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Outline M ANAGEMENT OF C ARDIOVASCULAR R ISK IN D IABETES Review the cardiovascular risk associated with diabetes Discuss current medical therapies and optimal approach to Have we turned the corner? reducing CVD risk in patients with

  1. Outline M ANAGEMENT OF C ARDIOVASCULAR R ISK IN D IABETES • Review the cardiovascular risk associated with diabetes • Discuss current medical therapies and optimal approach to Have we turned the corner? reducing CVD risk in patients with diabetes • Introduce newer diabetes medications and their potential 33rd Annual Advances in Heart Disease impact on improving residual CVD risk December 16, 2016 Binh An P. Phan, MD Associate Professor of Medicine Division of Cardiology San Francisco General Hospital University of California, San Francisco Disclosures: none Diabetes in the Pima Native Americans Incidence of CHD death in Pima vs. Framingham Diabetic 16.0 per 1000 person-years at risk 15 Non-diabetic Rates of CHD Deaths 10.9 10 11.6 40 % with diabetes 5.7 5 5.0 20 2.6 0 0 0 Pima Framingham Pima Framingham 0 White Black Mexican Pima Men Women American Harris et al. Diabetes. 1987. Nelson et al. Circulation 1990. 1

  2. MRFIT: CV risk associated with diabetes What is the CVD risk associated Non-diabetic Age-adjusted CV death rate per Diabetic with diabetes? 126 N=347,978 Avg f/u 12 yrs 10,000 pt-years 90 Diabetes CVD 58 48 30 24 13 7 None 1 only 2 only All 3 Number of CV risk factors (cholesterol > 200mg/dL, smoking, SBP > 120 mmHg) Stamler et al. Diabetes Care 1993. East West Study: diabetes as CV equivalent to CAD British Heart Study: diabetes duration and CHD risk Non-diabetic, n=1373 Diabetic, n=1059 DM with no MI No DM or MI with no DM MI 45.0% Late onset Early onset (n=358) (n=3197) 7-year Incidence of (n=307) (n=107) CVD Rate MI (%) per 1,000 13.5 22.7 28.5 34.5 person-yrs 20.2% 18.8% Age- adjusted HR 1 (ref) 1.59 (1.19-2.12) 2.61 (1.73-3.96) 2.35 (1.88-2.95) (95% CI) 3.5% Early onset: dx < 60 yrs-old, avg diabetes duration 16.7 yrs no MI + MI No MI +MI Late onset: dx ≥ 60 yrs-old; avg diabetes duration 4.9 yrs Haffner et al. NEJM 1998. Wannamethee et al. Arch Intern Med 2011. 2

  3. British Heart Study: diabetes duration and CHD risk Strong Heart Study: risk factors and CHD risk in DM CVD events 10-year incidence of CHD (%) 66.9 Non-fatal CHD 60 All-cause mortality Fatal CHD 60 per 1,000 patient years ND=non-diabetic DM=diabetes mellitus Event rate 44.4 40 40 38.0 36.6 20.3 20 19.7 20 ND DM DM DM DM ND DM 0-1 2-7 ≥ 8 1-2 RF 3-4 RF 5-6 RF 7-9 RF No prior CHD CHD Duration of diabetes, years RF: sex, LDL >100 mg/dl, albuminuria (>300 mg/g creatinine), HTN, HDL <40 mg/dl, TG >150 mg/dl, smoking, fibrinogen >352 mg/dl, and DM>20 years. Wannamethee et al. Arch Intern Med 2011. Howard et al. Diabetes Care 2006. Relationship of fasting blood glucose and CV risk Relationship of HbA1c and CV risk without DM Fasting blood glucose CVD Risk HR (95% CI) Study No. RR for CHD per 1% HbA1c higher Known diabetes > 132 mg/dl 2.36 (2.02-2.76) EPIC-Norfolk 529 < 132 mg/dl 1.61 (1.42-1.82) Rancho Bernardo 329 Wang et al. 241 No known diabetes ARIC 235 > 132 mg/dl 1.78 (1.56-2.03) CHS 96 109.8-132 mg/dl 1.17 (1.08-1.26) FOS 76 100.8-109.7 mg/dl 1.11 (1.04-1.18) BWHHS 60 70.2-100.7 mg/dl 1.00 (0.95-1.06) NWAHS 42 <70.2 mg/dl 1.07 (0.97-1.18) AUSDiab 31 1.20 (1.10-1.31) Overall 1639 0.8 1 2 4 0.5 0.75 1 1.5 2 Emerging Risk Factors Collaboration. Lancet 2010. Sarwar et al. Plos Med 2010. 3

  4. CV risk from blood glucose, cholesterol, and SBP Impact of DM duration and risk factors on CHD risk 4.0 CHD equivalence threshold 3.0 HR (95% CI) DM 2.0 CHD risk diagnosis Additive CHD risk based on DM duration and risk factors 1.0 70 110 150 100 190 260 120 140 160 10 years DM duration Mean fasting blood Mean cholesterol Mean systolic blood glucose (mg/dl) (mg/dl) pressure (mmHg) Age Emerging Risk Factors Collaboration. Lancet 2010. UKPDS: Intensive glucose lowering on risk reduction How do you lower CVD risk Microvascular 25% p=0.01 associated with diabetes? disease Retinopathy 21% p=0.015 Diabetes Duration HTN Lipids Smoking CVD Albuminuria 33% p<0.001 MI 16% p=0.052 Mortality 6% p=0.44 Risk Reduction (%) Mean achieved A1c: 7.0% (Intensive rx) vs. 7.9% (conventional rx) UK Prospective Diabetes Study Group. Lancet 1998. 4

  5. UKPDS post-study: 10 year follow up, legacy effect DCCT follow-up: long term intensive glucose control Microvascular 24% p=0.001 disease DCCT Trial EDIC observation MI 15% P=0.014 Mortality 13% P=0.007 Risk Reduction (%) 9 Follow-up Conventional HbA1c % Median 8 7 Intensive 6 Mean achieved A1c: 7.0% (Intensive rx) vs. 9% (conventional rx) 1977 1997 2007 Holman et al. NEJM 2008. DCCT/EDIC Research Group. NEJM 2005. Meta-analysis of intensive glucose rx on CHD events Syst-Eur: HTN rx reduces CV events in diabetes Trial OR (95% CI) Overall CVD All CV Fatal, non- Fatal, non- mortality mortality events fatal CVA fatal CVD HbA1c events Standard Intensive UKPDS 7.9% 7.0% 0.75 (0.54-1.04) - 10 Reduction in Event Rate 8% PROactive 7.6% 7.0% 0.81 (0.65-1.00) 16% for Active Rx (%) ADVANCE 7.0% 6.4% 0.92 (0.78-1.07) 36% 22% VADT 8.4% 6.9% 0.85 (0.62-1.17) 25% - 30 ACCORD 7.5% 6.4% 0.82 (0.68-0.99) 41% Overall 0.85 (0.77-0.93) - 50 57% 0.6 0.8 1 62% Intensive rx better Standard rx better 69% - 70 Diabetic, n=492 70% Non-diabetic Lowering HbA1c by 0.9% associated with 15% RR reduction in CHD events. Kausik et al. Lancet 2009. Tuomilehto et al. NEJM 1999. 5

  6. Benefit of intensive LDL-C lowering in diabetes CV benefits of different interventions in diabetics Primary event rate (%) Aggressive Aggressive Difference in Per Per Per lipid-lowering lipid-lowering LDL-C Treatment Control better worse P (mg/dL) 1 mmo/L 0.9% lower 4 mmHg lower SBP lower LDL-C HbA1C TNT 0.75 Diabetes, CHD 13.8 17.9 0.026 22* - 2 ASCOT-LLA 0.77 Diabetes, HTN 9.2 11.9 0.036 35 † CV events - 4 prevented per CARDS 0.63 Diabetes, no CVD 5.8 9.0 0.001 46 † 200 DM patients - 6 treated for 5 yrs HPS 0.73 39 † - 8 All diabetes 9.4 12.6 <0.0001 0.67 39 † Diabetes, no CVD 9.3 13.5 0.0003 - 12 0.5 0.7 0.9 1 1.7 CV relative risk *Atorvastatin 10 vs 80 mg/day † Statin vs placebo Sheperd et al. Diabetes Care 2005. Sever et al. Diabetes Care 2005. HPS. Lancet 2003. Sattar et al. Diabetologia 2013. Steno-2: Multi-factorial intensive rx in diabetes Diabetes drug development 60 GLP-1 agonists Intensive Rx • BP < 130/80 SGLT2 inhibitors 50 Conventional • A1c < 6.5% N = 80 DPP-4 inhibitors Primary • TC < 175 mg/dL 40 53% RRR composite • TG < 150 mg/dL P = 0.01 TZD outcome* 30 (%) Basal insulin 20 Rapid-acting insulin Intensive N = 80 10 Alpha glucosidase inhibitor 0 Metformin Insulin Sulfonylurea 0 12 24 36 48 60 72 84 96 Follow-up (months) 1920 1960 1970 1980 1990 2000 2010 *CV death, MI, stroke, CABG/PCI, amputation, PAD surgery FDA requires CV outcomes data Gaede et al. NEJM 2003. DeFronzo et al. Curr Med Res Opin 2008. 6

  7. Mechanisms of action of traditional diabetes drugs Actions of GLP-1 agonists and SGLT-2 inhibitors α-Glucosidase inhibitors Thiazolidinediones (TZD) Action GLP-1 agonist SGLT-2 inhibitor Intestine: ↓glucose Muscle and adipose absorption Primary Stimulates insulin secretion, Inhibits sodium–glucose tissue: ↓insulin resistance mechanism inhibits glucagon secretion, cotransporter 2 (SGLT2) ↑glucose uptake decreases glucose inhibitor, which prevents production, increase insulin renal glucose resorption Biguanides sensitivity Blood Cardiovascular Increase cardiac contractility Lowers blood pressure by glucose and cardiac output inhibiting sodium Liver: ↓hepatic reabsorption glucose output ↑glucose uptake Metabolic Causes weight loss through Induces weight loss from suppression of appetite and altered energy balance reduced gastric emptying with glucose wasting Pancreas: Sulfonylureas ↑insulin secretion GLP-1: glucagon-like protein-1, SGLT-2: sodium-glucose co-transporter-2 Krentz et al. Drugs 2005. DeFronzo et al. Curr Med Res Opin 2008. LEADER trial: GLP-1 in high CVD risk diabetics LEADER trial: GLP-1 in high CVD risk diabetics Liraglutide Placebo (N=4,668) (N=4,672) Baseline Male sex 3011 (64.5) 2992 (64.0) 9,340 diabetics at high ASCVD risk Age, yrs 64.2 ± 7.2 64.4 ± 7.2 • > 50 yo with ASCVD, CKD, HF • Diabetes duration, yrs 12.8 ± 8.0 12.9 ± 8.1 ≥ 60 yo with +1 CVD risk factor HbA1c, % 8.7 ± 1.6 8.7 ± 1.5 Liraglutide Placebo Established CVD (age>50) 3831 (82.1) 3767 (80.6) Median-follow-up 3.8 years CVD risk factors (age ≥ 60) 837 (17.9) 905 (19.4) Primary endpoint: first occurence of CV death, non-fatal MI, non-fatal CVA Marso et al. NEJM 2016. Marso et al. NEJM 2016. 7

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