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

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

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. http://www.easd.org/index.php?option=com_content&view=featured&Itemid=435 4/WHO fact-sheet/p1/ ¶3,5

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. http://www.idf.org/sites/default/files/EN_6E_Atlas_Full_0.pdf . b. www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. 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

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

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, 2015. Abstract 67. b. Hiromura M, et al. EASD Annual Meeting, 2015. Abstract 68. c. Reichetzeder C, et al. EASD Annual Meeting, 2015. Abstract 70. d. Darsalia V, et al. EASD Annual Meeting, 2015. Abstract 71. e. Terasaki M, et al. EASD Annual Meeting, 2015. Abstract 72. 2/Brigham/ p438/col1/para 3 3/Dull/p 33/ col 1/para1 4/WHO fact-sheet/p1/ ¶3,5

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, 2015. Abstract 72.

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, 2015. Abstract 128.

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 41.80 [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, 2015. Abstract 128.

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, 2015. Abstract 129.

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 (1.00-1.22) 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, 2015. Abstract 129.

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 2010-2012 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, 2015. Abstract 130. Berg B, et al. EASD Annual Meeting, 2015. Abstract 130.

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, 2015. Abstract 130.

German CREST Study: Patient Outcomes Events Crude HR (95% CI) P-value PSM HR (95% CI) Adjusted HR (95% CI) Death 3.3 (2.5-4.3) <.001 1.4 (0.9-2.3) .120 2.0 (1.5-2.6) MACE 1.9 (1.4-2.4) 1.4 (0.9-2.2) .137 1.3 (1.0-1.7) <.05 T2DM-related hospitalization 3.0 (1.9-4.6) 4.1 (1.6-10.9) <.005 2.8 (1.8-4.4) Composite outcome* 2.5 (2.1-3.0) 1.6 (1.2-2.3 1.8 (1.5-2.1) HRs/adjusted HRs reported for SU exposure in comparison with MET exposure. *Any event, whichever came first. Berg B, et al. EASD Annual Meeting, 2015. Abstract 130.

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, 2015. Abstract 132.

Summary of HRs for MACE-plus Events by Study Overall HR for MACE-plus for BIL vs comparator was 0.82 (0.53-1.27) 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, 2015. Abstract 132.

EMPA-REG OUTCOME Study: Empagliflozin, CV Outcomes, and Mortality in T2DM Zinman B, et al. N Engl J Med. 2015 Sept 17 [Epub ahead of print].

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. 2015 Sept 17 [Epub ahead of print].

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.

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.

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.

EMPA-REG OUTCOME: CV Death, MI, and Stroke IMAGE NO LONGER AVAILABLE Zinman B, et al. N Engl J Med. 2015 Sept 17 [Epub ahead of print].

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.

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.

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%

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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