This document summarizes key information from a presentation on optimal prevention of cardiovascular outcomes in type 2 diabetes: 1) Type 2 diabetes significantly increases the risk of cardiovascular disease and other chronic complications. Both intensive lipid and blood pressure lowering through medications like statins and ACE inhibitors have been shown to reduce cardiovascular events. 2) While glucose lowering also aims to reduce cardiovascular risk, trials yielded mixed results. Intensive control increased mortality in ACCORD but showed long-term benefits after the UKPDS trial. Current guidelines target HbA1c under 7%. 3) The choice of glucose-lowering medications is also important. Rosiglitazone increased cardiovascular risk and was withdrawn. Ongoing monitoring of

1. The Optimal Prevention in CV
outcomes in T2DM : A Brief Review
Neil R Poulter
Co-Director Imperial Clinical Trials Unit
And International Centre for Circulatory Health
Imperial College London UK
CREOLE Investigators Meeting
Nairobi : 26th April 2018

2. Diabetic
retinopathy
Leading cause of
blindness in adults
Diabetic nephropathy
Leading cause of
end-stage renal disease
CV disease
Stroke
2- to 4-fold increase
in CV mortality and stroke
Diabetic
neuropathy
Leading cause of
non-traumatic lower
extremity amputations
8 out of 10 individuals with
diabetes die from CV events
Peripheral vascular
disease
Major risk factor for lower
extremity amputation
Chronic complications of diabetes
IDF. Diabetes Atlas, 7th edition. 2015. www.idf.org/diabetesatlas
CV, cardiovascular

3. Global Burden of Disease
World
2015 415 million
2040 642 million

4. Preventing Cardiovascular Events in Patients with Diabetes
i. Intensifying all interventions
ii. Lipid lowering
iii.Blood pressure lowering
iv.Glycaemic control

5. CABG, corornary artery bypass graft; CVD, cardiovascular disease; MI, myocardial infarction; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease
Gaede P, et al. N Engl J Med 2003;348:383–393
Steno-2: CVD Event Reduction
Event Conventional Intensive
Cardiovascular death 7 7
MI: non-fatal 17 5
CABG 10 5
PCI 5 0
Stroke: non-fatal 20 3
Amputations 14 7
Revascularisation for PVD 12 6
85 events
in 35 patients
33 events
in 19 patients

6. Can we reduce macrovascular events
in Type 2 diabetes?
Lipid lowering?(ii)

7. 979 (10.5%)
3441 (9.6%)
4420 (9.8%)
627 (6.7%)
2807 (7.9%)
3434 (7.6%)
501 (5.4%)
1116 (3.2%)
1617 (3.7%)
1782 (19.2%)
6212 (17.4%)
7994 (17.8%)
Control
Effects on major vascular events of 1 mmol/L reduction
in LDL-C: Patients with and without diabetes from 14 RCTs
CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; RCT, randomised controlled trial; RR, relative risk
CTT Collaboration. Lancet 2008;371:117–125
Major vascular event
and prior diabetes
Major coronary event
Diabetes
No diabetes
Any major coronary event
Test for heterogeneity within subgroup: x2
1 = 0.1; p=0.8
Coronary revascularisation
Diabetes
No diabetes
Any Coronary revascularisation
Test for heterogeneity within subgroup: x2
1 = 0.1; p=0.8
Stroke
Diabetes
No diabetes
Any stroke
Test for heterogeneity within subgroup: x2
1 = 0.8; p=0.4
Major vascular event
Diabetes
No diabetes
Any major vascular event
Test for heterogeneity within subgroup: x2
1 = 0.0; p=0.9
1465 (15.6%)
4889 (13.7%)
6354 (14.1%)
407 (4.4%)
933 (2.7%)
1340 (3.0%)
491 (5.2%)
2129 (6.0%)
2620 (5.8%)
776 (8.3%)
2561 (7.2%)
3337 (7.4%)
Treatment
0.78 (0.69-0.87)
0.77 (0.73-0.81)
0.77 (0.74-0.80)
0.75 (0.64-0.88)
0.76 (0.72-0.81)
0.76 (0.73-0.80)
0.79 (0.67-0.93)
0.84 (0.76-0.93)
0.83 (0.77-0.88)
0.79 (0.72-0.86)
0.79 (0.76-0.82)
0.79 (0.77-0.81)
RR (CI)
0.5 0.0 1.5
Treatment better Control better
Events (%)
RR (99% CI)
RR (95% CI)

8. Can we reduce macrovascular events
in Type 2 diabetes?
YES
Lipid lowering(ii)
Blood pressure lowering(iii)

9. Among patients with Type 2 diabetes, blood pressure
lowering was associated with improved mortality and other
clinical outcomes
Effect of a 10 mmHg reduction in systolic blood pressure
Meta-analysis data based on 40 trials (N=100,354)
Outcome
No. of
studies Events Participants
BP lowering
Events Participants
Control
Relative risk
(95% CI)
Favours
BP lowering
Favours
control
Mortality
Cardiovascular disease
Coronary heart disease
Stroke
Heart failure
Renal failure
Retinopathy
Albuminuria
20
17
17
19
13
9
7
7
2334
3230
1390
1350
1235
596
844
2799
27,693
25,756
26,150
27,614
21,684
19,835
9781
13,804
2319
3280
1449
1475
1348
560
905
3163
25,864
24,862
24,761
26,447
20,791
18,912
9566
12,821
0.87 (0.78, 0.96)
0.89 (0.83, 0.95)
0.88 (0.80, 0.98)
0.73 (0.64, 0.83)
0.86 (0.74, 1.00)
0.91 (0.74, 1.12)
0.87 (0.76, 0.99)
0.83 (0.79, 0.87)
0.5 1.0 2.0
Relative risk (95% CI)
BP, blood pressure; CI, confidence interval
Emdin CA, et al. JAMA 2015;313:603–615

10. BP Lowering
What with?

11. “During the remaining year of the study,
a private detective identified 6 additional
documented non-fatal MIs!”
Schrier et al. N Engl J Med 2000;343:1969
BP-lowering in T2DM:
ABCD: ‘additional follow-up’
BP, blood pressure; MI, myocardial infarction; T2DM, type 2 diabetes mellitus

12. Before After
Endpoint CCB ACE CCB ACE
Myocardial
infarction
25 5 27 9
Congestive heart
failure
6 5 8 10
ACE, angiotensin converting enzyme; CCB, calcium channel blockers Schrier et al. N Engl J Med 2000;343:1969
ABCD: The detective impact

13. ACE inhibitors and ARB’s in T2DM: Effects on
Proteinuria and Mortality
Treatment (Micro/Macro)
Albuminuria
RRR vs placebo
Mortality
RRR vs placebo
ACE inhibitors -29% [0.56, 0.89] -16% [0.56, 0.89]
ARBs -10% NS +12% NS
Lv J et al. Cochrane Collaboration 2012

14. BP Lowering
How Far?

15. Mean no. of medications prescribed
Intensive 3.2 3.4 3.4 3.5 3.5 3.5 3.4 3.4
Standard 1.9 2.1 2.1 2.2 2.2 2.3 2.3 2.3
Intensive 2174 2071 1973 1792 1150 445 156 156
Standard 2208 2136 2077 1860 1241 504 203 201
No. of patients
140
130
120
110
0
0 1 2 3 4 5 6 7 8
Years since randomisation
Intensive
Standard
Systolicpressure(mmHg)
ACCORD: SBP changes
SBP, systolic blood pressure

16. ACCORD: Significant reduction in stroke outcomes
CI, confidence interval; HR, hazard ratio; SBP, systolic blood pressure
Cushman WC, et al. N Engl J Med 2010;362:1575–1585
Total strokeNonfatal stroke
Intensive Standard
HR: 0.59
(95% CI: 0.39, 0.89)
P=0.01
0 1 2 3 4 5 6 7 8
20
15
10
5
0
Years post-randomisationPatientswithevents(%)
Annual rate
0.32%
Annual rate
0.53%
HR: 0.63
(95% CI: 0.41, 0.96)
P=0.03
20
15
10
5
0
0 1 2 3 4 5
Years post-randomisation
Patientswithevents(%)
6 7 8
Annual rate
0.30%
Annual rate
0.47%
Patients with Type 2 diabetes (N=4733) assigned to either intensive BP lowering (SBP <120 mmHg) or standard
control (SBP <140 mmHg)

17. Patients
Guidelines Uncomplicated hypertension Diabetes Chronic renal failure
USA (JNC7 [2003]) <140/90 mmHg <130/80 mmHg <130/80 mmHg
USA (‘JNC8’ [2014]) <150/90 mmHg (60+ years) <140/90 mmHg <140/90 mmHg
<140/90 mmHg (<60 years)
ASH/ISH 2013 <150/90 mmHg (80+ years) <140/90 mmHg <140/90 mmHg
<140/90 mmHg
Europe (ESH 2013) <140/90 mmHg <140/85 mmHg <140/90 mmHg
China (CSH 2005) <140/90 mmHg
≤150 mmHg SBP for elderly)
<130/80 mmHg <130/80 mmHg
Russia <140/90 mmHg <130/80 mmHg <130/80 mmHg
Korea (KSH 2004) <140/90 mmHg <130/80 mmHg <130/80 mmHg
WHO-ISH (2003) SBP <140 mmHg <130/80 mmHg <130/80 mmHg
BHS IV 2004 <140/85 mmHg <130/80 mmHg <130/80 mmHg
Blood Pressure Targets
SBP, systolic blood pressure
CHEP (2014) <140/90 mmHg <130/80 mmHg <130/80 mmHg

18. A Personal View
TARGET – 130 mmHg
Endorsed by ISH!
Weber et al. Hypertension 2016
Resource dependant
Implications for thresholds

19. Can we reduce macrovascular events in Type 2 diabetes?
YES
Lipid lowering(ii)
Blood pressure lowering(iii)
Glucose lowering(iv)
YES

20. EPIC-NORFOLK study (1995–2003): 4662 men (45–79 years)
HbA1c (%)
Event
CHD CV Death
<5.0 1.00 1.00 1.00
5.0– 1.56 1.23† 1.25†
5.5– 2.00 1.56 1.57
6.0– 2.13 1.79 1.80
6.5– 3.44 3.03 3.49
≥7.0 7.07 5.01 3.38
Known diabetes 4.82 3.32 3.68
Relative risks for cardiovascular events and deaths
†non-significant
CHD, coronary heart disease; CV, cardiovascular
Khaw KT, et al. Ann Int Med 2004;141:413–420

21. • Strength
• Dose response
• Temporal sequence
• Independence
• Consistency
• Coherence (plausible)
• Predictive
• Reversible
✓
✓
✓
✓
✓
✓
✓
?
From association to cause

22. How low?
Glucose Lowering

23. Intensive Glycaemic Control Increased
All-cause Mortality (ACCORD)
aMajor CV event: non-fatal MI, non-fatal stroke or cardiovascular death
CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction
ACCORD Study Group. N Engl J Med 2008;358:2545–2559
• Non-significant reduction in CV events in intensive group
(HR=0.90; P=0.16)
Primary outcomea
Mortality did not increase in other outcome trials
(e.g. VADT and ADVANCE)
• Increased mortality in intensive group
(HR=1.22; P=0.04)
Death from any cause
Standard therapy
Intensive therapy
Patientswithevents(%)
25
20
15
10
5
0
0 1 2 3 4 5 6
Time (years)
Patientswithevents(%)
25
20
15
10
5
0
0 1 2 3 4 5 6
Time (years)

24. • The latest outcomes trials investigating the effect
of intensive vs standard glucose control on CV
outcomes have not provided a clear answer
• The ADA has recently updated the recommended
target HbA1c from <6.5% to <7.0% for macrovascular
risk reduction
ADA, American Diabetes Association; CV, cardiovascular; HbA1c, glycated haemoglobin
ADA. Diabetes Care 2010;33(Suppl. 1):S11–S61

25. Glucose-lowering:
What with?

26. CV Benefits of Tight Glycaemic Control 10 Years After
Intensive Treatment Discontinuation (UKPDS)
HR, hazard ratio; MI, myocardial infarction; SU, sulfonylurea
Holman RR, et al. N Engl J Med 2008;359:1577–1589
SU/insulin vs conventional
Events (%)
SU/insulin:
Conventional:
0.4
0.6
0.8
1.0
1.2
1.4
Hazardratio
MI
HR=0.84
P=0.052
HR=0.85
P=0.014
1997 1999 2001 2003 2005 2007
21 24 27 31 34 34
18 21 24 27 30 32
Metformin vs conventional
1.4
Hazardratio
0.4
0.6
0.8
1.0
1.2
MI
HR=0.61
P=0.010
HR=0.67
P=0.005
Events (%)
Metformin:
Conventional:
1997 1999 2001 2003 2005 2007
24 27 30 34 38 41
14 16 20 23 24 29

27. Rosiglitazone was associated with a significant
increase in the risk of MI and with an increase in
the risk of death from CV causes that had
borderline significance.
Rosiglitazone – 2007
CV, cardiovascular; MI, myocardial infarction
Nissen SE, Wolski K. N Engl J Med 2007;356:2457–2471
“
”

28. Clinical Trial Results Scenarios and Likelihood
of Approvability
CI, confidence interval; HR, hazard ratio
Hirshberg B, Raz I. Diabetes Care 2011;34(Suppl. 2):S101–S106
Upper
limit of
95% CI
Non-inferiority
boundary
HR 1.8
Non-inferiority
boundary
HR 1.3
0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2.0 2.2
Hazard ratio
Superiority
Non-inferiority
Non-inferiority
Inferior
Under-powered
Approvable: No need
for post-marketing study
Approvable: Need
for post-marketing study
Not approvable

29. ALECARDIO
(Aleglitazar, PPAR-αγ ) n=7226;
follow-up 2.0 years
Termin. Q3 2013 – RESULTS
Insulin
20192015 20202013 2014 2016 2017 2018
PPAR-αγ
2021
SGLT2i
EMPA-REG OUTCOME
(Empagliflozin, SGLT2i)
n=7000; duration up to 5 years
Q2 2015 – RESULTS
CANVAS
(Canagliflozin, SGLT2i)
n=4418; duration 4+ years
Completion Q2 2017
DECLARE-TIMI-58
(Forxiga, SGLT2i)
n=17,276; duration ~6 years
Completion Q2 2019
CANVAS-R
(Canagliflozin, SGLT2i)
n=5826; duration ~3 years
Completion Q1 2017
NCT01986881
(Ertugliflozin, SGLT2i)
n=3900; duration ~6.3 years
Completion Q2 2020
CREDENCE (cardio-renal)
(Canagliflozin, SGLT2i)
n= 3700; duration ~5.5 years
Completion Q1 2020
DEVOTE
(Insulin degludec, insulin)
n=7637; duration ~5 years
Completion Q3 2016
GLP-1 RA
ELIXA
(Lyxumia, GLP-1 RA)
n=6000; duration ~4 years
Q1 2015 – RESULTS
FREEDOM
(ITCA 650, GLP-1 RA in DUROS)
n=4000; duration ~2 years
Completion Q3 2018
REWIND
(Dulaglutide, QW GLP-1 RA)
n=9622; duration ~6.5 years
Completion Q2 2019
SUSTAIN 6
(Semaglutide, GLP-1 RA)
n=3297; duration ~2.8 years
Completion Q1 2016
LEADER
(Victoza®, GLP-1 RA)
n=9341; duration 3.5–5 years
Completion Q4 2015
EXSCEL
(Bydureon, QW GLP-1 RA)
n=14,000; duration ~7.5 years
Completion Q2 2018
HARMONY OUTCOME
(Tanzeum, QW GLP-1 RA)
n~9400; duration ~4 years
Completion Q2 2019
DPP4i
TECOS
(Januvia, DPP4i)
n=14,000; duration ~4–5 years
Q4 2014 – RESULTS
SAVOR TIMI-53
(Onglyza, DPP4i)
n=16,492; follow-up ~2 years
Q2 2013 – RESULTS
EXAMINE
(Nesina, DPP4i) n=5380;
follow-up ~1.5 years
Q3 2013 – RESULTS
CAROLINA
(Tradjenta, DPP4i vs SU)
n=6000; duration ~8 years
Completion Q3 2018
CARMELINA
(Tradjenta, DPP4i)
n=8000; duration ~4 years
Completion Q1 2018
NCT01703208
(Omarigliptin, QW DPP4i)
n=4302; duration ~3 years
Completion Q4 2020
Cardiovascular outcomes trials
Boxes with broken lines are for completed CVOTs
CVOT, cardiovascular outcome trial; DPP4, dipeptidyl peptidase-4; GLP-1 RA, glucagon-like peptide-1 receptor agonist; SGLT2i, sodium glucose co-transporter 2 inhibitor; SU, sulphonylurea
Source: clinicaltrials.gov (January 2015)

30. Drug comparison trials
Study Drug Key baseline characteristics Follow-up CVD CVD death
All-cause
death
4HF or hHF
ALECARDIO1 Aleglitazar
N=7226
Type 2 diabetes and recent acute
coronary syndrome
2 years
↔ ↔ ↔ ↔
ORIGIN2 Insulin
N=12,537
CV risk factors, impaired fasting
glucose, impaired glucose tolerance,
or Type 2 diabetes
6.2 years
↔ ↔ ↔ ↔
SAVOR-TIMI 533 Saxagliptin
N=16,492
Type 2 diabetes and established CVD
or ≥2 CV risk factors
2.1 years
↔ ↔ ↔ ↑
EXAMINE4,5 Alogliptin
N=5380
Type 2 diabetes and history of acute
coronary syndrome
3 years
↔ ↔ ↔ ↔
TECOS6 Sitagliptin
N=14,724
Type 2 diabetes and established CVD
18 months
↔ ↔ ↔ ↔
ELIXA7 Lixisenatide
N=6068
Type 2 diabetes and a recent acute
coronary syndrome event
2 years
↔ ↔ ↔ ↔

31. Target trials
Study
HbA1c
targets, %
Key baseline characteristics Follow-up CVD CVD death
All-cause
death
4HF or hHF
ACCORD core study1 Intensive: 6.4
Standard: 7.5
N=10,251
Type 2 diabetes with established CVD or
additional risk factors
3.5 years
↔ ↑ ↑ ↔
ADVANCE core study2 Intensive: 6.5
Standard: 7.3
N=11,140
Type 2 diabetes with history of CVD or at
least one other risk factor
5 years
↔ ↔ ↔ ↔
VADT core study3 Intensive: 6.9
Standard: 8.4
N=1791
Type 2 diabetes with other CV risk
factors
5.6 years
↔ ↔ ↔ ↔
ACCORDION4 Intensive: 7.8
Standard: 8.0
N=8601
Type 2 diabetes with established CVD or
additional risk factors
8.8 years
↔ ↑ ↔ ↔
ADVANCE-ON5 Intensive: 7.0
Standard: 7.1
N=8494
Type 2 diabetes with history CVD or at
least one other risk factor
5.9 years
↔ ↔ ↔ NA
VADT extension6 ETD: 0.2–0.3
N=1391
Type 2 diabetes with other CV risk
factors
9.8 years
↓ ↔ ↔ ↔

32. Why do the cardiovascular outcomes trials in T2DM
conflict with epidemiology-based expectations?
• Epidemiological association is not causal?
• Trial results wrong due to power/chance?
• Treating an aetiological factor does not necessarily
guarantee reversibility of effect
• Interventions cause other “off-target” damage
• Intervention too short and/or too small
• Wrong populations studied – e.g. too late
T2DM, type 2 diabetes mellitus

33. Press Release
Jardiance®
demonstratedcardiovascular(CV) risk reductionin
people with type 2 diabetesat high risk for CV events
Ingelheim, Germany and Indianapolis, US, 20 August, 2015 – Boehringer
Ingelheim and Eli Lilly and Company today announced positive top-line results from
EMPA-REG OUTCOME®
. This is a long-term clinical trial investigating
cardiovascular (CV) outcomes for Jardiance®
(empagliflozin) in more than 7,000
adults with type 2 diabetes (T2D) at high risk for CV events. EMPA-REG
OUTCOME®
met its primary endpoint and demonstrated superiority of Jardiance®
,
when added to standard of care, in CV risk reduction. The primary endpoint was
defined as time to first occurrence of either CV death, or non-fatal myocardial
infarction or non-fatal stroke.
Jardiance® demonstrated cardiovascular (CV) risk
reduction in people with type 2 diabetes at high risk
for CV events
SGLT-2i, sodium glucose co‐transporter-2
Boehringer Ingelheim. 2015. www.boehringer-ingelheim.com/press-release/jardiance-demonstrated-cardiovascular-cv-risk-reduction-people-type-2-diabetes-high

34. Primary endpoint Death from cardiovascular causes
Death from any cause Hospitalisation for heart failure
EMPA-REG results
Zinman et al. N Engl J Med 2015;373:2117–28
HR=0.86
95% CI (0.74–0.99)
p=0.04 for superiority
Placebo
Empagliflozin
Patientswith
event(%)
20
15
10
5
0
0 6 12 18 24 30 36 42 48
Month
HR=0.68
95% CI (0.57–0.82)
p<0.001
Placebo
Empagliflozin
Patientswith
event(%)
15
10
5
0
0 6 12 18 24 30 36 42 48
Month
HR=0.65
95% CI (0.50–0.85)
p=0.002
Placebo
Empagliflozin
Patientswith
event(%)
7
4
2
0
0 6 12 18 24 30 36 42 48
Month
6
5
3
1
HR=0.62
95% CI (0.49–0.77)
p<0.001 Placebo
Empagliflozin
Patientswith
event(%)
9
8
4
2
0
0 6 12 18 24 30 36 42 48
Month
7
6
5
3
1
CI, confidence interval; HR, hazard ratio

35. Cardiovascular endpoints
*95.02% CI
CV, cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular event;
MI, myocardial infarction
1. Zinman et al. N Engl J Med 2015;373:2117–28;
2. Marso et al. N Engl J Med 2016;375:311–22
EMPA-REG OUTCOME1
HR (95% CI) p-value
3-point MACE 0.86 (0.74–0.99)* 0.04
CV death 0.62 (0.49–0.77) <0.0001
Non-fatal MI 0.87 (0.70–1.09) 0.22
Non-fatal stroke 1.24 (0.92–1.67) 0.16
Hospitalisation
for heart failure
0.65 (0.50–0.85) 0.002
LEADER2
Favours empagliflozin Favours placebo
0.25 1.000.50 2.00
HR (95% CI) p-value
3-point MACE 0.87 (0.78–0.97) 0.01
CV death 0.78 (0.66–0.93) 0.007
Non-fatal MI 0.88 (0.75–1.03) 0.11
Non-fatal stroke 0.89 (0.72–1.11) 0.30
Hospitalisation for
heart failure 0.87 (0.73–1.05) 0.14
Favours liraglutide Favours placebo
0.50 1.00 1.50

36. Newer glucose-lowering agents have been shown to improve CV
outcomes in patients with Type 2 diabetes and CV disease or CV
risk factors
0 1 2
Primary efficacy endpoint
Secondary efficacy endpoint
Death from any cause
Death from CV causes
Myocardial infarction
Stroke
Hospitalisation for unstable angina
Coronary revascularisation
Microvascular event
hHF or death from CV causes
excluding fatal stroke
0.86 (0.74, 0.99)
0.89 (0.78, 1.01)
0.68 (0.57, 0.82)
0.62 (0.49, 0.77)
0.87 (0.70, 1.09)
1.18 (0.89, 1.56)
0.65 (0.50, 0.85)
0.86 (0.72, 1.04)
0.66 (0.55, 0.79)
0.99 (0.74, 1.34)
HR (95% CI)
HRs for pre-specified clinical endpoints (95% CI)
0.5 1 1.5 2
Favours
placebo
Favours
empagliflozin
Favours
placebo
Favours
liraglutide
EMPA-REG OUTCOME1 LEADER3 SUSTAIN-64
hHF
0.87 (0.78, 0.97)
0.88 (0.81, 0.96)
0.85 (0.74, 0.97)
0.78 (0.66, 0.93)
0.86 (0.73, 1.00)
0.86 (0.71, 1.06)
0.87 (0.73, 1.05)
0.86 (0.72, 1.04)
0.84 (0.73, 0.97)
0.98 (0.76, 1.26)
HR (95% CI)
0 0.5 1 1.5
Favours
placebo
Favours
semaglutide
0.74 (0.58, 0.95)
0.74 (0.62, 0.89)
1.05 (0.74, 1.50)
0.98 (0.65, 1.48)
0.74 (0.51, 1.08)
0.61 (0.38, 0.99)
1.11 (0.77, 1.61
0.65 (0.50, 0.86)
0.82 (0.47, 1.44)
HR (95% CI)
0 0.5 1 1.5
Favours
placebo
Favours
canagliflozin
CANVAS2,a
0.86 (0.75, 0.97)
0.87 (0.74, 1.01)
0.87 (0.72, 1.06)
0.85 (0.69, 1.05)
0.90 (0.71, 1.15)
0.67 (0.52, 0.87)a
HR (95% CI)

37. Why/how did empagliflozin, canagliflozin, liraglutide &
semaglutide work?
• Chance ?
• Glucose-lowering ?
• Blood pressure benefits ?
• Weight reduction ?
• Incipient heart failure ?
• Other(s) ?

38. CVOT, cardiovascular outcome trial.
Clinical practice recommendations have changed in
response to new CVOTs
Status as of April 2018
201820172016
Norway
Latvia
Italy
Position paper
Slovakia
Switzerland
Germany
Canada Bulgaria
USA
Brazil
Turkey
Denmark – Cardio
Bosnia and
Herzegovina
Hungary
Czech
Republic
Slovenia
Sweden
Spain
Cataluna,
Andalucia
Scotland
Greece
Poland
France
Finland
USA
Korea

39. 1. Diet and lifestyle are the critical determinants of T2DM and merit
routine intervention
2. Treat those with T2DM with a statin (irrespective of lipid levels)
3. Treat those with T2DM with BP lowering (irrespective of BP level?)
4. Aspirin use for high-risk patients with T2DM?
5. Lower glucose in T2DM – microvascular benefits clear ± long-term
macrovascular benefits. Method of reduction matters
Conclusions
BP, blood pressure; T2DM, Type 2 diabetes mellitus