Diabetes and Cardiovascular Risk Management Denise M. Kolanczyk, PharmD, BCPS-AQ Cardiology

Diabetes and Cardiovascular Risk Management Denise M. Kolanczyk, PharmD, BCPS-AQ Cardiology

Disclosures In compliance with the accrediting board policies, the American Diabetes Association requires the following disclosure to the participants: NAME OF PRESENTER: Denise M. Kolanczyk, PharmD, BCPS-AQ Cardiology

Learning Objectives Define cardiovascular risk and assess the non-modifiable and modifiable risk factors Describe the benefits of early intervention Identify methods for early identification and management of risk factors

Focus on Cardiovascular Risk A comprehensive approach to patient care Multiple disease pathways and risk factors considered to facilitate earlier intervention Early assessment and targeted intervention needed to treat and prevent all risk factors associated with cardiovascular diseases (CVD) and diabetes

Cardiovascular Disease Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality in diabetes. Acute coronary syndromes (ACSs), a history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, peripheral arterial disease presumed to be of atherosclerotic origin Common conditions coexisting with type 2 diabetes are clear risk factors for ASCVD. Hypertension and dyslipidemia Diabetes itself confers independent risk

Individualized Glycemic Targets A1C <7.0% Preprandial plasma glucose Peak postprandial plasma glucose 80-130 mg/dl <180 mg/dl More or less stringent goals may be appropriate for individual patients. American Diabetes Association. Diabetes Care. 2017:40(Suppl. 1):S48-S56.

Hypertension Goals for people with diabetes and hypertension Systolic Diastolic Blood pressure <140 mmhg <90 mmhg Goal Lower targets (<130 mmhg, <80 mmhg) may be appropriate for certain individuals if it can be achieved without undue treatment burden. American Diabetes Association. Diabetes Care. 2017:40(Suppl. 1):S75.

Lipid Management Intensify lifestyle therapy and optimize glycemic control in patients with: Triglycerides 150 mg/dl; and/or Low HDL cholesterol <40 mg/dl for men <50 mg/dl for women American Diabetes Association. Diabetes Care. 2017:40(Suppl. 1):S79.

Case Study Introduction Mrs. M is a 47-year-old music teacher. She has diabetes and a 20-pack-year smoking history. Her HDL is 35 mg/dl and her LDL is 145 mg/dl. She has tried with little success to control her cholesterol with diet, she is not physically active and continues to smoke a pack a day. Continued

Case Study (cont d) Discussion Question What are Mrs. M s cardiovascular risks factors and what would you recommend to curb her risk of ASCVD? A. Smoking and she should be enrolled in a smoking cessation program B. LDL 100 mg/dl and high intensity statin therapy C. Age, gender and presence of diabetes and she should be recommended lifestyle therapy D. A, B and C

Statin Therapy Age Risk factors Recommended statin intensity* Monitoring with lipid panel <40 years None ASCVD risk factor(s)** ASCVD None Moderate or high High Annually or as needed to monitor adherence *With lifestyle therapy **LDL 100 mg/dl, BP, smoking, chronic kidney disease, albuminuria, family history of premature ASCVD Continued American Diabetes Association. Diabetes Care. 2017:40(Suppl. 1):S86.

Statin Therapy (cont d) Age Risk factors Recommended statin intensity* Monitoring with lipid panel 40-75 years None ASCVD risk factor(s)** ASCVD ACS and LDL cholesterol 50 mg/dl (1.3 mmol/l) or history of ASCVD but cannot tolerate high-dose statins American Diabetes Association. Diabetes Care. 2017:40(Suppl. 1):S86. Moderate High High Moderate plus ezetimibe As needed to monitor adherence *With lifestyle therapy **LDL 100 mg/dl, BP, smoking, chronic kidney disease, albuminuria, Continued family history of premature ASCVD

Statin Therapy (cont d) Age Risk factors Recommended statin intensity* Monitoring with lipid panel >75 years None ASCVD risk factor(s)** ASCVD ACS and LDL cholesterol 50 mg/dl (1.3 mmol/l) or history of ASCVD but cannot tolerate high-dose statins American Diabetes Association. Diabetes Care. 2017:40(Suppl. 1):S86. Moderate Moderate to high High Moderate plus ezetimibe As needed to monitor adherence *With lifestyle therapy **LDL 100 mg/dl, BP, smoking, chronic kidney disease, albuminuria, family history of premature ASCVD

High- and Moderate-Intensity Statin Therapy High-intensity statin therapy (lowers LDL cholesterol by 50%) Atorvastatin 40-80 mg Rosuvastatin 20-40 mg Moderate-intensity statin therapy (lowers LDL cholesterol by 30 to <50%) Atorvastatin 10-20 mg Rosuvastatin 5-10 mg Simvastatin 20-40 mg Pravastatin 40-80 mg Lovastatin 40 mg Fluvastatin XL 80 mg Pitavastatin 2-4 mg Note: Once-daily dosing. XL = extended release

Impact of Diabetes on Cardiovascular Mortality Mortality per 1,000 persons 50 40 30 20 10 + + + + 0 1 2 3 Number of risk factors* Patients with diabetes Patients without diabetes * Risk factors analyzed were smoking, dyslipidemia, and hypertension Expert Committee Report. Diabetes Care 1989;12:573-579.

Observations: History of T2DM Cardiometabolic risk Insulin sensitivity Insulin secretion Associated risk factors Hypertension Dyslipidemia Atherogenesis Complications Microvascular Fasting blood glucose Euglycemia Age (years) Type 2 Diabetes ADA. Therapy for Diabetes Mellitus and Related Disorders, 5th Edition. United States, 2009.

Risk Factors Non-modifiable Age Race/ethnicity Gender Family history Modifiable Overweight/obesity Inflammation, hypercoagulation Smoking Physical inactivity Unhealthy diet Insulin resistance Abnormal lipid metabolism Hypertension

Cardiometabolic Risk Overweight/obesity Abnormal lipid metabolism Genetics Age Insulin resistance Insulin resistance syndrome Lipids BP Glucose Smoking, physical inactivity, unhealthy eating? Hypertension Cardiometabolic risk Global diabetes/cvd risk LDL ApoB HDL Triglycerides Age, race, gender, family history Inflammation, hypercoagulation ADA. Therapy for Diabetes Mellitus and Related Disorders, 5th Edition. United States, 2009.

Early Treatment and CVD Risks

Diabetes: Not Always CVD Risk Equivalent CHD equivalence threshold CHD risk Diagnosis Age ~ 8-10 years duration Sattar N. Diabetologia 2013;56:686-95.

Think-Pair-Share If Mrs. M was 52-years-old and had a father who suffered a stroke at age 65 years, how would this information alter your treatment recommendations?

Antiplatelet Agents Consider aspirin therapy (75 162 mg/day) in people not at increased risk for bleeding As a primary prevention strategy in those with T1DM or T2DM at increased cardiovascular risk Includes most men or women with diabetes age 50 years who have at least one additional major risk factor, including: - Family history of premature ASCVD (onset under age 55 in a male relative or 65 in a female relative) - Hypertension - Smoking - Dyslipidemia - Albuminuria American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2017; 40(Suppl 1):S75-S87.

Coronary Artery Disease Screening: In asymptomatic patients, routine screening for CAD isn t recommended and doesn t improve outcomes, provided ASCVD risk factors are treated. Consider investigations for CAD with: - Atypical cardiac symptoms (e.g., unexplained dyspnea, chest discomfort) - Signs or symptoms of associated vascular disease including carotid bruits, transient ischemic attack, stroke, claudication or PAD - EKG abnormalities (e.g. Q waves) American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2017; 40(Suppl 1):S75-S87.

Long-Term Effects of Intensive Glucose in Newly Dx Patients Hazard ratio Hazard ratio 1.4 1.2 1.0 0.8 0.6 0.4 1.4 1.2 1.0 0.8 0.6 0.4 Microvascular disease 1997 1999 2001 2003 2005 2007 Number of events Con: 121 155 187 205 212 222 Int: 225 277 338 378 406 429 Microvascular disease Number of events Con: 38 58 70 73 74 78 Int: 24 37 44 52 58 66 Holman RR, et al. N Engl J Med 2008;359:1577-89. Intensive (SU/Ins) vs. Conventional glucose control HR = 0.76 p = 0.001 Hazard ratio Hazard ratio 1.4 1.2 1.0 0.8 0.6 0.4 Myocardial infarction 1997 1999 2001 2003 2005 2007 Number of events Con: 186 212 239 271 296 319 Int: 387 450 513 573 636 678 Intensive (metformin) vs. Conventional glucose control HR = 0.64 1.4 All cause mortality p = 0.30 1.2 1.0 0.8 0.6 0.4 1997 1999 2001 2003 2005 2007 1997 1999 2001 2003 2005 2007 Number of events Con:89 113 136 160 183 217 Int: 50 70 86 110 123 152 HR = 0.85 p = 0.014 HR = 0.73 p = 0.002

Pre-2008 Working Hypothesis DM micro and macrovascular complications glucose is major physiologic problem in DM Therefore glucose will improve DM and micro and macrovascular risk So, 1 goal of DM therapy to glucose, regardless of mechanism True for microvascular complications and supported by T1DM data

2017 Working Hypothesis Common conditions coexisting with T2D (e.g., hypertension, dyslipidemia) are clear risk factors for ASCVD Diabetes itself confers independent risk Control individual cardiovascular risk factors to prevent/slow CVD in people with diabetes Systematically assess all patients with diabetes for cardiovascular risk factors American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2017; 40(Suppl 1):S75-S87.

Proportion with events 0.25 0.20 0.15 0.10 0.05 0.0 ACCORD All-Cause Mortality and Primary Outcome Event Curves Mortality HR = 1.22 (95% CI =1.01-1.46) p = 0.04 1.41% vs. 1.14% /yr 0 1 2 3 4 5 6 Years Adapted from: ACCORD. N Engl J Med 2008;358:2545-59. intensive 5128 4972 4803 3250 1748 523 506 5123 4971 4700 3180 1642 49 480 standard Proportion with events Intensive Standard Primary outcome (composite nonfatal MI, nonfatal stroke, CVD death) 0.25 0.20 0.15 0.10 0.05 0.0 HR = 0.90 (95% CI = 0.78-1.04) p = 0.16 2.3% vs. 2.1% /yr standard intensive 0 1 2 3 4 5 6 Years 5128 4832 4390 2839 1337 475 448 5123 4827 4262 2702 1186 440 395 Intensive Standard

CVD Risk in Type 2 Diabetes: Summary of RCTs Intensive vs less intensive glycemic control 1 ACCORD ADVANCE UKPDS VADT Cardiovascular events Individual glucose-lowering drug vs placebo (since 2008 FDA guidance) SAVOR-TIMI 53 (DPP4i - saxagliptin) 2 EXAMINE (DPP4i - alogliptin) 3 TECOS (DPP4i - sitagliptin) 4 ELIXA (GLP-1 RA - lixisenatide) 5 EMPA-REG OUTCOME (SGLT2i empagliflozin) 6 LEADER (GLP-1RA liraglutide) 7 Mortality

EMPA-REG OUTCOME and LEADER EMPA-REG OUTCOME LEADER - CV death, non-fatal MI, or non-fatal stroke CV death, non-fatal MI, or non-fatal stroke CI: confidence interval; CV: cardiovascular; HR: hazard ratio; MI: myocardial infarction. Zinman B et al. N Engl J Med 2015;373:2117-2128.

Meta-Analysis of Intensive Glucose Control Trials Pooled analysis of the UKPDS, ACCORD, ADVANCE, and VADT trials yielded a 16% overall reduction in nonfatal MI. The absolute overall risk reduction was 9 events per 1000 patients over 5 years of treatment. n = 27,802 Events/Total (n/n) Event Intensive Conventional Nonfatal MI 611/14,662 598/13,140 Fatal MI 540/14,662 Nonfatal stroke 423/14,662 437/13,140 362/13,140 Fatal stroke 88/14,662 76/13,140 PAD 409/9534 433/8017 0.5 1.0 2.0 Relative Risk (95% CI) Relative Risk Risk Difference (95% CI) (95% CI) 0.84 (0.75-0.94) 9 ( 16 to 3) 0.94 (0.75-1.18) 3 ( 10 to 4) 0.98 (0.82-1.17) 3 ( 7 to 2) 0.87 (0.63-1.20) 0 ( 2 to 1) 0.91 (0.79-1.03) 3 ( 5 to 1) In overall analysis, intensive glucose control had no significant effect on: CV mortality (relative risk 0.97 [95% CI, 0.76-1.24]) or all-cause mortality (relative risk 0.98 [95% CI, 0.84-1.15]) Kelly TN, et al. Ann Intern Med 2009;151(6):394-403.

Legacy of Bad Metabolic Memory Before entering VADT intensive treatment arm After entering VADT intensive treatment arm HbA 1c (%) 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 Generation of a bad glycemic legacy Drives risk of complications Modelling the prior history of patients recruited in VADT illustrates the drawbacks of late intervention Del Prato S, et al. Int J Clin Pract 2010;64:295 304. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Time since diagnosis (years)

Insulin Resistance

Case Study Review Mrs. M is 47 years old. She has diabetes and a 20-pack-year smoking history. Her HDL is 35 mg/dl and her LDL is 145 mg/dl. She has tried with little success to control her cholesterol with diet; she is not physically active and continues to smoke a pack a day.

Think-Pair-Share If Mrs. M had a BMI of 27 kg/m 2, how would this information alter your treatment plan?

Factors Affecting Insulin Resistance Overweight/fat distribution Age Genetic predisposition Activity level Medications Puberty Pregnancy

CHD mortality (per 1000) Insulin Resistance and CHD Mortality Paris Prospective Study 3 2 1 0 29 30-50 51-72 73-114 115 Quintiles (pmol) of fasting plasma insulin Insulin sensitive Insulin resistant p <.01 (n = 943) Fontbonne AM, Eschwège EM. Diabetes Care. 1991;14:461-9.

Multiple Factors Associated with Obesity Give Rise to Increased Risk of CVD Primary metabolic disturbance Intermediate vascular disease risk factor Insulin resistance Hypertension Intravascular pathology Clinical event Dyslipidemia Overnutrition Despres JP, Lemieux I. Nature. 2006;444:881-87. Hyperglycemia Hyperinsulinemia Inflammation Impaired fibrinolysis Endothelial dysfunction Atherosclerosis Coronary arteries Carotid arteries Cerebral arteries Aorta Peripheral arteries Hypercoagulability CVD

Waist Circumference Is Correlated with Visceral Adipose Tissue (r = 0.80) Despres JP, et al. BMJ. 2001;322:716-20.

Abdominal Obesity Is Associated with Increased Risk of Coronary Heart Disease Waist circumference is independently associated with increased age-adjusted risk of CHD, even after adjusting for BMI and other CV risk factors. Relative Risk 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Rexrode KM, et al. JAMA. 1998;280:1843-8. Rexrode KM, et al. Int J Obes (Lond). 2001;25:1047-56. p for trend =.007 (women) p for trend =.001 (men) 2.08 1.00 1.00 1.27 1.01 2.31 1.34 1.26 2.44 1 2 3 4 5 Quintiles of Waist Circumference 1.60

The Look AHEAD Trial: Study Design Patients: - 5,145 individuals with T2DM, aged 45 74 years, with BMI >25 kg/m 2 (>27 kg/m 2 if taking insulin). Treatment: - An intensive lifestyle intervention (ILI) involving group and individual meetings to achieve and maintain weight loss through decreased caloric intake and increased physical activity was compared with a diabetes support and education (DSE) condition. The Look AHEAD Research Group. Diabetes Care. 2007;30:1374-83.

The Look AHEAD Trial: Results Participants assigned to ILI lost an average 8.6% of their initial weight vs. 0.7% in DSE group. Mean fitness increased in ILI by 20.9% vs. 5.8% in DSE. A greater proportion of ILI participants had reductions in diabetes, hypertension, and lipid-lowering medicines. Mean A1C dropped from 7.3 to 6.6% in ILI vs. from 7.3% to 7.2% in DSE. Systolic and diastolic pressure, triglycerides, HDL cholesterol, and urine albumin-to-creatinine ratio improved significantly more in ILI than in DSE. The Look AHEAD Research Group. Diabetes Care. 2007;30:1374-83.

Look AHEAD: Benefits of Weight Loss Magnitude of weight loss at 1 year was strongly (p<0.0001) associated with improvements in glycemia, blood pressure, triglycerides, and HDL cholesterol, but not with LDL cholesterol. Improvement was greater with weight loss of 10-15%. Conclusions: - Even modest weight loss of 5-10% is associated with significant improvements in cardiovascular risk factors. - No impact on MI, stroke, death Wing RR, et al. Diabetes Care 2011. 34:1481-1486. Wing RR, et al. N Engl J Med 2013;369:145 154

Impact of Baseline Smoking on Myocardial Infarction in T2DM: UKPDS Hazards ratio (95% CI) Never smoked 1 Ex-smoker 1.08 (0.75-1.54) Current smoker 1.58 (1.11-2.25) Turner RC, et al. BMJ. 1998;316:823-8.

Inflammation/Hypercoagulation Proinflammatory/prothrombotic factors underlie cardiovascular risk. Inflammation is a major component of atherogenesis and other cardiovascular problems. Obesity in DM is associated with inflammation. Ross R. N Engl J Med. 1999;340:115-126. Ballantyne CH, Nambi V. Atherosclerosis suppl 2005; 6: 21-9. McLaughlin T, et al. Circulation. 2002;106:2908-12.

Summary: Cardiovascular Risk Assessing a patient s cardiovascular risk is important to prevent ASCVD and T2DM. Modifiable risk factors such as physical inactivity and smoking can be minimized. Identification of these modifiable risk factors allows for the initiation of lifestyle and pharmacologic strategies. Early detection of risk factors allows for implementation of preventive strategies. CVD risks are irreversible. Early intervention and risk management can prevent and delay progression of T2DM.

Thank You!