Effectiveness of a Novel ω-3 Krill Oil Agent in Patients With Severe Hypertriglyceridemia: A Randomized Clinical Trial.

Importance: Intense interest exists in novel ω-3 formulations with high bioavailability to reduce blood triglyceride (TG) levels. Objective: To determine the phase 3 efficacy and safety of a naturally derived krill oil with eicosapentaenoic acid and docosahexaenoic acid as both phospholipid esters (PLs) and free fatty acids (FFAs) (ω-3-PL/FFA [CaPre]), measured by fasting TG levels and other lipid parameters in severe hypertriglyceridemia. Design, Setting, and Participants: This study pooled the results of 2 identical randomized, double-blind, placebo-controlled trials. TRILOGY 1 (Study of CaPre in Lowering Very High Triglycerides) enrolled participants at 71 US centers from January 23, 2018, to November 20, 2019; TRILOGY 2 enrolled participants at 93 US, Canadian, and Mexican centers from April 6, 2018, to January 9, 2020. Patients with fasting TG levels from 500 to 1500 mg/dL, with or without stable treatment with statins, fibrates, or other agents to lower cholesterol levels, were eligible to participate. Interventions: Randomization (2.5:1.0) to ω-3-PL/FFA, 4 g/d, vs placebo (cornstarch) for 26 weeks. Main Outcomes and Measures: The primary outcome was the mean percentage of change in TG levels at 12 weeks; persistence at 26 weeks was the key secondary outcome. Other prespecified secondary outcomes were effects on levels of non-high-density lipoprotein cholesterol (non-HDL-C), very-low-density lipoprotein cholesterol (VLDL-C), HDL-C, and low-density lipoprotein cholesterol (LDL-C); safety and tolerability; and TG level changes in prespecified subgroups. Results: A total of 520 patients were randomized, with a mean (SD) age of 54.9 (11.2) years (339 men [65.2%]), mean (SD) body mass index of 31.5 (5.1), and baseline mean (SD) TG level of 701 (222) mg/dL. Two hundred fifty-six patients (49.2%) were of Hispanic or Latino ethnicity; 275 (52.9%) had diabetes; and 248 (47.7%) were receiving statins. In the intention-to-treat analysis, TG levels were reduced by 26.0% (95% CI, 20.5%-31.5%) in the ω-3-PL/FFA group and 15.1% (95% CI, 6.6%-23.5%) in the placebo group at 12 weeks (mean treatment difference, -10.9% [95% CI, -20.4% to -1.5%]; P = .02), with reductions persisting at 26 weeks (mean treatment difference, -12.7% [95% CI, -23.1% to -2.4%]; P = .02). Compared with placebo, ω-3-PL/FFA had no significant effect at 12 weeks on mean treatment differences for non-HDL-C (-3.2% [95% CI, -8.0% to 1.6%]; P = .18), VLDL-C (-3.8% [95% CI, -12.2% to 4.7%]; P = .38), HDL-C (0.7% [95% CI, -3.7% to 5.1%]; P = .77), or LDL-C (4.5% [95% CI, -5.9% to 14.8%]; P = .40) levels; corresponding differences at 26 weeks were -5.8% (95% CI, -11.3% to -0.3%; P = .04) for non-HDL-C levels, -9.1% (95% CI, -21.5% to 3.2%; P = .15) for VLDL-C levels, 1.9% (95% CI, -4.8% to 8.6%; P = .57) for HDL-C levels, and 6.3% (95% CI, -12.4% to 25.0%; P = .51) for LDL-C levels. Effects on the primary end point did not vary significantly by age, sex, race and ethnicity, country, qualifying TG level, diabetes, or fibrate use but tended to be larger among patients taking statins or cholesterol absorption inhibitors at baseline (mean treatment difference, -19.5% [95% CI, -34.5% to -4.6%]; P = .08 for interaction) and with lower (less than median) baseline blood eicosapentaenoic acid plus docosahexaenoic acid levels (-19.5% [95% CI, -33.8% to -5.3%]; P = .08 for interaction). ω-3-PL/FFA was well tolerated, with a safety profile similar to that of placebo. Conclusions and Relevance: This study found that ω-3 -PL/FFA, a novel krill oil-derived ω-3 formulation, reduced TG levels and was safe and well tolerated in patients with severe hypertriglyceridemia. Trial Registration: ClinicalTrials.gov Identifiers: NCT03398005 and NCT03361501.

Comparing patients' prescribed, self-reported, and actual intake of supplemental eicosapentaenoic acid + docosahexaenoic acid.

BACKGROUND: Dietary fish oil supplements containing the omega-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are frequently used for cardiovascular benefit. However, several factors may limit the intake of prescribed doses. OBJECTIVE: The objective of this study is to compare the prescribed, patient self-reported, and actual intake of supplemental EPA + DHA doses in a lipid-specialty clinic and identify common barriers and influences to therapy. METHODS: Seventy-six patients prescribed supplemental fish oil were randomly selected to participate in a 28-item cross-sectional survey for evaluating patient knowledge and intake of prescribed supplemental EPA + DHA doses. Self-reported data were collected during a follow-up clinic visit, whereas actual intake was determined when patients had access to their fish oil bottle. These data were compared with their chart-documented prescribed EPA + DHA dose. RESULTS: Many patients were well-educated and had attended the lipid-specialty clinic for approximately 2 years but only 28.9% were confident that they could accurately recall their daily EPA + DHA dose. There were statistically significant differences between the prescribed doses and patients' self-reported doses (3600 mg vs 2750 mg, P = .014), as well as between prescribed doses and actual intake (3600 mg vs 1575 mg, P < .001). Patients reported multiple barriers and influences to explain their use of fish oil products. CONCLUSION: Most patients using supplemental fish oil in a lipid-specialty clinic were not taking the prescribed amount of EPA + DHA, with many using markedly lower than prescribed doses. This is likely because of several factors including the complexities of supplemental fish oil doses and labeling, product availability, and discount sales. These findings suggest that supplemental fish oil requires continuous education and dosing guidance.

The Role of Nutraceuticals in Statin Intolerant Patients.

Statins are the most common drugs administered for patients with cardiovascular disease. However, due to statin-associated muscle symptoms, adherence to statin therapy is challenging in clinical practice. Certain nutraceuticals, such as red yeast rice, bergamot, berberine, artichoke, soluble fiber, and plant sterols and stanols alone or in combination with each other, as well as with ezetimibe, might be considered as an alternative or add-on therapy to statins, although there is still insufficient evidence available with respect to long-term safety and effectiveness on cardiovascular disease prevention and treatment. These nutraceuticals could exert significant lipid-lowering activity and might present multiple non-lipid-lowering actions, including improvement of endothelial dysfunction and arterial stiffness, as well as anti-inflammatory and antioxidative properties. The aim of this expert opinion paper is to provide the first attempt at recommendation on the management of statin intolerance through the use of nutraceuticals with particular attention on those with effective low-density lipoprotein cholesterol reduction.

Variability in Potency Among Commercial Preparations of Berberine.

Berberine is an isoquinoline alkaloid plant extract that is widely available as a dietary supplement in the United States and has demonstrated efficacy in the treatment of type 2 diabetes mellitus and dyslipidemia. Because of its increased use and purported pharmacological properties, potential variations in product quality could pose a barrier to berberine's safety and effectiveness in clinical practice. Thus, this study evaluated the potency of dietary supplements containing berberine available in the U.S. commercial market. Fifteen unique dietary supplements containing berberine were purchased through U.S. dietary supplement vendors. For each product, berberine was extracted from 3 unique capsules and analyzed by ultra-high-performance liquid chromatography tandem mass spectrometry. Percentage content based on the product label claim was determined for each product. The average berberine content across the products was found to be 75% ± 25% of the product label claim, with product potency ranging from 33% to 100%. Nine of the 15 tested products (60%) failed to meet the potency standards of 90% to 110% of labeled content claim, as commonly required of pharmaceutical preparations by the U.S. Pharmacopeial Convention. Evaluation of the relationship between product cost and the measured potency failed to demonstrate an association between quality and cost. Variability in product quality may significantly contribute to inconsistencies in the safety and effectiveness of berberine. In addition, the quality of the berberine product cannot be inferred from its cost.

Statins and almonds to lower lipoproteins (the STALL Study).

BACKGROUND: Dietary supplementation with almonds has demonstrated dose-dependent decreases in low-density lipoprotein cholesterol (LDL-C), likely because of their composition of beneficial nutrients including mono- and polyunsaturated fatty acids, fiber, and protein. OBJECTIVE: The primary objective of this study was to determine the changes in the lipid profile (LDL-C, high-density lipoprotein cholesterol [HDL-C], triglycerides, total cholesterol, non-HDL-C), LDL-C particle size, and lipoprotein (a) when 100 g of almonds daily were added to background statin therapy for 4 weeks. METHODS: Subjects (N = 48) receiving a consistent statin dose were randomized to 100 g of almonds daily and to The National Cholesterol Education Program Adult Treatment Panel's third report Therapeutic Lifestyle Changes Diet counseling (almond group; n = 22) or solely Adult Treatment Panel's third report Therapeutic Lifestyle Changes Diet counseling (non-almond group; n = 26), for 4 weeks. RESULTS: No significant changes in weight and weekly physical activity were noted between the 2 groups from baseline. However, the almond group consumed significantly more calories at 4 weeks compared with controls. The almond group experienced a 4.9% reduction in non-HDL-C compared with a 3.5% increase for the non-almond group (P = .02). Additionally, notable improvements were observed in LDL-C and triglycerides, but did not achieve statistical significance (P = .068 for both parameters). There was also a shift from LDL pattern A to pattern B particles (P = .003) in the almond group. No significant differences in total cholesterol (P = .1), HDL-C (P = .3), or lipoprotein (a) (P = .1) were observed. CONCLUSION: Adding 100 g of almonds daily to chronic statin therapy for 4 weeks significantly reduced non-HDL-C. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00603876.

Analysis of vitamin D levels in patients with and without statin-associated myalgia - a systematic review and meta-analysis of 7 studies with 2420 patients.

INTRODUCTION: Vitamin D (vit D) deficiency may be associated with an increased risk of statin-related symptomatic myalgia in statin-treated patients. The aim of this meta-analysis was to substantiate the role of serum vitamin D levels in statin-associated myalgia. METHODS: The search included PUBMED, Cochrane Library, Scopus, and EMBASE from January 1, 1987 to April 1, 2014 to identify studies that investigated the impact of vit D levels in statin-treated subjects with and without myalgia. Two independent reviewers extracted data on study characteristics, methods and outcomes. Quantitative data synthesis was performed using a fixed-effect model. RESULTS: The electronic search yielded 437 articles; of those 20 were scrutinized as full texts and 13 studies were considered unsuitable. The final analysis included 7 studies with 2420 statin-treated patients divided into subgroups of patients with (n=666 [27.5%]) or without (n=1754) myalgia. Plasma vit D concentrations in the symptomatic and asymptomatic subgroups were 28.4±13.80ng/mL and 34.86±11.63ng/mL, respectively. The combination of data from individual observational studies showed that vit D plasma concentrations were significantly lower in patients with statin-associated myalgia compared with patients not manifesting this side effect (weighted mean difference -9.41ng/mL; 95% confidence interval: -10.17 to -8.64; p<0.00001). CONCLUSIONS: This meta-analysis provides evidence that low vit D levels are associated with myalgia in patients on statin therapy. Randomized controlled trials are necessary to establish whether vitamin D supplementation reduces the risk for statin-associated myalgia.

Effects of Xuezhikang in patients with dyslipidemia: a multicenter, randomized, placebo-controlled study.

BACKGROUND: Xuezhikang (XZK) is an extract of fermented red yeast rice that has lipid-lowering properties. OBJECTIVE: To evaluate the effects of XZK on lipids in subjects with dyslipidemia but no coronary heart disease. METHODS: A total of 116 adults with baseline non-high-density lipoprotein cholesterol (non-HDL-C) levels of approximately 208 mg/dL and low-density lipoprotein cholesterol (LDL-C) levels of approximately 175 mg/dL were randomized to either placebo or XZK 1200 or 2400 mg daily and treated for 12 weeks. RESULTS: A majority of the patients were white (53.4%) or Asian (37.1%). Daily XZK 1200 mg and 2400 mg for 4 to 12 weeks resulted in statistically significant (P < .001) and clinically meaningful decreases in non-HDL-C (∼24% reduction) and LDL-C (∼27% reduction) compared with placebo. XZK treatment at either dose enabled approximately 50% of subjects to reduce their LDL-C levels by ≥ 30%. Doubling the XZK daily dose from 1200 to 2400 mg at treatment week 8 caused an additional 4.6% reduction in LDL-C. Significant benefits were also observed across secondary efficacy variables, including total cholesterol (TC), apolipoprotein B (Apo B), triglycerides, HDL-C, the TC/HDL-C ratio, and the Apo B/Apo A-I ratio, at treatment week 8 or 12. XZK was safe and well tolerated. Safety and tolerability profiles were similar across treatment groups. Most adverse events were gastrointestinal. No subject experienced myopathy or markedly elevated liver transaminases or creatine kinase. CONCLUSION: Xuezhikang significantly reduced non-HDL-C and LDL-C, and was well tolerated. Further, longer-term studies in more diverse patient populations are needed to corroborate these findings.

Apple pectin for the reduction of niacin-induced flushing.

BACKGROUND: Niacin, or vitamin B3, when used in high doses can significantly improve the levels of all major lipoproteins. Despite these benefits, the use of niacin is greatly limited secondary to benign yet bothersome cutaneous flushing primarily involving the face and upper extremities. Pretreatment with aspirin or other prostaglandin inhibitors has demonstrated significant reductions in niacin-induced flushing (NIF), but other treatment options are needed. Clinical and anecdotal evidence suggests the ingestion of pectin-containing fruits (eg, apple) mitigates NIF; however, clinical trials evaluating this are nonexistent. OBJECTIVE: That pretreatment with encapsulated apple pectin would limit the incidence, severity, time of initiation, and duration of NIF. METHODS: We enrolled 100 niacin-naïve subjects (n = 25 per group) and preteated them in a double-blind manner with apple pectin, apple pectin + aspirin, aspirin, or placebo, followed by a one-time 1000 mg dose of niacin extended-release (niacin ER). Subjects then assessed major flushing parameters hourly for the next 6 hours with a validated visual analog scale. RESULTS: Apple pectin and aspirin each significantly lowered the duration of NIF and produced nonsignificant but positive improvements in all other major flushing parameters compared with placebo. CONCLUSION: Apple pectin may potentially be an alternative to aspirin for the prevention of NIF. Larger trials are needed to further evaluate the benefit of pectin on NIF.

Pseudohypertriglyceridemia: two cases of probable glycerol kinase deficiency.

The National Cholesterol Educational Program Adult Treatment Panel's third report define borderline-high, high, and very high triglycerides as serum levels of 150-199 mg/dL, 200-499 mg/dL, and ≥500 mg/dL, respectively. Hypertriglyceridemia (HTG) is generally very responsive to both therapeutic lifestyle changes (TLC), and drug therapy, with niacin, omega-3 fatty acids, fibrates, and statins, each reducing levels by ~10-50%. This paper presents two cases of patients who were aggressively treated for significant HTG with little response to therapy. Although most measured triglyceride (TG) values in these patients were markedly elevated, periodic concentrations were reported as normal. When this occurs, the clinician must immediately think of the diagnosis 'pseudohypertriglyceridemia' or as it is more aptly termed 'glycerolemia' secondary to glycerol kinase deficiency (GKD).

The high-dose rosuvastatin once weekly study (the HD-ROWS).

BACKGROUND: Alternative dosing is often used clinically to address common barriers with statin therapy, such as intolerance and cost. Previous findings have demonstrated significant and clinically similar reductions in low-density lipoprotein (LDL) cholesterol to daily dosing, when comparing similar total weekly doses. OBJECTIVE: To determine whether rosuvastatin 80 mg once weekly produced comparable lipid and high-sensitivity C-reactive protein (hsCRP) changes to atorvastatin 10 mg daily, when measured at key points after last dose. METHODS: This was a randomized, double-blind, parallel group, 8-week pilot study. Eligible subjects, 18 to 65 years of age, had documented dyslipidemia with LDL cholesterol >100 mg/dL and triglycerides <200 mg/dL. Participants were randomized to receive either rosuvastatin 80 mg once weekly (n = 10) or atorvastatin 10 mg daily (n = 10), for 8 weeks. Lipid panels and hsCRP were measured at baseline and 1-4 and 5-8 days after the last dose. RESULTS: Participants in each arm experienced significant and comparable reductions from baseline in total cholesterol, total cholesterol/high-density lipoprotein cholesterol ratio, non-high-density lipoprotein cholesterol, and overall LDL cholesterol (-29%). Changes in high-density lipoprotein cholesterol, triglycerides, and hsCRP were nonsignificant and similar between groups. Each regimen was well tolerated, with no major adverse events reported. CONCLUSION: Rosuvastatin 80 mg once weekly produced comparable lipid changes to atorvastatin 10 mg daily when measured at specific points after the last dose. Our findings support previous data demonstrating a significant reduction in LDL-C with once weekly statin dosing.

Modified-policosanol does not reduce plasma lipoproteins in hyperlipidemic patients when used alone or in combination with statin therapy.

Policosanol is a poorly absorbed nutritional supplement used primarily for cholesterol management. Findings from previous trials evaluating the effects of policosanol are mixed with early data reporting positive lipid effects while more recent studies indicate negligible efficacy. We hypothesized that re-formulating policosanol would result in an improvement in major lipoproteins and possibly provide some explanation for previously conflicting trial data. Our primary objectives were to assess the efficacy and safety of modified-policosanol (MP) on the major lipoproteins among hyperlipidemic subjects receiving background statin therapy or as monotherapy. This 8-week clinical trial consisted of 3 arms. Subjects receiving chronic statin therapy (N = 36) were randomized in a double-blind design to MP 20 mg daily or placebo. In the third arm, subjects not receiving statin therapy (N = 18) were assigned open-label MP 20 mg daily. The utilization of MP when added to background statin therapy or as monotherapy resulted in no significant changes in major lipoproteins (all p > 0.05). The MP therapy was well tolerated with no major adverse events reported. Consistent with recent clinical trial data, MP demonstrated an excellent safety profile but produced no significant effects on major lipoproteins when used as monotherapy or when given with concomitant statin therapy.

Important considerations for treatment with dietary supplement versus prescription niacin products.

Niacin is a water-soluble B vitamin (B3) known to have favorable effects on multiple lipid parameters, including raising high-density lipoprotein cholesterol (HDL-C) levels and lowering triglycerides (TGs), lipoprotein(a), and low-density lipoprotein cholesterol (LDL-C). Although LDL-C remains the primary target of lipid-altering therapy, current guidelines emphasize HDL-C and other modifiable lipid factors as key secondary targets. Thus, niacin is considered an important therapeutic option to help reduce the risk of cardiovascular disease in patients with mixed dyslipidemia who, in addition to high LDL-C, have elevated TGs and low HDL-C. Although available prescription niacin products, including immediate-release niacin (IR; Niacor) and an extended-release niacin formulation (Niaspan), have demonstrated safety and efficacy in randomized clinical trials, confusion remains among health care providers and their patients regarding the various commercially available nonprescription dietary supplement niacin products. These dietary supplements, which include IR, sustained-release (SR), and "no-flush" or "flush-free" niacin products, are not subject to the same stringent US Food and Drug Administration regulations as prescription drugs. In fact, both the American Heart Association and the American Pharmacists Association recommend against the use of dietary supplement niacin as a substitute for prescription niacin. Although some dietary supplement IR and SR niacin products have demonstrated a lipid response in clinical trials, products labeled as "no-flush" or "flush-free" that are intended to avoid the common niacin-associated adverse effect of flushing generally contain minimal or no free, pharmacologically active niacin and therefore lack beneficial lipid-modifying effects. To clarify important differences between available prescription and dietary supplement niacin products, this article contrasts current regulatory standards for dietary supplements and prescription drugs and provides an overview of available clinical data from key trials of niacin.