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2003 Thomson Professional Postgraduate Services ATP III: Management of Diabetic Dyslipidemia Primary target of therapy: identification of LDL-C; goal for persons with diabetes: 220220220 TG 123 mg/dL TG 123 mg/dL Fasting TG and Risk for CHD Death: Paris Prospective Study 2003 Thomson Professional Postgraduate Services TM 1999 Professional Postgraduate Services 0 1 2 3 CHD mortality (per 1,000) Fontbonne AM et al. Diabetes Care. 1991;14:461-469. 2930-5051-7273-114115 Quintiles (pmol) of fasting plasma insulin P4 hr/wk 0.0011225 Fiber intake 15 g/1,000 kcal 0.0011126 Saturated-fat intake 5% % of subjects P value*ControlsInterventionGoals 2002 Thomson Professional Postgraduate Services 2003 Thomson Professional Postgraduate Services Finnish Diabetes Prevention Study: Reduction in Risk for Diabetes* Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350. 11% 23% 0 5 10 15 20 25 InterventionControl (n=265) (n=257) * *P P50% of patients with newly diagnosed type 2 diabetes have CHD Risk for atherosclerotic events is 2- to 4-fold greater in diabetics than in nondiabetics Atherosclerosis accounts for 65% of all diabetic mortality 40% due to ischemic heart disease 15% due to other heart disease 10% due to cerebrovascular disease 2003 Thomson Professional Postgraduate Services TM 1999 Professional Postgraduate Services Framingham Heart Study 30-Year Follow-Up: CVD Events in Patients With Diabetes (Ages 35-64) 10 9 20 11 9638 19 3* 30 0 2 4 6 8 10 Age-adjusted annual rate/1,000 MenWomen Total CVDCHDCardiac failure Intermittent claudication Stroke Risk ratio P40 mg/dL 2003 Thomson Professional Postgraduate Services 2003 Thomson Professional Postgraduate Services ADA: Treatment Decisions by LDL-C Levels* in Adults With Type 2 Diabetes InitiationLDL-CInitiationLDL-C Statuslevelgoallevelgoal With CHD, PVD, or CVD100100100100 Without CHD, PVD, and CVD100100130100 *Values represent mg/dL. Some authorities recommend initiation of drug therapy between 100 and 129 mg/dL. CHD=coronary heart disease; PVD=peripheral vascular disease; CVD=cardiovascular disease Medical nutrition Medical nutrition txtxDrug txDrug tx ADA. Diabetes Care. 2003;26(suppl 1):S83-S86. 2003 Thomson Professional Postgraduate Services 2003 Thomson Professional Postgraduate Services ADA: Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults LDL-C lowering first choice: HMG-CoA reductase inhibitors (statins) second choice: bile acid binding resin or fenofibrate HDL-C raising behavioral interventions (weight loss, physical activity, smoking cessation) difficult to achieve except with niacin, which should be used with caution, or fibric acid derivative TG lowering* first priority: glycemic control fibric acid derivative (gemfibrozil, fenofibrate) statins (moderately effective at high dose in patients with TG and LDL-C) *Behavioral modification is also a first-line intervention. ADA. Diabetes Care. 2003;26(suppl 1):S83-S86. 2003 Thomson Professional Postgraduate Services 2003 Thomson Professional Postgraduate Services ADA: Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults (contd) Combined hyperlipidemia first choice: improved glycemic control plus high-dose statin second choice: improved glycemic control plus statin* plus fibric acid derivative* (gemfibrozil or fenofibrate) third choice: improved glycemic control plus resin plus fibric acid derivative or improved glycemic control plus statin* plus niacin* (glycemic control must be monitored carefully) ADA. Diabetes Care. 2003;26(suppl 1):S83-S86. *Combination of statins with niacin and especially with gemfibrozil or fenofibrate may carry an increased risk for muscle toxicity. 2003 Thomson Professional Postgraduate Services 2003 Thomson Professional Postgraduate Services ADA: CHD Risk Stratification Based on Lipoprotein Levels* in Adults With Type 2 Diabetes RiskLDL-CHDL-CTG High13040400 Borderline100-12940-59150-399 Low10060150 *Values represent mg/dL. For women, HDL-C should be increased by 10 mg/dL. ADA. Diabetes Care. 2003;26(suppl 1):S83-S86. 2003 Thomson Professional Postgraduate Services TM 1999 Professional Postgraduate ServicesHaffner SM et al. N Engl J Med. 1998;339:229-234. 012345678 0 20 40 60 80 100 Nondiabetic subjects without prior MI (n=1,304) Diabetic subjects without prior MI (n=890) Nondiabetic subjects with prior MI (n=69) Diabetic subjects with prior MI (n=169) Survival (%) Year Risk Similar in Patients With Type 2 Diabetes and No Prior MI vs Nondiabetic Subjects With Prior MI 2003 Thomson Professional Postgraduate Services TM 1999 Professional Postgraduate Services Secondary Prevention: CHD Risk Reduction in the 4S Subgroup of Patients With Diabetes Pyrl K et al. Diabetes Care. 1997;20:614-620. Total mortality232167 2415 CHD mortality17299 1712 Major CHD event578407 4424 Any CHD event871667 5641 CABG or PTCA363238 2015 Cerebrovascular event9070 125 Any atherosclerotic event961750 6146 Nondiabetic Diabetic PS 00.81.01.21.4 RR with 95% CIs No. patientsSimvastatinPlacebo with eventsbetterbetter 2003 Thomson Professional Postgraduate Services TM 1999 Professional Postgraduate Services 0.60 0.70 0.80 0.90 1.00 4S: Total Mortality Reduction in a Subgroup of Patients With Diabetes Pyrl K et al. Diabetes Care. 1997;20:614-620. Proportion alive Yr since randomization - P=0.08 - P=0.001 Diabetic, simvastatin Diabetic, placebo Nondiabetic, simvastatin Nondiabetic, placebo 29% 43% 2003 Thomson Professional Postgraduate Services TM 1999 Professional Postgraduate Services 4S: Major CHD Event Reduction in a Subgroup of Patients With Diabetes Pyrl K et al. Diabetes Care. 1997;20:614-620. Proportion without major CHD event Yr since randomization - P=0.002 - P=0.0001 Diabetic, simvastatin Diabetic, placebo Nondiabetic, simvastatin Nondiabetic, placebo 32% 55% 2003 Thomson Professional Postgraduate Services 2003 Thomson Professional Postgraduate Services 2003 Thomson Professional Postgraduate Services TM 2001, Professional Postgraduate Services WOSCOPS: Development of Type 2 Diabetes Kaplan-Meier plots of time to development of type 2 diabetes according to treatment assignment. Freeman DJ et al. Circulation. 2001;103:357-362. % diabetic Years in study 00.511.522.533.544.555.5 6 5 4 3 2 1 0 Placebo Pravastatin 40 mg/d 2003 Thomson Professional Postgraduate Services First population-based study to evaluate nonHDL-C as predictor of CVD risk in patients with diabetes NonHDL-C: TC minus HDL-C (ie, all apolipoprotein B-containing atherogenic lipoproteins) VLDL, IDL, LDL, lipoprotein(a) May be useful marker of combined risk for all lipoprotein changes observed in diabetes ATP III recommends that nonHDL-C be used as secondary treatment target in people with TG 200 mg/dL, especially with diabetes or the metabolic syndrome Strong Heart Study: NonHDL-C as CVD Risk Predictor in Patients With Diabetes 2003 Thomson Professional Postgraduate Services Lu W et al. Diabetes Care. 2003;26:16-23. 2003 Thomson Professional Postgraduate Services 2003 Thomson Professional Postgraduate Services Strong Heart Study: NonHDL-C Compared With Other CVD Risk Predictors HR = hazard ratio. Data from Lu W et al. Diabetes Care. 2003;26:16-23. TC:HDL-C ratio TG LDL-C HDL-C NonHDL-C Lipoprotein 00.511.522.533.54 Men (n = 772) 0.511.522.5 Women (n = 1,336) Decreased HRIncreased HRDecreased HRIncreased HR 2003 Thomson Professional Postgraduate Services 2003 Thomson Professional Postgraduate Services Steno-2: Effect of Therapies on Selected Risk Factors Gaede P et al. N Engl J Med. 2003;348:383-393. 0 5 6 7 8 9 10 11 012345678 0 110 120 130 140 150 160 170 012345678 0 65 70 75 80 85 90 95 012345678 SBP (mm Hg) HbA1c (%) Follow-up (yr) Conventional therapy Intensive therapy Intensive therapy Conventional therapy Conventional therapy Intensive therapy DBP (mm Hg) 0 50 100 150 200 250 300 350 012345678 0 50 75 100 125 150 175 200 012345678 0 50 100 150 200 250 300 350 012345678 TG (mg/dL) LDL-C (mg/dL) TC (mg/dL) Follow-up (yr) Conventional therapy Intensive therapy Intensive therapy Conventional therapy Intensive therapy Conventional therapy 2003 Thomson Professional Postgraduate Services 2003 Thomson Professional Postgraduate Services Steno-2: Primary Composite End Point or Surgery for PAD Gaede P et al. N Engl J Med. 2003;348:383-393. No. at Risk Conventional tx 80 72 70 63 59 50 44 41 13 Intensive tx80 78 74 71 66 63 61 59 19 Follow-up (mo) 0 12 24 36 48 60 72 84 96 60 50 40 30 20 10 0 Conventional therapy Intensive therapy P = 0.007 % PAD=peripheral artery disease. (log-rank test) 2003 Thomson Professional Postgraduate Services % HPS Substudy: First Major Vascular Event in Patients With Diabetes Follow-up (years) Placebo Simvastatin Benefit/1,000-11334475158 P0.0001 0123456 0 5 10 15 20 25 30 HPS Collaborative Group. HPS Collaborative Group. LancetLancet. 2003;361:2005-2016 2003;361:2005-2016. 2003 Thomson Professional Postgraduate Services HPS Substudy: First Major Coronary Event and Stroke by Prior Diabetes Status Simvastatin (10,269) Placebo (10,267) Rate ratio (95% CI) Statin betterPlacebo better Vascular event 361:2005-2016 2003;361:2005-2016. 2003 Thomson Professional Postgraduate Servi