History of Presenting Illness:
A 41-year-old man presents with dyslipidemia, hypertension, and a history of myocardial infarction (MI) at age 37. He does not smoke, is physically inactive, and consumes a diet high in saturated fat. Medications include a high intensity statin (atorvastatin), a beta-blocker, an angiotensin converting enzyme inhibitor, and aspirin. Blood pressure is 110/80 mm Hg, body mass index is 32 kg/m2, and waist circumference is 43 inches.
Laboratory Data:
- Total cholesterol: 148 mg/dL
- Triglycerides: 210 mg/dL
- High-density lipoprotein cholesterol (HDL-C): 29 mg/dL
- Friedewald estimated low-density lipoprotein cholesterol (LDL-C): 77 mg/dL
- Non-HDL-C: 119 mg/dL
- Fasting glucose: 115 mg/dL
- HbA1C 5.9%
- AST/ALT WNL
- TSH WNL
Electrocardiogram (ECG):
Normal sinus rhythm, normal ECG
The correct answer is: B. Focus on improvements in lifestyle habits (development of an aerobic exercise program, heart-healthy eating and sustained weight loss).
Currently, there is insufficient evidence from clinical trials to routinely recommend HDL-targeted therapy for additional event reduction in high-risk patients with coronary artery disease (CAD).
Fibrates
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial1, in which 5,518 men and women with type 2 diabetes received simvastatin (20-40 mg/day) and either fenofibrate (160 or 54 mg/day depending on renal function) or placebo, demonstrated that the combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal MI, or nonfatal stroke compared with simvastatin alone. While this trial did not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in high-risk patients with type 2 diabetes, analyses of the dyslipidemic group (triglyceride level >200 mg/dL, HDL-C <35 mg/dL) indicated a strong trend to lower outcomes on fenofibrate compared with placebo in those with both high triglycerides and low HDL-C.
Niacin
The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial2 randomized 3,414 men and women with CAD and well-controlled LDL-C on background statin with or without ezetimibe to extended-release niacin or placebo. This trial demonstrated that there was no difference in the time to first event for the composite of coronary heart disease death, non-fatal MI, ischemic stroke, hospitalization for acute coronary syndrome or symptom-driven coronary or cerebral revascularization between the two treatment groups. In post hoc analysis, however, the risk for the primary endpoint was reduced by 37% in those with baseline triglycerides ≥200 mg/dL and HDL-C <32 mg/dL.
The recent results from the Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial3 concur with that of AIM-HIGH. In HPS2-THRIVE, 25,673 high-risk patients with a history of MI or CAD, cerebrovascular atherosclerotic disease, peripheral arterial disease or diabetes mellitus were treated with either simvastatin and extended-release niacin/laropiprant or simvastatin alone. The addition of extended-release niacin/laropiprant to the statin did not significantly reduce the risk of major cardiovascular events. However, the combination of simvastatin/extended-release niacin/laropiprant was associated with a highly significant excess of fatal or nonfatal serious adverse events, including a 55% increase in disturbances in diabetes control in those with diabetes, a 32% increase in the diagnosis of diabetes in those not diabetic as well as gastrointestinal (bleeding, peptic ulceration), musculoskeletal (myopathy) and skin-related events. There were, however, trends for benefit in the dyslipidemic subgroup as seen in ACCORD. It is not entirely clear the contribution of laropriprant to observed side effects.
Clinical Recommendation
This is a high-risk patient who is being treated aggressively with high intensity statin therapy to lower his LDL-C, the primary target of therapy. However, his HDL-C remains low. While, numerous studies have associated an increase in HDL-C with slowing the rate of progression of atherosclerotic disease, the causal nature of such findings was not established. Moreover, regarding the impact on risk for cardiovascular events, there is currently insufficient evidence to routinely recommend either a fibrate or extended-release niacin for this patient. Given that this patient has both high triglycerides and low HDL-C, the addition of either of these medications to his statin could be considered based on the subgroup analyses of the ACCORD and AIM-HIGH trials.4 However, recent data from the HPS2-THRIVE trial indicating a 32% increase in the diagnoses of diabetes in those that were not diabetic are of concern, as this patient has metabolic syndrome and is pre-diabetic. Other lipid lowering therapies (e.g., bile acid sequestrant, ezetimibe) might be considered based on shared decision making between the patient and clinician, particularly because the non-HDL-C level remains suboptimal in this very high-risk patient.
Nonetheless, the first step of highest priority is to reinforce adherence to proven therapy (high intensity statin) and work with his care provider to improve lifestyle habits and reduce his weight. As this patient is already several years out from his MI at a very early age, and despite this has poor lifestyle habits, and metabolic syndrome, a high level of support in meeting lifestyle goals is necessary. He should follow with his primary care provider and cardiologist regularly and should be offered a nutrition referral. To help increase his physical activity level, a pedometer combined with a personalized daily step goal may also serve useful. The recently updated recommendations by the American Heart Association (AHA)/American College of Cardiology (ACC) for heart-healthy eating and aerobic physical activity5 in addition to those by The Obesity Society/AHA/ACC for sustained weight loss6 may also be helpful for this patient.
References
- ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
- AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67.
- HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-12.
- Toth PP, Barylski M, Nikolic D, et al. Should low high-density lipoprotein cholesterol (HDLC) be treated? Best Prac Res Clin Endoc Metab 2014;28:353-68.
- Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2960-84.
- Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol 2014;63:2985–3023.
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