Cardiovascular Risk Reduction and Other Co-morbidities in Type 2 Diabetes Following this presentation, you will be able to: Describe the relationship between major CV risk factors and CVD outcomes Select therapeutic modalities available to practitioners to improve CV risk factors Recognize the implications of recent large trials on clinical decisions guiding choice and targets for blood pressure and lipid abnormalities Discuss other co-morbid/microvascular conditions seen in patients with type 2 diabetes Explain the role of pharmacologic intervention in the treatment of type 2 diabetes ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker; CV = cardiovascular; CVD = cardiovascular disease
Vascular Disease Events in Patients with Diabetes (Age 35-64): Framingham Heart Study, 30-year Follow-up Risk Ratio 10 8 Men Women Age-adjusted annual rate/1,000 9 10 (Relative to subjects without diabetes P<0.001 *P<0.05) 6 4 2 20 19 6 3* 9 11 38 30 0 CHD Stroke Intermittent claudication Diabetes is a Vascular Disease Cardiac failure Total CVD Adapted from Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease. In Ruderman N et al, eds. Oxford; 1992.
Abdominal Obesity and Increased Risk of Cardiovascular Events: HOPE Study Adjusted Relative Risk 1.4 Waist circumference (in): 1.29 Tertile 1 Tertile 2 Tertile 3 Men <37.4 37.4 40.5 >40.5 1.27 Women <34.3 34.3 38.5 >38.5 1.35 1.2 1.17 1.16 1.14 1 1 1 1 0.8 Dagenais GR, et al. Am Heart J. Jan 2005;149(1):54-60. CVD death MI All-cause deaths *Adjusted for BMI, age, smoking, sex, CVD disease, DM, HDL-cholesterol, total-c BMI = body mass index; CVD = cardiovascular disease; DM = diabetes mellitus; HDL = high-density lipoprotein cholesterol; MI = myocardial infarction
NCEP-ATP III 2001 Guidelines: Clinical Identification of the Metabolic Syndrome 3 of the following are needed for diagnosis Risk Factor Abdominal obesity -men -women Triglycerides HDL -men -women Blood pressure Fasting glucose Defining Level Waist circumference >102 cm (>40 in) >88 cm (>35 in) 150 mg/dl <40 mg/dl <50 mg/dl 130/ 85 mmhg 110 mg/dl 100 mg/dl HDL = high density lipoprotein cholesterol; NCEP ATP III = Third Nation Cholesterol Education Program Adult Treatment Panel NCEP- Expert ATP III Report, JAMA. 2001;285(19):2486-2497
Metabolic Syndrome and Risk of Incident Cardiovascular Events and Death: A Systematic Review and Meta-Analysis of Longitudinal Studies 37 eligible studies including 43 cohorts (inception 1971 to 1997; N=172,573), utilizing either the NCEP, WHO, or modified versions Outcome Studies (N) RR 95% CI CV event 11 2.18 1.63-2.93 CHD event 18 1.65 1.37-1.99 CV death 10 1.91 1.47-2.49 CHD death 7 1.60 1.28-2.01 Death 12 1.60 1.37-1.92 CHD = coronary heart disease; CI = confidence interval; CV = cardiovascular; NCEP = National Cholesterol Education Program; RR = relative risk; WHO = World Heath Organization 0.5 1 2 5 Decreased risk Increased risk Gami AS, et al. J Amer Coll Cardiology. 2007;49(4):403-414
Benefits of Aggressive LDL-C Lowering in Diabetes (and Residual Risk) Primary Event Rate, % Treatment Control Aggressive Lipid-lowering Better Aggressive Lipid-lowering Worse P Difference in LDL-C, mg/dl TNT Diabetes, CHD 13.8 17.9 0.75.026 22* ASCOT-LLA Diabetes, HTN 9.2 11.9 0.77.036 35 CARDS Diabetes, no CVD 5.8 9.0 0.63 0.73.001 46 HPS All diabetes 9.4 12.6 0.67 <.0001 39 Diabetes, no CVD 9.3 13.5 0.5 0.7 0.9 1 1.7.0003 39 Relative Risk *Atorvastatin 10 vs 80 mg/day Statin vs placebo Shepherd J, et al. Diabetes Care.2006;9:1220-1226; Sever PS,et al. Diabetes Care. 2005;28:1151-1157; Collins R, et al. Lancet. 2003;361:2005-2016; Colhoun HM, et al. Lancet. 2004;364:685-696. 7
Collaborative Atorvastatin Diabetes Study (CARDS) Consistent Statin Effects on Primary Endpoint Components n (% randomized) Event Placebo Atorvastatin Risk reduction (95% CI) Primary outcome 127 (9.0) 83 (5.8) 37% (17 52) p = 0.001 Acute coronary events Coronary revascularization 77 (5.5) 51 (3.6) 36% (9 55) 34 (2.4) 24 (1.7) 31% ( 16 59) Stroke 39 (2.8) 21 (1.5) 48% (11 69) 0.2 0.4 0.6 0.8 1.0 1.2 Favors Atorvastatin Hazard ratio Favors Placebo Colhoun HM, et al, for CARDS Investigators. Lancet. 2004;364:685-696.
PROVE-IT TIMI 22, Primary Endpoint All-cause Death or Major Cardiovascular Events 30 25 Pravastatin 40mg (26.3%) 16% RRR (P = 0.005) % with event 20 15 10 Atorvastatin 80mg (22.4%) Residual Risk 5 0 0 3 6 9 12 15 18 21 24 27 30 Months of follow-up Cannon CP, Braunwald E, McCabe CH, et al. N Engl J Med 2004;350:15
AACE 2013 Dyslipidemia Management Algorithm When Atherogenic Markers not at goal: To Lower LDL-C: To Lower Non-HDL-C, TG: Intensify statin and/or, add ezetimibe and/or colesevelam and/or niacin Intensify statin and/or Rx-grade omega-3 ethyl esters and/or fibrates and/or niacin To Lower Apo B, LDL-P: Intensify statin and/or add ezetimibe and/or colesevelam Apo B = apolipoprotein B; HDL-C = high density lipoprotein cholesterol; LDL-C = low density lipoprotein cholesterol; TG = triglyceride Garber AJ, Chair, Task Force, AACE Comprehensive Diabetes Management Algorithm 2013 Consensus Statement, Endocrine Practice. 2013;19(suppl 2):1-48.
Proprotein convertase subtilisin-kexitin 9 PCSK9 is widely distributed in Liver, Intestine, kidneys and CNS Regulates plasma LDL-C levels through increased degradation of LDL receptor proteins Overexpression of PCSK9 results in increased circulating levels of LDL-C Single point mutations associated with increased proprotein convertase function may result in familial autosomal dominant hyperlipidemia and increased risk of early MI and stroke New Eng J Med 2011;365:2507-2518
PCSK9 Inhibitors Reduce LDL-C levels Have been shown to reduce Cardiovascular endpoints New Eng J Med 2015;372:1489-1499 New Eng J Med 2015;372 1500-1509
PCSK9 inhibitors Indications Adjunct to diet and maximally tolerated statin therapy in adults Heterozygous familial hypercholesterolemia Clinical atherosclerotic CV disease who require additional lowering of LDL-C Side effects Injection site reactions Myalgias Neurocognitive (confusion,impaired memory) Dosage :Alirocumab (Praluent ) R Evolucumab (Repatha) R 75 mg/2 weeks or 150 mg / 2 weeks 140 mg /2 weeks or 420mg/month
Residual Cardiovascular Risk, Even After Treatment With Statins Despite high-dose statin therapy, there is high residual risk in patients with diabetes, low HDL, elevated triglycerides, and other risk factors Therefore, these other risk factors should be addressed HDL = high density lipoprotein cholesterol Davidson, M, AACE 2011, presentation; Garber AJ, Chair, Task Force, AACE Comprehensive Diabetes Management Algorithm 2013 Consensus Statement, Endocrine Practice. 2013;19(suppl 2):1-48
HDL s Complexity: Anti-Atherogenic Actions Reverse Cholesterol Transport Cellular Cholesterol Efflux Anti-infectious Anti-inflammatory Anti-thrombotic HDL-C Apo A-I / II Anti-oxidative Endothelial Repair Anti-apoptotic Vasodilatory Chapman MJ, et al. Curr Med Res Opin. 2004;20:1253-1268. Assmann G, et al. Annu Rev Med. 2003;53:321-341. 15
Niacin Despite high-dose statin therapy, there is high residual risk in patients with diabetes, low HDL, elevated triglycerides, and other risk factors Although niacin, or nicotinic acid (vitamin B 3 ) has been shown to increase HDL cholesterol, the results of recent large clinical trials have shown little cardiovascular protection for patients with diabetes Outcomes indicate that while low HDL is associated with poor outcomes, increasing HDL does not appear to be protective for major vascular events. HDL = high density lipoprotein cholesterol Michos ED. J Am Coll Cardiol. 2012;59(23):2058-2064.; HPS2-THRIVE Collaborative Group. N Engl J Med 2014; 371:203-212. Lloyd- Jones D. N Engl J Med 2014; 371:271-273.
Risk of CHD by Triglyceride Level 3 The Framingham Heart Study 2.5 Relative 2 CHD Risk 1.5 Men N = 5127 Women 1 0.5 CHD = coronary heart disease 0 50 100 150 200 250 300 350 400 Triglyceride Level, mg/dl Castelli WP. Am J Cardiol. 1992;70:3H-9H.
ACCORD-LIPID: Primary Outcomes Possible Benefit Confined to the High Triglycerides/Low HDL-C Subgroup Major fatal or non-fatal CV events (%) Analysis of fenofibrate benefit in pre-specified high TG/low HDL subgroup vs. all others 20 18 16 14 12 10 8 6 4 2 0 17.32 79 456 31% RRR, adjusted P = 0.057 12.37 10.11 10.11 Simva Simva + Fen Simva Simva + Feno High triglycerides ( 204 mg/dl) and low HDL ( 34 mg/dl) 17.6% (n=941) of entire cohort ACCORD Study Group, NEJM. 2010; 362:1563-1574 60 485 High TG/low HDL-C subgroup had 70% higher event rate 231 2284 No benefit for less than moderate dyslipidemia All others in entire cohort 82.4% (n=4548) of entire cohort CV = cardiovascular; Fen = fenofibrate; HDL-C = high-density lipoprotein cholesterol; Simva = simvastatin; TG = triglyceride 229 2264
Algorithm for Managing Severe Hypertriglyceridemia (SH) Acute management SH +/- pancreatitis Dietary measures: NPO; I.V. fluids; Insulin, if diabetes Chronic management SH Dietary measures: Low carbohydrate, low-fat <20 g LC-FA/day, MCT, abstinence from alcohol If TG not at desirable level Add Rx-grade Omega-3 fatty acids Add fibrates to OM-3 fatty acids Add niacin to fibrates and OM-3 fatty acids Consider medium chain TG If poorly responsive, apheresis (plasmapheresis) until TG <1000 mg/dl When TGs are lowered to <500 mg/dl, secondary targets become non-hdl-c, LDL-C, LDL-P; begin statin therapy Modified from Ewald N, Kloer H-U. Clin Res Cardiol Suppl. 2012;7:31-35. HDL-C = high density lipoprotein cholesterol; I.V. = intravenous; LC-FA = long chain fatty acids LDL-C = low density lipoprotein cholesterol; LDL P = low density lipoprotein particles; MCT = medium-chain triglycerides; NPO = nothing by mouth; TG = triglyceride
2013 AACE Blood Pressure Management Algorithm Hypertension ACEi or ARB Goal: Systolic ~130 mmhg Diastolic ~80 mmhg For initial blood pressure >150/100 ACEi Or ARB + Thiazide Calcium Channel Blocker Beta-blocker If not at goal (2-3 months) If not at goal (2-3 months) Add next agent from the above group, repeat If not at goal (2-3 months) Additional choices (alpha-blockers, central agents, vasodilators, spironolactone) Achievement of target blood pressure is critical Add beta-blocker or calcium channel blocker or thiazide diuretic Garber AJ, Chair, Task Force, AACE Comprehensive Diabetes Management Algorithm 2013 Consensus Statement, Endocrine Practice. 2013;19(suppl 2):1-48
Risk Reduction (%) Effect of Intensive BP Lowering on Risk of Micro- and Macrovascular Complications: UKPDS 0 Myocardial infarction Any diabetesrelated endpoint Diabetesrelated death Retinopathy Renal failure Stroke Vision deterioration Heart failure -10-20 -30-40 -50-60 -21-24 -32-34 -42-44 Benefits of 144/82 mm/hg vs 154/87 mm/hg -47-56 UKPDS Group. UKPDS 38. BMJ. 1998;317:703-713. 21
Guideline Recommendations for Uncomplicated and Complicated Hypertension Type of hypertension BP goal (mmhg) Uncomplicated <140/90 Complicated Diabetes mellitus <130/80 Kidney disease <130/80* Other high risk (stroke, MI) <130/80 *Lower if proteinuria is >1 g/day. Chobanian et al. Hypertension. 2003;42:1206 52.; Torre JJ, et al. Endocr Pract. 2006;12:193-222. Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.; Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. 22
Beta-Blockers in Diabetic Patients: Post-MI 2024-patient study (340 had diabetes [DM] and 281 survived hospitalization for acute MI); of the 127 patients with diabetes taking -blockers, 80% received propranolol and 20% received other -blockers 100 No DM; -blockers 90 Survival (%) DM; -blockers No DM; No -blockers 80 DM; No -blockers 0 0 60 120 180 240 300 360 Time (days) Kjekshus J et al. Eur Heart J. 1990;11:43-50.
Beta-Blocker Recommendations for T2DM Recommend the use of beta-blocker in type 2 diabetes patients with heart failure and/or history of myocardial infarction Beta-blockers may be used safely in patients using blood pressure control Early trials indicated that glucose metabolism may be adversely affected by some beta-blockers; however, newer agents such bisoprolol and carvedilol have not been shown to have this effect Beta-blockers may mask some signs and symptoms of hypoglycemia in patients with longstanding diabetes, particularly patients on insulin Kjekshus J et al. Eur Heart J. 1990;11:43-50; Erdmann E. Eur Heart J Suppl (2009) 11 (suppl A): A21-A25; Wai B, Kearney LG, Hare DL et al. Cardiovascular Diabetology 2012, 11:14
Glucose Control and CHD Events Ray KK, et al. Lancet. 2009;373:1765-1772. 25
CV Outcome Cumulative incidence Proportion With MI Intensive Glycemic Control and Long-term Macrovascular Risk in Younger Patients With Shorter Duration of Disease DCCT T1DM, 5-6 years duration (N=1441) UKPDS T2DM, newly diagnosed (N=4209) 0.12 42% risk reduction P=0.02 1.0 15% risk reduction P=0.01 0.10 0.8 0.08 0.06 0.04 0.02 Randomized treatment Conventional Intensive 0.6 0.4 0.2 Randomized treatment Conventional Intensive 0.00 0 5 10 15 20 Years No. at Risk Conventional 714 688 618 92 Intensive 705 683 629 113 0.0 0 5 10 15 20 25 Years 1138 1013 857 578 221 20 2729 2488 2097 1459 577 66 CV, cardiovascular; DCCT, Diabetes Control and Complications Trial; MI, myocardial infarction; UKPDS, United Kingdom Prospective Diabetes Study. Nathan DM, et al. N Engl 26 J Med. 2005;353:2643-2653. Holman RR, et al. N Engl J Med. 2008;359:1577-1589.
The Prevalence of U.S. Adults with Diabetes Achieving A1C, Blood Pressure, and LDL-C Goals: 1998 2010: NHANES Percent (%) 1988-1994 1999-2002 2003-2006 2007-2010 60 50 40 43.144.1 57 52.5 51.1 44.2 38.1 33.2 35.3 48 56.2 30 20 10 9.9 4.5 7 12 18.8 0 A1C<7.0% BP<130/80 LDL<100mg/dL All 3 at Goal Still a long way to go A1C = glycated hemoglobin; BP = blood pressure; LDL/LDL-C = low density lipoprotein cholesterol Casagrande SS, Fradkin JE, Saydah SH, Rust KF, Cowie CC. Diabetes Care 2013;36:2271-2279
Treating the ABCs Reduces Diabetic Complications Strategy Complication Reduction of Complication Blood glucose control Myocardial infarction 16% 1 Blood pressure control Lipid control Cardiovascular disease Heart failure Stroke Diabetes-related deaths Coronary heart disease mortality Major coronary heart disease event Any atherosclerotic event Cerebrovascular disease event 51% 2 56% 3 44% 3 32% 3 35% 4 55% 5 37% 5 53% 4 1 UKPDS Study Group (UKPDS 33). Lancet. 1998;352:837-853. 4 Grover SA, et al. Circulation. 2000;102:722-727. 2 Hansson L, et al. Lancet. 1998;351:1755-1762. 5 Pyŏrälä K, et al. Diabetes Care. 1997;20:614-620. 3 UKPDS Study Group (UKPDS 38). BMJ. 1998;317:703-713.
ADA Recommendations for Aspirin Therapy in Diabetes Aspirin 75-162 mg/day recommended as Secondary prevention in patients with diabetes and history of CVD Primary prevention for patients with diabetes and 10- year CVD risk >10% Do not use for primary prevention in patients with lower CVD risk because potential adverse effects (eg, bleeding) are likely to offset potential benefits Use clopidogrel 75 mg/day for those with CVD and documented aspirin allergy Combination therapy with aspirin and clopidogrel is reasonable for 1 year after ACS ADA. Diabetes Care.2011;34:S31. 29
Summary Major CV risk factors and CVD outcomes Therapeutic modalities available to clinicians to improve CV risk factors Implications of recent large trials on clinical decisions guiding choice and targets for blood pressure and lipid abnormalities Additional co-morbid/microvascular conditions seen in patients with T2DM Role of pharmacologic intervention in the treatment of type 2 diabetes