An Approach to Lipid Management in Patients with Cardiometabolic Risk

DAVID G. CARMOUCHE

Note by Bill Bestermann, MD. Dr. David Carmouche works at the Baton Rouge Clinic in Baton Rouge, Louisiana.  He runs a Center for Cardiovascular Disease Prevention within the clinic and works full time in clinical practice producing optimal medical therapy in high risk patients.  Dr. Carmouche is certified in lipid management by the National Lipid Association, and is recognized by his peers as an expert in lipid management.

He is actively involved in multiple leadership roles that are characterized by the common theme of more effectively treating cardiovascular disease with lifestyle and medical interventions. A group of about 20 academic and community cardiovascular risk experts asked him to lead the development of the cholesterol treatment section of a program describing optimal medical therapy for metabolic syndrome patients.

On C&C, we have already posted a basic protocol for priority cardiovascular conditions.  That base protocol is an excellent beginning in the management of the metabolic syndrome patient, but after that protocol is applied, substantial numbers of  patients will still not be managed to the appropriate lipid targets.  Coronary artery disease is primarily driven by lipid abnormalities.  Here in just a few pages Dr Carmouche has laid out the rationale for aggressive cholesterol management, clear techniques to determine the level of risk and treatment targets, and finally a very practical management protocol to help you protect your patients in real clinical practice.

An Approach to Lipid Management in Patients with Cardiometabolic Risk

Introduction

Patients with metabolic syndrome, type 2 diabetes mellitus, polycystic ovarian syndrome, and other insulin resistance syndromes are at increased risk for cardiovascular events.  Lipid modification is an important and proven strategy in risk reduction.  Although the 2001 NCEP ATP III guidelines were updated [1] in 2004, the field of cardiovascular risk assessment, stratification, and treatment has moved ahead rapidly.  This paper represents the best application of the best clinical evidence available today within a single CV Prevention Center with strong clinical lipidology experience.  This algorithm has been effective in managing a group of high-risk patients in the southeastern United States.

Cardiometabolic Risk

Patients with cardiometabolic risk (CMR) share a common phenotype.  Most have evidence of excess adiposity, most notably in the upper body.  In the setting of calorie excess and physical inactivity, this excess body weight becomes associated with lipid abnormalities (high triglycerides, low HDL-C, small dense LDL), hypertension, and hyperglycemia.  Patients with increased CMR also have evidence of an activated inflammatory response and hypercoagulability.  Most patients with type 2 diabetes have metabolic syndrome as well.

Risk Categories

Patients with metabolic syndrome or diabetes have a high lifetime risk [2] for cardiovascular events.  Framingham risk calculation [3] offers a 10-year estimate for hard CHD endpoints, but this calculation is of limited use once patients with cardiometabolic risk have been identified.  Atherosclerosis is detectable by age 2 [4] and is prevalent by the end of the second decade in susceptible individuals.  As many fatal cardiovascular events are the presenting sign of clinically-evident atherosclerosis, treatment must begin at the time of risk recognition, even if short-term calculated risk is low.

Highest risk – We consider patients with established, clinically-manifest atherosclerosis to be at the highest risk.  This includes patients with coronary artery disease (heart attack, angina with an abnormal stress test or heart catheterization, previous angioplasty and/or stent, and coronary artery bypass surgery), stroke or TIA, symptomatic carotid artery atherosclerosis, peripheral artery disease with or without claudication, and abdominal aortic aneurysm.

Increased risk – Patients without any clinical manifestation of atherosclerosis mentioned above who, nonetheless, have cardiometabolic risk on the basis of type 2 diabetes, metabolic syndrome (we use the NCEP criteria [5]: any 3: TG > 150 mg/dL, HDL < 40 mg/dL in men and < 50 mg/dL in women, waist circumference > 40 inches in men and > 35 inches in women, BP > 130/85, and fasting glucose > 100 mg/dL), or polycystic ovarian syndrome fit this category.  Patients with cardiometabolic risk have a substantial increase risk for cardiovascular events and vascular death.  As such, their lifetime risk is elevated regardless of Framingham risk score.

Risk Modifiers

Sub-clinical atherosclerosis imaging – Some patients with cardiometabolic risk have advanced atherosclerosis that has not yet become clinically-recognized.  Newer tools allow for further discrimination of such patients and reclassification into the highest risk groups.  Two imaging studies, coronary artery calcium score (CACS) [6] and carotid intima-media thickness (CIMT) [7] by B-mode ultrasound, have been validated as measures which can identify patients at increased risk above routine risk scoring schemes.  Patients with a CACS > 100 are felt to have substantial coronary artery plaque and were found to be at significant risk in the ongoing Multi-Ethnic Study of Atherosclerosis (MESA) [8].  Likewise, patients with either raised carotid artery plaques or with a CIMT > 1mm have high risk for future heart attack and stroke.

The choice of imaging modality used is based on availability and reliability, cost (CIMT is usually 2-3 times more expensive), age of the patient, and concern for radiation exposure (in the case of CACS).  In the only large study [9] to compare the two modalities directly, CACS was slightly superior at predicting cardiovascular events, while CIMT performed better for stroke prediction.

Markers of inflammation – Atherosclerosis is now understood to be a chronic inflammatory disease of the arterial wall.  The complex interaction between oxidized LDL and immune system cells in the subendothelial space contributes to the establishment and progression of plaques.  Several serum markers of inflammation [10] have been shown to correlate with more advanced atherosclerosis and event risk.  The two most studied are high-sensitivity C-reactive protein (hs-CRP) and lipoprotein-associated phospholipase-A2 (Lp-PLA2.)

Hs-CRP [11] is produced by the liver in response to systemic inflammatory stimuli.  While likely not pathogenic in atherosclerosis, hs-CRP repeatedly has shown its ability to risk stratify untreated patients and predict future events in treated patients.  The recent JUPITER trial [12] showed conclusively that patients with “normal” LDL-C (average 108 mg/dL), but elevated hs-CRP > 2 mg/dL, benefitted substantially from treatment with rosuvastatin 20 mg compared with a placebo treated group.  As such, we use a persistent elevation of hs-CRP > 2mg/dL (the better of two measurements 2-4 weeks apart) as a marker of enhanced vascular risk.

Lp-PLA2 [13] is an enzyme secreted by tissue macrophages in atherosclerotic plaque.  It travels with LDL particles and is activated at the time of LDL oxidation.  This enzyme produces inflammatory mediators which up regulate adhesion molecules on the endothelial surface and promote programmed macrophage cell death, expansion of the lipid core in plaques, and ultimately plaque rupture.  Unlike hs-CRP, Lp-PLA2 is pathologic in its role in the arterial wall.  Its activity is not influenced by non-vascular inflammation, and levels > 200 mg/dL are associated with increased risk of coronary events and stroke.

Figure 1 summarizes our risk stratification strategy for patients with cardiometabolic risk.

Lipid Goals

Our lipid goals are based on a patient’s risk category.  The table below summarizes these goals:

Risk Category	Lipid Goals
Highest riskEstablished clinical atherosclerosis – CAD, CVA or TIA, carotid atherosclerosis, PAD, AAA or cardiometabolic risk group with:  Hs-CRP > 2 mg/dL, Lp-PLA2 > 200 mg/dL, CACS > 100, or CIMT > 1 mm or raised plaque	LDL-C < 70 mg/dL, andNon-HDL-C < 100 mg/dL, or  apoB < 80 mg/dL, or LDL particles < 1000 nmol/L
Increased riskMetabolic syndrome, type 2 diabetes mellitus, or polycystic ovarian syndrome without any of the risk modifiers listed above	LDL-C < 100 mg/dL, andNon-HDL-C < 130 mg/dL, or  Apo B < 90 mg/dL, or LDL particles < 1300/nmol/L

We utilize the NCEP ATP III guidelines to determine LDL-C goals.  Patients in our “highest risk” group overlap completely with the NCEP’s “very high risk group.”  For patients at “increased risk,” we are more aggressive than the NCEP which offers an optional LDL-C goal of < 100 for patients with an 11-20% Framingham risk.  We have attempted to simplify treatment by consolidating all cardiometabolic risk patients into a single risk group with uniform treatment goals.  This seems appropriate since LDL-C is known to underestimate [14] atherogenic lipoprotein concentrations.  Given that, the chance of substantial over-treatment seems small.

A growing body of evidence [15] suggests that lipoproteins other than LDL contribute to vascular disease.  In patients with cardiometabolic risk, these lipoproteins include VLDL, VLDL remnants, and intermediate density lipoproteins (IDL.)  NCEP ATP III accounts for these particles by suggesting a non-HDL-C goal of 30 mg/dL above the LDL-C goal, but only in patients with triglycerides > 200 mg/dL.  We have retained this as an optional target but favor achieving it in all patients, not just those with TG > 200 mg/dL.  Alternate, and perhaps more attractive, markers of atherogenic lipoprotein burden are apoB and LDL particle determination by nuclear magnetic resonance.

ApoB [16] has been shown in several epidemiologic and prospective clinical trials to outperform non-HDL-C in cardiovascular risk prediction.  The assay is reasonably standardized and widely available through reference laboratories.  The recently released Canadian Cardiovascular Society lipid guideline [17] established an apoB goal of < 80 mg/dL as an alternate primary target of therapy in high risk Canadian patients.  In the United States, the ADA/ACC Consensus Statement [18] on the treatment of dyslipidemia in patients with cardiometabolic risk suggested an apoB target of < 80 mg/dL in the highest risk patients and < 90 mg/dL in patients without cardiovascular disease, but with multiple risk factors.

Likewise, LDL particle (LDL-P) measurement by NMR has a robust data set [19] establishing its role in cardiovascular risk prediction, especially in patients on therapy.  There are no widely established LDL-P therapeutic targets.  We have chosen an LDL-P < 1000 nmol/L for the highest risk patient population as it represents the 20th percentile for the MESA population (LDL-C 100 mg/dL = 20th percentile of Framingham offspring cohort.)  An LDL-P of < 1300 nmol/L correlates with the 50th percentile for the same population, (LDL-C 130 mg/dL = 50th percentile of Framingham offspring cohort), and is our target for the “increased risk” group.

No clinical studies to date have prospectively assessed the superiority of apoB- or LDL-P-based therapy over treatment based on standard lipids.  However, the fact remains that too many cardiovascular events occur in patients treated to NCEP ATP III guidelines.  A very interesting paper from the Get with the Guidelines [20] CAD program described the distribution of baseline lipids of some 136,000 patients admitted for CHD.  Nearly half had LDL-C values < 100 mg/dL, and a substantial number were at ATP III goals.

Clinical Management

Primary therapy involves lifestyle modification.  We stress the importance of regular physical activity, at least 150 min. /week, and educate our patients that more exercise is better.  We counsel patients on the adverse health issues related to smoking and provide written information on smoking cessation.  In patients with more severe dyslipidemia and obesity, we have had success with a low-calorie, complex carbohydrate, higher protein, low saturated fat eating style.  We utilize the Glycemic Index [21] of carbohydrates to educate patients on finding healthier forms of carbohydrates.  Several well-received resources which portray a similar style of eating include South Beach Diet [22] and the Mediterranean Diet [23].

We have little enthusiasm for nutritional supplements for LDL-C reduction, with two exceptions.  We do favor the addition of 5-10 grams of soluble fiber [24] and 2000 mg of plant sterols or stanols [25].  These substances induce a moderate (10-20%) reduction in LDL-C.

Nearly all of our patients with cardiometabolic risk will require statin-based therapy, and we routinely choose drugs from this class as initial therapy based on the robust clinical information [26] supporting these drugs for reductions in total mortality, CHD death, and any vascular death.  Although we encourage the utilization of generic statins when feasible, we attempt to pick a statin with potency that makes LDL-C goal attainment feasible in the fewest titrations.

Figure 2 describes our treatment algorithm.  For patients who require < 50% reduction in LDL-C, options include simvastatin 40 mg (we rarely use simvastatin 80 mg because of the significant increase in myalgia and hepatic dysfunction noted at this dose), pravastatin 40-80 mg, lovastatin 40-80 mg, fluvastatin XL 80 mg, and pitavastatin 2-4 mg.  These doses are preferred based on the NCEP’s suggestion that at least a 30% LDL-C reduction [27] is needed to realize the benefits demonstrated in most statin trials.

Patients requiring > 50% LDL-C reductions have limited options: atorvastatin 40-80 mg, rosuvastatin 20-40 mg, and simvastatin/ezetimibe 10/20-10/40 mg.

Statin-intolerant [28] patients should have a TSH measurement to exclude undiagnosed or undertreated hypothyroidism.  A recent paper [29] also suggested that 25-(OH)Vitamin D3 deficiency may exacerbate statin myalgia.  Replacement in that study was associated with improved tolerability of statins.  Coenzyme Q10 (CoQ10) plays an important role in mitochondrial function, and serum levels are reduced during statin treatment.  As such, there has been an interest in providing oral CoQ10 supplementation [30] to patients with statin myalgia.  Clinical trials addressing this strategy are small and largely inconclusive.  Despite that, the substance is generally safe and well-tolerated, and many patients anecdotally state improvement in clinical muscle symptoms.  It is clearly possible that this is a placebo effect.  We recommend a 200 mg dose based on the more positive trials.

Alternate-day [31] or twice-weekly dosing of the longer half-life statins (rosuvastatin and atorvastatin) is frequently successful.  We prefer 2.5-5 mg of rosuvastatin or 5-10 mg of atorvastatin.  Finally, drug adherence is very important with all chronic disease medicines, but especially with statins.  Nearly half [32] the patients prescribed a statin will have discontinued it by 6 months.  As such, we allow patients to dose their statin whenever it is convenient.  Earlier statins were prescribed at night, but the newer, more potent statins (rosuvastatin, atorvastatin, and pitavastatin) have long half-lives and are amenable to dosing at any convenient time.

The National Lipid Association has provided an important update [33] on statin safety that is a must-read for anyone who treats lipids.  It describes the current science on safety issues and safety monitoring.  We measure AST and ALT with each follow-up lab test.  However, we only measure CPK in patients at high risk for rhabdomyolysis (elderly, thin, female, baseline renal dysfunction or hepatic impairment, or polypharmacy.)

At the 4-6 week initial follow-up, if LDL-C is not at goal, we will switch to the more potent statin or add ezetimibe 10 mg.  For patients with diabetes, an alternative option is colesevelam, either as a single 3.75 gram dose of dissolving powder or as three 625 mg tablets twice per day.  Colesevalam reduces hemoglobin A1c by approximately 0.5% but is expensive and has some tolerability issues.

Once LDL-C targets have been achieved, we calculate non-HDL-C, or (in patients who can afford the extra cost) we measure LDL-P by NMR or apoB.  Our secondary goal is to bring these numbers to goal.  Usually, this requires the addition of other lipid drugs, specifically fibrates, nicotinic acid, or omega-3 fatty acids.  The clinical trial support for the addition of these substances to statin-based therapy is much more limited.  The recently published ACCORD Trial [34] failed to show a statistically-significant reduction in the composite primary endpoint when fenofibrate was added to statin therapy versus placebo.  In a pre-specified subgroup analysis, however, the group of patients with the most severe dyslipidemia (TG > 200, HDL < 35) did receive a statistically-important reduction in non-fatal MI.

Niacin has been studied in combination with statins in angiographic trials (HATS trial [35]) and in carotid IMT change trials (ARBITER 2 [36], 3 [37], and 6 [38].)  Each of these trials was positive in favor of adding niacin to statins.  Large, prospective, randomized trials (AIM-HIGH, HPS2-Thrive) with clinical endpoints are underway and will likely provide conclusive information.

Omega-3 fatty acid supplementation with statin therapy in high-risk patients has been studied in even fewer trials with the most promising being the Japanese JELIS trial [39].  Omega-3 fatty acids effectively reduce triglycerides (approximately 10% per 1000 mg of DHA+EPA), have little effect on HDL-C, and can actually raise LDL-C.

Figure 3 portrays our use of these add-on medications as well as our safety monitoring.

Severe Triglyceride Elevation

While LDL-C is the primary target for lipid-lowering therapy for the prevention of cardiovascular events, we will occasionally encounter patients with severe hypertriglyceridemia (> 500 mg/dL.)  These patients are at high risk for acute pancreatitis and require treatment of elevated triglycerides before turning one’s attention to LDL-C.

Figure 4 summarizes our approach to patients with severe triglyceride elevation.  Our first goal is to identify other substances or medications which can significantly increase triglycerides.  Common offenders include: oral estrogens (though transdermal or depot injection forms are acceptable), alcohol, corticosteroids, thiazide diuretics, and first and second generation beta-blockers (atenolol, propranolol, bisoprolol, pindolol, acebutolol, and metoprolol.)  Carvedilol and nebivolol appear to have less effect on triglycerides and are acceptable alternatives.  These medications should be discontinued or dosages minimized if possible.

Next, we carefully exclude undiagnosed or under-treated diabetes.  We perform fasting glucose and hemoglobin A1c at a minimum.  For patients with mildly elevated hemoglobin A1c (6.0-6.4%) we will perform a 2-hour post-glucola glucose.  Alternatively, patients can drink 2 regular Cokes to get roughly 75 grams of glucose.  A 2-hour glucose of > 200 mg/dL is diagnostic of diabetes.  Intensive diabetes management will frequently resolve hypertriglyceridemia.

Finally, we ask patients to avoid all alcohol, reduce their weight if overweight or obese, minimize saturated fats and simple sugars, and exercise.  We utilize fibrates and/or high-dose (4000 mg/day) omega-3 fatty acids to medically reduce triglycerides.  We recheck lipids in 2-4 week intervals until the triglyceride level is below 500 mg/dL.  We then treat LDL-C to the appropriate goal.

General Patient Flow

Figure 5 summarizes our patient flow for lipid treatment.  At the initial visit (40 minutes, as a little time spent on the front end gaining buy-in and explaining the rationale for treatment pays huge dividends in terms of drug adherence and lifestyle change), we establish risk categories, define treatment goals, and discuss the role of lipids and lipoproteins in the development and progression of vascular disease.  We stress the fact that the disease is modifiable, regardless of whether patients have already experienced clinical events.

Once lipid-lowering therapy is started, we re-test patients in 4-6 week intervals.  Our purpose is to get early buy-in by showing the power of modern lipid-lowering therapies.  At each subsequent visit, we celebrate successes (lab and lifestyle efforts), evaluate barriers to adherence (drug costs, side effects, confusion, depression, and formulary issues.)  As the regimen becomes more intensive and complex, we spend more time on safety monitoring and long-term compliance with treatment.  Once patients are at goal, we will see them in 3-6 month intervals based on patient preference, reliability, and other pertinent clinical factors.

Clinical Lipidologists

The National Lipid Association [40] was instrumental in the development of the American Board of Clinical Lipidology to define a curriculum and identify expertise in lipid management and vascular medicine.  Lipidologists are a useful resource for difficult and unusual cases such as apparent drug resistance, statin-intolerance, familial hypercholesterolemia, and progressive vascular disease in the setting of “normal” lipids.  A directory [41]of clinical lipidologists is available online.