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ABSTRACTIntroductionDyslipidemia plays a crucial role in the development of atherosclerotic cardiovascular diseases.Areas coveredThis article explores the emerging therapeutic targets for the treatment of dyslipidemia and provides novel insights into this field. Thus, it aims to contribute to the understanding and advancement of therapeutic options for managing dyslipidemia.Expert opinionOptimizing the use of available first- and second-line lipid-lowering drugs allows us to adequately control low-density lipoprotein cholesterol (LDL-C) levels, even in statin-intolerant individuals and in patients at high and very high risk of developing cardiovascular diseases who must reach more aggressive LDL-C targets. The drugs under development will further improve our ability to manage the overall lipid-related cardiovascular disease risk and target other dyslipidemia biomarkers.

Purpose: The potential mechanisms of endocrine therapy for thrombosis remain currently unclear, and more studies are warranted for further investigation and elucidation. However, high plasma concentration of lipoprotein(a) (Lp(a)) is a recognized prothrombotic factor. The aim of our study was to systematically evaluate the effect of different anti-oestrogen therapy on plasma Lp(a) level in postmenopausal women. Methods: A systematic literature search was conducted in multiple electronic databases to identify the randomized, double-blind, placebo-controlled clinical studies on this topic. Effect size for changes in Lp(a) was expressed as mean difference (MD) and 95% confidence intervals (CI). Results: Data were pooled from 10 clinical trials comprising 24 treatment arms, which included 2049 women (1128 women in the active-treated arms and 921 women in the control arms). Meta-analysis of data suggested that anti-oestrogen therapy in women significantly reduced Lp(a) [MD = −5.92% (95%CI: −9.05%,−2.8%)]. Conclusions: This observation is of both clinical and pathophysiological relevance, also in view that the identification of molecular determinants and cellular pathways implicated in Lp(a) synthesis and metabolism is still of concern as a critical issue in lipidology and CV prevention.

Coronavirus-19 disease (COVID-19) continues to spread throughout the world. It is known that among patients with hypertension, diabetes, chronic respiratory disease, or cardiovascular diseases, COVID-19 is associated with greater morbidity and mortality compared with patients without these conditions. This correlation is of great importance in pregnant women affected by COVID-19, since it usually leads to the development of a serious clinical complication. In particular, managing hypertensive disorders in pregnancy can be problematic because antihypertensive medications may interact pharmacologically with drugs used to treat COVID-19. This review focuses on the safety of drug treatment for COVID-19 in pregnant women treated with antihypertensive medication. Several databases were searched to identify relevant literature. A few antihypertensive drugs and antithrombotic treatments are known for having a beneficial effect in the management of hypertension and hypertensive disorders in pregnancy. In this review, we focus on the expected drug–drug interactions with the experimental agents most often used to treat COVID-19. The current indications for the management of hypertension-related disorders in pregnancy maintain their validity, while the risk of pharmacological interaction with the currently tested anti-SARS-CoV-2 medications is relatively low.

The Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension conceived and designed an ad hoc study aimed at searching for prognostic cut-off values of serum uric acid (SUA) in predicting combined (fatal and non-fatal) cerebrovascular (CBV) events in the whole database. The URic acid Right for heArt Health study is a nationwide, multicenter, observational cohort study involving data on subjects aged 18–95 years recruited on a regional community basis from all the territory of Italy under the patronage of the Italian Society of Hypertension with a mean follow-up period of 120.7 ± 61.8 months. A total of 14,588 subjects were included in the analysis. A prognostic cut-off value of SUA able to discriminate combined CBV events (>4.79 mg/dL or >284.91 µmol/L) was identified by means of receiver operating characteristic curve in the whole database. Multivariate Cox regression analysis adjusted for confounders (age, sex, arterial hypertension, diabetes, chronic kidney disease, smoking habit, ethanol intake, body mass index, low-density lipoprotein cholesterol, and use of diuretics) identified an independent association between SUA and combined CBV events in the whole database (HR 1.249, 95% confidence interval, 1.041–1.497, p= 0.016). The results of the present study confirm that SUA is an independent risk marker for CBV events after adjusting for potential confounding variables, including arterial hypertension, and demonstrate that >4.79 mg/dL is a valid prognostic cut-off value.

Cardiovascular (CV) diseases are burdened by high mortality and morbidity, being responsible for half of the deaths in Europe. Although hypertension is recognized as the most important CV risk factor, hypertension awareness and blood pressure (BP) control are still unsatisfactory. In 2017, 30.6% of a >10 000 individual sample who took part in the May Measurement Month (MMM) campaign in Italy was found to have high BP. To raise awareness on the hypertension issue and to report BP data on a nation-wide scale in Italy. In the frame of the MMM campaign, an opportunistic cross-sectional survey of volunteers aged ≥18 was carried out in May 2018. Blood pressure measurement, the definition of hypertension and statistical analysis followed the standard MMM protocol. Screenings were conducted in multiple sites by health care personnel. Among the 5554 people screened (females: 48.3%, mean age 58 ± 17 years) mean BP was 127/77 mmHg, and after imputations, 1462 (26.3%) participants were found to have high BP levels. Body mass index >25 was associated with higher systolic BP and diastolic BP (DBP), while diabetes was associated with high DBP only. Our data provide a nation-wide snapshot of BP control in a sample of individuals participating in a national health care campaign, and confirm the power of this kind of healthcare-related activities in reaching a significant number of people to raise awareness on health topics. The apparent positive trend in BP control compared to available data from other similar campaigns carried out during the past years needs to be confirmed with more methodologically robust studies.

ABSTRACTIntroductionAlthough statin therapy is a powerful lipid-lowering strategy, only one-fifth of statin users currently reach their lipid goals. In addition, statin treatment alone has relatively low efficacy in reducing other lipid fractions than low-density lipoprotein-cholesterol (LDL-C). In such cases, most guidelines recommend adding the cholesterol absorption inhibitor ezetimibe.Areas coveredThis paper summarizes the main pharmacological characteristics of rosuvastatin and ezetimibe (mechanism of action, metabolism), their lipid-lowering and pleiotropic effects, with particular attention to the clinical effects of the combined drugs in hypercholesterolemia and mixed dyslipidemia patients (such as the ones affected by diabetes mellitus and Acquired Immune Deficiency Syndrome (AIDS)).Expert opinionThe additive effect of rosuvastatin and ezetimibe helps to reach lipid goals in a large number of high-risk patients, while avoiding some safety issues related to high dosages of intensive statin therapy. Patients with diabetes receive additional benefits from ezetimibe as they seem to absorb cholesterol more effectively than non-diabetic ones, because of increased NPC1L1 gene expression. Ezetimibe augments rosuvastatin triglyceride-lowering and anti-inflammatory effects, as well. Taking into account its excellent safety profile and lack of clinically relevant drug-drug interactions, the rosuvastatin/ezetimibe association is a valuable alternative to statin dose uptitration.

Background: The etiopathogenetic mechanisms of peripheral neuropathies include genetic, traumatic, toxic, metabolic, infectious, nutritional, inflammatory and paraneoplastic causes. Their treatment should primarily address their contributing causes. However, symptomatic therapy is also key in these conditions, particularly in pain relief. Method: Relevant studies were identified using the PubMed electronic database in January 2017. After a preliminary search, we focused on the single compounds for which randomized controlled trials versus placebo or comparing high and low doses were performed. Studies in which a combination of different compounds was tested were not considered, with the exception of complex B multivitamins. Results: Several nutraceuticals have been used in the treatment of peripheral neuropathies and seem promising, due to assumed neurotrophic action, low toxicity and favorable metabolic profile. We performed a review of the literature to evaluate safety and effectiveness of nutraceutical compounds in peripheral neuropathies, focusing on the single agents for which randomized controlled trials versus placebo were performed. Vitamin B complex, alpha lipoic acid, L-acetylcarnitine, vitamin E and Coenzyme Q proved effective to different extents in neuropathic pain in polyneuropathies. They all proved less consistently effective on other neuropathic symptoms, neuropathic signs and neurophysiological parameters. All the considered compounds were tolerable even for long periods, however alpha lipoic acid at doses equal or larger than 1200 mg/die was associated with nausea and vomiting in a large number of patients. Conclusion: The findings of this review confirm a possible role for some adequately dosed nutraceuticals in the management of peripheral neuropathy.

ABSTRACTIntroduction: Cardiovascular diseases (CVDs) are the leading cause of mortality and disability in developed countries, whereas a large portion of patients in primary prevention have uncontrolled level of CVD risk factors. Dietary supplementation with bioactive natural compounds with demonstrated lipid-lowering effects is currently supported by the international guidelines for CVD prevention and some international expert panels.Areas covered: This review provides insights on issues concerning the tolerability and safety of the most commonly used nutraceuticals with demonstrated lipid-lowering effect in humans. They will be then divided into three main categories according to their mechanism of action (cholesterol synthesis inhibitors, intestinal cholesterol absorption inhibitors, and LDL-C excretion stimulants) and their pharmacological profile will be discussed.Expert opinion: A growing body of preclinical, epidemiological and clinical evidence has defined the tolerability and safety profile of the most commonly used lipid-lowering nutraceuticals. In the most part of cases, the side effects are mild and reversible. However, detailed knowledge of specific health risks and pharmacological interactions for each individual compound is needed for the management of frail patients, such as children, elderly, patients with liver or renal failure, and patients consuming numerous drugs.

ABSTRACTIntroduction: Cholesterol lowering treatment is mainly based on statins eventually associated to adjunctive drugs of different class such as ezetimibe. In the present review, we analysed the pharmacokinetics, efficacy and safety of ezetimibe + simvastatin drug association.Areas covered: The bio-equivalence of ezetimibe and simvastatin when co-administrated in separate tablets or combined in a single pill is well documented. Ezetimibe is absorbed in small intestine, reaching peak plasma concentrations in 4–12 h, with a plasma half-life of 22 h. Simvastatin, ingested as a prodrug, is hydrolyzed in liver to its active beta-hydroxyacid metabolite, reaching peak plasma concentrations in 2–4 h, with a plasma half-life of approximately 5 h. The available evidence support the clinical efficacy of this drug combination, both in term of LDL-cholesterol reduction and cardiovascular risk decrease.Expert opinion: The synergistic action of these two drugs and the efficacy and safety extensively demonstrated of their association (in particular in the large IMProved Reduction of Outcomes: Vytorin Efficacy International Trial -IMPROVE-IT-) promote its clinical use, especially in subjects with high cardiovascular risk who need to optimize their LDL-Cholesterolemia, but also in patients who cannot tolerate high-dose of more powerful statins.

ABSTRACTIntroduction: LDL-cholesterol (LDL-C) is one of the most well-established risk factors for CV disease. Indeed, therapies that decrease LDL-C are proven to effectively reduce the risk of atherosclerotic CV disease. Monoclonal antibodies (mAbs) that target proprotein convertase subtilisin/kexin type 9 (PCSK9) have recently gained traction as a promising therapeutic strategy.Areas covered: In this review, the authors discuss the effectiveness of mAbs against PCSK9 in lowering low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipid fractions. The discontinuation in the development of bococizumab due to efficacy and safety concerns, and the initial promising data about inclisiran, a long-acting small inhibiting RNA molecule against PCSK9 synthesis, is also discussed.Expert opinion: Initial data about cardiovascular (CV) outcomes in large scale, long-term studies suggest a possible further therapeutic pathway for LDL-C reduction, and currently support the notion that further LDL-C reduction, obtained with PCSK9 inhibition on top of best available therapy, provides increased CV protection in subjects at very high CV risk. The development and marketing of mAbs against PCSK9 could help to redefine current therapeutic strategies aimed at reducing cardiovascular (CV) morbidity and risk, through the reduction of LDL-C concentrations. The cost-effectiveness of these emerging drugs is yet to be established.

ABSTRACTIntroduction: While some cholesteryl ester transfer protein inhibitors have had their clinical study interrupted because of no or adverse effects on cardiovascular disease, anacetrapib (MK-0859) is being evaluated in Phase III cardiovascular outcomes trials. We review its pharmacokinetic properties.Areas covered: The apparent anacetrapib terminal elimination half-life after a single dose is 9–62 h in the fasted state and 42–83 h in the fed state. After repeat administrations, a biphasic elimination profile with a long terminal elimination phase (~60–80 h) was observed, although the effective half-life was ~20 h. The steady state appeared to be reached after ~7 days of dosing with 0.85- to 2.8-fold accumulation for AUC0–24 and Cmax, respectively. The unchanged drug is mainly eliminated with feces; renal impairment does not seem be a limitation to the use of the drug. However, liver impairment could cause an increase in the anacetrapib level, especially when associated with CYP3A4 inhibitors, since it is a moderately sensitive CYP3A substrate.Expert opinion: Given the interesting pharmacokinetic profile, and if the preliminary data on cardiovascular outcomes is confirmed, anacetrapib could find a relevant role as a moderately expensive drug between standard lipid-lowering treatment and the new expensive PCKS9 inhibitors.

Berberine is a plant alkaloid with various biological activities. A large body of literature support different pharmacological actions of berberine that could be interesting in the management of metabolic diseases associated with high cardiovascular disease risk, such as mixed hyperlipidemia, insulin resistance, metabolic syndrome and Type 2 diabetes. Numerous preclinical in vitroand in vivostudies support all these effects. Moreover, it seems that berberine also exerts anti-inflammatory and antiproliferative effects that could play a role in the development of atherosclerosis and its clinical consequences. Recently, the metabolic effects of berberine have also been demonstrated in humans, opening new perspectives for the use of this molecule in patient therapy. Larger and longer studies need to be carried out to implement the definition of the therapeutic role of berberine in humans.

Objective: Familial Combined Hyperlipoproteinemic (FCH) is a disorder of lipid metabolism characterized by an increased risk of premature coronary heart disease. Our aim is to estimate the prevalence of FCH subjects in a large North-Italian rural population monitored for 32 years (1972-2004). Methods: In the 2004 Brisighella Heart Study (BHS) survey, 1303 subjects were tested in five or more four-yearly surveys (mean age: 63.7±14.9 years). The individual plasma lipid phenotype by Fredrickson classification was attributed for each survey on the basis of low density lipoprotein (LDL)-cholesterol and triglycerides. A primary dyslipoproteinemia was suspected on the basis of personal and family history, body mass index and dietary habits. Results: At the end of the longitudinal study, the subjects with variable phenotype in the studied population were 17.2% and among primary hyperlipoproteinemics 36.3%. Mean IIb phenotype prevalence was 12.3 ± 6.3% in all hyperlipoproteinemics, while it was 33.4 ± 11.9% in potential FCH subjects. Only 7 subjects were constantly IIb during the observation time and four of them are certainly secondary hyperlipoproteinemics. The Ilb phenotype prevalence was significantly more variable than the Ila phenotypes. The 3.1% of the studied subjects have been selected as candidates for a FCH diagnosis without significant differences between sexes. Conclusion: Our data suggest the existence of a long-term primary variability of the individual plasma lipid phenotype. The prevalence of FCH in the general population appears to be near 2%.

The objective of this trial was to compare the metabolic effects of long-term treatment with doxazosin to those of irbesartan in patients with type 2 diabetes and hypertension. We evaluated 96 hypertensive diabetic patients who were randomized to 12 months of double-blind treatment with doxazosin 4 mg/d or irbesartan 300 mg/d. At the end of the study, systolic and diastolic blood pressure (SBP and DBP) were significantly reduced from 152 to 140 mm Hg and from 97 to 87 mm Hg, respectively, with doxazosin (P< 0.01). SBP and DBP were reduced from 150 to 134 mm Hg and from 94 to 83 mm Hg, respectively, with irbesartan (P< 0.01). Irbesartan had significantly better antihypertensive efficacy than doxazosin (P< 0.05). Doxazosin had the greatest effect on glucose metabolism and lipid parameters, with significant (P≤ 0.05) reductions observed at study end compared with baseline in glycosylated hemoglobin, fasting plasma glucose, fasting plasma insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and Homeostasis Model Assessment Index. In conclusion, both doxazosin and irbesartan reduced BP during long-term treatment, but not to recommended levels, and doxazosin had the more beneficial effect on glucose metabolism and lipid profile.

Serum lipoprotein (a) Lp(a) is a lipidic parameter, strictly under genetic control. Lp(a) levels vary in different dyslipidaemias according to the underlying disease.