Dyslipidemia/Lipid management in Diabetes

M ECHANISMS R ELATING I NSULIN R ESISTANCE AND D YSLIPIDEMIA  TG  Apo B  VLDL (hepatic lipase) Kidney (CETP)CEHDL TG Apo A-1 (CETP) (lipoprotein or hepatic lipase) SD LDL LDL TGCE Fat Cells Liver Insulin IR X  FFA 2

 Elevated total TG  Reduced HDL-C  Small, dense LDL-C D YSLIPIDEMIA IN THE I NSULIN R ESISTANCE S YNDROME 3

 Increased susceptibility to oxidation  Increased vascular permeability  glycation of LDL may be enhanced in diabetes, impairing recognition of the lipoprotein by its hepatoreceptor and extending its half-life  Association with high TG and low HDL S MALL D ENSE LDL AND CHD: P OTENTIAL A THEROGENIC M ECHANISMS 4

 Accumulation of chylomicron remnants of VLDL s  Generation of small, dense LDL-C  Association with low HDL-C  Increased coagulability -  plasminogen activator inhibitor (PAI-1) -  factor VIIc - Activation of prothrombin to thrombin H YPERTRIGLYCERIDEMIA AND CHD R ISK : A SSOCIATED A BNORMALITIES 5

 Heart Protection Study, a large (N = 20,536), randomized, placebo-controlled trial of the use of simvastatin 40 mg in high-risk patients, roughly 29% of the study participants had T2DM  demonstrated a highly significant 12% RR reduction in all-cause mortality and an 18% RR reduction in coronary mortality 6

 The Collaborative Atorvastatin Diabetes Study (CARDS) was a large (N = 2838), randomized, placebo-controlled trial that assessed the benefit of atorvastatin 10 mg/day  After a median of 3.9 years follow-up, patients treated with atorvastatin had an RR reduction for first cardiovascular event of 37% (95% CI, 52% to 17% reduction; P =.001), compared with placebo- treated patients 7

 The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER)844 was randomized, double-blind study in which patients were assigned to receive extended- release niacin 500 mg titrated to 1000 mg daily (n = 87) or placebo (n = 80)  The primary end point of the study was change in CIMT after 1 year of niacin treatment. Despite a significant 21% increase in HDL-cholesterl difference in CIMT progression between the niacin- and placebotreated groups only tended toward significance (P =.08) 8

Trial (VA-HIT), men given gemfibrozil had lower rates of coronary events and strokes The ACCORD trial provided important information regarding the use of fibrates in patients with T2DM. This trial investigated whether combination therapy with simvastatin plus fenofibrate, compared with simvastatin alone. In a prespecified subgroup with a high triglyceride ratio (triglycerides ≥204 mg/dL and HDL ≤34 mg/dL), fenofibrate was better 9

 In most adult patients with diabetes, measure fasting lipid profile at least annually. (B)  In adults with low-risk lipid values (LDL cholesterol,100 mg/dL, HDL cholesterol.50 mg/dL, and triglycerides,150 mg/dL), lipid assessments may be repeated every 2 years. (E). 10

 Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels, for diabetic patients: with overt CVD (A). And without CVD who are over the age of 40 years and have one or more other CVD risk factors (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria) (A).  For lower-risk patients than the above (e.g., without overt CVD and under the age of 40 years), statin therapy should be considered in addition to lifestyle therapy if LDL cholesterol remains above 100 mg/dL or in those wit multiple CVD risk factors. (C) 11

Treatment recommendations and goals Lifestyle modification focusing on the reduction of saturated fat, trans fat, and cholesterol intake; increase of n-3 fatty acids, viscous, weight loss (if indicated); and increased physical activity. Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels, for diabetic patients with overt CVD (A). 12

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 In individuals without overt CVD, the goal is LDL cholesterol,100 mg/dL. (B)  In individuals with overt CVD, a lower LDL cholesterol goal of,70 mg/dL, using a high dose of a statin, is an option. (B)  If drug-treated patients do not reach the above targets on maximal tolerated statin therapy, a reduction in LDL cholesterol of ;30– 40%. (B) 14

 For most patients with diabetes, the first priority of dyslipidemia therapy (unless severe hypertriglyceridemia with risk of pancreatitis is the immediate issue) is to lower LDL cholesterol to a target goal of,100 mg/dL (2.60 mmol/L).  Although the data are not definitive, consideration should be given to similar lipid-lowering goals in type 1 diabetic patients as in type 2 diabetic patients, particularly if they have other cardiovascular risk factors. 15

 Inhibition of cholesterol biosynthesis by statins upregulates LDL receptors and enhances clearance of LDL.  Statins also reduce the release of lipoproteins from the liver.  At high doses, statins decrease triglyceride level  They reduce LDL-C by 20% to 60%. 16

 LDL-C lowering is seen within 1 to 2 weeks after the start of therapy and is stable in about 4 to 6 weeks.  Atorvastatin and rosuvastatin have long half-lives, about 14 hours and 21 hours.  The other statins have half-lives of about 2 to 3 hours  Lovastatin given with food, usually with the evening meal.  pravastatin, simvastatin, and fluvastatin can be given without food, preferably in the evening.  Atorvastatin, rosuvastatin, and extended-release formulation of statins can be given at any time during the day. 17

nonalcoholic hepatic steatosis is not a contraindication. Hepatic function tests should be obtained at baseline and at 6 and 12 weeks. If aminotransferases remain greater than 3 times the upper limit of normal, consider changing to a different statin and identify other contributing conditions or drugs. Statins are contraindicated in pregnancy and nursing and in patients with significant hepatic dysfunction. 18

 Triglycerides levels,150 mg/dL (1.7 mmol/L) and HDL cholesterol.40 mg/dL (1.0 mmol/L) in men and.50 mg/dL (1.3 mmol/L) in women are desirable (C).However, LDL cholesterol targeted statin therapy remains the preferred strategy. (A)  Combination therapy has been shown not to provide additional cardiovascular benefit above statin therapy alone and is not generally recommended. (A) 19

Low levels of HDL cholesterol, often associated with elevated triglyceride level. However, 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 CVD outcomes, although the study was done in a nondiabetic cohort. Gemfibrozil has been shown to decrease rates of CVD events. 20

 Hypertriglyceridemia should be addressed with dietary and lifestyle changes. Severe hypertriglyceridemia (.1,000 mg/dL) may warrant immediate pharmacological therapy (fibric acid derivative, niacin, or fish oil).  therapy targeting HDL cholesterol or triglycerides lacks the strong evidence base of statin therapy. 21

1) with clinical ASCVD, 2) primary elevations of LDL–C >190 mg/d 3) diabetes aged 40 to 75 years with LDL– C 70 to189 mg/dL and without clinical ASCVD 4) without clinical ASCVD or diabetes with LDL–C 70 to189 mg/dL and estimated 10-year ASCVD risk >7.5%. 22

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