Many randomized clinical trials (RCTs) and meta-analyses have contributed to the lipid management guidelines over the past two decades.
Which of the following statements is NOT correct?
The JUPITER trial demonstrated that in individuals without documented cardiovascular disease (CVD) and median LDL-C of 108 mg/dL, aggressive statin therapy with rosuvastatin offered greater benefit in individuals with ultrasensitive C-reactive protein (usCRP) >2 versus <2 mg/L. JUPITER demonstrated that primary prevention patients with only modest elevations in LDL-C but elevated usCRP above 2 mg/L benefited from treatment with statins. However, the trial only enrolled individuals with usCRP >2 mg/L. There was no comparison arm to individuals with low LDL-C and low usCRP. While ASCOT-LLA showed reductions in nonfatal MI and CHD death, coronary events or procedures, stroke, and chronic stable angina, but did not show a reduction in total mortality. However, this trial did demonstrate that initiation of moderate intensity statin therapy in higher-risk individuals without clinical CVD and without significant elevations in LDLC significantly reduced CVD events. The study with average LDL-C at entry of 130 mg/dL was stopped early by the safety monitoring board. Primary prevention trials WOSCOPS and AFCAPS/TexCAPS and secondary prevention trials including 4S, CARE, PIPID, and Heart Protection Study (HPS) across a wide range of pretreatment LDL-C and using various statins demonstrated approximately 1% reduction in CVD events for every 1% reduction in LDL-C.
The Framingham Risk Score (FRS) was popularized in the National Cholesterol Education Project: Adult Treatment Panel (NCEP ATP) III guidelines.
Potential limitations of the FRS include the following:
1. Does not take family history into account
2. May overestimate lifetime risk in individuals ≤50 years of age with ≥1 NCEP risk factor
3. May not accurately calculate risk in certain ethnic groups because original Framingham population was almost entirely of European origin
4. Incorporates risk due to insulin-resistant conditions such as metabolic syndrome
5. Does not include emerging risk factors such as CRP, lipoprotein(a), and apoB
1, 3, and 5. In making treatment decisions regarding initiation and intensity of treatment for dyslipidemia in patients without documented CVD or diabetes, assessment of future risk of CVD development is important. In individuals with two or more standard cardiovascular risk factors (hypertension, family history, low HDL-C, and smoking), the FRS can be used to calculate 10-year risk of MI or coronary disease mortality. The calculator is based on assessment of TC (or LDL-C), HDL-C, hypertension history, age, and smoking stratified by gender. It does not incorporate family history, assessment of metabolic syndrome, or other nontraditional risk markers such as usCRP, lipoprotein(a), and CACS. Risk may be underestimated in younger individuals and data may not be transferable to ethnic groups not well represented in the cohort. Other risk assessment tools include some of these additional risk markers such as the Reynolds Risk Score (usCRP and family history), PROCAM (prospective cardiovascular Münster heart study) Score (TG and family history), and SHAPE (Screening for heart attack prevention and education) guidelines (carotid intimal medial thickness [CIMT] and CACS). The recent 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults has promoted a new Pooled Cohort Equations risk calculator that incorporates race into the calculation and stroke as an outcome event.
Based on the definition proposed by the NCEP ATP III guidelines, metabolic syndrome would be present if three or more of five criteria were present.
Which of the following is NOT one of the criteria?
HDL-C of <40 mg/dL in men and women. Metabolic syndrome is characterized by abdominal obesity, an atherogenic dyslipidemia with elevated TG, increased number of small LDL particles, low HDL-C, elevated BP, insulin resistance (glucose intolerance), a prothrombotic state, and a proinflammatory state. There is an increased risk of CVD development of two- to fourfold in individuals with metabolic syndrome. Focus of treatment should be on intensive lifestyle intervention. In the NCEP ATP III recommendations for diagnosis of metabolic syndrome, cutoffs for HDL-C are <40 mg/dL in men but <50 mg/dL in women. The other criteria listed are correct. Modifications since initial publication include lowering the fasting glucose cutoff to 100 mg/dL and populationspecific waist circumferences such as ≥90 cm in men and ≥80 cm in women of South Asian ancestry. Metabolic syndrome is present if three or more of these criteria are identified.
NCEP ATP III was published in 2001. Modifications to NCEP ATP III published in 2004 include all of the following except that:
Both higher-dose statins and addition of fibrates and niacin to achieve non-HDL-C goals should be considered to achieve secondary targets and to further reduce cardiovascular event rate. Between NCEP ATP III in 2001 and the update in 2004, multiple randomized controlled clinical trials offered new information supporting more aggressive treatment of hyperlipidemia and led to lowering the treatment goals and pretreatment LDL-C cutoffs for treatment in high- and intermediate-risk individuals (Table below).
Treatment Goals and Low-Density Lipoprotein Cholesterol Levels for Initiation of Pharmacologic Therapies Based on Modifications of the National Cholesterol Education Project: Adult Treatment Panel III Guidelines in 2004:
The HPS demonstrated statin benefit in high-risk patients even with low pretreatment LDL-C. The ASCOTT LLA and Collaborative Atorvastatin Diabetes Study (CARDS) trials showed benefit when treating high-risk primary prevention patients with hypertension or DM even if LDL-C was not significantly elevated. Studies such as Treat to New Targets (TNT) and PROVE-IT TIMI-22 demonstrated that increasing the intensity of LDL-C lowering using higher doses or more potent statins in secondary prevention populations was associated with incremental cardiovascular risk reduction. The guidelines recommend that in treating individuals with hyperlipidemia the first priority of treatment is to lower LDL-C; the first line of drug therapy to manage LDL-C is statin therapy and intensity of therapy should be selected to achieve at least a 30% to 40% LDL reduction. Intensity of therapy and LDL-C goals should be based on level of CVD risk. Although NCEP ATP III recommended non-HDL-C (TC minus HDL-C) as a secondary therapeutic goal after achieving LDL-C goals and considering addition of niacin and fibrates to achieve this goal, this has not yet been definitively shown in clinical trials to reduce adverse cardiovascular events when added to adequate statin therapy.
A 53-year-old obese, sedentary woman undergoes lipid screening, revealing TC of 310, TG of 720, HDL-C of 41. LDL-C was not calculated due to elevated TG. HbA1c is 5.9 and thyroid-stimulating hormone (TSH) is normal. NCEP ATP III guideline recommendations for TGs and HDL-C management include all but which of the following:
Non–HDL-C goal equals the LDL-C goal +30 mg/dL. Although the ADA, the American Association of Clinical Endocrinologists (AACE), and the AHA/ACC women’s preventive guidelines set specific goals for TG below 150 mg/dL and HDL-C >50/40 mg/dL in women/men, NCEP ATP III guidelines do not and instead focus on non–HDL-C targets. The primary target for therapy is LDL-C reduction and statins remain the primary therapy for reducing LDL-C. However, in individuals with TGs >500 mg/dL initial therapy with aggressive diet and lifestyle intervention and medications should be first addressed. Non–HDL-C is recommended as a secondary target after achieving LDL-C goals if TG are greater than 200 mg/dL with therapeutic options to lower non–HDL-C including more intense LDL-C lowering or addition of niacin, fibrates, or high-dose omega-3 fish oils. Bile acid sequestrants should be avoided in individuals with TG over 300 mg/dL.
NCEP ATP III recognizes a role for HDL-C as an important determinant of risk and if low a reason to achieve LDL-C and non–HDL-C goals as well as cause to emphasize diet and exercise. Although specific treatment to raise HDL-C may be considered in very high-risk individuals, the best therapies to accomplish this are not known and clinical trials documenting CVD risk reduction with HDL-C–directed therapies are lacking. An appropriate approach to HDL-C management is lifestyle. Dietary changes are associated with a 3% to 15% increase in HDL-C with an average 0.35 mg/dL increase in HDL for each 1 kg of weight loss. About 120 to 180 minutes of aerobic exercise a week and discontinuation of smoking can each raise HDL-C by 5% to 10%.
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