Thomas Dayspring, MD, FACP, FNLA, NCMP Director of Cardiovascular Education

1. American Diabetes Association Clinical 2012 Practice Recommendations Dyslipidemia/Lipid Management Thomas Dayspring, MD, FACP, FNLA, NCMP Directorof Cardiovascular Education The Foundation for Health Improvement and Technology Richmond, Virginia

2. American Diabetes Association Dyslipidemia/Lipid Management 2012 • Measure fasting lipid profile annually • In adults with low risk lipid values • LDL-C < 100 mg/dL, HDL-C > 50 mg/dL and TG < 150 mg/dL, lipid assessments may be repeated every two years DiabetesCare2012;35(suppl1):S30-34

3. American Diabetes Association Dyslipidemia/Lipid Management 2012 Treatment Recommendations • Lifestyle modification focusing on reduction of saturated fat, trans fat and cholesterol intake • Increase of n-3 fatty acids • Increase viscous fiber, and plant stanols/sterols • Weight loss (if indicated) • Increased physical activity DiabetesCare2012;35(suppl1):S30-34

4. American Diabetes Association Dyslipidemia/Lipid Management 2010 Treatment Recommendations • Statin Therapy should be added to lifestyle regardless of baseline lipid levels for diabetics: • With overt CVD • Without overt CVD who are over the age of 40 and have one or more CVD risk factors • For lower risk patients (without over CVD < age 40), statins should be considered if LDL-C is > 100 mg/dL or in those with multiple CVD risk factors DiabetesCare2012;35(suppl1):S30-34

5. American Diabetes Association Dyslipidemia/Lipid Management 2012 Treatment Recommendations • In individuals with overt CVD, a lower LDL-C goal of < 70 mg/dL using a high dose of statin is an option • If drug-treated patients do not reach goal on maximally tolerated statin a reduction of ~30-40% from baseline is an alternative goal • TG levels < 150 mg/dL and HDL-C > 40 mg/dL in men and 50 mg/dL in women are desirable • However LDL-C targeted statin therapy remains the preferred strategy DiabetesCare2012;35(suppl1):S30-34

6. American Diabetes Association Dyslipidemia/Lipid Management 2012 Treatment Recommendations • If targets are not reached on maximally tolerated doses of statins, combination therapy using statins and other lipid-lowering agents may be considered to achieve lipid targets • These have not been evaluated in clinical outcome studies for CVD outcomes or safety • Statin therapy is contraindicated in pregnancy DiabetesCare2012;35(suppl1):S30-34

7. American Diabetes Association Dyslipidemia/Lipid Management 2012 • Low levels of HDL-C, often associated with high TG levels are the most prevalent pattern of dyslipidemia in T2DM • The evidence base for drugs that target these lipid fractions is significantly less robust than that for statin therapy • Nicotinic acid has been shown to reduce outcomes although the study was done in nondiabetics • Gemfibrozil has been shown to reduce events in subjects without diabetes and in the diabetic subgroup in one of the larger trials • In a large trial specific to diabetics, fenofibrate failed to reduce overall CVD events DiabetesCare2012;35(suppl1):S30-34

8. American Diabetes Association Dyslipidemia/Lipid Management 2012 • For most patients with diabetes, the first priority of dyslipidemia therapy (unless severe hypertriglyceridemia is the immediate issue) is to lower LDL cholesterol to a target goal of ,100mg/dL. • Lifestyle intervention, including nutrition therapy, increased physical activity, weight loss, and smoking cessation, may allow some patients to reach lipid goals. • Glycemic control can also beneficially modify plasma lipid levels, particularly in patients with very high triglycerides and poor glycemic control. DiabetesCare2012;35(suppl1):S30-34

9. American Diabetes Association Dyslipidemia/Lipid Management 2012 • Very little clinical trial evidence exists for T2DM under the age of 40 or for T1DM patients of any age • In the Heart Protection trial, the subgroup of 600 patients with T1DM (lower age limit 40) had a proportionately similar risk reduction in risk as those with T2DM • Although the data are not definitive, consideration should be given to similar lipid-lowering goals in T1DM as those in T2DM, particularly if they have other CVD risk factors DiabetesCare2012;35(suppl1):S30-34

10. American Diabetes Association Dyslipidemia/Lipid Management 2012 • Recent clinical trials in high-risk patients, such as those with acute coronary syndromes or previous cardiovascular events, have demonstrated that more aggressive therapy with high doses of statins to achieve an LDL cholesterol of,70 mg/dL led to a significant reduction in further events. • Therefore, a reduction in LDL cholesterol to a goal of ,70 mg/dL is an option in very-high risk diabetic patients with overt CVD DiabetesCare2012;35(suppl1):S30-34

11. American Diabetes Association Dyslipidemia/Lipid Management 2012 • In individual patients, LDL-C lowering with statins is highly variable • Reduction of CVD events with statins correlates very closely with LDL-C lowering. • When maximally tolerated doses of statins fail to significantly lower LDL-C (<30% from baseline) the primary aim of combination therapy should be to achieve additional LDL-C lowering • Niacin, fenofibrate, ezetimibe and bile acid sequestrants all offer additional LDL-C lowering • The evidence that combination therapy provides a significant increment in CVD risk reduction remains elusive DiabetesCare2012;35(suppl1):S30-34

12. American Diabetes Association Dyslipidemia/Lipid Management 2012 • Some experts recommend a greater focus on non–HDL cholesterol and apolipoprotein B (apoB) in patients who are likely to have small LDL particles, such as people with diabetes DiabetesCare2012;35(suppl1):S30-34

13. American Diabetes Association Dyslipidemia/Lipid Management 2012 • Severe hypertriglyceridemia may warrant immediate therapy with lifestyle and pharmacologic therapy (fibric acid or niacin) to reduce the risk of pancreatitis • In the absence of severe hypertriglyceridemia, targeting HDL-C or TG has intuitive appeal but lacks the evidence of statin therapy • If the HDL-C is < 40 mg/dL and the LDL-C is between 100 -129 mg/dL, gemfibrozil or niacin might be used especially if intolerant to statins DiabetesCare2012;35(suppl1):S30-34

14. American Diabetes Association Dyslipidemia/Lipid Management 2012 • Niacin is the most effective drug for raising HDL-C. • It can significantly increase blood glucose at high doses, but recent studies demonstrate that at modest doses (750–2,000 mg/day), significant improvements in LDL cholesterol, HDL cholesterol, and triglyceride levels are accompanied by only modest changes in glucose that are generally amenable to adjustment of diabetes therapy. DiabetesCare2012;35(suppl1):S30-34

15. American Diabetes Association Dyslipidemia/Lipid Management 2012 • Combination therapy with a statin/fibrate or statin/niacin may be efficacious for treatment of all three lipid fractions, but this combination is associated with an increase risk for abnormal aminase levels, myositis or rhabdomyolysis. • Rhabdomyolysis risk is higher with the higher doses of statins and with renal insufficiency and seems to be lower when statins are combined with fenofibrate than gemfibrozil DiabetesCare2012;35(suppl1):S30-34

16. American Diabetes Association Dyslipidemia/Lipid Management 2012 • In the recent ACCORD study, the combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal MI, or nonfatal stroke, as compared with simvastatin alone, in patients with type 2 diabetes who were at high risk for CVD. • However, prespecifiedsubgroup analyses suggested heterogeneity in treatment effects according to sex, with a benefit of combination therapy for men and possible harm for women, and a possible benefit for patients with both triglyceride level ≥ 204 mg/dL and HDL cholesterol level ≤ 34 mg/dL DiabetesCare2012;35(suppl1):S30-34

17. American Diabetes Association Dyslipidemia/Lipid Management 2012 • The AIM-HIGH trial randomized over 3,000 patients (about one-third with diabetes) to statin therapy plus or minus addition of extended release niacin. • The trial was halted early due to no difference in the primary CVD outcome and a possible increase in ischemic stroke in those on combination therapy DiabetesCare2012;35(suppl1):S30-34

18. American Diabetes Association Dyslipidemia/Lipid Management 2012 Summary of Glycemic, BP and Lipid Control A1C Blood Pressure Lipids LDL-C < 7.0%* < 130/80 † < 100 mg/dL ‡ DiabetesCare2012;35(suppl1):S30-34

19. American Diabetes Association Dyslipidemia/Lipid Management 2012 Summary of Glycemic, BP and Lipid Control • More or less stringent glycemic goals may be appropriate for individual patients. Goals should be individualized based on duration of diabetes, age/life expectancy, comorbid conditions, known CVD or advanced microvascular complications, hypoglycemia unawareness, individual and patient considerations. • † Based on patient characteristics and response to therapy, higher or lower SBP targets may be appropriate. • ‡ In individuals with overt CVD, a lower LDL-C goal of ,70 mg/dL (1.8 mmol/L), using a high dose of a statin, is an option. DiabetesCare2012;35(suppl1):S30-34

20. American Diabetes Association Dyslipidemia/Lipid Management 2012 CVD prevention Statin Dose & Comparator LDL-C Reduction Study RRR ARR 50 34 17 13 18 34 35 19 8 36% 186 to 118 29% 112-79 31% 123–84 27% 136-99 22% 99-77 31% 124-86 40% 118-71 30% 114-80 34% 125-82 42.5 12.7 7.5 5.4 4.7 6.0 4 1.9 0.9 4s-DM 2˚ ASPEN 2˚ 2˚ HPS-DM 2˚ CARE-DM 2˚ TNT-DM 2˚ HPS-DM 1˚ CARDS 1˚ ASPEN 1˚ ASCOT-DM 1˚ Simva 20-40 vsPlbo Atorva 10 vsPlbo Simva 40 vsPlbo Prava 40 vsPlbo Atorva 80 vsAtorva 10 Simva 40 vsPlbo Atorva 10 vsPlbo Atorva 10 vsPlbo Atorva 10 vsPlbo DiabetesCare2012;35(suppl1):S30-34