High-Density Lipoprotein Therapy: Is There Hope?

The treatment of lipid abnormalities generally has focused on low-density lipoprotein cholesterol (LDL-C) reduction based on extensive clinical trials and the National Cholesterol Education Program Adult Treatment Panel III guidelines. Unfortunately, it has become increasingly clear that a significant percentage of patients continue to have cardiovascular events despite being on LDL-C–lowering medications and having LDL-C levels below 100 mg/dL. Numerous epidemiologic studies have associated low high-density lipoprotein cholesterol (HDL-C) levels with increased risk of cardiovascular disease (CVD). Furthermore, recent data show that up to 55% of patients hospitalized for CVD have low HDL-C levels (<40 mg/dL) on admission, suggesting a possible target for further reducing CVD. Low HDL-C also is part of the atherogenic phenotype associated with obesity, glucose intolerance, and hypertension, termed the metabolic syndrome, and often is seen in patients with insulin resistance states. In general, the first line of therapy for increasing HDL-C in patients with levels below 40 mg/dL is lifestyle modification with smoking cessation, exercise, weight loss, and diet modifications. The pharmacologic treatment of isolated low HDL-C in patients without coronary disease is controversial but should be considered in those with a strong family history of CVD. In patients with coronary artery disease and isolated low HDL-C, statins remain the first-line therapy and should be instituted after lifestyle modifications, with the goal of increasing HDL-C above 40 mg/dL. If concomitant hypertriglyceridemia is present, a fibrate or niacin should be considered. Although statins do offer some HDL-C–raising properties, they tend to have modest effects. If treatment goals have not been achieved with either lifestyle changes or statin therapy, then the next agent of choice is niacin. Among the various HDL-C–raising therapies, niacin continues to be the most potent therapeutic option available. There are several novel HDL-C therapies in the research pipeline; however, only one class of medications is relatively close to clinical use, the cholesteryl ester transferase protein (CETP) inhibitors. Although one of the CETP inhibitors, torcetrapib, has received much negative attention from a large randomized trial showing increased mortality associated with its use, the overall class of therapeutic agents may still hold some benefit. Currently, two new CETP inhibitors without the off-target effects of torcetrapib are undergoing clinical research. Overall, the use of HDL-C–modifying agents likely will increase over the next decade.     

The Role of Non-HDL Cholesterol in Risk Stratification for Coronary Artery Disease

Despite aggressive lipid-lowering therapy, patients continue to be at significant risk of coronary heart disease (CHD). Assessment of non–high-density lipoprotein cholesterol (non–HDL-C) provides a measure of cholesterol contained in all atherogenic particles. In the third Adult Treatment Panel (ATP III) guidelines of the US National Cholesterol Education Program, non–HDL-C was introduced as a secondary target of therapy in persons with triglycerides ≥200 mg/dL. A recent meta-analysis of the relationship between non–HDL-C reduction and CHD risk showed non–HDL-C as an important target of therapy for CHD prevention. Most lipid-modifying drugs used as monotherapy have a 1:1 relationship between percent non–HDL-C lowering and percent CHD reduction. In the EPIC-Norfolk prospective population study, 21,448 participants without diabetes or CHD between 45 and 79 years of age were followed for 11.0 years. Participants with high non–HDL-C levels were at increased CHD risk independently of their LDL-C levels. Also, compared to apolipoprotein B, non–HDL-C appears to be a better choice given the fact that no additional tests or costs are needed and established cut points are already available. Future guidelines should emphasize the importance of non–HDL-C for guiding cardiovascular prevention strategies with an increased need to have non–HDL-C reported on routine lipid panels.     

Is combined lipid-regulating therapy safe and feasible for the very old patients with mixed dyslipidemia?

Objectives To detect the efficacy and safety of combined lipid-regulating therapies in the very old patients with mixed dyslipidemia and determine an appropriate therapy for them. Methods Four hundred and fifty patients aged over 75 with mixed dyslipidemia were divided into five groups according to different combination therapies. Lipid levels and drug related adverse events were tested during the study. Results Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were reduced in every group compared to baseline: statin + ezetimibe: -30.0% and -55.5%; statin + policosanol: -31.1% and -51.2%; statin + fibrates: -23.7% and -44.6%; statin + niacin: -25.2% and -43.0%; and niacin + fibrates: -11.3% and -23.5%. The target achievement rates of LDL-C all exceeded 50%, except in niacin + fibrates (42.0%); statin + ezetimibe: 57.0%; statin + policosanol: 56.0%; statin + niacin: 52.0%; and statin + fibrates: 50.0%. However, overall, the niacin + fibrates group was the most effective in decreasing triglyceride (TG) and increasing high-density lipoprotein cholesterol (HDL-C) as follows: niacin + fibrates: -39.3% and 28.6%; statin + fibrates: -29.3% and 18.4%; statin + niacin: -18.5% and 16.7%; statin + ezetimibe: -17.1% and 7.1%; and statin + policosanol: -15.6% and 9.5%. The achievement rates of TG and HDL-C levels in niacin + fibrates (58.0% and 39.0%) were better than the other four groups: statin + niacin (34.0% and 34.0%), statin + fibrates (43.0% and 28.0%), statin + policosanol (30.0% and 24.0%) and statin + ezetimibe (28.0% and 25.0%). Patients in all five groups experiencing drug adverse events were only 2% and no severe adverse events occurred. Conclusions Statin + ezetimibe was the most effective group in lowering TC and LDL-C levels, while niacin + fibrates was the most effective in decreasing TG and increasing HDL-C levels. The commonly used combined lipid-regulating therapies with common dosages in this study were all quite safe and feasible for the very old patients with mixed hyperlipidemia.     

Inhibition of CETP as a novel therapeutic strategy for reducing the risk of atherosclerotic disease.

Lowering low-density lipoprotein cholesterol (LDL-C) levels with statins is a proven strategy for reducing the risk of atherothrombotic cardiovascular disease (CVD). Yet, despite the success of statins in reducing cardiovascular event rates in at-risk patients, many will still experience further events. There is, therefore, a need to develop suitable therapies to reduce this residual risk. Low high-density lipoprotein cholesterol (HDL-C) levels are an important independent risk factor for CVD. Though fibrates, niacin, and statins have been shown to modestly raise HDL-C, there is increasing recognition of the need to develop therapies that can increase HDL-C more robustly. Such therapies may help supplement the LDL-C-lowering benefits of statins. Inhibition of cholesteryl ester transfer protein (CETP) has been identified as a possible strategy for substantially increasing HDL-C levels and CETP inhibitors have demonstrated clinical efficacy, in terms of increasing HDL-C, in preliminary clinical trials, and clinical trials based on outcomes are ongoing. Two CETP inhibitors, JTT-705 and torcetrapib, are now being evaluated more extensively.     

HDL-C and triglyceride levels: relationship to coronary heart disease and treatment with statins

The association between low-density lipoprotein cholesterol (LDL-C) levels and risk of coronary heart disease (CHD) is well established and LDL-C-lowering is currently the primary target for the treatment of dyslipidemia. However, low levels of high-density lipoprotein cholesterol (HDL-C), and high levels of triglycerides (TG) are also risk factors for CHD and modifying levels of these lipid subfractions, in addition to LDL-C lowering, may have clinical benefits in many patients.Statins are the first-line drug therapy for the treatment of dyslipidemia because of their efficacy in lowering LDL-C and good tolerability. Statins also have beneficial effects on TG and HDL-C levels although they differ in the degree to which they modify the levels of these lipoproteins. Improvements across the atherogenic components of the lipid profile may be optimized by the co-administration of a statin with a fibrate, niacin or omega-3 fatty acids; however, particular combination therapies have been associated with side effects and may be poorly tolerated. Newer combinations with better tolerability, or new statins with improved efficacy on non-LDL-C lipid subfractions, would be welcome additions to the currently available therapies for the treatment of dyslipidemia.     

Combination drug therapy for hyperlipidemia

Low-dose combination hypolipidemic therapy may be the best approach to achieve the stringent target low-density lipoprotein cholesterol (LDL-C) levels recommended by the latest National Cholesterol Education Program guidelines in patients with multiple risk factors or existing coronary heart disease. Three randomized, double-blind clinical trials have investigated the efficacy and safety of low-dose fluvastatin, a new, wholly synthetic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, in combination with bile acid sequestrants, fibric acid derivatives, and niacin, respectively. Low-dose fluvastatin coupled with low-dose cholestyramine proved to be significantly more effective than higher doses of either agent alone in reducing LDL-C levels in patients with hypercholesterolemia. The combination was well tolerated, with most adverse events attributable to the gastrointestinal effects of cholestyramine. In patients with heterozygous familial hypercholesterolemia and severely elevated LDL-C and triglyceride (TG) levels, the combination of fluvastatin with bezafibrate was equivalent to fluvastatin plus cholestyramine in lowering LDL-C levels but was superior in raising high-density lipoprotein cholesterol (HDL-C) levels and reducing TG levels. Bezafibrate was considerably better tolerated than cholestyramine. Neither regimen was associated with untoward elevations in hepatic transaminase or creatine phosphokinase levels. Combination therapy with fluvastatin and niacin reduced LDL-C levels by more than 30% in 90% of hypercholesterolemic subjects studied and decreased these levels by more than 40% in 60% of these subjects. The combination also increased HDL-C levels by 36.4%, decreased TG levels by 32%, and reduced lipoprotein (a) levels by 37%. These modifications were achieved without adverse hepatic or myopathic effects. In summary, low-dose fluvastatin can be safely and effective combined with either bile acids, fibrates, or niacin to achie greater reductions in LDL-C than standard monotherapy.     

Low HDL-C: a secondary target of dyslipidemia therapy

Current guidelines for the prevention of coronary heart disease (CHD) focus on lowering low-density lipoprotein cholesterol (LDL-C) as the primary target of lipid-modifying therapy. However, there is increasing interest in high-density lipoprotein cholesterol (HDL-C) as a secondary target of therapy. A wealth of epidemiologic data demonstrate that low levels of HDL-C are associated with an increased risk of CHD events, and data from large-scale clinical trials with statins and fibrates indicate that observed clinical benefits are related, at least in part, to improvements in HDL-C levels. Raising HDL-C levels with therapeutic lifestyle changes and pharmacologic intervention might afford opportunities to further reduce the risk of CHD beyond LDL-C lowering. Statins are first-line pharmacotherapy for dyslipidemia and can also improve HDL-C levels, although the extent to which they modify HDL-C varies. Combining a fibrate or niacin with statin therapy raises HDL-C more than a statin alone but might be associated with reduced tolerability and increased adverse reactions. Several new therapeutic approaches to raising HDL-C are in development, including an HDL mimetic and inhibitors of cholesteryl ester transfer protein. Although lowering LDL-C remains the primary target of lipid-modifying therapy, dyslipidemia therapies that are efficacious for both LDL-C reduction and raising HDL-C might offer further improvements in CHD risk reduction.     

Targeting cardiovascular risk associated with both low density and high density lipoproteins using statin-niacin combination therapy

BACKGROUND: Cardiovascular risk might be reduced by targeted changes in both low density and high density lipoprotein cholesterol (LDL-C and HDL-C). This dual strategy will require a well tolerated, effective regimen, as well as a better understanding of how HDL-C may be targeted. DESIGN: An open-label, uncontrolled, retrospective cohort study of combined statin-niacin therapy. METHODS: We reviewed all patients ( n= 132) started on this combination in a referral lipid clinic over a 6.5-year period for tolerability, safety and effectiveness. RESULTS: Combined therapy was tolerated by 77% of patients. No serious adverse events attributable to medication were encountered. In drug-naive patients (n = 37), moderate doses of statin and niacin (mean 1180 mg/day) reduced LDL-C 31% and increased HDL-C 29% ( P< 0.002, both comparisons). At niacin doses >or= 1000 mg/day (mean 1480) added to a constant statin regimen (n=29), HDL-C increased 20% ( P< 0.001). Even at niacin doses < 1000 mg/day (mean 580, n= 23), HDL-C increased 13% ( P< 0.05). Although mean HDL-C increased, the initial and final HDL-C distributions were broad and largely overlapping. Any chosen cutpoint for HDL-C goal would apply to only a minority of patients. The total/HDL cholesterol ratio had narrower distributions, as the percentage of patients with ratio < 5.0 increased from 17% to 67%. CONCLUSION: Combined statin-niacin therapy lowers LDL-C and raises HDL-C with acceptable tolerance and safety. If treating LDL-C is the primary goal, consistent with current guidelines, then a strategy of targeting the total/HDL cholesterol ratio as a secondary goal is applicable to more patients than targeting HDL-C itself.     

Effective use of combination lipid therapy

Despite the benefits of statin therapy, low-density lipoprotein cholesterol (LDL-C) management remains suboptimal and many patients do not achieve their recommended target goals. The aim of combination lipid drug therapy in high-risk patients is to achieve LDL-C and non-high-density lipoprotein cholesterol (HDL-C) goals with a minimum of serious adverse effects. Although statins are the drug of first choice, statin monotherapy may be limited by intolerance of dose escalation or failure to attain non-HDL-C goals in those with mixed hyperlipidemia. Statins plus bile acid resins or ezetimibe can achieve greater than 50% reduction in LDL-C, with little or no increase in adverse effects. Fibrates, niacin, and omega-3 fatty acids, when added to statins, can reduce triglycerides, increase HDL-C, and reduce non-HDL-C to a greater extent than statin monotherapy. The safety profile of combination lipid therapy is acceptable, if the global coronary heart disease risk of the patient is high, thus producing a favorable risk to benefit ratio. Careful surveillance of hepatic transaminases, avoidance of gemfibrozil in statin-fibrate combinations, and awareness of statin-concomitant drug interactions is key to safe and efficacious use of combination lipid drug therapy.     

Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study)

International guidelines recommend lower target cholesterol levels and treatment of low high-density lipoprotein cholesterol (HDL-C) and elevated triglycerides for patients at moderately high to high coronary heart disease (CHD) risk. Combination therapy is often required to achieve multiple lipid treatment goals, and > or =50% reduction in low-density lipoprotein cholesterol (LDL-C) is needed in some patients to achieve aggressive LDL-C targets. In this context, we evaluated comparative effects on lipid levels of combination therapy at low to moderate doses with a statin plus extended-release niacin (niacin ER), a statin plus ezetimibe, and a highly potent statin alone. This was an open-label, multicenter, 12-week study in 292 patients (50% women) who qualified for drug therapy based on number of CHD risk factors. Patients were randomized to four parallel arms, titrated from low to moderate or high doses: atorvastatin/niacin ER, rosuvastatin/niacin ER, simvastatin/ezetimibe, or rosuvastatin alone. Baseline mean values were, for LDL-C 197 mg/dL (5.1 mmol/L), HDL-C 49 mg/dL (1.3 mmol/L), triglycerides 168 mg/dL (1.9 mmol/L). There were no significant differences among treatment groups in the change from baseline in LDL-C at pre-specified timepoints during treatment. All groups lowered LDL-C by approximately 50% or more (range -49 to -57%), achieving mean levels of 82-98 mg/dL (2.1-2.5 mmol/L). Changes in non-HDL-C (range -46 to -55%) mirrored those for LDL-C and did not differ among treatment groups. Statin/niacin ER combination regimens also increased HDL-C and large HDL (HDL2) and lowered triglycerides and lipoprotein (a) significantly more than other regimens. No drug-related myopathy or hepatotoxicity was observed. In this study, low to moderate dose combination therapy with a statin and niacin ER provided broad control of lipids and lipoproteins independently associated with CHD.     

Therapy to reduce risk of coronary heart disease

Recent primary and secondary intervention studies have shown that reduction of low-density lipoprotein cholesterol (LDL-C) with statins significantly reduced coronary heart disease (CHD) morbidity and mortality. However, many patients with dyslipidemia who have or are at risk for CHD do not reach target LDL-C goals. The recently updated National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines identify a group of patients at very high risk for CHD for more aggressive LDL-C reduction and reaffirm the importance of high-density lipoprotein cholesterol (HDL-C) by raising the categorical threshold to 40 mg/dl. Lipid-lowering therapy needs to be more aggressive in both primary and secondary prevention settings, and therapy should be considered to increase HDL-C as well as lower LDL-C in order to improve patient outcomes. Both combination therapy and the next generation of statins may provide improved efficacy across the dyslipidemia spectrum.     

Do We Know When and How to Lower Lipoprotein(a)?

Opinion statement  

Currently, there are significant data to support a link between lipoprotein(a) [Lp(a)] levels and cardiovascular risk. However, there has not been a clinical trial examining the effects of Lp(a) reduction on cardiovascular risk in a primary prevention population. Until such a trial is conducted, current consensus supports using an Lp(a) percentile greater than 75% for race and gender as a risk stratification tool to target more aggressive low-density lipoprotein cholesterol (LDL-C) or apolipoprotein B (apoB) goals. Therefore, Lp(a) measurements should be considered in the following patients: individuals with early-onset vascular disease determined by clinical presentation or subclinical imaging, intermediate and high Framingham risk patients with a family history of premature coronary disease, and low Framingham risk patients with a family history and low high-density lipoprotein cholesterol (HDL-C) levels. Once LDL-C goals are met, Lp(a) levels may be taken into account in selecting secondary agents to reach more aggressive secondary goals, including non-HDL-C and apoB. To achieve Lp(a) reduction, one evidence-based approach is to initiate therapy with low-dose aspirin and extended-release niacin, titrated from 0.5 g up to 2 g over several weeks. If higher doses of niacin are desired, crystalline niacin allows for titration to a dosage as high as 2 g three times a day; however, the flushing side effect usually is quite prominent. Although hormone replacement therapy (HRT) has been shown to lower Lp(a), there are no indications for using HRT for primary or secondary prevention; therefore, we do not advocate initiating it solely for Lp(a) reduction. LDL apheresis is an option to lower LDL-C levels in patients with homozygous familial hypercholesterolemia who are not responsive to medical therapy. Although it does lower Lp(a), there is no treatment indication for this. A recent study supports the cholesterol absorption inhibitor ezetimibe’s ability to lower Lp(a), a finding that deserves further investigation as it has not been previously reported in multiple ezetimibe trials. Additionally, the apoB messenger RNA antisense therapy mipomersen currently is in phase 3 trials and may serve as a potential inhibitor of Lp(a) production. Ultimately, more trial evidence is needed to determine whether lowering Lp(a) actually reduces cardiovascular risk, although this may be difficult to isolate without a specific Lp(a)-lowering therapy.     

Residual risk in statin-treated patients: Future therapeutic options

Statin therapy for aggressive low-density lipoprotein cholesterol (LDL-C) reduction reduces cardiovascular morbidity and mortality. However, even on maximal statin therapy, high-risk patients have substantial residual risk of coronary heart disease (CHD). Certain subgroups, such as individuals with diabetes mellitus, low high-density lipoprotein cholesterol (HDL-C), metabolic syndrome, or other comorbidities, have a particularly high residual risk. Patients at high risk for future CHD events often require multiple aggressive risk-reduction therapies (eg, antiplatelet agents, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, beta-blockade, cholesterol and/or diabetes management, and lifestyle interventions) to further lower their overall cardiovascular risk. For cholesterol management, combination therapy may be required to attain optimal levels of LDL-C, HDL-C, and non-HDL-C.     

HDL and CETP Inhibition: Will This DEFINE the Future?

OPINION STATEMENT: The premature stopping of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health) study due to futility has called into question the clinical value of high-density lipoprotein cholesterol (HDL-C) increases. The failure of estrogen therapy in the HERS (Heart and Estrogen/progestin Replacement Study) trial and the cholesteryl ester transfer protein (CETP) inhibitors torcetrapib (in the ILLUMINATE [Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events] trial) and, most recently, dalcetrapib in the dal-OUTCOMES trial has cast doubt on the "HDL-raising hypothesis" for providing additional benefits on top of statin therapy. The AIM-HIGH trial was designed to equalize low-density lipoprotein cholesterol (LDL-C) levels between the two treatment groups while the niacin arm would have a higher HDL-C. The study population included patients with low HDL-C and cardiovascular disease (CVD); because this population has a high residual risk for CVD on statin therapy, these patients were most likely to benefit from the niacin HDL-C-raising effect. These findings are disappointing because clinicians have used extended-release niacin to treat patients with low HDL-C because niacin has demonstrated benefit in earlier reported studies in conjunction with statins and other drugs, as observed in the Cholesterol Lowering Atherosclerosis Study (CLAS) and the HDL-Atherosclerosis Treatment Study (HATS). In the Coronary Drug Project, niacin alone was shown to reduce myocardial infarction, stroke, and the need for coronary bypass surgery. Niacin does not increase the number of HDL particles to the same extent it raises HDL-C. Niacin alters the composition of HDL, making the particle larger, which is similar to the effects of CETP inhibition on HDL. Both niacin and CETP inhibitors decrease the catabolism of HDL, thereby increasing the size of the HDL particle and raising HDL-C. Dalcetrapib, which does not decrease LDL-C while raising HDL-C, was recently discontinued from clinical development due to a interim analysis that determined that the study was futile. Anacetrapib, which markedly increases HDL-C while also significantly lowering LDL-C, remains in clinical development, with a large cardiovascular end point trial currently enrolling 30,000 high-risk patients. For now, the goal remains the achievement of LDL-C and non-HDL targets, and low HDL-c remains a significant independent risk factor, but there is insufficient evidence that raising HDL-C will provide a clinical benefit.     

Efficacy of extended-release niacin with lovastatin for hypercholesterolemia: assessing all reasonable doses with innovative surface graph analysis

BACKGROUND: Combination therapy to improve the total lipid profile may achieve greater coronary risk reductions than lowering low-density lipoprotein cholesterol (LDL-C) alone. A new extended-release niacin (niacin ER)/lovastatin tablet substantially lowers LDL-C, triglyceride, and lipoprotein(a) levels and raises high-density lipoprotein cholesterol (HDL-C) level. We evaluated these serum lipid responses to niacin ER/lovastatin at all clinically reasonable doses. METHODS: Men (n = 85) and women (n = 79) with type IIa or IIb primary hyperlipidemia after diet were randomized among 5 parallel treatment arms. Each arm had 5 sequential 4-week treatment periods: niacin ER (starting at 500 mg/d, increasing in 500-mg increments to 2500 mg/d); lovastatin (starting at 10 mg, increasing to 20 mg, then 40 mg/d); and 3 combinations arms, each with a constant lovastatin dose and escalating niacin ER doses. RESULTS: For primary comparisons, mean LDL-C level reductions from baseline were greater with niacin ER/lovastatin (1500/20 mg) than with lovastatin (20 mg) (35% vs 22%, P<.001) and with niacin ER/lovastatin (2000/40 mg) than with lovastatin (40 mg) (46% vs 24%, P<.001). Each 500-mg increase in niacin ER, on average, decreased LDL-C levels an additional 4% and increased HDL-C levels 8%. The maximum recommended dose (2000/40 mg/d) increased HDL-C levels 29% and decreased LDL-C levels 46%, triglyceride levels 38%, and lipoprotein(a) levels 14%. All lipid responses were dose dependent and generally additive. Graphs of the dose-response relationships as 3-dimensional surfaces documented the strength and consistency of these responses. CONCLUSIONS: Niacin ER/lovastatin combination therapy substantially improves 4 major lipoprotein levels associated with atherosclerotic disease. Dose-response surfaces provide a practical guide for dose selection.     

What Combination Therapy with a Statin,If Any,Would You Recommend?

The latest recommended goals for blood lipid levels may require multiple lipid drugs. Lower doses in combination may render more efficacy and safety than highest doses of single agents. Except for isolated hypoalphalipoproteinemia (a low level of high-density lipoprotein cholesterol), therapies will start with a statin. All marketed statins are acceptable. The choice may be based on dose- efficacy and patient’s tolerability. High-potency statins (eg, atorvastatin, simvastatin, or rosuvastatin) are often chosen. Currently, generic statins, such as simvastatin, lovastatin, pravastatin, and fluvastatin, offer cost benefits. The choice of added agent depends on the “residual lipoprotein abnormalities” after statin therapy, efficacy, compliance issues, and cost. Approved “combined” preparations improve cost and compliance. To further lower low-density lipoprotein cholesterol, ezetimibe is a safe, efficacious choice, pending resolution of a controversial trial’s results. Colesevelam is moderately effective and the best tolerated bile acids sequestrant. In combined dyslipidemias, extended-release niacin is the best tolerated niacin preparation; other quality-controlled immediate-release preparations have similar safety and efficacy but produce more flushing of the skin. Niacin or fenofibrate is effective in normalizing high-density lipoprotein and triglyceride levels persisting after statin therapy. Agents approved by the US Food and Drug Administration and the latest guidelines of the National Cholesterol Education Program, American Heart Association/American College of Cardiology provide choices and indications of drug combinations.     

Management of Hypertriglyceridemia in the Diabetic Patient

The hypertriglyceridemia of diabetes can be classified into mild to moderate (triglycerides between 150–499 mg/dL) and severe hypertriglyceridemia (triglycerides ≥500 mg/dL). As in any other individuals with hypertriglyceridemia, secondary causes need to be excluded. The management of severe hypertriglyceridemia (chylomicronemia syndrome) includes aggressive reduction of triglycerides with intravenous insulin, fibrates, omega-3 fatty acids, and/or niacin therapy to avert the risk of pancreatitis. In patients with mild to moderate hypertriglyceridemia, the treatment of choice is statin therapy to achieve the low-density lipoprotein (LDL) and non-high-density lipoprotein (HDL) target goals. The evidence base would favor niacin therapy in combination with statin therapy to achieve the goals pertaining to LDL cholesterol and non-HDL cholesterol. The data about the combination of fibrate therapy with statin therapy are disappointing.     

Residual Cardiovascular Risk Despite Optimal LDL Cholesterol Reduction with Statins: The Evidence,Etiology, and Therapeutic Challenges

This review captures the existence, cause, and treatment challenges of residual cardiovascular risk (CVR) after aggressive low-density lipoprotein cholesterol (LDL-C) reduction. Scientific evidence implicates low high-density lipoprotein cholesterol (HDL-C) and high triglycerides (TG) in the CVR observed after LDL-C lowering. However, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial with fenofibrate, the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) study with torcetrapib, and the recently terminated Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study with niacin, do not clearly attribute risk reduction value to HDL-C/TG modulation. The optimum approach to long-term lipid-modifying therapies for CVR reduction remains uncertain. Consequently, absolute risk modulation via lifestyle changes remains the centerpiece of a strategy addressing the physiologic drivers of CVR associated with HDL-C/TG, especially in the context of diabetes/metabolic syndrome.     

Low high-density lipoprotein cholesterol and cardiovascular disease: risk reduction with statin therapy

A low level of high-density lipoprotein cholesterol (HDL-C) is a major risk factor for cardiovascular disease; however, patients with low levels of HDL-C without raised low-density lipoprotein cholesterol (LDL-C) levels are not currently eligible for lipid-lowering therapy. Many individuals with low levels of HDL-C have a combination of cardiovascular risk factors that include high LDL particle concentrations. Lowering LDL particle concentration and its surrogate measure, LDL-C, is an important approach to reducing cardiovascular risk. Statins are the most effective agents for lowering levels of LDL and can significantly increase levels of HDL-C. Extending statin therapy to patients with low levels of HDL-C but with LDL-C levels below target may have benefits for cardiovascular disease reduction in these patients.     

The triglyceride-high-density lipoprotein axis: an important target of therapy?

Coronary heart disease is the single largest cause of morbidity and mortality in the United States. The link between elevated low-density lipoprotein cholesterol (LDL-C) levels and coronary heart disease (CHD) has been clearly established. However, triglycerides (TG) are increasingly believed to be independently associated with CHD, while high-density lipoprotein cholesterol (HDL-C) is inversely associated with CHD risk. High TG and low HDL often occur together, often with normal levels of LDL-C, and can be described as abnormalities of the TG-HDL axis. This lipid abnormality is a fundamental characteristic of patients with the metabolic syndrome, a condition strongly associated with the development of both type 2 diabetes and CHD. Patients with high TG and low HDL-C should be aggressively treated with therapeutic lifestyle changes. For high-risk patients, lipid-modifying therapy that specifically addresses the TG-HDL axis should also be considered. Current pharmacologic treatment options for such patients include statins, fibrates, niacin, fish oils, and combinations thereof. Several new pharmacologic approaches to treating the TG-HDL axis are currently being investigated. More clinical trial data is needed to test the hypothesis that pharmacologic therapy targeting the TG-HDL axis reduces atherosclerosis and cardiovascular events.