Management of diabetes

1. Copyright © 2017 IQVIA. All rights reserved.
September 2018
SGLT2-i CVOT & T2D
Discussion Stimuli

2. 1
Please indicate how you are currently managing the below Type 2
diabetes products
T2D Products Restrictions (reimbursement status, etc.)
SGLT2-i
Jardiance (empagliflozin)
Invokana (canagliflozin)
Farxiga (dapagliflozin)
Glyxambi (empagliflozin/linagliptin)
Synjardy (empagliflozin/metformin)
Xigduo XR (dapagliflozin/metformin)
DPP4-i
Januvia (sitagliptin)
Onglyza (saxagliptin)
Tradjenta (linagliptin)
Nesina (alogliptin )
GLP1-RA
Byetta/Bydureon (exenatide)
Victoza (liraglutide)
Tanzeum (albiglutide)
Trulicity (dulaglutide)
Ozempic (semaglutide)

3. 2
SGLT-2i CVOT Trial Summary
Completed CVOTs # of Patients Patient Population Outcomes
EMPA-REG
(11/2015) Empagliflozin Cardiovascular
Outcome Event Trial in Type 2
Diabetes Mellitus Patients
7,020
• Adult patients with
established CV disease
only
• Adults (≥18 years of age)
with a BMI of 45 or less and
an estimated glomerular
filtration rate (eGFR) of at
least 30 ml per minute per
1.73 m2 of body-surface
area, with established
cardiovascular disease
Superior* vs placebo for primary composite cardiovascular
outcome and of death from any cause when added to SoC
(primary endpoint occurred in 10.5% in empa group vs 12.1% in
placebo group;
P=0.04 for superiority; secondary endpoint of primary composite
plus hospitalization for unstable angina occurred in 12.8% in
empa group vs 14.3% in placebo group)
2018 EMA label includes reduction in CV mortality when used
adjunct to SoC in patients with eCVD
CANVAS
(8/2017)
Canagliflozin cardiovascular
assessment study Versus
placebo
10,142
• Type 2 diabetes and an
elevated risk of
cardiovascular disease
Superior vs placebo for cardiovascular events
(primary endpoint occurred in 26.9 in cana group vs. 31.5
participants in placebo group per 1000 patient-years;
P<0.001 for noninferiority; P=0.02 for superiority)
Superiority was not shown for the first secondary outcome (death
from any cause; P=0.24); estimates for fatal secondary outcomes
are not considered to be significant
Greater risk of amputation at toe or metatarsal level vs placebo
2018 EMA label update to include CANVAS trial data
Label includes a special warning and precaution for use:
increase in cases of lower limb amputation (primarily of the toe)
has been observed in patients treated with canagliflozin
*** Special warnings and
SGLT-2i
Source: IQVIA expertise; ClinicalTrials.gov; NEJM.org, ema.europa.eu

4. 3
Draft ADA/EASD consensus statement treatment pathway
IQVIA - SGLT2-i CVOT EU Discussion Stimuil
Metformin and lifestyle management
Established ASCVD or HF
Without Established ASCVD or HF
Need to minimize
hypoglycemia
Need to address weight loss or
concerned about weight-related
comorbidities
If no such
issues identified
or cost is a
major issue
No
No
Yes
1
2
3
4
ASCVD = atherosclerotic cardiovascular disease; SU =sulfonylurea; TZD = Thiazolidinediones
• GLP1-RA with proven
CVD benefit
• SGLT2-i with proven
CVD benefit if eGFR
adequate
• SGLT2-i
• GLP1-RA
• TZD
• DPP4-i
• SGLT2-i
• GLP-1 with good
efficacy for weight loss
• SU
• TZD
Decision Tree for Recommended T2D Agents

5. 4
A number of key outcomes trials are expected to read out in the
near future
Trial Product Class Study Focus
Target
Enrollment
Expected
Readout
DECLARE SGLT-2i
• Long-term CV outcomes versus placebo (up to
6 years)
~17,000 H2 2018
CAROLINA DPP4-i
• Long-term CV outcomes versus single active
comparator (glimepiride)
~6,100 H1 2019
CREDENCE* SGLT-2i
• Renal outcomes versus placebo (up to 5.5
years)
~4,400 H2 2019
Source: IQVIA expertise; ClinicalTrials.gov
*Note: CREDENCE Trial stopped early as of July 16, 2018 based on achieved efficacy endpoints, with full readout expected in early H2 2018
DPP4-i
SGLT-2i

6. 5
DECLARE – Scenario 2
IQVIA - SGLT2-i CVOT US Discussion Stimuil
DECLARE (Forxiga, (dapagliflozin), CV)
Scenario 2
Overview
• Met safety endpoint by demonstrating non-inferiority on MACE
• Demonstrated superiority vs placebo on one of the 2 co-primary efficacy endpoints; the
composite of CV Death or hospitalization for heart failure (HHF) in the study population
(includes patients with established CVD & Multiple Risk Factors)
• Subgroup analysis demonstrated superiority only in the established CVD subgroup
and only a trend towards superiority in the MRF population
• No indication update
• Information on reduced risk of CV death for patients with established CVD included in
SmPC
• No algorithm update

7. 6
DECLARE – Scenario 1
IQVIA - SGLT2-i CVOT US Discussion Stimuil
DECLARE (Forxiga, (dapagliflozin), CV)
Scenario 1
Overview
• Met safety endpoint by demonstrating non-inferiority on 3-point MACE
• Demonstrated superiority vs placebo on one of the 2 co-primary efficacy
endpoints; the composite of CV Death or hospitalization for heart failure (HHF) in the
study population (includes patients with established CVD & Multiple Risk Factors)
• Subgroup analysis demonstrated superiority on both population subgroups.
• No indication update
• Information on reduced risk of CV death for patients with high CV risk for both,
established CVD and/or patients with Multiple Risk Factors included in SmPC
• No algorithm update

8. 7
DECLARE study is evaluating CV events with Forxiga vs. placebo
in CVD and MRF patients
Source: IQVIA expertise; ClinicalTrials.gov; American Journal of Nephrology; http://www.timi.org
Trial elements Evaluate the effect of dapagliflozin on the incidence of cardiovascular events
Product class • SGLT-2i Trial length • 6 years Target enrollment • ~17,000
Primary expected
outcome
• Composite endpoint of cardiovascular death, myocardial infarction (MI) or ischemic stroke
Co-primary endpoints :
• Composite endpoint of cardiovascular death, myocardial infarction (MI) or ischemic stroke
And
• Composite endpoint of CV death or hospitalization due to heart failure
Secondary
expected
outcome
• Renal composite endpoint: Confirmed sustained ≥40% decrease in eGFR to eGFR <60 ml/min/1.73m2 and/or ESRD
and/or renal or CV death
• All-cause mortality
Trial comparator • Placebo
Patient
Population
• ≥40 y.o.
• T2D
• 40% of patients with established CVD
• Remaining 60% of patient have multiple risk factors (MRF) for CVD (defined as men age ≥ 55 years or women ≥60 years,
with at least one of dyslipidaemia, hypertension or smoking).
Expected Readout • H2 2018/ Early 2019

9. 8
CAROLINA study is evaluating CV events with Trajenta vs. SU in
CVD and MRF patients
Trial elements Evaluate cardiovascular outcome study of linagliptin versus glimepiride in patients with type 2 diabetes
Product class • DPP4-i Trial length • 8 years Target enrollment • ~ 6,100
Primary expected
outcome
• Composite endpoint cardiovascular death (including fatal stroke and fatal myocardial infarction), non-fatal myocardial
infarction MI (excluding silent MI) or non-fatal stroke
Secondary
expected
outcome
• Any components of cardiovascular death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI), non-fatal
stroke or hospitalization for unstable angina pectoris
• Maintained glycaemic control
• Transitions in albuminuria classes between baseline and final visit
• Change from baseline to Final Visit in diabetes related laboratory parameters (HbA1c, fasting plasma glucose, total
cholesterol, LDL/HDL cholesterol, etc.)
• Beta-cell function sub-study
• Continuous glucose monitoring sub-study
• Cognition sub-study
Trial comparator • Glimepiride
Patient
Population
• 40 – 85 y.o.
• BMI ≤ 45
• Elevated glycosylated hemoglobin
• Pre-existing CV disease OR specified diabetes end-organ damage OR age => 70 years OR two or more specified
cardiovascular risk factor
Expected Readout • H1 2019
Source: IQVIA expertise; ClinicalTrials.gov; American Journal of Nephrology; http://www.timi.org

10. 9
CAROLINA – Scenario 2
IQVIA - SGLT2-i CVOT US Discussion Stimuil
CAROLINA (Trajenta (linagliptin), CV)
Scenario 2
Overview
• Demonstrated non-inferiority vs. SU on 3 point MACE for the total trial population
• No indication update

11. 10
CAROLINA – Scenario 1
IQVIA - SGLT2-i CVOT US Discussion Stimuil
CAROLINA (Trajenta (linagliptin), CV)
Scenario 1
Overview
• Demonstrated superiority over SU on 3 point MACE for the total trial population
• Trial information included in SmPC
• No indication update

12. 11
CREDENCE is evaluating Invokana vs. placebo for preventing kidney and
cardiovascular outcomes in patients with diabetes and established kidney disease
Trial elements Evaluation of the Effects of Canagliflozin on Renal and CV outcomes
Product class • SGLT-2i Trial length • 5-5.5 years Target enrollment • ~4,400 (>=30 yrs )
Primary expected
outcome
• Composite of end-stage kidney disease (ESKD), doubling of serum creatinine, and renal or cardiovascular death
Secondary
expected
outcome
• Composite of cardiovascular death and hospitalized congestive heart failure
• Cardiovascular death
• All-cause death
• Renal composite endpoint of end-stage kidney disease (ESKD), doubling of serum creatinine, and renal death
• Cardiovascular composite endpoint of cardiovascular death, non-fatal myocardial infarction (MI), non-fatal stroke,
hospitalized congestive heart failure, and hospitalized unstable angina
Trial comparator • Placebo
Patient
Population
• T2D with HbA1c >= 6.5% and <= 12.0%
• Participants need to be on a stable maximum tolerated labeled daily dose of an angiotensin-converting enzyme inhibitor
(ACEi) or angiotensin receptor blocker (ARB) for at least 4 weeks prior to randomization
• Patients are required to have an estimated glomerular filtration rate (eGFR) ≥30 to <90 mL/min/1.73 m2 and albuminuria
(urine albumin:creatinine ratio [UACR] >300 to ≤5,000 mg/g [33.9–565.6 mg/mmol]).
Expected Readout • H2 2019
Source: IQVIA expertise; ClinicalTrials.gov; American Journal of Nephrology; http://www.timi.org

13. 12
CREDENCE – Scenario 1
IQVIA - SGLT2-i CVOT US Discussion Stimuil
CREDENCE (Invokana (canagliflozin), Renal)
Scenario 1
Overview
• Demonstrated superiority vs placebo in composite of end-stage kidney disease (ESKD),
doubling of serum creatinine, and renal or cardiovascular death
• No indication update
• Information on slowing progression of renal disease in patients with diabetic nephropathy
included in SmPC
• No algorithm update

14. 13
CREDENCE – Additional Information if Required During Interview
• July 16, 2018 - Janssen announced that the Phase 3 CREDENCE (Canagliflozin and Renal Events in Diabetes with
Established Nephropathy Clinical Evaluation) clinical trial, evaluating the efficacy and safety of INVOKANA®
(canagliflozin) versus placebo when used in addition to standard of care for patients with chronic kidney disease (CKD)
and type 2 diabetes (T2D), is being stopped early based on the achievement of pre-specified efficacy criteria.
• The decision is based on a recommendation from the study's Independent Data Monitoring Committee (IDMC) that met
to review the data during a planned interim analysis. This recommendation was based on demonstration of efficacy,
as the trial had achieved pre-specified criteria for the primary composite endpoint of end-stage kidney disease
(time to dialysis or kidney transplantation), doubling of serum creatinine, and renal or cardiovascular (CV) death,
when used in addition to standard of care.

15. 14
Trial outcomes scenario 1
Trial Product Class Potential Scenarios
DECLARE SGLT-2i
• Reduced risk of CV death for patients
with established CVD
CAROLINA DPP4-i • Superiority vs SU on 3-point MACE
CREDENCE SGLT-2i
• Slowing progression of renal disease in
patients with diabetic nephropathy
DPP4-i
SGLT-2i
Please also assume that ADA/EASD Consensus Statement is released as discussed previously

16. 15
Trial outcomes scenario 2
Trial Product Class Potential Scenarios
DECLARE SGLT-2i
• Reduced risk of CV death for patients
with high CV risk
CAROLINA DPP4-i • Non-inferiority vs. SU on 3 point MACE
CREDENCE SGLT-2i
• Slowing progression of renal disease in
patients with diabetic nephropathy
DPP4-i
SGLT-2i
Please also assume that ADA/EASD Consensus Statement is released as discussed previously

17. 16
Trial outcomes scenario 3
Trial Product Class Potential Scenarios
DECLARE SGLT-2i
• Reduced risk of CV death for patients
with high CV risk as well as for those
with Multiple Risk Factors (MRF)
CAROLINA DPP4-i • Non-inferiority vs. SU
CREDENCE SGLT-2i
• Slowing progression of renal disease in
patients with diabetic nephropathy
DPP4-i
SGLT-2i
Please also assume that ADA/EASD Consensus Statement is released as discussed previously

18. 17
Appendix

19. 18
EASD treatment guidelines for T2D (simplified)
Current EASD treatment guidelines of T2D recommend multiple
therapies to achieve optimal HbA1C target
Lifestyle - healthy eating, weight control, physician activity, diabetes education
Monotherapy Dual therapy
Combination
therapy
Triple therapy
Metformin
If HbA1C target not achieved after 3 months of previous treatment line, proceed to next category
Metformin
Insulin (basal) or
choice of 1 drug
from non-insulin
T2D
medications*
Metformin
Insulin (basal) or
choice of 1 drug
from non-insulin
T2D medications*
Basal insulin
Other drug from
non-insulin T2D
medications or
(basal) insulin
Metformin
Meal-time insulin
or GLP-1
* Non-insulin T2D drug classes: No specific preference - choice dependent on a variety of patient- and disease-specific factors):
Sulfonylureas (SU); Thiazolidinedione (TZD); DPP4-i Inhibitors (DPP4-i); SGLT-2 Inhibitors (SGLT-2); GLP-1 Agonists (GLP-1)
Key takeaways
• New EASD guidelines expected in
2018
• EASD considers interval of 3
months before switching to a
different line of therapy
• Metformin is recommended
across all lines of therapy
Source: EASD guidelines 2015
To be shared with interviewees as pre-read

20. 19
redGDPS treatment guidelines for T2D (simplified)
Spanish treatment guidelines are released at regional level,
therefore T2D treatment can vary among relevant physicians
Lifestyle - healthy eating, weight control, physician activity, diabetes education
Monotherapy Dual therapy
Triple comb./
Insulin therapy
Metformin
Key takeaways
• In addition to regional guidelines,
medical experts have joined
together to release a guideline
and treatment recommendation
for physicians across Spain
• Spanish redGDPS treatment
algorithm separates T2D patients
by HbA1c score into three groups
• Patients suffering from HbA1c
scores >10% are considered to be
directly treated with a dual therapy
and therefore skip mono
metformin therapy
Source: redGDPS guideline (2016)
Metformin
+ SU/ DPP4-i/ pioglitazone/
SGLT-2
Previous dual therapy + oral
non-insulin T2D drugs/
GLP-1/basal insulin
or
Insulin based treatment
Metformin
+ SU/ DPP4-i/ Insulin
Non-insulin T2D drug classes: Sulfonylureas (SU); DPP4-i Inhibitors (DPP4-i); SGLT-2 Inhibitors (SGLT-2); GLP-1 Agonists (GLP-1)
HbA1c
<8%
HbA1c
8-10%
HbA1c
>10%
To be shared with interviewees as pre-read