Residual Cardiovascular Disease Risk Research Articles

Lipids and Lipoproteins in Risk Prediction.

Ischemic heart disease remains the leading cause of death worldwide. Low-density lipoprotein cholesterol (LDL-C) has proved to have a causal relationship with atherosclerotic cardiovascular disease. Lowering LDL-C improves outcomes, although some patients continue to have residual risk of cardiovascular disease. Cardiovascular risk prediction calculators are routinely used in to identify patients most at risk. Research into other lipoprotein factors has suggested that they may have advantages over LDL-C and improve the ability to identify those most at risk. Although some technology is not widely available, there is potential for better risk prediction in specific groups.

Diabetes and lipid metabolism.

The authors review the association between diabetes mellitus (DM) and aberrations of lipid metabolism related to DM, diabetic dyslipidemia (DD). DM is considered as a major health burden worldwide and one of the most important modifiable cardiovascular disease (CVD) risk factors. This applies to both the developed and the developing countries, especially the latter. While patients with type 1 DM, 10% of all DM cases, usually do not have dyslipidemia, DD is frequent among patients with type 2 DM (T2DM) (prevalence > 75%) and is mainly a mixed dyslipidemia [increase in triglycerides (TGs), low high-density lipoprotein cholesterol (HDL-C), and small-dense (atherogenic), low-density lipoprotein cholesterol (LDL-C) particles]. The components of DD, which is characterized by quantitative (mentioned above), qualitative, and kinetic abnormalities all contributing to CVD risk, are mostly related to insulin resistance. Statins, ezetimibe, and PCSK9 inhibitors can be used in monotherapy or consecutively in combinations if needed. Statins compose the main drug. For the residual CVD risk after statin treatment, the use of statin-fibrate combinations is indicated only in patients with mixed dyslipidemia. In conclusion, DD is a major health problem worldwide. It is a significant CVD risk factor and should be treated according to current guidelines. The means today exist to normalize all quantitative, qualitative, and kinetic aberrations of DD, thereby reducing CVD risk.

Residual risk of cardiovascular disease: high blood lipoprotein (a)

Residual risk of cardiovascular disease: high blood lipoprotein (a)

Incidence of cardiovascular disease in individuals affected by recent changes to US blood pressure treatment guidelines.

We evaluated the incidence of cardiovascular disease (CVD) in individuals whose blood pressure (BP) management strategy would change with adoption of recent US hypertension guidelines in two large, community-based cohorts with different racial and geographic compositions: the Framingham and Jackson Heart Studies (FHS and JHS). We assigned 11 237 FHS (mean age 46, 53% women) and 2948 JHS (mean age 55, 69% women) participants free of CVD and chronic kidney disease to one of five categories representing different treatment recommendations between 2014 Evidence-Based Guidelines for the Management of High Blood Pressure in Adults: Report from the Panel Members Appointed to the Eighth Joint National Committee and The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines. Absolute incidence rates (incidence rate; per 1000 person-years) and multivariable-adjusted hazard ratios were calculated for each group; cohort-specific results were combined using fixed effect meta-analysis. CVD events occurred in 1047 FHS and 230 JHS participants during mean follow-up times of 11 and 8.9 years, respectively. Compared with individuals without hypertension, those with BP 140-149/<90 mmHg had increased risk for CVD regardless of treatment status [hazard ratio for untreated BP 140-149/<90 mmHg 1.96, 95% confidence interval (CI) 1.40-2.75; hazard ratio for treated BP 140-149/<90 mmHg 3.37, 95% CI 2.37-4.78]. The risk for those with treated BP 140-149/<90 mmHg was consistent in those aged at least 60 years (hazard ratio: 2.61, 95% CI 1.75-3.90). Statistical power was limited to evaluate the effect of diabetes. Individuals with treated BP 140-149/<90 mmHg have increased risk of CVD compared with those without hypertension including in participants at least 60 years. The 2014 Evidence-Based Guidelines for the Management of High Blood Pressure in Adults: Report from the Panel Members Appointed to the Eighth Joint National Committee recommendations to treat BP levels less aggressively may be associated with substantial residual CVD risk.

Relations of GlycA and lipoprotein particle subspecies with cardiovascular events and mortality: A post hoc analysis of the AIM-HIGH trial

The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes trial showed no incremental benefit of extended-release niacin (ERN) therapy added to simvastatin in subjects with cardiovascular disease (CVD). To examine the effects of ERN treatment on lipoprotein particles and GlycA, a new marker of systemic inflammation, and their relations with incident CVD events including mortality. GlycA and very low-density lipoprotein, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) particle subclasses were quantified by nuclear magnetic resonance spectroscopy using available stored baseline (n=2754) and 1-year in-trial (n=2581) samples. Associations with CVD events and all-cause mortality were assessed using multivariable Cox proportional hazards regression adjusted for age, sex, diabetes, treatment assignment, and lipoproteins. Compared to placebo, ERN treatment lowered very low-density lipoprotein and LDL and increased HDL particle concentrations, increased LDL and HDL particle sizes (all P<.0001), but did not affect GlycA. Baseline and in-trial GlycA levels were associated with increased risk of CVD events: hazard ratio (HR) per SD increment, 1.17 (95% confidence interval [CI], 1.06-1.28) and 1.13 (1.02-1.26), respectively. However, none of the lipoprotein particle classes or subclasses was associated with incident CVD. By contrast, all-cause mortality was significantly associated with both GlycA (baseline HR: 1.46 [1.22-1.75]; in-trial HR: 1.41 [1.24-1.60]) and low levels of small HDL particles (baseline HR: 0.69 [0.56-0.86]; in-trial HR: 0.69 [0.56-0.86]). This Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes trial post hoc substudy indicates that inflammation, as indexed by GlycA, is unaffected by ERN treatment but is significantly associated with the residual risk of CVD and death in patients treated to low levels of LDL cholesterol.

Evaluation of Lipid Profile and Residual Cardiovascular Risk in Patients Prior to Initiation of Niaspan Therapy

Background: Despite significant impact of statins, there are a number of patients with residual risk of cardio vascular disease who have optimally controlled low-density lipoprotein cholesterol (LDL-C). Niaspan (extended-release nicotinic acid or niacin-ER) is indicated for its use as monotherapy for the treatment of very high triglyceride (TG) levels and for the raising of high-density lipoprotein cholesterol (HDL-C) representing those residual risk populations. The patient characteristics and lipid profile, prior to initiation of therapy, in the real-world clinical setting has not been well documented. Objectives: This study evaluated lipid levels among patients initiating Niaspan in real-world clinical practice. Methods: Patients with a first prescription of Niaspan were identified using electronic medical record data from GE. Lipid values were categorized into optimal and nonoptimal TG or HDL-C levels. Results: There were 89 091 new users. Most patients had nonoptimal TG, HDL-C, TG/HDL-C ratio, LDL-C, and non-HDL-C levels. Among those with nonoptimal TG and HDL, the ratio of TG to HDL-C was higher among younger age groups (mean ratio 12.0 in males; 10.58 in females aged 18 to &lt;40 years). TG was significantly correlated with non-HDL-C (0.41, P &lt; .001) but not with LDL-C. Among those with LDL-C &lt;100 mg/dL, 64.3% had nonoptimal TG/HDL-C ratio and approximately 70% had non-HDL-C ≥130 mg/dL. More than a third of the patients had diagnosis of coronary heart disease or coronary heart disease risk equivalent. Conclusion: Majority of Niaspan users had nonoptimal TG and/or HDL-C. The correlation of nonoptimal TG levels with non-HDL-C levels further support that Niaspan was targeted to population with residual risk for cardiovascular disease.

Targeted LOWering of Central Blood Pressure in patients with hypertension: Baseline recruitment, rationale and design of a randomized controlled trial (The LOW CBP study)

BackgroundHigh blood pressure (BP) is the most common modifiable cause of death from cardiovascular disease. Lowering BP with medication improves patient outcomes, but even in populations with normal upper arm (brachial) BP there remains considerable residual risk for cardiovascular disease and this may be due to persistently elevated central BP. There has never been a trial to determine the value of targeted central BP lowering among patients with hypertension, and this was the aim of this study. MethodsThis is a multi-centre, randomized, open-label, blinded endpoint trial among 308 patients treated for uncomplicated hypertension with controlled brachial BP (<140/90mmHg) but elevated central BP (≥0.5SD above age- and sex-specific normal values). Baseline recruitment has been completed. Participants were randomized to intervention with spironolactone (25mg/d) or usual care and are being followed over 24months, with the primary outcome being left ventricular mass index (using cardiac magnetic resonance imaging). Brachial and central BP will be measured in the clinic, at home over 7-days and by 24-h ambulatory monitoring. Aortic stiffness will be assessed by carotid-to-femoral pulse wave velocity. Primary (intention to treat) analysis will determine the role of central versus brachial BP for predicting changes in left ventricular mass index. ConclusionsCompared with control, intervention is expected to significantly lower left ventricular mass index, and this effect is expected to be independently correlated with central BP lowering. These findings would support the concept of central BP as an important therapeutic target in hypertension management. Results are expected in 2018.

Remnant lipoproteins.

To review recent advances in the field of remnant lipoproteins and remnant cholesterol with a focus on cardiovascular disease risk. In line with previous years' research, current observational, genetic, and mechanistic studies find remnant lipoproteins (defined in different ways) to be involved in atherosclerosis development and cardiovascular disease risk. High concentrations of remnant cholesterol could explain some of the residual risk of cardiovascular disease seen after LDL cholesterol lowering. This will be increasingly important as populations worldwide become more obese and more have diabetes, both of which elevate remnant cholesterol concentrations. Many smaller scale studies and post hoc analyses show that remnant cholesterol can be lowered by different types of drugs; however, results from large scale studies with the primary aim of reducing cardiovascular disease risk through lowering of remnant cholesterol in individuals with elevated concentrations are still missing, although some are under way. Remnant cholesterol is a risk factor for cardiovascular disease, and can be lowered by different types of drugs; however, large scale studies of cardiovascular disease risk reduction through remnant lipoprotein lowering are under way.

HDL therapies — past, present and future

For a number of years, high-density lipoprotein (HDL) has been recognized to have an athero-protective role by promoting reverse lipid transport, a process facilitating the cholesterol efflux from atherosclerotic plaques in the artery wall and its elimination by the liver via biliary excretion.On the contrary, low-density lipoprotein (LDL) particles carry cholesterol to the organs and tissues where it can be used to produce hormones or maintain cell metabolism. When an imbalance develops, as a result of either an excess level of cholesterol associated with LDL (LDL-C) or a less effective cholesterol elimination by HDL (HDL-C), this causes an excess of cholesterol to be transported to the tissues and promotes the deposition of cholesterol. This often occurs in the artery walls, particularly in the coronary arteries. There is no approved medical treatment for directly suppressing or treating the atherosclerotic plaque once it is formed. Epidemiological studies have shown that the risk of developing cardio-vascular disease (CVD) is higher in patients with low levels of HDL-C regardless of LDL-C levels, even in patients optimally treated with LDL-C-lowering therapies. These data highlight that low HDL-C and low HDL particle number is an important target of therapies aiming to reduce the residual risk of CVD.

Lipoprotein(a): A Lipoprotein Whose Time Has Come.

Cardiovascular disease is a leading cause of morbidity and mortality in the USA and around the world. While we are now able to achieve significant low-density lipoprotein cholesterol (LDL-C) lowering with current therapies, many patients remain at risk for cardiovascular disease (CVD). Elevated lipoprotein(a) [Lp(a)] has been shown to be an independent risk factor for CVD and accounts for some of the residual CVD risk after LDL-C lowering in several large clinical trials. Moreover, there is now strong evidence supporting the causal relationship between Lp(a) and aortic stenosis as well as peripheral arterial disease. Despite the growing interest in this lipoprotein, the current therapeutic options for Lp(a) reduction are limited. Our general approach in patients with elevated Lp(a) levels is to aggressively manage other modifiable cardiovascular risk factors including lifestyle modification, consideration of aspirin therapy, and LDL-C lowering. Unfortunately, there are conflicting reports on how effective this strategy is at reducing the risk for cardiovascular events attributed to elevated Lp(a). As a result, targeted Lp(a)-lowering strategies are needed. Lp(a) therapeutics is an active area of research with several promising classes of pharmacotherapies under investigation to address this causal biomarker.

Abstract 626: Apabetalone (Rvx-208), a Selective Bet Protein Inhibitor, Reduces Expression of Acute Phase Response Markers in vitro and in Patients With Cardiovascular Disease and Chronic Kidney Disease

Apabetalone is an inhibitor of the epigenetic readers bromodomain and extraterminal (BET) proteins, currently in a phase 3 outcomes trial in patients with cardiovascular disease (CVD) and diabetes mellitus. A post hoc analysis of phase 2b trials demonstrated a 55% relative risk reduction in major adverse cardiac events in CVD patients. Elevated inflammatory markers correlate with CVD. Inflammation also accompanies chronic kidney disease (CKD) and CKD patients are at risk of CVD. Previous research has shown that apabetalone modulates pathways that contribute to chronic inflammation, including the acute phase response (APR). Here, pathway analysis of gene microarrays showed downregulation of APR by apabetalone in primary human hepatocytes (PHH). Real-time PCR and ELISA analysis of RVX-208 treated PHHs confirmed that APR genes that correlate with CVD are suppressed by 20 to 95%, including CRP, ceruloplasmin (CP), serum amyloid P (SAP), PAI-1, alpha 2-macroglobulin (A2M), complement C2, C3 and C5, MBL2, serum amyloid A and interleukin 18. Apabetalone decreased IL-6-induced expression of CP, SAP and A2M, with most striking effects on CRP (-75%). Apabetalone also decreased LPS-induced expression of SAP in a mouse endotoxemia model. To assess effects of apabetalone on inflammatory mediators in CVD patients, SOMAscan™ 1.3K proteomic analysis was performed on plasma from phase 2b ASSERT (12 weeks; n=25) and ASSURE (26 weeks; n=47) clinical trials. This approach identified APR as the top downregulated pathway by apabetalone in both trials. APR biomarkers are elevated in CKD patients where they correlate with disease progression. To gain insight into the pharmacodynamics of the APR response to apabetalone, stage 4 CKD patients (n=8) received a single dose of the drug followed by plasma proteomics at several time points. At 12h post dose, APR was significantly downregulated by apabetalone. Of note, CRP was decreased in CKD patients after 12h of treatment (-7%, p=0.04) versus baseline, as well as in ASSERT (-43%, p=0.01) and ASSURE (-21%, p=0.02) trials versus placebo. Downregulation of the APR pathway by apabetalone may lead to reduced chronic inflammation in CVD and CKD patients and contribute to the reduction in MACE in patients with high residual CVD risk.

Abstract P351: Remnant Cholesterol and Cardiovascular Disease Outcomes in Chronic Kidney Transplant Recipients

Remnant cholesterol (RC) is the cholesterol content of circulating triglyceride-rich lipoproteins. Studies employing a simple calculation of RC from routine lipid/lipoprotein measures have demonstrated associations between RC levels and cardiovascular disease (CVD) outcomes in both observational study, and lipid lowering clinical trial cohorts. There are no published data evaluating the potential relationship between remnant cholesterol and CVD in chronic kidney transplant recipients [KTRs], a population with excess risk for fatal and non-fatal CVD. RC was calculated, using non-fasting plasma samples, as total cholesterol - [HDL cholesterol + LDL cholesterol] in n=3002 FAVORIT trial [NCT00064753] participants at randomization (mean 37.6, standard deviation ± 21.3, range 4-230 mg/dl). During a median follow-up of 4.0-years, the cohort experienced n=419 CVD outcomes [myocardial infarction, stroke, resuscitated sudden death, CVD death, and CVD procedural events, pooled]. Multivariable logistic regression modeling revealed that each 10 mg/dl increase of RC conferred a 16.4% increase [95% CI, 3.6-30.8%] in CVD risk adjusted for age, baseline CVD, diabetes, smoking, race, sex, body-mass index, LDL, HDL, natural log triglycerides, estimated glomerular filtration rate, natural log urinary albumin/creatinine, type of kidney graft, graft vintage, and the use of calcineurin inhibitors, steroids, or lipid lowering drugs. Given the residual risk for CVD after recommended LDL levels are achieved, these data suggest that interventions [i.e., such as eicosapentaenoic acid ethyl ester, which can lower RC by ~25-30%; Atherosclerosis 2016; 253: 81-87] targeting elevated RC concentrations in KTRs, merit consideration.

A New Approach to PCSK9 Therapeutics.

PCSK9 inhibition is an effective therapy to reduce LDL cholesterol (LDL-C) and cardiovascular events. A recent study shows that one or two doses of inclisiran, a long-acting synthetic small-interfering RNA (siRNA) that selectively targets hepatic PCSK9, causes a sustained reduction of plasma LDL-C for up to 6 months. Pending further studies of safety and efficacy, this may represent an important addition to the armamentarium for inhibiting PCSK9.

Dyslipidemia in diabetes mellitus and cardiovascular disease.

Patients with diabetes have a high residual risk for cardiovascular disease (CVD) and adverse outcomes despite statin therapy and lifestyle modifications. Particular to individuals with diabetes is the pattern of elevated triglycerides, small dense low density lipoprotein cholesterol, and reduced levels of high density lipoprotein cholesterol, described as dyslipidemia of diabetes. The role of combination therapy with an additional agent such as niacin, ezetimibe, fenofibrate, and n-3 fatty acids has been studied; however, at the same time, these agents have come under criticism for their limitations. We performed a review of key trials assessing the benefit of combination therapy to reduce CVD risk from dyslipidemia. Of the currently available agents that can be used in combination with statins, ezetimibe has the most favorable risk profile, with a recent trial demonstrating modest incremental benefit when given in addition to statins. PCSK9 inhibitors are a promising category, although clinical outcome data in individuals with diabetes are pending.

N-3 Polyunsaturated Fatty Acids: Promising Nutrients for Preventing Cardiovascular Disease.

The adoption of the Western-style diet, with decreased fish intake and lack of exercise, has increased the prevalence of cardiovascular disease (CVD) in Japan. Statin treatment has been established to reduce the risk of cardiovascular events; however, 60%–70% of these events occur despite its use. Thus, the residual risk for CVD should be identified and resolved to reduce further cardiovascular events. The serum levels of n-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid and docosahexaenoic acid, are reportedly associated with an increased incidence of cardiovascular events and mortality, whereas the addition of n-3 PUFA treatment to the statin treatment decreases cardiovascular events. Similar to statins, n-3 PUFAs have pleiotropic effects in addition to lipid-modifying effects. Pre-clinical and clinical studies have shown that n-3 PUFAs prevent cardiovascular events by ameliorating endothelial function and attenuating lipid accumulation, vascular inflammation, and macrophage recruitment, thereby causing coronary plaque development and rupture. Taken together, n-3 PUFAs are comprehensively able to attenuate the atherogenic response. Therefore, n-3 PUFA intake is recommended to prevent cardiovascular events, particularly in patients with multiple cardiovascular risk factors.

Relative Contributions of Arterial Stiffness and Hypertension to Cardiovascular Disease: The Framingham Heart Study.

BackgroundThe presence and implications of abnormal arterial stiffness, a potential independent predictor of outcomes, in community‐dwelling treated hypertensives is unknown. Furthermore, limited data exist regarding the risk of cardiovascular disease (CVD) associated with arterial stiffness across the entire range of blood pressure.Methods and ResultsWe measured carotid‐femoral pulse wave velocity (PWV) and classical CVD risk factors in 2127 community‐dwelling participants (mean age 60 years, 57% women) of The Framingham Offspring Cohort. The participants were divided into 4 groups according to hypertension (yes/no, defined as blood pressure ≥140/90 mm Hg or use of antihypertensive treatment) and PWV status (high/low based on age‐ and sex‐specific median values) and followed up for CVD events (CVD death, myocardial infarction, unstable angina, heart failure, and stroke). Sixty percent (233 of 390) of controlled and 90% (232 of 258) of uncontrolled treated hypertensives had high PWV. The multivariable‐adjusted risk for CVD events (n=248, median follow‐up 12.6 years) rose from normotension with low PWV (reference) to normotension with high PWV (hazard ratio 1.29, 95% CI 0.83–2.00) and from hypertension with low PWV (hazard ratio 1.54, 95% CI 1.01–2.36) to hypertension with high PWV (hazard ratio 2.25, 95% CI 1.54–3.29).ConclusionsA substantial proportion of treated hypertensives have high arterial stiffness, a finding that may explain some of the notable residual CVD risk associated with even well‐controlled hypertension. High PWV is associated with a trend towards increasing CVD risk in both nonhypertensives and hypertensives, a finding that may support the use of arterial stiffness measurements in both populations.

Abstract 108: Relative Contributions of Arterial Stiffness and Hypertension to CVD Risk: The Framingham Heart Study

Introduction: The presence and implications of abnormal arterial stiffness, a potential independent predictor of outcomes, in community-dwelling treated hypertensives is unknown. Furthermore, limited data exist regarding the risk of cardiovascular disease (CVD) associated with arterial stiffness across the entire range of blood pressure. Methods: We measured carotid-femoral pulse wave velocity (PWV) and classical CVD risk factors in participants of The Framingham Offspring Cohort. The participants were divided into 4 groups according to hypertension (yes/no), and PWV status (high/low based on age- and sex-specific median values) and followed up for CVD events (CVD death, myocardial infarction, unstable angina, heart failure, and stroke). Results: We studied 2127 community-dwelling individuals (60 years, 57% women). 60% (233 of 390) of controlled and 90% (232 of 258) of uncontrolled treated hypertensives had high PWV. The multivariable-adjusted risk for CVD events ( n =248, median follow-up 12.6 years; Figure) rose from normotension with low PWV (reference) to normotension with high PWV (hazard ratio [HR] 1.33, 95% confidence interval [95% CI] 0.86-2.05) and from hypertension with low PWV (HR 1.53, 95% CI 1.00-2.34) to hypertension with high PWV (HR 2.31, 95% CI 1.58-3.36). Conclusions: A substantial proportion of treated hypertensives have high arterial stiffness, a finding that may explain some of the notable residual CVD risk associated in this group. High PWV is associated with a trend towards increasing CVD risk in both non-hypertensives and hypertensives supporting the use of arterial stiffness measurements in both populations.

Abstract 428: Lipoprotein(a) Targeting With RNAi Delivery Platforms in Transgenic Mice and Cynomolgus Monkeys

Background: Meta-analyses of clinical studies have demonstrated that high levels of lipoprotein(a), known as Lp(a), correlate with residual risk of cardiovascular disease (CVD) while Mendelian genetic studies indicate that Lp(a) is an independent cause of CVD. Lp(a) is a complex lipoprotein particle similar in structure to LDL (consisting of cholesterol, triglycerides, phospholipids and apoB-100), but contains the genetically variable liver-expressed protein apo(a). Lp(a) may contribute to atherosclerosis by targeting oxidized phospholipids to vascular injury sites, promoting both inflammation and accumulation of lipids. Methods: RNA interference (RNAi) based approaches for reducing liver apo(a) expression were developed using both a targeted intravenous platform called Dynamic Polyconjugates (DPC) TM and a subcutaneous (SQ) format. The DPC platform comprises an RNAi trigger conjugated to cholesterol, and a hepatocyte-targeted, membrane active peptide to promote endosomal release of the RNAi trigger. The SQ platform is an RNAi trigger targeted to liver by N-acetyl galactosamine in a proprietary format. RNAi activity was assessed in two different humanized transgenic mice and cynomolgus monkeys. Results: In Lp(a) transgenic mice expressing human apo(a) and apoB-100 genes, treatment with a single DPC dose reduced serum Lp(a) by &gt;98% at nadir and &gt;90% for &gt;5 weeks. A single DPC injection in cynomolgus monkeys resulted in &gt;95% reduction in endogenous Lp(a) particles at 5 weeks post injection, without significant changes in toxicity biomarkers. Treatment with a SQ RNAi trigger reduced serum apo(a) in transgenic mice by &gt;90% at nadir, while that in monkeys reached 64% reduction of Lp(a). Additional modifications to the RNAi trigger improved both depth and duration of knockdown in transgenic mice. Conclusion: Long-duration reductions in circulating apo(a) and Lp(a) have been shown with hepatocyte-directed delivery of apo(a)-specific RNAi triggers in mice and monkeys. This represents an intriguing mechanism to evaluate in humans for reducing residual risk of CVD in LDL-controlled individuals with elevated Lp(a).

PCSK9 inhibitors in the prevention of cardiovascular disease.

Reducing plasma levels of low-density lipoprotein cholesterol (LDL-C) remains the cornerstone in the primary and secondary prevention of cardiovascular disease. However, lack of efficacy and adverse effects mean that a substantial proportion of patients fail to achieve acceptable LDL-C levels with currently available lipid-lowering drugs. Over the last decade, inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic strategy to reduce residual cardiovascular disease risk. Binding of PCSK9 to the LDL receptor targets the receptor for lysosomal degradation. The recognition that inhibition of PCSK9 increases LDL receptor activity has led to the development of a number of approaches to directly target PCSK9. Numerous monoclonal antibodies against PCSK9 are currently being evaluated in phase 3 trials, involving various patient categories on different background lipid-lowering therapies. Current evidence shows reductions in LDL-C levels of up to 70 % may be achieved with PCSK9 inhibition, independent of background statin therapy. This review examines the most recent evidence and future prospects for the use of PCSK9 inhibitors in the prevention of cardiovascular disease.

Prescription omega-3 fatty acid products: considerations for patients with diabetes mellitus.

Type 2 diabetes mellitus (T2DM) and metabolic syndrome contribute to hypertriglyceridemia, which may increase residual risk of cardiovascular disease in patients with elevated triglyceride (TG) levels despite optimal low-density lipoprotein cholesterol (LDL-C) levels with statin therapy. Prescription products containing the long-chain omega-3 fatty acids (OM3FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are an effective strategy for reducing TG levels. This article provides an overview of prescription OM3FAs, including relevant clinical data in patients with T2DM and/or metabolic syndrome. Prescription OM3FAs contain either combinations of DHA and EPA (omega-3-acid ethyl esters, omega-3-carboxylic acids, omega-3-acid ethyl esters A) or EPA alone (icosapent ethyl). These products are well tolerated and can be used safely with statins. Randomized controlled trials have demonstrated that all prescription OM3FAs produce statistically significant reductions in TG levels compared with placebo; however, differential effects on LDL-C levels have been reported. Products containing DHA may increase LDL-C levels, whereas the EPA-only product did not increase LDL-C levels compared with placebo. Because increases in LDL-C levels may be unwanted in patients with T2DM and/or dyslipidemia, the EPA-only product should not be replaced with products containing DHA. Available data on the effects of OM3FAs in patients with diabetes and/or metabolic syndrome support that these products can be used safely in patients with T2DM and have beneficial effects on atherogenic parameters; in particular, the EPA-only prescription product significantly reduced TG, non-high-density lipoprotein cholesterol, Apo B, remnant lipoprotein cholesterol, and high-sensitivity CRP levels without increasing LDL-C levels compared with placebo. Ongoing studies of the effects of prescription OM3FAs on cardiovascular outcomes will help determine whether these products will emerge as effective add-on options to statin therapy for reduction of residual cardiovascular disease risk.