Causes of death in Diabetes

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2 Rates of CV events in Diabetes patients Respiratory4.2 Cancer 7.6 Diabetes 1.3 CV disease 17.3 Causes of death in Diabetes per 10,000 person-years Framingham 5 X increase In diabetes MI Stroke Heart failure

3 Onset of CV event can be sudden IVUS vh 1 year later Angina

4 Management of type 2DM: 2016 state of the art CV endpoints / death Atrial fibrillation Diastolic dysfunction Hypoglycemia/syncope Microvascular endpoints Remaining clinical challenges Prevention Eye disease prevention Diabetes vasculopathy /PVDx

5 HYPERTENSION Macrovascular events ACS Heart failure Stroke PVDx Microvascular events #1 Blindness Kidney Neuropathy All important

6 20 20 Years of life remaining Years Healthy CAD MI CHF Stroke Framingham 40 year follow up N=5070 Eur Heart J 2002; 23:

7 LAD FFR 0.85 Metformin for diabetes HbA1c 8.9 in lab

8 DEFER study: background Fractional Flow Reserve, calculated from coronary pressure measurement, is an accurate, invasive, and lesion-specific index to demonstrate or exclude whether a particular coronary stenosis can cause reversible ischemia. FFR can be determined easily, in the cath-lab, immediately prior to a planned intervention FFR based strategy for PCI in equivocal stenosis ( DEFER Study) Patients scheduled for PCI without Proof of Ischemia (n=325)

9 Patients scheduled for PCI without Proof of Ischemia (n=325) Randomization deferral of PTCA (167) performance of PTCA (158) FFR 0.75 (91) FFR < 0.75 (76) FFR < 0.75 (68) FFR 0.75 (90) No PTCA PTCA PTCA PTCA DEFER Group REFERENCE Group PERFORM Group

10 Event free survival (%) Less CV events in patients deferred with FFR >0.75 (.80) Defer Perform Reference (FFR < 0.75) p=0.52 p=0.17 p= Years of Follow-up J Am Coll Cardiol. 2007;49(21):

11 Just returned to ER with chest pain.cath 6 months ago

12 DAPT trial DOI: /CIRCULATIONAHA

13 MAYBE Diabetes N=Diabetes 8257/11648 ASA AntiP DOI: /CIRCULATIONAHA

14 DOI: /CIRCULATIONAHA

15 Diabetes patient after MI and receives DES.. Conclusions In patients with DM, continued thienopyridine beyond 1-year after coronary stenting is associated with reduced risk of MI, although this benefit is attenuated when compared with patients without DM. DOI: /CIRCULATIONAHA

16 Short look at incretins

17 Introduction 2-5% per yr SAVOR 7-8% per yr CV event rate per year EXAMINE 4.5% per yr P=NS TECOS 4.5% per yr DPP 4 inhibitors EMPA-REG SGLT2 inhibitors HbA1c? SDF1 Diastolic stiffness Platelets Reduction in CV death Reduction in heart failure Reduction in all cause mortality Safe & well tolerated

18 Age Yearly events HbA1c HT Hx CVDx SAVOR EXAMINE TECOS EMPA-REG 75

19 Cardiovascular endpoint trials in diabetes

20 What is the estimated CV event rate in 1 year for type 2 diabetes patients with ACS 1. <1% % % 4. 20% Percent Acute coronary syndrome within days, age 18 post treatment..examine Months

21 Type 2 diabetes (A1c 6.5% and 8.0%) 50 years old Preexisting vascular disease Primary Composite Cardiovascular Outcome Time to first occurrence of: Cardiovascular-related death Nonfatal myocardial infarction Nonfatal stroke Hospitalization for unstable angina Green JB et al. NEJM 2015; DOI: /NEJMoa

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23 Overview-DPPIV inhibitor trials

24 SAVOR EXAMINE-5380 TECOS Patient type CAD-stable ACS CAD stable Yearly CV events 2-3% 7-8% 4-5% Age HT 81% 83% 75-80% Statins Large % 90% 80% ACE blockers 82% 79% HbA1c Hx of HF 12.7% 27.8% 18% Hx of CAD 78% 100% 100% GFR 30-50cc % Insulin 40% 30% 23% Chilton 2015

25 Percentage % Hospitalization for Heart Failure NS 1.14 ( ) P=NS NS All 3 NS NS 1 0 Significant++ Drug Placebo SAVOR EXAMINE TECOS ALL 3 Not significant ++ (3.5% vs. 2.8%; hazard ratio, 1.27; 95% CI, 1.07 to 1.51; P = 0.007) 3-4 years Chilton 2015

26 Drugs reducing CV events in diabetes Aspirin Statins All have off target side effects Beta blockers & CCB RAAS blockers Thiazide like diuretics? Metformin? PPAR Others drugs in small studies Hypoglycemic drugs EMPA-REG

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28 CV death Heart failure All cause mortality Cardiovascular endpoint trials in diabetes

29 Blood pressure CV Benefits of BP Reduction in Type 2 Diabetes 32% reduction in diabetes related death mmhg UKPDS 38 18% reduction in risk of CV death 38% reduction in risk of CV death ADVANCE EMPA-REG UKPDS 38 ADVANCE EMPA-REG SBP reduction

30 Biomechanics of vulnerable vascular wall Thin cap Endothelial cells (dysfunction al) ROS MCP1 Vascular wall Macrophages MMPs Wall stress (BP) Stress concentrations form within the fibrotic cap due to stiffness of the cap with respect to the normal vessel wall Thin fibrous cap Necrotic core Intravascular Ultrasound Lumen Atherosclerosis Lipid/necrotic core Yellow Blood vessel wal NIRS- lipids

31 SODIUM LOSS Kidney Int Suppl 2011: S20 S27 Diabetes Care 2009; 32: Diabetes 2011; 60 (Suppl 1): A582 A643 31

32 Results-EMPA REG

33 Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 490/ / CV death 172/ / Non-fatal MI 213/ / Non-fatal stroke 150/ / (0.74, 0.99)* (0.49, 0.77) (0.70, 1.09) (0.92, 1.67) < Favours empagliflozin Favours placebo 33

34 Adjusted mean (SE) waist circumference (cm) Placebo Empagliflozin 10 mg Empagliflozin 25 mg Week Placebo Empagliflozin 10 mg Empagliflozin 25 mg

35 Percentage 0.62 ( ) < CV deaths CV mortality (MI, CVA) drives the primary endpoint 0.87 ( ) Non fatal MI Placebo Non fatal CVA Empa Hosp HF DOI: /NEJMoa EASD 2015

36 ( ) < ARR=2.2% Percentage No significant effect on MI or stroke.. Benefit not atherosclerotic related? Placebo Empa All deaths not attributed to the categories of CV death and not attributed to a non-cv cause were presumed CV deaths DOI: /NEJMoa EASD 2015

37 Immediate benefit

38 Percentage Control 4.1 Hosp for HF 2.7 Empa Hosp for HF/death Excluded stroke 0.65 ( ) P< ( ) P<0.001 BP difference 4/2 mm Hg

39 BP difference 4/2 mm Hg DOI: /NEJMoa EASD 2015

40 SGLT2 inhibitor significantly improves arterial stiffness in diabetes Measure of arterial stiffness ADA 2015 Chilton et al

41 Possible hemodynamic mechanisms

42 Increased stiffness: increased atherosclerosis the reflected wave arrives at the heart closer to systole, placing a greater load on the heart-increased work

43 ASCOT: Differing effect of statin added to -blocker-based or CCB-based therapy CHD and nonfatal MI Events/1000 patient-years P (interaction between lipid lowering and BP lowering) = NS NS P = Atenolol* Amlodipine 9.8 P < Atorvastatin (+ placebo) + Atorvastatin (10 mg) *Atenolol ( mg) ± bendroflumethiazide ( mg) Amlodipine (5 10 mg) ± perindopril (4 8 mg) Sever PS et al. Circulation. 2005; 112(suppl II):II-134. Abstract 730. Sever PS et al. AHA Scientific Sessions. Nov 2005.

44 CAFÉ in ASCOT Affects of Reduced Central Aortic Pressure Peripheral BP Primary objective: a comparison of the effects of the 2 treatment regimens on central aortic pressures derived from applanation tonometry Conduit Artery Function Evaluation (CAFÉ) trial Sphygmocor Substudy of ASCOT BPLA (n=2199) Compared central aortic pressure Amlodipine group Atenolol group Examples of peripheral (A) and corresponding derived central aortic (B) waveforms from patients of equal age treated with atenolol (solid line) or amlodipine (broken line) as monotherapy, achieving equivalent brachial blood pressures. Derived central aortic pressure Circ March7, 2006;113:000

45 Abdominal aorta This is about as normal as an adult aorta in America get CV risk factors + diabetes

46 Precath patient with diabetes 40% of individuals with PAD have no leg pain Heart Disease and Stroke Statistics 2015 Update AHA

47 Closing comments

48 1 m/s PWV-- risk increase of 15% for cardiovascular events and all-cause mortality J Am Coll Cardiol 2010; 55: Cardiovascular Diabetology 2014, 13:28

49 pulse wave velocity

50 Possible mechanisms involved in CV benefits of SGLT2 Wall stress Waist circumference / adipocytes Arterial wall stiffness Metabolic changes Glucose Lipids Insulin Leptin Other Sympathetic nervous system Endothelium Reactive oxygen species / inflammation Circadian rhythm Microvascular Chilton 2015 pending publication

51 Heart needs a diet Global risk reduction best choice

52 Cardiovascular treatment of diabetes: REDUCE CV deaths!! Safe and no significant hypoglycemia EMPAgliflozin Reduces significantly CV death Safe, no hypoglycemia or HF SAVOR EXAMINE TECOS CV reduction? No CV benefit

53 DEATH Simvastatin 1 for 5.4 years Ramipril 2 for 5 years Empagliflozin for 3 years High CV risk 5% diabetes, 26% hypertension Pre-statin era High CV risk 38% diabetes, 46% hypertension Pre-ACEi/ARB era <29% statin T2DM with high CV risk 92% hypertension >80% ACEi/ARB >75% statin S investigator. Lancet 1994; 344: ,; 2. HOPE investigator N Engl J Med 2000;342:145-53,