Reflections: An Aggressively Managed Lipidologist Can Have an Acute Coronary Syndrome

Author Edwin Ferguson, MD, is a 70-year-old practicing preventive cardiologist and certified clinical lipidologist who, despite 20 years of treatment for dyslipidemia, recently had an ST elevation myocardial infarction (STEMI). His cardiovascular journey began in medical school when, despite his normotension and normal weight, testing revealed a triglyceride (TG)/high-density lipoprotein (HDL) axis abnormality.1(Table 1) A decade later, his lipid panel remained abnormal and untreated. At that time no guidelines were cognizant of the importance of non-high-density lipoprotein cholesterol (non-HDL-C) or that an elevated TG/HDL-C ratio was a clue to the presence of insulin resistance (IR).

In 1994, exertional tightness in his back prompted Ferguson to undergo a positron emission tomography (PET) scan, which revealed coronary artery disease (CAD) with reduced coronary perfusion in the left anterior descending (LAD) and circumflex arteries. His lipid concentrations remained abnormal and an elevated lipoprotein (a) [Lp(a)] mass was discovered. Ferguson reduced dietary saturated fat and carbohydrates and started a vigorous exercise program. His medication regimen consisted of diltiazem SR (slow-release) 180 mg twice a day, aspirin 81 mg daily, simvastatin 20 mg, and immediate-release niacin titrated to 2,000 mg/daily with minimal flushing. Niacin subsequently raised the homocysteine level and elevated his glucose levels into the 90s (mg/dL), but also induced acanthosis nigricans. Metformin was started and titrated to 2,250 mg daily. Exercise-related transient episodes of atrial fibrillation, another potential niacin side effect,2,3 ceased after starting metoprolol and ramapril.

Subsequently, on-treatment lipid concentrations and lipoprotein concentrations dramatically improved, meeting guideline-advised goals.4 Blood pressure remained excellent, averaging 110-130/60 mmHg. He switched from simvastatin to atorvastatin and then, in 2004, to rosuvastatin 20 mg daily. A follow-up PET scan in 1997 showed substantial perfusion improvements. In 2005, a low omega-3 index led to omega-3 supplementation and, in 2012, a cholesterol synthesis/absorption biomarker panel revealed significantly elevated (3 to 4 X ULN)  absorption markers (sitosterol, campesterol, and cholestanol).5 Ezetimibe therapy was started at 10 mg daily, leading to further lipid/lipoprotein improvements. In 2013, sleep apnea was diagnosed and treated with nasal CPAP. In 2014, despite normoglycemia, novel biomarkers of insulin resistance and beta-cell function demonstrated significant abnormalities, including elevated leptin and reduced adiponectin.6 His body mass index was high normal, and his exercise was limited to walking two miles a day.

Many lipidologists were stunned with the results of the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial and the “Heart Protection Study 2 - Treatment of HDL to Reduce the Incidence of Vascular Events  (HPS2-THRIVE)” trial.7,8 In both studies, adding niacin or niacin/ laropiprant to patients on statins or statins plus ezetimibe brought no additional outcome benefit and revealed an incidence of niacin-related side effects not previously appreciated. Dr. Ferguson decided to stop the niacin but remained on a rosuvastatin plus ezetimibe regimen. Off niacin, his lipid/lipoprotein concentrations worsened. On statin/ezetimibe, his absorption markers were normal and the cholesterol synthesis biomarker, desmosterol concentration, was low — as often is seen on statin therapy.

Two months after stopping niacin, Dr. Ferguson had a STEMI. Angiography revealed the older, moderate LAD calcified stenosis and a 75 to 85 percent more proximal calcified nondominant left circumflex lesion, both with a normal thrombolysis in myocardial infarction 3 (TIMI 3) flow score. A drug-eluting stent was placed in the mid-right coronary artery and successfully reduced a 99 percent suspected plaque rupture lesion to zero percent occlusion. After the acute coronary syndrome (ACS), his medication regimen comprised: rosuvastatin 20 mg a day, ezetimibe 10 mg a day, metoprolol XL 50 mg once a day, ramipril 5 mg three times daily, ethyl ester fish oil (EPA and DHA) 4 grams a day, methylfolate 3 mg with vitamin B12 and B6 one a day, vitaminapy. D3 4,000 units (capsules) one a day, metformin 2,250 mg a day, aspirin 81 mg daily and prasugrel. After being stabilized, Dr. Ferguson was stunned that he had had an ACS, in spite of aggressive therapy with “good if not excellent” lipid/lipoprotein concentrations. So what might explain his residual risk?

Analysis of Framingham Offspring Study data9 and several genetic disorders10 suggests that far more important than any given absolute lipid/lipoprotein concentrations is the exposure of the vasculature to such concentrations over years and decades. For most of Dr. Ferguson’s life, lipid-associated risk was untreated and his arteries were continuously subjected to that exposure. Despite the fact that niacin did not meet the primary endpoint in its only randomized prospective outcome trial, the Coronary Drug Project,11 it was promoted by too many, in large part because of its ability to increase HDL-C and reduce Lp(a) mass.3 The AIM-HIGH and HPS2-THRIVE trials suggest that such niacin-induced lipid changes bring no outcome benefits. Lipidologists are now recognizing that a major risk related to low HDL-C is hyperbetalipoproteinemia.12 Many still advocate niacin as an apo B-lowering drug,13 ignoring the fact that adding niacin to statin or to statin plus ezetimibe in AIM- HIGH further lowered apo B by 13 percent yet produced no additional outcome benefit.14 Analysis of the HPS2-THRIVE data revealed that, among the randomized patients, 13,542 were on simvastatin monotherapy and 12,131 needed ezetimibe co-administration to achieve LDL-C goals.  The number of major events reported, regardless of niacin or placebo group assignment, was 1,894 (14 percent) in the simvastatin group and 1,560 (12.8 percent) in the simvastatin-plus-ezetimibe group.15

Amazingly, this later finding forecasted the “IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) results, a randomized trial showing simvastatin plus ezetimibe was superior to simvastatin alone in reducing events and cholesterol in ACS patients.16  (Figure 1) At the same time came data showing that loss of function of the Niemann-Pick C1-Like 1 protein, ezetimibe’s target, is associated with reductions in both lifelong LDL-C concentrations and incidence of atherosclerotic endpoints.17 In view of Dr. Ferguson’s hyperabsorptive state, likely aggravated by statin18  or statin + niacin therapy,19 ezetimibe should have been used far sooner than it was.

Other potential contributors to his residual risk include:

1. Increased concentrations of phytosterols, the atherogenicity of which is under debate.20,21 Data from the Scandinavian Simvastatin Survival Study (4S) showed that statin therapy did not reduce events in patients with hyperabsorption of cholesterol, leading the study’s author to conclude in 1998 that cholesterol- absorption blockers might improve statin efficacy.22
2. Belated lowering of hyperhomocysteinemia related to MTHFR C677T and A1298C mutations with methylated folic acid and vitamin B12.23,24
3. Belated recognition6 and treatment of insulin resistance and beta-cell strain, despite normoglycemia. In retrospect, Dr. Ferguson admits his lifestyle had slipped for three to four years prior to the ACS, as he felt somewhat protected by the medications.25
4. Increased concentrations of Lp(a)mass and the genomic variation in Lp(a) are major risk factors for atherothrombotic events,26 but despite the fact that niacin dramatically reduced his Lp(a) mass and Lp(a)-P — similar to the AIM-HIGH results — there was no clinical benefit.14 Interestingly, rosuvastatin 20 mg daily, which had no effect on Lp(a) mass in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study, lowered cardiovascular (CV) events significantly in those with high Lp(a).27

Dr. Ferguson’s case reminds us that as clinical lipidologistis we need to: 1) optimize statin therapy by using additional therapies to maximally reduce apo B or its many surrogates, 2) aggressively attack insulin resistance, and to control homocysteinemia. Importantly, all of these preventive approaches need to be started much earlier in life. Beyond lifestyle, ezetimibe and bile acid-binding agents such as colesevelam are excellent and safer than niacin add-on-to-statins therapies to help achieve physiologic cholesterol and apo B levels goals, which we now know are far lower than we previously thought.

Acknowledgements
We thank Dawn L. Thiselton, PhD, for editorial assistance.

Disclosure statement: Dr. Ferguson has received speaker honorarium for Health Diagnostic Lab Inc. Dr. Dayspring has received consulting fees from Health Diagnostic Lab Inc., AstraZeneca, and Merck. He’s received speaking honorarium from AstraZeneca and was a minor stakeholder for GSK and Amarin.

References are listed on page 39 of the PDF.