1. 2015 EASD In Review: CV Risk management in t2dm
Faculty:
Lars Rydén, MD, PhD
Senior Professor, Cardiology
Department of Medicine
Karolinska Institute;
Cardiologist
Karolinska University Hospital
Stockholm, Sweden

2. Program Overview
1/van Deuren/ p144/col1/ para2
In this program, we will be discussing new clinical research regarding CV risk management in patients with T2DM, which was recently presented at the 2015 EASD Annual Meeting
2/Brigham/ p438/col1/ para3
3/Dull/p 33/ col1/para1
4/WHO fact sheet/p1/ para3
5/Rosenstein 2001/p1379/ fig1
1/van Deuren/ p144/col1/ para2; p146/ col1/para3
2/Brigham/ p438/col1/para 3
3/Dull/p 33/ col 1/para1
4/WHO fact-sheet/p1/ ¶3,5

3. EASD Annual Meeting
1/van Deuren/ p144/col1/ para2
Leading international forum for diabetes research and medicine[a]
Presented key developments in diabetes research from around the world and across a variety of disciplines
New data on CV effects of antihyperglycemic agents
2/Brigham/ p438/col1/ para3
3/Dull/p 33/ col1/para1
4/WHO fact sheet/p1/ para3
5/Rosenstein 2001/p1379/ fig1
1/van Deuren/ p144/col1/ para2; p146/ col1/para3
2/Brigham/ p438/col1/para 3
3/Dull/p 33/ col 1/para1 a.
4/WHO fact-sheet/p1/ ¶3,5

4. T2DM and CVD
1/van Deuren/ p144/col1/ para2
T2DM is prevalent: 382 million people, globally, currently live with diabetes[a]
T2DM is a major risk factor for CVD
CVD is the most common cause of death, accounting for up to 70% of all deaths[b]
CV risk is not well managed in patients with T2DM[c]; new data may help improve care
2/Brigham/ p438/col1/ para3
3/Dull/p 33/ col1/para1
4/WHO fact sheet/p1/ para3
5/Rosenstein 2001/p1379/ fig1
1/van Deuren/ p144/col1/ para2; p146/ col1/para3
2/Brigham/ p438/col1/para 3
a. . b.
c. Anselmino M, et al. Eur J Cardiovasc Prev Rehabil. 2007;14:28-36.
3/Dull/p 33/ col 1/para1
4/WHO fact-sheet/p1/ ¶3,5

5. Research at EASD Related to T2DM and CV Risk
1/van Deuren/ p144/col1/ para2
Animal/experimental research
Clinical evaluations
Large prospective CV outcome trial
EMPA-REG OUTCOME
2/Brigham/ p438/col1/ para3
3/Dull/p 33/ col1/para1
4/WHO fact sheet/p1/ para3
5/Rosenstein 2001/p1379/ fig1
1/van Deuren/ p144/col1/ para2; p146/ col1/para3
2/Brigham/ p438/col1/para 3
3/Dull/p 33/ col 1/para1
4/WHO fact-sheet/p1/ ¶3,5

6. Research at EASD Related to T2DM and CV Risk
1/van Deuren/ p144/col1/ para2
Animal/experimental research
Multiple presentations devoted to understanding mechanistic effects of newer antihyperglycemic agents, including DPP-4 inhibitors and SGLT2 inhibitors[a-e]
2/Brigham/ p438/col1/ para3
3/Dull/p 33/ col1/para1
4/WHO fact sheet/p1/ para3
5/Rosenstein 2001/p1379/ fig1
1/van Deuren/ p144/col1/ para2; p146/ col1/para3
a. Sakai Y, et al. EASD Annual Meeting, Abstract 67.
b. Hiromura M, et al. EASD Annual Meeting, Abstract 68.
c. Reichetzeder C, et al. EASD Annual Meeting, Abstract 70.
d. Darsalia V, et al. EASD Annual Meeting, Abstract 71.
e. Terasaki M, et al. EASD Annual Meeting, Abstract 72.
2/Brigham/ p438/col1/para 3
3/Dull/p 33/ col 1/para1
4/WHO fact-sheet/p1/ ¶3,5

7. Amelioration of Hyperglycemia With SGLT2 Inhibition Prevents Atherosclerosis in Diabetic Mice Independent of Insulin Action
SGLT2 inhibition exerts antiatherogenic effects by normalization of blood glucose levels in T1DM and T2DM through preventing foam cell formation of peritoneal macrophages, which is independent of insulin action
Type 1 diabetic Apoe-/- mice
SGLT2 inhibition decreased FBG, HbA1c, and glucose-AUC after OGTT vs placebo
SGLT2 inhibition significantly decreased atherosclerotic lesions and foam cell formation (33- 34%, P<.01)
Type 2 diabetic db/db mice with hyperinsulinemia
SGLT2 inhibition decreased body weight, plasma TG, FBG, and HbA1c
Foam cell formation was suppressed by the SGLT2 inhibition (34%, P<.01), which correlated to the HbA1c levels (r=0.88, P<.01, n=36), but insignificantly to lipid levels (r=-0.46, P=.06) or insulin (r=- 0.15, P=.56)
Gene expressions of scavenger receptors were upregulated, while ABCA1 (a key molecule for cholesterol efflux) was downregulated in peritoneal macrophages obtained from both types of diabetic mice
SGLT2 inhibition decreased expressions of scavenger receptors by approximately 30 to 40% and increased ABCA1 by 42%
Terasaki M, et al. EASD Annual Meeting, Abstract 72.

8. Increased Risk of CV-related Events With SUs Compared To Other Antihyperglycemic Drugs
Conducted a systemic review involving studies that compared SU with placebo/no intervention or other antihyperglycemic drugs to evaluate the effect of different glucose-lowering treatments on CV risk and mortality
Study population
84 RCTs, included 36,573 patients
26 observational studies, included 1,553,856 patients
Baxter C, et al. EASD Annual Meeting, Abstract 128.

9. Increased Risk of CV-related Events With SUs Compared With Other Antihyperglycemic Drugs (cont)
Treatment with an SU was associated with a significantly higher risk for all-cause mortality and CV-related mortality when compared with all other treatments
Risk of all-cause mortality (HR 1.26 [1.10, 1.44]) SU vs all treatments
CV-related mortality (HR 1.46 [1.21, 1.77]) vs all treatments
Risk for MI
Significantly higher for SUs vs DPP-4 (HR 2.54 [1.14, 6.57])
Elevated vs SGLT-2s (HR [1.64; 360.4])
Risk for stroke significantly higher for SUs vs DPP-4s, GLP-1RAs, TZDs, insulin
Baxter C, et al. EASD Annual Meeting, Abstract 128.

10. 68,351 patients were identified and included in the analysis
Second-line Treatment With SUs vs DPP-4 Inhibitors Is Associated With Risk of CVD, All-cause Mortality and Severe Hypoglycemia
Retrospective evaluation of Swedish Prescribed Drug Register to determine all-cause mortality and severe hypoglycemia in T2DM patients who initiate second- line treatment with either SU or DPP-4
68,351 patients were identified and included in the analysis
The 2 most frequent dual-combination were MET + SU (64%) and MET + DPP-4 (15%)
Eriksson JW, et al. EASD Annual Meeting, Abstract 129.

11. Adjusted Risk of Fatal/Nonfatal CVD in Patients on Second-Line Treatment With MET + SU vs MET + DPP-4
Adjusted HR (95% CI)
1.11 ( )
No. at risk
MET+SU
43584
36905
29906
23377
16949
11607
6603
2108
MET+DPP-4
10551
7971
5878
1097
2748
1546
359
Eriksson JW, et al. EASD Annual Meeting, Abstract 129.

12. Treatment Characteristics and Outcomes With SU vs MET in Incident T2DM: Results of the German CREST Study
Cohort study using German AOK PLUS-claims data set from to determine:
(1) Characteristics of new-onset T2DM patients having started either a MET or SU monotherapy, and
(2) Whether these therapies are associated with different mortality outcomes
Berg B, et al. EASD Annual Meeting, Abstract 130.
Berg B, et al. EASD Annual Meeting, Abstract 130.

13. German CREST Study: Study Population Treatment Characteristics
New-onset T2DM patients having initiated either SU or MET monotherapy
Cohort of T2DM-incidence pts
Unmatched
PS Matched SU
MET N
35,661
904
7874
730
Age (yrs)
65.9
70.2
61.4
P<.001
66.7
67.5
Gender (% female)
54.2
54.7
50.3
P<.05
53.3
52.5
Macrovascular complications (baseline)
1.9%
5.2%
4.2% NS
4.8%
4.4%
Antithrombotic agent (baseline)
15.7%
21.7%
15.8%
16.6%
15.1%
Antihypertensive agent (baseline)
14.8%
5.1%
5.3%
4.1%
Lipid-lowering agent (baseline)
18.2%
22.7%
22.9%
22.2%
22.5%
Berg B, et al. EASD Annual Meeting, Abstract 130.

14. German CREST Study: Patient Outcomes
Events
Crude HR (95% CI)
P-value
PSM HR (95% CI)
Adjusted HR (95% CI)
Death
3.3 ( )
<.001
1.4 ( )
.120
2.0 ( )
MACE
1.9 ( )
1.4 ( )
.137
1.3 ( )
<.05
T2DM-related hospitalization
3.0 ( )
4.1 ( )
<.005
2.8 ( )
Composite outcome*
2.5 ( )
1.6 (
1.8 ( )
HRs/adjusted HRs reported for SU exposure in comparison with MET exposure.
*Any event, whichever came first.
Berg B, et al. EASD Annual Meeting, Abstract 130.

15. No Difference In MACE With BIL vs Comparator Insulins In T1DM or T2DM
Prespecified meta-analysis across BIL development program to determine differences among different insulin therapies on CVD risk
Included one phase 2 study (12-week) and six phase 3 studies (26-78 weeks) of BIL vs glargine or NPH
Pooled population included 5872 patients
Mean age 54.1 ± 13.3 years; 56% men
Baseline demographic and clinical characteristics, including use of statins or other lipid-lowering drugs, were similar between BIL and comparators
Bergenstal R, et al. EASD Annual Meeting, Abstract 132.

16. Summary of HRs for MACE-plus Events by Study
Overall HR for MACE-plus for BIL vs comparator was 0.82 ( )
Although there were only 12 MACE-plus events in T1DM, the HR favoring BIL was nominally statistically significant
Favors Comparator
Favors BIL
95% CI
(0.53, 1.27)
(0.07, 0.91)
(0.14, 9.86)
(0.46, 1.99)
(0.48, 3.10)
(0.18, 1.43)
(0.17, 119)
T1DM
T2DM
Bergenstal R, et al. EASD Annual Meeting, Abstract 132.

17. EMPA-REG OUTCOME Study: Empagliflozin, CV Outcomes, and Mortality in T2DM
Zinman B, et al. N Engl J Med Sept 17 [Epub ahead of print].

18. EMPA-REG OUTCOME: Trial Design
Placebo (n=2333)
Screening
(n=11531)
Randomized 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
Treatment assignment double masked
The trial was to continue until at least 691 patients experienced an adjudicated primary outcome event
Zinman B, et al. N Engl J Med Sept 17 [Epub ahead of print].

19. EMPA-REG OUTCOME: Primary Endpoint, 3-Point MACE*
IMAGE NO LONGER AVAILABLE
From Zinman B, et al. N Engl J Med. 2015; Sept 17 [Epub ahead of print]. Copyright © 2015 Massachusetts Medical Society Reprinted with permission from Massachusetts Medical Society.

20. EMPA-REG OUTCOME: CV Death
IMAGE NO LONGER AVAILABLE
From Zinman B, et al. N Engl J Med. 2015; Sept 17 [Epub ahead of print]. Copyright © 2015 Massachusetts Medical Society.
Reprinted with permission from Massachusetts Medical Society.

21. EMPA-REG OUTCOME: CV Death By Treatment Group
IMAGE NO LONGER AVAILABLE
From Zinman B, et al. N Engl J Med. 2015;Suppl: Sept 17 [Epub ahead of print]. Copyright © 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

22. EMPA-REG OUTCOME: CV Death, MI, and Stroke
IMAGE NO LONGER AVAILABLE
Zinman B, et al. N Engl J Med Sept 17 [Epub ahead of print].

23. EMPA-REG OUTCOME: All-cause Mortality
IMAGE NO LONGER AVAILABLE
From Zinman B, et al. N Engl J Med. 2015; Sept 17 [Epub ahead of print]. Copyright © 2015 Massachusetts Medical Society.
Reprinted with permission from Massachusetts Medical Society.

24. EMPA-REG OUTCOME: Hospitalizations for HF
IMAGE NO LONGER AVAILABLE
From N Engl J Med. Zinman B, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. 2015; Sept 17 [Epub ahead of print]. Copyright © 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

25. EMPA-REG OUTCOME Study: Summary
Empagliflozin reduced risk for 3-point MACE by 14%
Empagliflozin reduced CV death by 38%
Empagliflozin improved survival by reducing all-cause mortality by 32%
Empagliflozin reduced HF hospitalizations by 35%

26. Ongoing CV Outcomes Trials for New Antihyperglycemic Agents
Study
Drug
Expected Completion
Patients
Inclusion Criteria
LEADER
Liraglutide
October 2015
9340
CVD or age/CV risk factors
SUSTAIN 6
Semaglutide
January 2016
3260
DECLARE-TIMI 58
Dapagliflozin
April 2019
17,150
CV risk factors
CANVAS
Canagliflozin
June 2017
4411
CVD or CV risk factors
CARMELINA
Linagliptin
January 2018
8300
CV risk
CAROLINA
September 2018
EXSCEL
Exenatide
April 2018
14,000
T2DM alone
REWIND
Dulaglutide
9622

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