You see a 52-year-old man with a history of type 2 DM on metformin. He has a history of hypertension controlled on amlodipine and an angiotensin-converting enzyme inhibitor. His BMI is 31.7 and waste circumference is 41 inches. His father had a coronary stent at the age of 54. He has the following fasting laboratory values:
The best initial treatment for this patient’s dyslipidemia would be:
Atorvastatin 40 mg/day. Patients with diabetes are CHD risk equivalent patients and therefore at high cardiovascular risk and candidates for aggressive lipid-lowering therapy. The NCEP ATP III update in 2004, ACC/ADA consensus statement in 2008, and the ADA and AAACE (American Association of Clinical Endocrinologists) guidelines in 2013 all support a primary LDL-C goal of <70 mg/dL and secondary non–HDL-C goal of <100 mg/dL. In addition, the consensus statement and recent ADA/AACE guidelines recommend considering apoB of <80 mg/dL and LDL-P of <1,000 as secondary targets for therapy. usCRP is a marker for CVD risk and reduced by many therapies including statins and lifestyle interventions but is not a recognized specific target or therapeutic goal (tables below).
Treatment Goals: American Diabetes Association/American College of Cardiology Consensus Statement 2008:
American Association of Clinical Endocrinologist Lipid Targets for Patients with Type 2 Diabetes:
The first-line therapy is statins, at a dose needed to achieve LDL-C reductions of at least 30% to 40%. Only atorvastatin 40 mg/day would achieve recommended treatment goals. Simvastatin at this dose is unlikely to result in sufficient LDL-C reduction to achieve goals and since the FDA alert in 2011, doses higher than 20 mg are not recommended in combination with amlodipine. Monotherapy with ezetimibe generally lowers LDL-C <20% and outcome benefit has not been demonstrated. Although LDL-C is not significantly elevated and the TG and HDL-C abnormalities may be improved by the other listed therapies, statins remain the primary treatment choice, supported by beneficial outcome data in trials such as CARDS and diabetic subsets in other large prospective trials and meta-analyses. Outcome data regarding cardiovascular risk reduction with these other listed therapies are lacking or less robust. New lipid treatment guidelines from the ACC/AHA published in November 2013 recommend a different approach to the management of lipids. These new guidelines support therapy initiation and intensity dependent on the level of risk and they recognize that most patients with diabetes are candidates for high-intensity statin therapy (defined as a statin able to achieve >50% reduction in LDL-C, e.g., 40 to 80 mg of atorvastatin or 20 to 40 mg of rosuvastatin).
The patient was started on rosuvastatin 20 mg/day, metformin dose was increased, an aerobic exercise program was recommended, and he was referred for dietary advice. Repeat laboratory values in 4 months are as follows:
The most appropriate additional therapies recommended by NCEP ATP II at this time would include all but:
All of the above. On statin therapy, the LDL-C goal of <70 mg/dL has been achieved but non–HDL-C remains above an ideal goal of <100 mg/dL. Any of these therapies would help to achieve the secondary non–HDL-C goals. NCEP ATP III recommends intensification of statins, further LDL-C lowering with non-statin therapies, niacin, or fibrates to achieve secondary non–HDL-C goal. There are clinical trial data to support further risk reduction with intensification of statin therapy although outcome data are absent when niacin, fibrates, fish oil, or ezetimibe is added to adequate statin therapy. Intensification of lifestyle interventions should be a part of any pharmacologic intervention in this patient. The patient is on a high-intensity statin with <50% reduction in LDL-C. Based on new ACC/AHA 2013 guidelines for management of hyperlipidemia, there is insufficient RTC evidence that adding additional therapies will further reduce cardiovascular events. Intensification of statin therapy does appear to offer benefit. In individuals receiving maximum tolerated intensity of statin with less than anticipated therapeutic response and in high-risk groups, the addition of non-statin therapy may be considered if the CVD risk reduction benefits outweigh the adverse effects.
This patient with diabetes is considered at high risk for CVD events.
Which of the following statements is not true in regard to patients with diabetes?
NHANES data from 2010 indicate that although goals of HbA1c <7 mg/dL, systolic BP <130 mmHg, and LDL-C <100 mg/dL are recommended for diabetics, only 32% of diabetics in the survey currently achieve all three of these goals. The NHANES survey in 2010 demonstrated that although greater than 50% of diabetic patients achieved LDL <100 mg/dL, systolic BP <130 mmHg, or HbA1c <7 mg/dL, only <20% achieved all three goals. Studies such as the East-West study in 1998 demonstrated that a diabetic without CHD history had a similar approximate 20% incidence of MI over 7 years compared with a nondiabetic with known previous MI. Diabetics have a two- to fourfold increased risk of CVD events and the majority of deaths in patients with diabetes are due to CVD, accounting for up to 75% of deaths. These observations emphasize the concept of diabetes as a CHD equivalent and a rationale for intensive therapy of hyperlipidemia.
Additional markers beyond standard risk factors have been shown to help reclassify risk assessment particularly in individuals in an intermediate-risk category (e.g., FRS of 10% to 20% or American College of Cardiology [ACC]/AHA guideline risk score of 5% to 7.5%). All but one of the following may be useful in hyperlipidemia treatment decisions:
HDL particle size and number. usCRP has been shown in studies such as the Women’s Health Study (WHS) to reclassify risk when added to the FRS and in the JUPITER trial to be a factor in determining benefit of early statin therapy for primary prevention of CVD. Similar reclassification of risk has been demonstrated with anatomic measurements for preclinical atherosclerosis such as CACS and CIMT. Post hoc analyses of studies such as the WHS and MESA (multi-ethnic study of atherosclerosis) have demonstrated LDL-P to be a better predictor of future cardiovascular risk, and the National Lipid Association has recommended it as a tool for further risk assessment. However, data supporting the benefit and use of HDL particle size and number in assessing risk and guiding treatment are absent. NCEP ATP III recommends that intermediate-risk patients (FRS 10% to 20% estimated 10-year risk) with these additional risk markers should be considered for more intensive therapies. The ACC/AHA hyperlipidemia guidelines in 2013 suggest that in selected individuals, particularly those with a 10-year CVD risk of 5% to 7.5% not falling into defined treatment groups for high- or moderate-intensity statin therapy, factors including LDLC >160 mg/dL, family history of premature CVD, usCRP >2 mg/dL, CACS >300 Agatston units or >75th percentile for age/sex/ethnicity, and ankle brachial index <0.9 may be used to consider initiation or intensification of pharmacologic therapy.
Major differences in the ACC/AHA hyperlipidemia treatment guidelines of 2013 compared with NCEP ATP III recommendations include all of the following except:
1. elimination of LDL-C and non–HDL-C targets for therapy.
2. a focus on risk reduction targeting therapy to four major groups demonstrated to benefit from statin therapy based on RCT data rather than targeted to risk category and LDL-C level.
3. replacing the FRS with a newly developed risk calculator that includes ethnicity and family history and broadens the outcome events to include stroke.
4. that since the absolute benefit in CVD risk reduction is proportional to the baseline risk of the individual and to the intensity of statin therapy, treatment is focused on intensity of statin treatment and does not recommend use of low-dose statin therapies.
5. that decreasing statin dose is reasonable if LDL-C on therapy is <40 mg/dL.
None, all are true. The ACC/AHA 2013 guidelines have attempted to offer recommendations based on a balance of benefit and therapeutic risk of treatment strategies as supported whenever possible by RTCs. The guidelines are based on observations including the absolute benefit in CVD risk reduction is proportional to baseline risk; cholesterol-lowering medications used in clinical trials (particularly statins) reduce risk of cardiovascular events proportional to the intensity of stain therapy rather than LDL-C achieved and therefore more intensive statin therapy could reduce risk more than moderate- or lower-intensity statin therapy; and statins are associated with similar relative risk reductions for CVD events across the majority of patient groups studied, and little clinical trial evidence to support use of other non-statin therapies particularly when added to treatment with statins. Therefore, in these guidelines a greater degree of emphasis is placed on level of treatment with statins and less on other lipidlowering therapies either alone or in combination with statins. Patients or groups at higher baseline absolute risk will derive greater absolute benefit from initiation of statin therapy over a period of 5 to 10 years as studied in clinical trials. Like the NCEP ATP III recommendations, intensity of therapy is based on a measure of level of CVD risk but defined as dose or potency of statin therapy to be used rather than titration to specific LDL-C and non– HDL-C goals. Both sets of guidelines recommend statin therapy as primary and most beneficial therapy for CVD risk reduction although the ACC/AHA recommendations deemphasize the use of add-on non-statin therapies in the absence of RCT data and balance the risk of pharmacologic therapies in lower-risk populations. The ACC/AHA guidelines position treatment of TGs and use of non–HDL-C in treatment decision making as future clinical questions to be addressed and updated after future clinical trials. It should be mentioned that since these guidelines have appeared many have offered criticism of the document, including the elimination of LDL-C targets and concern with use of a new risk assessment tool that has not been prospectively validated, may overexpand treatment of lower-risk populations, and delay treatment in other high-risk populations. It should be remembered that these are guidelines and not doctrine and individual treatment plans should be tailored to the individual patient’s risk and needs after carefully assessing side effects and risk of treatment and discussion with the patient.
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