Faculty. Robert S. Busch, MD, FACE Director of Clinical Research Albany Medical Faculty: Community Endocrine Group Albany, NY

Faculty Robert S. Busch, MD, FACE Director of Clinical Research Albany Medical Faculty: Community Endocrine Group Albany, NY 2

Disclosures Robert S. Busch, MD, FACE serves as a speaker for Astra Zeneca, Eli Lilly, Boehringer Ingelheim and Novo Nordisk. 3

Learning Objectives 1. Recognize the importance of C-V risk management in the patient with Type 2 DM 2. Describe the mechanism of action and capabilities of PCSK-9 therapies 4

PATIENTS WITH DIABETES REMAIN AT INCREASED RISK FOR ASCVD EVENTS Events Per 10,000 Among Adults 160 140 120 100 80 60 40 20 4S (1994) HOPE (2000) Diabetes/Acute MI No Diabetes/Acute MI Diabetes/Stroke No Diabetes/Stroke 0 1990 1995 2000 2005 2010 1. Gregg EW, Li Y, Wang J, et al. Changes in Diabetes-Related Complications in the United States, 1990-2010. N Engl J Med. 2014;370(16):1514-23. Epub 2014/04/18. doi: 10.1056/NEJMoa1310799. PubMed PMID: 24738668. Risk 50 80% 5

Type 2 DM is a Progressive Disease CLINICAL DIAGNOSIS Glucose (mg/dl) 350 300 250 200 150 100 50 Post-prandial Glucose Fasting Glucose 250 200 150 100 50 0 Compensated β-cell Function Obesity Insulin Level Decreasing β-cell Function IGT Diabetes Insulin Resistance Uncontrolled hyperglycemia Relative Insulin Resistance Clinical Features Macrovascular changes Microvascular changes Years -10-5 0 5 10 15 20 25 30 Adapted from Type 2 Diabetes BASICS: International Diabetes Center; 2000. 6

The Ticking Clock Hypothesis Type 2 DM is associated with microvascular and macrovascular complications. Duration of DM and severity of glycemia are primarily associated with microvascular disease. Metabolic disturbances during the prediabetic period may contribute to macrovascular disease. Macrovascular complications: the clock starts ticking years before the onset of clinical diabetes. Haffner SM et al. JAMA. 1990;263:2893-8. 7

The ABC s of Diabetes A1C (and ASA) < 7.0% (ACE < 6.5%) Blood Pressure* < 140/90 mmhg (125/75 mmhg) Cholesterol** LDL-C < 100 mg/dl (<70 mg/dl?) Non-HDL-C < 130 mg/dl (<100 mg/dl?) HDL-C > 40 mg/dl (> 50 mg/dl in women) TG s < 150 mg/dl Smoking Cessation ADA. Standards of Medical Care in Diabetes 2016. Diabetes Care 2016;39:S1-S106. * JNC 8: < 140/90 mmhg AACE: <130/80 ** NCEP 4: high-dose statin therapy recommended; >50% LDL-C reduction 12

Steno Study Design 160 type 2 diabetics with microalbuminuria Randomized treatment assignments Conventional : Treatment for multiple risk factors from general practitioner, in accordance with 1988 Danish Medical Association guidelines Intensive : Treatment for multiple risk factors by a project team (physician, nurse, dietician) at Steno Diabetes Center, involving strict treatment goals Endpoints Primary: CV death, MI, CVA, revascularization, amputation Secondary: nephropathy, retinopathy, neuropathy Eight-year follow-up Gaede et al. N Engl J Med 2003;348:383-93. 13

Steno-2: Macrovascular Endpoints* 60 Percent with Event 50 40 30 20 10 Conventional (n = 80) Intensive (n = 80) 53% RRR P = 0.01 0 0 1 2 3 4 5 6 7 8 Years of Follow-Up *CV death, MI, CVA, revascularization, amputation Gaede et al. N Engl J Med 2003;348:383-93. 14

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22% RRR The Heart Outcomes Prevention Evaluation Study Investigators. NEJM. 2000;342:145-53. 19

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SIMVASTATIN: MAJOR VASCULAR EVENT by YEAR People suffering events (%) 30 25 20 15 10 5 PLACEBO SIMVASTATIN 0 0 1 2 3 4 5 6 Years of follow-up Benefit/1000 (SE): 5(3) 20(4) 35(5) 46(5) 54(7) 60(18) 21

SIMVASTATIN: CAUSE-SPECIFIC MORTALITY Cause of death SIMVASTATIN PLACEBO (10269) (10267) Rate ratio & 95% CI STATIN better PLACEBO better Vascular Coronary Other vascular ANY VASCULAR Non-vascular Neoplastic Respiratory Other medical Non-medical NON-VASCULAR ALL CAUSES 587 707 194 230 781 937 (7.6%) (9.1%) 359 345 90 114 82 90 16 21 547 570 (5.3%) (5.6%) 1328 1507 (12.9%) (14.7%) 17% SE 4 reduction (2P<0.0001) 5% SE 6 reduction (NS) 13% SE 4 reduction (2P<0.001) 0.4 0.6 0.8 1.0 1.2 1.4 22

SIMVASTATIN: MAJOR VASCULAR EVENTS Vascular event SIMVASTATIN PLACEBO (10269) (10267) Rate ratio & 95% CI STATIN better PLACEBO better Major coronary Any stroke Revascularisation ANY OF ABOVE 898 1212 444 585 939 1205 2033 2585 (19.8%) (25.2%) 24% SE 3 reduction (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4 25

CARDS 26

Type 2 diabetes Males or females 40-75 years of age CARDS Eligibility Criteria No clinical history of coronary, cerebrovascular or severe peripheral vascular disease LDL-C 4.14 mmol/l ( 160 mg/dl) TG 6.78 mmol/l ( 600 mg/dl) One of : Hypertension defined as receiving antihypertensive treatment or SBP 140 mm Hg or DBP 90 mm Hg Retinopathy Microalbuminuria or macroalbuminuria Current smoking 27

Primary Efficacy Parameters CARDS Endpoints Acute CHD death Non-fatal MI including silent MI Hospitalised unstable angina Resuscitated cardiac arrest Coronary revascularisation Stroke Major coronary events Secondary Efficacy Parameters Total mortality Any cardiovascular endpoint Lipid and lipoproteins

CARDS Patient Baseline Lipids* Total cholesterol (mmol/l) (mg/dl) Placebo Median (IQR) 5.4 (4.8-5.9) 207 (185-229) Atorvastatin Median (IQR) 5.4 (4.8-5.9) 207 (186-228) LDL-cholesterol (mmol/l) (mg/dl) 3.1 (2.6-3.6) 118 (100-137) 3.1 (2.6-3.6) 119 (100-138) HDL-cholesterol (mmol/l) (mg/dl) 1.4 (1.2-1.6) 53 (46-61) 1.3 (1.2-1.6) 52 (45-60) * Subject to final verification

Lipid Levels by Treatment 6 Total cholesterol (mmol/l) Average difference 26% 1.4 mmol/l (54mg/dL) p<0.0001 4 LDL cholesterol (mmol/l) Average difference 40% 1.2 mmol/l (46mg/dL) p<0.0001 4 2 3 2 1 0 0 0 1 2 3 4 4.5 0 1 2 3 4 4.5 Years of Study Years of Study Placebo Atorvastatin

Cumulative Hazard for Primary Endpoint Relative Risk Reduction 37% (95% CI: 17-52) Cumulative Hazard (%) 15 10 5 P=0.001 Placebo 127 events Atorvastatin 83 events Placebo Atorva 0 0 1 2 3 4 4.75 1410 1428 1351 1392 1306 1361 1022 1074 651 694 305 328 Years

Cumulative Hazard for All Cause Mortality Cumulative Hazard (%) 10 8 6 4 2 Relative Risk Reduction 27% (95%CI: -1-48) p=0.059 Placebo 82 deaths Atorvastatin 61 deaths 0 0 1 2 3 4 4.75 Years Placebo Atorva 1410 1428 1395 1418 1370 1401 1094 1110 709 730 332 351

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Ominous Octet DeFronzo RA. Diabetes. 2009;58:773-795. 38

Pro-Active Lancet 2005;366:1279-89. 39

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24% RRR 43 NEJM Feb 17, 2016 DOI: 10.1056/NEJMoa1506930

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SAVOR-TIMI-53 EXAMINE Patients with endpoint (%) T2D; HbA 1c 6.5 12.0%; 40 years + CVD; 55 (men) or 60 (women) years + CV risk factors (n=16,492) Saxagliptin (2.5 or 5 mg/day**) + standard of care Placebo + standard of care Patients with endpoint (%) T2D; HbA 1c 6.5 11.0%; ACS within 15 90 days (n=5380) Alogliptin (6.25, 12.5 or 25 mg/day*) + standard of care Placebo + standard of care Time (days) Time (months) TECOS ELIXA Patients with endpoint (%) T2D; HbA 1c 6.5 8.0%; 50 years; CVD history (n=14,671) Sitagliptin (100 or 50 mg/day***) + standard of care Placebo + standard of care T2D; HbA 1c 5.5 11.0%; ACS within 180 days (n=6068) Lixisenatide (10 or 20 µg/day ) + standard of care Placebo + standard of care ACS, acute coronary syndrome; CI, confidence interval; CV, cardiovascular; EXAMINE, Examination of Cardiovascular Outcomes: Alogliptin vs. Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome; HR, hazard ratio; MI, myocardial infarction; SAVOR TIMI-53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Time Diabetes in the Mellitus Thrombolysis trial (months) in Myocardial Infarction 53; T2D, type 2 diabetes; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin; UA, unstable angina White et al. N Engl J Med 2013;369:1327 35; Sciria et al. N Engl J Med 2013;369:1317 26; Green et al. N Engl J Med 2015;16;373:232 42; Time (months) Pfeffer et al. N Engl J Med 2015;373:2247 57 Patients with endpoint (%)

Selected CVOTs: Assessing CV benefit with antiglycemic agents EMPA-REG 1 LEADER 4 SUSTAIN-6 5 Population T2D + high CV risk T2D + high CV risk T2D Drug (Class) Empagliflozin (SGLT-2i) Liraglutide (GLP-1RA) Semaglutide (GLP-1RA) Objective Non-inferiority Non-inferiority Non-inferiority Endpoint 3-point MACE 3-point MACE 3-point MACE Results HR 0.86 HR 0.87 HR 0.74 3-point MACE: first occurrence of CV death, nonfatal MI or nonfatal stroke; MACE+: CV death, nonfatal MI, nonfatal stroke and hospitalisation for UA procedure ACS, acute coronary syndrome; CV, cardiovascular; CVOT, cardiovascular outcomes trial; GLP-1RA, glucagon-like peptide-1 receptor agonist; HR, hazard ratio; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; MACE, major adverse cardiovascular event; MI, myocardial infarction; SGLT-2i, sodium-glucose cotransporter-2 inhibitor; T2D, type 2 diabetes; UA, unstable angina 1. Zinman et al. N Engl J Med 2015;373:2117 28; 2. Green et al. N Engl J Med 2015;373:232 42; 3. Pfeffer et al. N Engl J Med 2015;373:2247 57; 4. Marso et al. N Engl J Med 2016;375:311 22; 5. Marso et al. N Engl J Med 2016;375:1834 44

CARDIOVASCULAR OUTCOME DATA FOR SGLT2 INHIBITORS Image: http://images.agoramedia.com/everydayhealth/gcms/10-amazing-facts-about-blood-vessels-722x406.jpg 48

SGLT-2 Inhibitors: Mechanism of Action (cont) Free Filtration of Solute Active Reabsorption Glucose SGLT-2 SGLT-1 Glucose Juxtoglomerular Complex Proximal Convoluted Tubules Type 2 Diabetes Loop of Henle

SGLT2 Inhibition Lowers T max, Allowing Elimination of Excess Glucose Overexpression of SGLT2 shifts T max to the right, allowing excess glucose to be reabsorbed SGLT2 inhibition shifts T max to the left, eliminating excess glucose Urinary Glucose Excretion (g/day) 125 100 75 50 25 Blockade of SGLT2 Normal T2DM SGLT2 inhibition T2DM 240 mg/dl T max 0 50 100 150 200 250 300 Plasma Glucose (mg/dl) Chao E, et al. Nature Rev Drug Discov. 2010;9:551-559; Bays H. Curr Med Res Opin. 2009;25:671-681; DeFronzo RA, et al. Diabetes Obes Metab. 2012;14:5-14; Gerich JE. Diabet Med. 2010;27:136-142; Kim Y, et al. Diabetes Metab Syndr Obes. 2012;5:313-327. 50

EMPA-REG 14% reduction of primary composite outcome: death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke 38% relative risk reduction of death from cardiovascular causes 32% relative risk reduction of death from any cause 35% relative risk reduction of hospitalization for heart failure NEJM, Nov 26 2015;373:2117-28 51

Primary Outcome Results EMPA-REG OUTCOME (EMPAGLIFLOZIN) 8 1.6% ARR 14% RRR 52

Primary Outcome Results EMPA-REG OUTCOME (EMPAGLIFLOZIN) 8 Outcome Pooled Empagliflozin (n = 4687) Placebo (n = 2333) Hazard Ratio (95% CI) Primary Composite Outcome, n (%) Death from Cardiovascular Causes, n (%) 490 (10.5) 282 (12.1) Assessment of Individual Primary Outcome Events 172 (3.7) 137 (5.9) 0.86 (0.74 to 0.99) 0.62 (0.49 to 0.77) Nonfatal Myocardial Infarction, n (%) 213 (4.5) 121 (5.2) 0.87 (0.70 to 1.09) Nonfatal Stroke, n (%) 150 (3.2) 60 (2.6) 1.24 (0.92 to 1.67) Abbreviation: CI confidence interval 53

June 14, 2016 39% reduction of incident or worsening nephropathy 44% relative risk reduction of doubling of serum creatinine 55% relative risk reduction of renal-replacement therapy 54

EMPA-REG Trial-Demonstrates Rapid Improvement in 3-Point MACE Empa 10, 25 mg or standard of care 20 15 10 5 Patients With Event, % Patients With Event, % Cumulative Incidence of the Primary Outcome a P=0.04 for superiority Hazard ratio, 0.86 (95.02% CI, 0.74 0.99) Placebo Empagliflozin 0 0 6 12 18 24 30 36 42 48 9 6 3 Cumulative Incidence of Death From CV Causes P<0.001 Hazard ratio, 0.62 (95% CI, 0.49 0.77) Death from a CV event, non-fatal MI, or stroke 14% risk reduction 38% risk reduction Placebo Empagliflozin 0 0 6 12 18 24 30 36 42 48 Patients With Event, % 7 6 5 4 3 2 1 P=0.002 Hazard ratio, 0.65 (95% CI, 0.50 0.85) Hospitalization for Heart Failure 35% risk reduction Placebo a Cumulative incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. N=7020 patients with T2DM at high risk of cardiovascular events. Empagliflozin 0 0 6 12 18 24 30 36 42 48 Month 55

Empa-Reg Renal Data Incidence of nephropathy by 39 % Warner C, et al. NEJM. DOI: 10.1056/NEJMoa1515920 56

CANVAS and CANVAS-R Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes Image: https://www.google.com/search?q=canvas&safe=off&rlz=1c1nhxl_enus702us702&source=lnms&tbm=isch&sa=x&ved=0ahukewjl6obczr7uahumvt4khzsuaakq_auicygc&biw=1364&bih=613#safe=off&tbm=isch&q=canvas+paint+clipart&imgrc=y4c-q7myhxzkjm: 57

Study Design CANVAS AND CANVAS-R (CANAGLIFLOZIN) 9 MULTICENTER, INTERNATIONAL, DOUBLE-BLIND, NON-INFERIORITY TO SUPERIORITY, PLACEBO-CONTROLLED, RANDOMIZED TRIAL Key Inclusion Criteria T2DM 7% HbA 1c 10.5% Antidiabetic medication naïve OR treated with 1 approved agent 30-years-old with symptomatic ASCVD OR 50-years-old with 2 CV risk factors egfr 30 ml/min/1.73 m 2 80% adherence during the 2-week placebo run-in period Key Exclusion Criteria T1DM Antidiabetic regimen not stable for at least 8 weeks 1 severe hypoglycemic episode 6 months prior to screening Acute ASCVD event occurring 3 months before screening egfr < 30 ml/min/1.73 m 2 58

Baseline Characteristics CANVAS AND CANVAS-R (CANAGLIFLOZIN) 9 Baseline Characteristics Canagliflozin (n = 5795) Placebo (n = 4347) Male, n (%) 3759 (64.9) 2750 (63.3) Age, years 63.2 ± 8.3 63.4 ± 8.2 Diabetes Duration, years 13.5 ± 7.7 13.7 ± 7.8 HbA 1c (%) 8.2 ± 0.9 8.2 ± 0.9 Body Mass Index (kg/m 2 ) 31.9 ± 5.9 32.0 ± 6.0 Established Cardiovascular Disease, n (%) 3756 (64.8) 2900 (66.7) egfr, MDRD (ml/min/1.73 m 2 ) 76.7 ± 20.3 76.2 ± 20.8 Median Urine Albumin-to-Creatinine Ratio (mg/g), [interquartile range] 12.4 [6.71 to 40.9] 12.1 [6.57 to 43.9] Neuropathy, n (%) 1787 (30.8) 1323 (30.4) Current Smoker, n (%) 1020 (17.6) 786 (18.1) Low-Density Lipoprotein Cholesterol (mg/dl) 88.9 ± 34.8 88.9 ± 34.8 Abbreviations: ± standard deviation; egfr estimated glomerular filtration rate; MDRD Modification of Diet in Renal Disease 59

Baseline Medications CANVAS AND CANVAS-R (CANAGLIFLOZIN) 9 Baseline Class/Medication Use Canagliflozin (n = 5795) Placebo (n = 4347) Antihypertensives, n (%) Not Available Not Available Renin-Angiotensin-Aldosterone System Inhibitors, n (%) 4645 (80.2) 3471 (79.8) Beta Blockers, n (%) 3039 (52.4) 2382 (54.8) Diuretics, n (%) 2536 (43.8) 1954 (45.0) Antilipemics, n (%) Not Available Not Available Statins, n (%) 4329 (74.7) 3270 (75.2) Ezetimibe, n (%) Not Available Not Available Antithrombotics, n (%) 4233 (73.0) 3233 (74.4) Aspirin, n (%) Not Available Not Available Antihyperglycemics, n (%) Not Available Not Available Insulin, n (%) 2890 (49.9) 2205 (50.7) Metformin, n (%) 4447 (76.7) 3378 (77.7) Sulfonylureas, n (%) 2528 (43.6) 1833 (42.2) 60

Primary Outcome Results CANVAS AND CANVAS-R (CANAGLIFLOZIN) 9 4.6* ARR 14% RRR *Events per 1000 patient years 61

Primary Outcome Results CANVAS AND CANVAS-R (CANAGLIFLOZIN) 9 Outcome Canagliflozin (n = 5795) Placebo (n = 4347) Hazard Ratio Number of Participants with an (95% CI) Event per 1000 Patient Years Primary Composite Outcome 26.9 31.5 Death from Cardiovascular Causes Assessment of Individual Primary Outcome Events 11.6 12.8 Nonfatal Myocardial Infarction 9.7 11.6 Nonfatal Stroke 7.1 8.4 Abbreviation: CI confidence interval 0.86 (0.75 to 0.97) 0.87 (0.72 to 1.06) 0.85 (0.69 to 1.05) 0.90 (0.71 to 1.15) 62

Safety Data CANVAS AND CANVAS-R (CANAGLIFLOZIN) 9 Outcome Canagliflozin* Placebo* EFFECTS HIGHEST OF CANAGLIFLOZIN LEVEL ON ATRAUMATIC LOWER Number ATRAUMATIC of Participants with an LOWER-LIMB Event per 1000 Patient Years AMPUTATIONS LIMB AMPUTATION IN THE INCANVAS KEY SUBGROUPS PROGRAM P Value Any Serious Adverse Event 104.3 120.0 0.04 Adverse Events Leading to Canagliflozin Placebo Outcome 35.5 32.8 Hazard Ratio 0.07 Discontinuation (Per 1000 Patient Years) (Per 1000 Patient Years) (95% CI) Adverse Events History of Interest of Amputation from the CANVAS Program Amputation 6.3 3.4 2.15 < 0.001 Yes 96.30 59.16 Diabetic Ketoacidosis 0.6 0.3 (1.11 to 0.14 4.19) Fracture, 1.88 No All 4.68 15.4 2.48 11.9 0.02 (1.27 to 2.78) Fracture, Low-Trauma 11.6 9.2 0.06 Genital Infections, Male History of Peripheral Vascular Disease 34.9 10.8 < 0.001 Yes Adverse 12.09 Events of Interest from CANVAS 8.16 1.39 (0.80 to 2.40) Hypoglycemia 50.0 46.4 0.20 2.34 Mycotic No Genital Infections, Female 5.20 68.8 2.41 17.5 (1.53 to < 3.58) 0.001 Volume Abbreviation: Depletion CI confidence interval 26.0 18.5 0.009 n* population size varies depending on the data set being analyzed 63

Cardiovascular Outcomes Data for Sodium-Glucose Cotransporter-2 Inhibitors Agent Empagliflozin (Jardiance) Canagliflozin (Invokana) Clinical Trial EMPA-REG 8 CANVAS/CANVAS-R 9 Study Design Intervention Patient Population Primary Composite Endpoint Primary Composite Endpoint Outcome, P vs. I DB, INT, MC, NI S, PC, R trial Empagliflozin 10 or 25 mg PO once daily 18-years-old; acute coronary event > 2 months before informed consent; T2DM (57% > 10 years duration); baseline HbA 1c : 8.1%; 99% with CV disease Death from CV causes, nonfatal MI (excluding silent MI), nonfatal stroke 12.1% vs. 10.5% [HR 0.86; 95% CI: 0.74 0.99; p < 0.001 for NI; p = 0.04 for S] DB, INT, MC, NI S, PC, R trial Canagliflozin 100 mg to 300 mg PO once daily 30-years-old with a coexisting CV condition or 50-years-old with 2 CV risk factors; T2DM (mean: 14 years); baseline HbA 1c : 8.2%; 65% with CV disease Death from CV causes, nonfatal MI (excluding silent MI), nonfatal stroke 31.5 vs. 26.9* [HR 0.86; 95% CI: 0.75 0.97; p < 0.001 for NI; p = 0.02 for S] ARR / RRR 1.6% / 13.2% 4.6* / 14.6% Number Needed to Treat 63 patients over 3.1 years * Number of participants with an event per 1000 patient years Abbreviations: ARR absolute risk reduction; CI confidence interval; CV cardiovascular; DB double-blind; HR hazard ratio; I intervention; INT international; MC multi-center; MI myocardial infarction; NI noninferiority; P placebo; PC placebo-controlled; PO by mouth; R randomized; RRR relative risk reduction; S superiority; T2DM type 2 diabetes mellitus 64

Proposed Cardioprotective Effects with SGLT2i 15 SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS PANCREATIC ADIPOSE TISSUE ALPHA CELLS LIVER FFA Ketones Glucagon Aortic Stiffness and Wall Stress Weight loss Preload Afterload Improved glycemic control Extracellular Fluid Volume Uric acid excretion NaCl/H 2 O excretion Angiotensin 1-7 AT 2 Blood pressure Systemic vascular resistance 65

Clinical Considerations SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS Advantages Disadvantages Appreciable reductions in HbA 1c Decrease in blood pressure and serum uric acid Placebo-like risk for hypoglycemia Positive cardiovascular outcomes data 8,9 Potential renal- 9,12 and heart failureprotective 13,14 effects Weight loss Amputations o Potentially unique to canagliflozin Cost Diabetic ketoacidoisis Genitourinary tract infections Increased LDL-C Polyuria Transient increase in serum creatinine Urinary tract infections leading to pyelonephritis and urosepsis Volume depletion/dizziness/hypotension Abbreviation: LDL-C low-density lipoprotein cholesterol 10. American Diabetes Association. Pharmacologic Approaches to Glycemic Treatment. Sec. 8. In Standards of Medical Care in Diabetes-2017. Diabetes Care 2017;40(Suppl. 1):S64 S74 11. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 2017 Executive Summary. Endocr Pract. 2017;23(2):207-38. Epub 2017/01/18. doi: 10.4158/ep161682.cs. PubMed PMID: 28095040. 66

Clinical Considerations SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS Patient education Polyuria Hydration Hygiene Signs and symptoms of DKA When to hold therapy 16 Patients at increased risk for amputations Glycosuria 2+ Image: http://www.nephrologynews.com/wp-content/uploads/2015/06/ts_diabetes_167164767.jpg 16. Handelsman Y, Henry RR, Bloomgarden ZT, et al. American Association of Clinical Endocrinologists and American College Of Endocrinology Position Statement on the Association of SGLT-2 Inhibitors and Diabetic Ketoacidosis. Endocr Pract. 2016;22(6):753-62. Epub 2016/04/16. doi: 10.4158/ep161292.ps. PubMed PMID: 27082665. 67

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NEJM June 13, 2016. 13% reduction of primary composite outcome: death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke 22% relative risk reduction of death from cardiovascular causes 15% relative risk reduction of death from any cause No change in relative risk reduction of hospitalization for heart failure 70

Study Design THE LEADER TRIAL (LIRAGLUTIDE) 29 MULTICENTER, INTERNATIONAL, DOUBLE-BLIND, NON-INFERIORITY TO SUPERIORITY, PLACEBO-CONTROLLED, RANDOMIZED TRIAL Key Inclusion Criteria T2DM HbA 1c 7% Antidiabetic medication naïve OR treated with 1 oral antidiabetic medication and/or long-acting, NPH or premixed insulin 50-years-old with established CVD or chronic renal failure OR 60-years-old with 1 CV risk factor Key Exclusion Criteria T1DM Use of a GLP-1 RA, DPP-4 inhibitor, pramlintide or rapid-acting insulin Family or personal history of MEN2 or medullary thyroid cancer Acute coronary or cerebrovascular event occurring 14 days before randomization 72

Primary outcomes in LEADER and EMPA-REG Timing of separation of treatment arms suggest different cardioprotective MoAs 3 Point MACE improvement not driven by glycemic efficacy! LEADER 1 EMPA-REG 2 Proportion of individuals with a MACE event (%) 20 15 10 5 0 HR: 0.87 (95% CI: 0.78;0.97) p=0.01 (superiority) Placebo Liraglutide 20 15 10 5 0 HR: 0.86 (95% CI: 0.74;0.99) p=0.04 (superiority) Placebo Empaglifozin 0 6 12 18 24 30 36 42 48 54 0 6 12 18 24 30 36 42 48 Time from randomisation (months) 3-point MACE: first occurrence of CV death, nonfatal MI or nonfatal stroke CI, confidence interval; HR, hazard ratio; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; MACE, major adverse cardiovascular event; MoA, mode of action 1. Marso et al. N Engl J Med 2016;375:311 22; 2. Zinman et al. N Engl J Med 2015;373:2117 28

Primary Outcome Results THE LEADER TRIAL (LIRAGLUTIDE) Outcome Primary Composite Outcome, n (%) Liraglutide (n = 4668) Placebo (n = 4672) 608 (13.0) 694 (14.9) Hazard Ratio (95% CI) 0.87 (0.78 to 0.97) Assessment of Individual Primary Outcome Events Death from Cardiovascular Causes, n (%) Nonfatal Myocardial Infarction, n (%) 219 (4.7) 278 (6.0) 281 (6.0) 317 (6.8) Nonfatal Stroke, n (%) 159 (3.4) 177 (3.8) 0.78 (0.66 to 0.93) 0.88 (0.75 to 1.03) 0.89 (0.72 to 1.11) Abbreviation: CI confidence interval 29. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-22. Epub 2016/06/14. doi: 10.1056/NEJMoa1603827. PubMed PMID: 27295427; PubMed Central PMCID: PMCPMC4985288. 74

GLP-1RA and SGLT-2i Proposed cardioprotective MoA Liraglutide Vasodilation Empagliflozin Proposed cardioprotective MoA 1,2 Plaque stability SGLT-2i Proposed cardioprotective MoA 3 Anti-atherosclerotic GLP-1R Reduced GLP-1RA platelet aggregation Anti-inflammatory effects Established effects Hyperglycaemia Weight Inflammation Visceral adiposity BP Endothelial function Blood flow Smooth muscle proliferation Platelet aggregation Increased glucose uptake and glucagon synthesis (adipose, muscle, liver) Decreased appetite and food intake (brain) Increased insulin secretion, decreased glucagon secretion (pancreas) Fluid reduction Hemodynamic effects Heart metabolism Glomeruli Increased Proximal glucose Established tubule effects filtration Hyperglycaemia Weight Visceral adiposity BP Distaltubule Increased urinary glucose excretion BP, blood pressure; GLP-1RA, glucagon-like peptide-1 receptor agonist; MoA, mode of action; SGLT-2i, sodium-glucose cotransporter-2 inhibitor 1. Marso N Engl J Med 2016;375:311 22; 2. Drucker. Cell Metab 2016;24:15 30; 3. Zinman et al. N Engl J Med 2015;373:2117 28

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Pending Diabetes CV Outcome Studies Schnell et al. Cardiovasc Diabetol. 2016;15:139-51. 80

Diabetes CV Outcome Studies 81

PCSK9 (Proprotein convertase subtilisin/kexin type 9) A secreted protein which targets the LDL receptor for degradation Gain of function mutations cause high LDL-C Loss of function mutations cause low LDL-C Inhibition lowers LDL-C levels Up-regulated by statin therapy 82

How is cholesterol removed from blood? LIVER Circulating LDL particles (which contain a large ApoB protein) are grabbed by an LDL receptor 83

How is cholesterol removed from blood? LIVER The entire complex is then internalized into the hepatocyte for LDL destruction 84

How is cholesterol removed from blood? Then the LDL particle is destroyed LIVER Before the LDL particle is destroyed, the LDL receptor migrates back to the hepatocyte cell surface so that it can grab more LDL molecules 85

How is cholesterol removed from blood? When PCSK9 is present, however, the LDL-C receptor gets stuck and cannot migrate back to the surface LIVER It therefore gets destroyed along with the LDL And the number of LDL-C receptors on the cell surface is depleted 86

The theory behind PCSK9 inhibitors LIVER X If PCSK9 is inhibited, the LDL-C receptor can migrate back to the cell surface And surface LDL receptors will be restored which will reduce the serum LDL-C level 87

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DOI: 10.1056/NEJMoa1615664