE-3 Pooled
EASE-2 and EASE-3
EASE-3 Pooled (Up to Week 52)
Empagliflozin Empagliflozin Empagliflozin
Placebo 2.5 mg Placebo 10 mg 25 mg
N=241 N=241 N=484 N=491 N=489
n (%) n (%) n (%) n (%) n (%)
≥1 AE 203 (84.2) 194 (80.5) 433 (89.5) 441 (89.8) 428 (87.5)
≥1 drug-related AEs by Investigator 56 (23.2) 70 (29.0) 158 (32.6) 221 (45.0) 226 (46.2)
≥1 AE leading to discontinuation 2 (0.8) 8 (3.3) 14 (2.9) 29 (5.9) 18 (3.7)
≥1 serious adverse events 16 (6.6) 13 (5.4) 44 (9.1) 64 (13.0) 42 (8.6)
Fatal outcome 0 0 0 0 1
CC-63Events of Special Interest
EASE-3 and EASE-2 and EASE-3 Pooled
EASE-2 and EASE-3
EASE-3 Pooled (Up to Week 52)
Empagliflozin Empagliflozin Empagliflozin
Placebo 2.5 mg Placebo 10 mg 25 mg
N=241 N=241 N=484 N=491 N=489
n (%) n (%) n (%) n (%) n (%)
Ketoacidosis (investigator-reported) 4 (1.7) 3 (1.2) 10 (2.1) 28 (5.7) 21 (4.3)
Severe hypoglycemia (investigator-reported) 8 (3.3) 6 (2.5) 22 (4.5) 21 (4.3) 17 (3.5)
Genital infections 6 (2.5) 10 (4.1) 16 (3.3) 55 (11.2) 56 (11.5)
Volume depletion 3 (1.2) 1 (0.4) 8 (1.7) 12 (2.4) 16 (3.3)
Urinary tract infections 13 (5.4) 13 (5.4) 45 (9.3) 49 (10.0) 39 (8.0)
Acute renal impairment 0 (0.0) 0 (0.0) 3 (0.6) 1 (0.2) 4 (0.8)
Hepatic events 1 (0.4) 1 (0.4) 7 (1.4) 8 (1.6) 8 (1.6)
Lower limb amputations 0 (0.0) 1 (0.4) 0 (0.0) 0 (0.0) 0 (0.0)
Bone fractures 2 (0.8) 5 (2.1) 8 (1.7) 14 (2.9) 5 (1.0)
CC-64Case Definitions for DKA Adjudication
Certain DKA=
Unlikely DKA but ketosis=
Acidosis + ketosis
single high ketone without
with or without DKA symptoms Acidosis Ketosis
a a c
acidosis or DKA symptoms
c
b b
Potential DKA=
• DKA symptoms + Acidosis or ketosis
Unlikely DKA=
DKA • Persistent high ketones
Normal pH or normal ketones symptoms b
irrespective of DKA symptoms
Final decision based on clinical judgement of the committee
CC-65Adjudication Results: Certain and Potential DKA
EASE-3
Placebo Empagliflozin 2.5 mg
N=241 N=241
Patients with certain DKA, n (%) 3 (1.2) 2 (0.8)
Number of events (rate per 100 PY) 3 (2.52) 2 (1.65)
Events by severity, n
Severe 1 0
Moderate 1 0
Mild 1 2
Patients with certain or potential DKA, n (%) 4 (1.7) 4 (1.7)
Number of events (rate per 100 PY) 4 (3.36) 5 (4.12)
Severe 1 0
Moderate 1 0
Mild 2 5
Unlikely DKA but ketosis 2 (0.8) 7 (2.9)
Unlikely DKA 1 (0.4) 0
CC-66Concordance in Investigator-reported and Adjudicated DKA
EASE-3
Empagliflozin
2.5 mg Placebo
Rate/ Rate/
n/N 100 PY n/N 100 PY RR (95% CI) p-value
Investigator-reported DKA 4/241 3.35 4/241 3.39 0.99 (0.23, 4.34) 0.9875
CEC certain DKA 2/241 1.65 3/241 2.52 0.65 (0.11, 3.90) 0.6398
CEC certain or potential DKA 5/241 4.16 4/241 3.40 1.23 (0.31, 4.86) 0.7723
0.1 0.3 1.0 4.0 16.0
Placebo Risk Higher Empagliflozin 2.5 mg Risk Higher
RR=Rate Ratio (negative binomial model) CC-67Concordance in Investigator-reported and Adjudicated DKA
EASE-2 and EASE-3 Pooled
Empagliflozin Placebo
Rate/ Rate/
n/N 100 PY n/N 100 PY RR (95% CI) p-value
Empagliflozin 2.5 mg
Investigator-reported DKA 4/241 3.35 4/241 3.39 0.99 (0.23, 4.34) 0.9875
CEC certain DKA 2/241 1.65 3/241 2.52 0.65 (0.11, 3.90) 0.6398
CEC certain or potential DKA 5/241 4.16 4/241 3.40 1.23 (0.31, 4.86) 0.7723
Empagliflozin 10 mg
Investigator-reported DKA 30/491 9.55 12/484 3.85 2.48 (1.18, 5.21) 0.0164
CEC certain DKA 21/491 6.10 6/484 1.78 3.42 (1.34, 8.75) 0.0104
CEC certain or potential DKA 37/491 11.20 12/484 3.64 3.08 (1.51, 6.25) 0.0019
Empagliflozin 25 mg
Investigator-reported DKA 23/489 7.07 12/484 3.85 1.84 (0.85, 3.95) 0.1205
CEC certain DKA 18/489 5.17 6/484 1.78 2.90 (1.11, 7.54) 0.0291
CEC certain or potential DKA 32/489 9.43 12/484 3.64 2.59 (1.26, 5.32) 0.0095
0.1 0.3 1.0 4.0 16.0
Placebo Risk Higher Empagliflozin Risk Higher
CC-68Certain or Potential DKA Rate Consistent Over Time
EASE-3 and EASE-2
Placebo Empagliflozin 2.5 mg Empagliflozin 10 mg Empagliflozin 25 mg
15.0
EASE-3 15.0 EASE-2
Patients (%)
10.0 10.0
Patients (%)
5.0 5.0
0.0 0.0
0 4 8 12 16 20 24 28 32 36 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60
Study Week Study Week
DKA rates in both EASE-3 and EASE-2 are comparable
CC-69DKA and Ketone-related Events
EASE-3
Empagliflozin
2.5 mg Placebo
Rate/ Rate/
n/N 100 PY n/N 100 PY RR (95% CI) p-value
Ketone-related events
Empagliflozin 2.5 mg 87/241 71.96 50/241 43.72 1.65 (0.97, 2.79) 0.0647
Investigator-reported DKA
Empagliflozin 2.5 mg 4/241 3.35 4/241 3.39 0.99 (0.23, 4.34) 0.9875
Certain DKA
Empagliflozin 2.5 mg 2/241 1.65 3/241 2.52 0.65 (0.11, 3.90) 0.6398
Certain or potential DKA
Empagliflozin 2.5 mg 5/241 4.16 4/241 3.40 1.23 (0.31, 4.86) 0.7723
0.1 0.3 1.0 4.0 16.0
Placebo Risk Higher Empagliflozin 2.5 mg Risk Higher
Cases of certain DKA were associated with known risk factors which
informs our risk mitigation strategy
RR=Rate Ratio (negative binomial model) CC-70Measures to Minimize DKA Risk
EASE Phase 3 Trials
Protocol and Point-of-care Trial
Patient device to measure Information
Information blood ketones Card
Daily during the placebo
DKA risk factors and run-in and the first
atypical presentation Highlights to emergency
4 weeks of treatment,
care staff on atypical
Caution around insulin thereafter – DKA presentation
dose adjustment 2-3 times a week and in
case of symptoms
CC-71Proposed Measures to Minimize DKA Risk:
Education of Healthcare Providers
Type 1 Diabetes Patient Wallet
Specific (Low Dose) Counselling Card
Prescribing Information
Information
Need for Discontinuation
Caution around Awareness of
appropriate in case of Need for ketone
insulin dose atypical DKA
patient surgery, acute monitoring
adjustment presentation
selection illness
CC-72Proposed Measures to Minimize DKA Risk:
Education of Patients
Type 1 Diabetes Wallet
Specific Card
Medication Guide
Actions in relation
Avoidance/
Need for ketone to conditions
management
monitoring pre-disposing
of risk factors
to DKA
CC-73Safety Conclusions
• No new safety signals identified
• With specific measures in place in clinical trial setting,
no imbalance was seen in the frequency of ketoacidosis
between empagliflozin 2.5 mg and placebo
– Dose selection is an integral part of DKA risk mitigation
CC-74Clinical Perspective
Bruce A. Perkins, MD MPH
Professor and Clinician Scientist
Sam and Judy Pencer Family Chair in Clinical Diabetes Research
University of Toronto
CC-75CC-76
Recent Innovations Show Comparable Efficacy
Interventions HbA1c Reductions
1. Insulin pump therapy1 ↓ 0.29-0.3%
2. Continuous glucose data2 ↓ 0.28%
3. Automated insulin delivery3 ↓ 0.26%
4. Pramlintide4 ↓ 0.3%
5. Empagliflozin 2.5 mg ↓ 0.28%
Is a 0.28 percent HbA1c benefit clinically meaningful?
1. Misso ML et al. Cochrane Database Syst Rev. 2010; Pala L et al. Acta Diabetologica 2019; REPOSE Study Group BMJ 2017; Retnakaran R et al. Diabetes Care 2004
2. Benkhadra K et al. Clin Endocrinol. (Oxf) 2017
3. Weisman et al. Lancet Diabetes Endocrinol 2017; Bekiari E et al. BMJ 2018
4. Qiao YC et al. Oncotarget 2017 CC-77Benefits Accompany the HbA1c Reduction
• Weight reduction
• No hypoglycemia increase
• Blood pressure reduction
• Patient satisfaction
CC-78Estimated Long-term Benefits
• CORE Diabetes Model (Centre for Outcomes REsearch, Switzerland)
– Independent established reference standard disease progression model
– Designed to project long-term health outcomes in diabetes
– T1D model derived from DCCT/EDIC findings
– Annual re-evaluation of its validity
• Modeling of life-long treatment with empagliflozin 2.5 mg estimated
to result in:
– 12% relative risk reduction of end stage renal disease
– 9% relative risk reduction of first major cardiovascular events
– an increase in life expectancy of ~ 5 months
The Mount Hood 4 Modelling Group. Computer Modeling of Diabetes and Its Complications. Diabetes Care 2007
McEwan P et al. Validation of the IMS CORE Diabetes Model. Value in Health 2014
Cardiovascular events: Myocardial infarction + stroke + chronic heart failure + peripheral arterial disease; ESRD: End stage renal disease; PDR: Proliferative diabetic retinopathy CC-79Key Considerations Regarding Diabetic Ketoacidosis
• Background population risk (5%): Requires better prevention
strategies
• There is a known dose-dependent mechanistic causal
relationship with SGLTi that increases risk in certain situations
– Component cause, neither necessary or sufficient
• We have successfully adapted therapies with DKA risk
into Type 1 diabetes practice
Weinstock RS et al. JCEM 2013; Fazeli-Farsani S et al. BMJ Open 2017; Hoshina et ak Diabetes Technol Ther 2018; Rosenstock J and
Ferrannini E Diabetes Care 2015 Fullerton B et al. Cochrane Database Sys Rev 2014 CC-80Current Use of SGLT Inhibition in Type 1 Diabetes
in the US
Conclusions
• “…the risk for DKA during off-label use was notable… [and] exceeded
the expectation based on clinical trials....”
CC-81Low Dose SGLT2 Inhibitor
Low-dose empagliflozin represents
a strategy to reduce DKA risk
CC-82Selecting Patients for SGLTi
• Adults
• Adherent to monitoring and insulin administration
• No recent DKA
• Willing to abstain from avoidable risk factors (e.g. low carb
diets, excessive alcohol intake)
• Understand and can act on a ketone testing and management
protocol
– Test regardless of glucose level
– Hold on sick days, prior to surgeries and hospitalizations
Danne T et al. Diabetes Care 2019; Goldenberg R et al. Diabetes Obes Metab 2019 CC-83International Consensus Recommendations
for DKA Mitigation with SGLT2 Inhibitors
Proposed
by Sponsor
• DKA causes and symptoms
• Euglycemic DKA
• Importance of ketone monitoring (how and when to monitor)
Patient education
• Treatment protocol to address ketosis
• Guidance in when to seek medical attention
• Wallet card
• Criteria for patient selection
• Ketosis - detection, prevention, treatment (stop SGLT2i,
HCP education insulin administration, carb and fluid consumption)
• Euglycemic DKA
• Wallet card
Dedicated Type 1 specific brand enables these educational measures
Garg S, et al. Diab Tech Ther 2018; Danne et al. Diabetes Care 2019; Goldenberg R et al. Diabetes Obes and Metab 2019 CC-84Benefits and Risks of the Type 1 Specific
Empagliflozin Dose
BENEFITS RISKS
• Improved glycemic control
• No ↑ hypoglycemia
• Weight ↓ • DKA
• Blood pressure ↓ • Genital infection
• ↑ patient satisfaction
We have a unique opportunity to provide patients with an expanded
panel of options for successful individualized therapy
CC-85Closing Remarks
Dr. Jyothis George, MBBS, PhD, FRCP, FACE
Head of Medicine – Empagliflozin, Boehringer Ingelheim
Associate Clinical Professor – University of Warwick
CC-86Proposed Indication For a Type 1 Diabetes
Specific Dose
Proposed indication for empagliflozin 2.5 mg:
Adjunct to insulin therapy to improve glycemic control
in adults with Type 1 diabetes
We propose
A Type 1 diabetes specific dose
A dedicated brand with Type 1 specific prescribing information
Patient and professional education
CC-87Additional Experts Available for Questions
Expert Title
Chief of Pediatric, Adolescent and Young Adult Section,
Lori Laffel, MD, MPH Head of Clinical, Behavioral and Outcomes Research,
Joslin Diabetes Center
Professor of Internal Medicine,
Darren K McGuire, MD, MHSc Director of Cardiology Clinical Trials Unit
University of Texas (UT) Southwestern Medical Center
Director, Leadership Sinai Centre for Diabetes
Bernard Zinman CM, Mount Sinai Hospital, Toronto, Ontario
MD, FRCPC, FACP
Professor of Medicine, University of Toronto
Additional information included in your print-out
CC-88Darren K. McGuire, MD, MHSc, FAHA, FACC, FESC
University of Texas Southwestern Medical Center, Dallas, Texas
• Distinguished Teaching Professor of Internal Medicine
• Director of the Parkland Hospital and Health System Outpatient
Cardiology clinics
• Expertise in large scale CV Outcomes clinical trial design and
execution, and drug registration/regulation, with a focus in the area
of diabetes and cardiovascular disease
• Has held leadership roles in many international CV outcomes trials,
including in the areas of Type 2 diabetes, obesity and lipids
• Primary research interest includes the long-term prevention of and risk-modification
for cardiovascular disease, especially among the population of patients with diabetes
• Vice Chair of the AHA Diabetes Committee, and a former member of the FDA Cardiovascular
and Renal Drugs Advisory Committee and continues as an ad hoc consultant for the FDA
• Deputy Editor of Circulation, Senior Editor of Diabetes and Vascular Disease Research
and co-editor of the textbook: Diabetes in Cardiovascular Disease: A Companion
to Braunwald’s Heart Disease
CC-89Lori Laffel, MD, MPH
Joslin Diabetes Center, Boston, Massachusetts
• Chief, Pediatric, Adolescent and Young Adult Section, Joslin Diabetes Center
• Head, Section of Clinical, Behavioral and Outcomes Research,
Joslin Diabetes Center
• Professor of Pediatrics, Harvard Medical School, Boston, MA
• Areas of expertise include pediatric diabetes, childhood obesity, behavioral
and outcomes research, and the assessment and translation of new
technologies in diabetes
• Has served on numerous advisory boards for International Society
of Pediatric and Adolescent Diabetes (ISPAD) and JDRF
• Member of the ADA’s Boston Leadership Board, Past member of the National Board
of Directors of the ADA, the National Committee for Professional Practice Guidelines, chair
on the ADA’s Working Group on Transitions in Care for Young Adults with Diabetes, and past
chair of ADA’s Youth Strategies Committee
• Co-author on multiple clinical guidelines addressing Type 1 diabetes
• Current regional editor for the Americas for the journal Diabetic Medicine, the primary journal
for the British Diabetes Association
CC-90Bernard Zinman, CM, MD, FRCPC, FACP
Lunenfeld-Tanebaum Research Institute, Mount Sinai Hospital, Toronto, Canada
• Stephen and Suzie Pustil Diabetes Research Scientist,
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital,
Toronto, Canada
• Professor of Medicine, University of Toronto
• Research interests include the long-term complications of diabetes mellitus,
the development of new therapies for Type 1 and Type 2 diabetes,
and studies directed at the prevention of diabetes
• Prolific researcher with leadership roles in numerous international studies
including the Diabetes Control and Complications Trial and Epidemiology of Diabetes
and Complications (DCCT/EDIC), the most comprehensive diabetes complications study
ever conducted in Type 1 diabetes
• Recipient of numerous awards including the Charles H. Best Medal for Distinguished Service
in the Cause of Diabetes (awarded to the DCCT Investigators), the ADA Outstanding Physician
Clinician Award, the Lifetime Achievement Award from the Canadian Diabetes Association
and appointment to the Order of Canada, in recognition of his achievements in diabetes patient
care and research
• Author of more than 550 publications in national and international journals
CC-91Backup Slides Shown During the Meeting
CC-92Exposure-Response Analysis – Blood Ketones
0.4
Blood Ketones at 26 Weeks (mmol/L)
0.3
0.3
Dose
0.2 Placebo
2.5 mg
0.2 10 mg
25 mg
0.1
0.1
0.0
0 2500 5000 7500 10000
Steady-State AUC (nmolꞏh/L)
AUC: Area under the concentration time curve
Red line: Simulated median, shaded area: 95% CI (n=500 simulations incorporating parameter uncertainty).
Typical subject: male gender, Multiple daily injections insulin, eGFR=98 (ml/min/1.73 m2), Weight=81 (kg), and HBA1C=8.1 (%) BU-695Patient Self-Measured Blood Ketone Readings
(Entire Treatment Period)
EASE-3 EASE-2 and EASE-3 Pooled (Up to Week 52)
Empagliflozin Empagliflozin Empagliflozin
Placebo 2.5 mg Placebo 10 mg 25 mg
Number of patients 241 241 484 491 489
Number of patients
240 (99.6) 235 (97.5) 462 (95.5) 479 (97.6) 479 (98.0)
with measurements, (%)
Number of patients
1 (0.4) 6 (2.5) 22 (4.5) 12 (2.4) 10 (2.0)
without measurements, (%)
Number of measurements 22350 22574 45776 51345 52245
BU-479Diagnostic Criteria for DKA Defined
by American Diabetes Association (ADA)
DKA
Mild Moderate Severe
Plasma glucose (mg/dL) >250 >250 >250
Arterial pH 7.25-7.30 7.00-7.24 12
Alteration in sensoria or mental obtundation Alert Alert/drowsy Stupor/coma
1. Nitroprusside reaction method
2. Calculation: 2[measured Na (mEq/L) + glucose (mg/dL)/18
3. Calculation: (Na+) - (Cl- + HCO3-) (mEq/L)
America Diabetes Association. Standards of Medical Care in Diabetes – 2014. Diabetes Care 37 (Suppl. 1), pp. S14–S80 BU-667Estimated Lifelong Clinical Impact of Glucometabolic
Benefits of Empagliflozin 2.5 mg
Empagliflozin 2.5 mg + Comparison vs
Insulin Therapy
Insulin Therapy Insulin Therapy
Pts with events per Pts with events per
Incidence rate RR (CI)
1000 years at risk (n) 1000 years at risk (n)
Diabetic eye disease
Proliferative diabetic retinopathy 11.7 13.7 0.85 (0.85-0.86)
Macular edema 18.3 20.5 0.89 (0.89-0.90)
Severe vision loss 12.5 13.9 0.90 (0.89-0.90)
Diabetic kidney disease
Diabetic nephropathy with proteinuria 11.1 12.7 0.87 (0.86-0.87)
End-stage kidney disease (ESKD) 4.3 4.9 0.88 (0.87-0.89)
Neuropathy 22.0 23.6 0.93 (0.93-0.94)
Cardiovascular disease
Myocardial infarction 8.2 8.8 0.93 (0.93-0.94)
Stroke 1.7 1.9 0.92 (0.90-0.94)
Peripheral arterial disease 7.4 7.8 0.95 (0.94-0.96)
Heart failure 2.2 2.4 0.91 (0.90-0.93)
Projected increase in life expectancy ~ 5 months1
Analysis was performed using the IQVIA Core Diabetes Model version 9.0. 1. In EASE-3 like population over a lifelong time horizon BU-374Estimated Lifelong Clinical Impact of Glucometabolic Benefits of
of Empagliflozin 2.5 mg in EASE-3 like patient population
Prevented events in
1000 patients (n)
Diabetic Neuropathy -42
Diabetic eye disease
Proliferative diabetic retinopathy -60
Macular edema -63
Severe vision loss -41
Diabetic kidney disease
Diabetic nephropathy with proteinuria -50
End-stage kidney disease (ESKD) -18
Cardiovascular disease -41
Myocardial infarction -18
Stroke -8
Heart failure -6
Peripheral arterial disease -9
Projected increase in life expectancy ~ 5 months
Note: All analyses performed using the IQVIA Core Diabetes Model version 9.0. Projected occurrence of first and recurrent events in the EASE-3 like population (1000 pts) BU-407Exposure-Response in Type 1 Diabetes
200
180 Empagliflozin 2.5 mg
Urinary Glucose Excretion (g)
160 Empagliflozin 5 mg
100%
140 Empagliflozin 10 mg
88% ~10%
120 ~30%
71%
100
80 • Potential empagliflozin 5 mg
60 dose close to effects of
empagliflozin 10 mg
40
20
• Empagliflozin 2.5 mg is real
differentiator from higher doses
0
0 1000 2000 3000 4000 5000
Empagliflozin Exposure (nmolꞏh/L)
BU-237Clinical Impact of Estimated Micro/Macrovascular Benefits vs. Excess
DKA Risk for Empagliflozin 2.5 mg in an EASE-3 Like Patient Population
Estimated Lifelong Benefits Estimated Yearly Excess DKA Risk
Events in 1000 Patients (n) Events in 1000 Patients (n)
Diabetic Neuropathy -42 DKA +23
Severe vision loss -41
End stage kidney disease -18
Major CV events -41
Total -142
CV events: myocardial infraction + stroke + heart failure + peripheral arterial disease
DKA: diabetic ketoacidosis for certain and potential events RR-1You can also read
