Macrovascular Management What s next beyond standard treatment?
Are Lifestyle Modifications Still Relevant in Diabetic Patients? Diet Omega-6 and omega-3 fatty acids have been shown to improve CVD risk factors and reduce CVD events in randomized controlled trials (RCTs) 1-6 A healthy diet greatly improves dyslipidemia and hypertension, even in obese patients who have not lost weight 7 Exercise Epidemiological studies suggest that physical activity can reduce the risk for CVD and type 2 diabetes (T2D) by up to 50% 8,9 In people with diabetes, increased physical activity was strongly inversely associated with mortality 10 Regular exercise improves insulin sensitivity and glycemic control, and has broad beneficial effects on the lipoprotein profile, including HDL-C, total cholesterol: HDL-C ratio and triglycerides, even in the absence of weight loss 11-14 A large study (42,847 men 40-75yrs without CVD at baseline) has shown that 68% of coronary events in statin-treated men would have been prevented by following a low-risk lifestyle 15 1. Schaefer EJ, et al. Curr Atheroscler Rep 2005;7:421-7. 2. Brousseau ME, et al. Curr Atheroscler Rep 2000;2:487-93. 3. Parikh P, et al. J Am Coll Cardiol 2005;45:1379-87. 4. de Lorgeril M, et al. Lancet 1994;343:1454-9. 5. Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto miocardico. Lancet 1999;354:447-55. 6. Marchioli R, et al. Circula8on 2002;105:1897-903. 7. Forsythe CE, et al. Lipids 2008;43:65-77. 8. Bassuk SS, et al. J Appl Physiol 2005;99:1193-204. 9. Jeon CY, et al. Diabetes Care 2007;30:744-52. 10. Trichopoulou A, et al. J Intern Med 2006;259:583-91. 11. DeFronzo RA, et al. Diabetes 1987;36:1379-85. 12. Sigal RJ, et al. Ann Intern Med 2007;147:357-69. 13. Kraus WE, et al. N Engl J Med 2002;347:1483-92. 14. Kodama S, et al. Arch Intern Med 2007;167:999-1008. 15. Chiuve SE, et al. Circula8on 2006;114:160-7.
Statin Therapy Fails to Completely Address Vascular Risk Elevated triglycerides (TG; > 150 mg/dl or 1.7 mmol/l) affects approx. 50% of adults with prior CVD 1 About 2/3 of statin-treated patients with CHD in the US who have controlled LDL-C have low HDL-C (< 40 mg/dl or 1 mmol/l in men; < 50 mg/dl or 1.3 mmol/l in women), despite achievement of aggressive LDL-C targets 2 (< 70 mg/dl or 1.8 mmol/l) Comparison of US data (NHANES 1976-80 vs. 1999-2006) 3 The prevalence of abnormal levels of LDL-C decreased by 7.2% While the prevalence of abnormal TC and HDL-C combined doubled, and the prevalence of abnormal TG tripled 1. Ninomiya JK, et al. Circula-on 2004;109:42-6. 2. Alsheikh- Ali AA, et al. Am J Cardiol 2007;100:1499-501. 3. Cohen JD, et al. Circula-on 2008;118:S1081-82.
Guidelines Increasingly Acknowledge the Importance of Atherogenic Dyslipidemia 2004: ATP III NCEP: Fibrates may have an adjunctive role in the treatment of patients with high TG/low HDL-C, especially in combination with statins 2005: IDF: Providing active management of the blood lipid profile (...) in addition to a statin, fenofibrate where serum TG > 2.3 mmol/l (>200 mg/dl), once LDL is optimally controlled as possible 2007: ESC: HDL-C<40 mg/dl (1.0 mmol/l) and TG >150 mg/dl (1.7 mmol/l) indicate increased risk of CVD. Fibrates cannot be recommended as 1st line treatments in T2D but may be considered in those with persistently low HDL-C. 2008: NICE: If cardiovascular risk is high, as usual in T2DM, consider adding a fibrate to a statin therapy if TG in the range of 2.3-4.5 mmol/l (200-400 mg/dl) despite the statin 2010: ADA: TG levels <150 mg/dl (1.7 mmol/l) and HDL-C >40 mg/dl (1.0 mmol/l) in men and >50 mg/dl in women are desirable. LDL-C targeted statin therapy remains the first line strategy Combination therapy with a statin and a fibrate or statin and niacin may be efficacious for treatment of all three lipid fractions.
Lipids and CVD - Guidelines Cholesterol Triglycerides HDL LDL IDL VLDL Anti Atherogenic Pro Atherogenic Lipoproteins 1) HDL-C and TG rich lipoproteins as secondary targets 1) HDL-C and TG rich lipoproteins as secondary targets
Current Approaches for Macrovascular Disease Risk Reduction Further reduction of LDL-C STATINS On Good-Optimal LDL-C levels (<100 mg/dl) Impact on HDL-C and TG: How?
Current Approaches for Macrovascular Disease Risk Reduction Further reduction of LDL-C High dose Statin or Statin+Ezetimibe STATINS On Good-Optimal LDL-C levels (<100 mg/dl) Impact on HDL-C and TG Statin+Fenofibrate Statin+Nicotinic Acid Statin+Fish oil (only effective on TG)
Macro- and Microvascular Management LDL-C lowering and Beyond LDL-C TARGET CURRENT APPROACH MACROVASCULAR DISEASE Significant reduction in CV morbi-mortality BUT Up 65 90% of CV events NOT Prevented No clear microvascular benefit MACROVASCULAR DISEASE Further reduction of CV event residual risk seen on statin therapy and optimal LDL-C levels ACCORD: Clinical benefit seen in patients with type 2 diabetes and atherogenic dyslipidemia MICROVASCULAR DISEASE Evidence of significant benefits on retinopathy and neuropathy, nephropathy Statin or statin+ezetimibe Statin+feno, statin+niacin TARGET Comprehensive HDL-C LDL-C + TG
Combination Therapy May be Necessary to Address Residual risk CARDIOMETABOLIC RISK REDUCTION Statins, ACE inhibitors-arbs, OAD EFFECTIVE Across gender, age and CVD risk groups etc Specific subgroups of patients continue to have HIGH RESIDUAL CV RISK RESIDUAL CV RISK REDUCTION INDIVIDUALIZED APPROACH (i.e. T2DM patients with low HDL, high TG Combo Statin and fenofibrate, or nicotinic acid) Zambon A. - Residual Risk Reduction Initiative 2010