Pathophysiology of cough with angiotensin-converting enzyme inhibitors: How to explain within-class differences?

Angiotensin converting enzyme inhibitors (ACEi) have consistently demonstrated improved survival and reduced risk of major cardiovascular events, across the spectrum of cardiovascular disease, including hypertension, coronary artery disease, myocardial infarction, and heart failure. The cardioprotective effects of ACEi result from inhibiting the conversion of angiotensin I to angiotensin II, and inhibition of bradykinin degradation. They are generally well tolerated but may cause the onset of a dry cough in some patients. This review presents current evidence on the incidence and mechanisms of cough associated with ACEi use, and then considers how to manage ACEi-related cough in clinical practice. The incidence of ACEi-induced cough in the published literature varies widely due to heterogeneity in the source data and lack of adequate controls. Incidence also varies among individual ACEi with agents such as perindopril, which has a high tissue ACE affinity, associated with a lower rate of cough. Evidence from real-world studies shows that the incidence of ACEi-associated cough is lower than rates reported in clinical trials. Patients who experience any dry cough are often switched to angiotensin- receptor blockers or other classes of antihypertensive drugs, regardless of cough severity. To avoid inappropriate discontinuation of ACEi in clinical practice, an alternative approach in patients with persistent cough is to perform a challenge/re-challenge to determine if re-introduction of ACEi is associated with recurrence of symptoms. Incidence of cough should not be considered a class effect for ACEi, and the patient may benefit by a switch from one ACEi to another. Every effort should be made to enable patients to continue ACEi therapy to reduce adverse cardiovascular outcomes and improve survival.

Safety and tolerability of injectable lipid-lowering drugs: an update of clinical data.

INTRODUCTION: Cardiovascular (CV) diseases are the leading cause of death and disability in the developed countries. Lipid-lowering therapy is a cornerstone of the CV risk modification strategy. The first line treatment for hyperlipidemia is statins, which decrease low-density lipoprotein cholesterol (LDL-C) by 30-50% and proportionally reduce the CV events. However, they are not always enough to achieve LDL-C goals in many patients, and some patients are statin intolerant. For this reason, new powerful injectable lipid-lowering drugs have been developed. AREAS COVERED: The aim of this narrative review was to summarize the more recent clinical data on safety and tolerability of injectable lipid-lowering drugs. After an attentive literature search, the authors resumed here information on proprotein convertase subtilisin/kexin 9 inhibitors (evolocumab and alirocumab), small interfering RNA molecule inclisiran, antisense oligonucleotides (mipomersen, volanesorsen, ISIS 681257), and drugs targeting angiopoietin-like protein 3 (evinacumab, IONIS-ANGPTL3Rx). EXPERT OPINION: Injectable lipid-lowering therapy for patients at high risk for CV disease complications or with severe inherited hypercholesterolemias can be an important element of the available therapeutic armamentarium. Clinical data prove the favorable risk-benefit profile of evolocumab, alirocumab, and inclisiran. Mipomersen, volanesorsen, ISIS 681257, evinacumab, and IONIS-ANGPTL3Rx safety is currently less extensively studied, especially in patients with comorbidities and polypharmacotherapy.

Safety and tolerability of available urate-lowering drugs: a critical review.

INTRODUCTION: Urate-lowering therapy (ULT) is the cornerstone of gout management, which is a widespread chronic illness characterized by hyperuricemia, arthropathy, tophus development, and urolithiasis. Since asymptomatic increased serum urate levels are associated with a higher risk of cardiovascular, renal and metabolic disorders, a larger use of ULTs in the general population is expected in the near future. AREAS COVERED: This review will focus on the safety and tolerability profile of the available urate-lowering drugs: xanthine oxidase inhibitors (XOIs), uricosuric agents and injectable uricases. EXPERT OPINION: Older drugs for ULT like allopurinol are well studied and extensively described from typical adverse effects (mild skin rash) to unusual fatal reactions, while febuxostat seems to be overall well tolerated. More evidence is required to define the safety profile of topiroxostat, arhalofenate, tranilast, and sulfinpyrazone. Furthermore, there are some unanswered questions about the pharmacological interactions of probenecid and the hepatotoxicity of benzbromarone. Despite a limited use in clinical practice, combination therapy with lesinurad or verinurad and XOI is not frequently accompanied by side effects. Rasburicase and pegloticase are usually well tolerated with some specific exceptions. Before prescribing UL drugs, physicians should take into account their safety profile tailoring the treatment on the patient characteristics.

Nutraceutical Approach to Peripheral Neuropathies: Evidence from Clinical Trials.

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.

Retargeting the management of hypercholesterolemia - focus on evolocumab.

Hypercholesterolemia is one of the main risk factors for atherosclerosis and cardiovascular diseases. The treatment is based on the modification of the diet and lifestyle and if necessary on a pharmacological therapy. The most widely used drugs are the inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (statins); nevertheless, many patients do not reach optimal levels of low-density lipoprotein-cholesterol (LDL-C) even with maximal dosage of statins (eventually associated to ezetimibe) or present side effects, which do not allow them to continue the treatment. Inhibitors of PCSK9 represent a new therapeutic approach for lowering LDL-C. Evolocumab and alirocumab are human monoclonal antibodies, which bind to extracellular PCSK9 and thus interfere with the degradation of low-density lipoprotein receptor. Evolocumab use is approved for the treatment of patients with heterozygous familial hypercholesterolemia (FH) and homozygous FH as an adjunct to diet and maximally tolerated statin therapy or for subjects with clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C. Phase III clinical trials have demonstrated the effectiveness of evolocumab (140 mg/every 2 weeks or 420 mg/month, via subcutaneous injection) in monotherapy and in combination with statins, in the treatment of patients intolerant to statins or with FH. In monotherapy, it reduces LDL-C by 55%, and its association with statins leads to a reduction of LDL-C by up to 63%-75%. Evolocumab has been demonstrated to be safe and well tolerated. Ongoing clinical trials are assessing the long-term effects of evolocumab on the incidence of cardiovascular risk, safety, and tolerability. This review resumes the available clinical evidence on the efficacy and safety of evolocumab, for which a relatively large amount of clinical data are currently available, and discusses the retargeting of cholesterol-lowering therapy in clinical practice.

Effects of a nutraceutical combination containing berberine (BRB), policosanol, and red yeast rice (RYR), on lipid profile in hypercholesterolemic patients: A meta-analysis of randomised controlled trials / Efectos de la combinación de productos nutricéuticos con berberina, policosanol y arroz de levadura roja en el lipidograma de pacientes con hipercolesterolemia: un metaanálisis de ensayos clínicos aleatorizados

Background and aim: A nutraceutical combination containing berberine, policosanol, and red yeast rice, largely marketed in Europe (Armolipid Plus®) (AP), has been reported to induce significant improvements in plasma lipids, insulin resistance and other components of the metabolic syndrome. However, literature study designs and results were heterogeneous and it was thus necessary to systematically review and meta-analyse all relevant randomised clinical trials (RCTs) to explore and quantify the effects of the dietary supplement AP on lipid profile. The aim of our meta-analysis was the evaluation of the effect of AP on lipid profile. Methods and results: We conducted a structures search on PubMed and Google Scholar to identify eligible articles published prior to 2015. Eleven RCTs were subjected to meta-analysis by means of random effects models using the Standardised Mean Differences approach (Hedges’ method) and the Mean Differences approach as a sensitivity analysis. Data from 11 randomised clinical trials, corresponding to 1970 nutraceutical combination and 1954 control patients (3924 total patients), were included after the peer evaluation and data extraction of two independent evaluators. Heterogeneity was significant in all models. A significant effect was found for all lipid parameters. The effect size (relative change from baseline (%)) was -1.3 (9.9%) for total cholesterol, -1.17 (-13.7%) for LDL-c, +0.17 (+3.7%) for HDL-c and -0.24 (-7.0%) for Triglycerides. Conclusion: This meta-analysis confirms that the nutraceutical combination containing berberine, policosanol, and red yeast rice has shown to be an effective product for the improvement of the lipid profile

Antecedentes y objetivos: Se ha observado que una combinación de productos nutricéuticos con berberina, policosanol y arroz de levadura roja, altamente comercializada en Europa (Armolipid Plus®) (AP), induce mejoras significativas del lipidograma, resistencia a la insulina y otros componentes del síndrome metabólico. Sin embargo, los diseños y resultados del estudio de la literatura fueron heterogéneos y por tanto es necesario realizar una revisión y metaanálisis sistemático de todos los ensayos clínicos aleatorizados (ECA) relevantes para explorar y cuantificar los efectos del suplemento dietético AP en el lipidograma. El objetivo de nuestro metaanálisis fue la evaluación del efecto de AP en el lipidograma. Métodos y resultados: Se llevó a cabo una búsqueda estructurada en PubMed y Google Scholar para identificar los artículos aptos para publicación antes del 2015. Se sometieron once ECA a metaanálisis por medio de modelos de efectos aleatorios utilizando el enfoque de diferencias medias estandarizadas (método Hedges) y el enfoque de diferencias medias estandarizadas como análisis de la sensibilidad. Los datos de los once ensayos clínicos aleatorizados, correspondientes a 1970 pacientes con combinación de productos nutricéuticos y 1954 pacientes de control (3924 pacientes en total), se incluyeron después de la evaluación científica externa y la extracción de datos de dos evaluadores independientes. La heterogeneidad fue significativa en todos los modelos. Se encontró un efecto significativo para todos los parámetros lipídicos. El tamaño del efecto (cambio relativo conforme a los valores de referencia, %) fue de -1,3 (9,9%) para el colesterol total, -1,17 (-13,7%) para el colesterol LDL, +0,17 (+3,7%) para el colesterol HDL y de -0,24 (-7%) para los triglicéridos. Conclusión: Este metaanálisis confirma que la combinación de productos nitrucéuticos con berberina, policosanol y arroz de levadura roja es un producto eficaz para la mejora del lipidograma

Randomised comparison of zofenopril and ramipril plus acetylsalicylic acid in postmyocardial infarction patients with left ventricular systolic dysfunction: a post hoc analysis of the SMILE-4 Study in patients according to levels of left ventricular ejection fraction at entry.

OBJECTIVE: Conflicting evidence exists on the benefits of treating patients with coronary artery disease and preserved left ventricular ejection fraction (LVEF) with an ACE inhibitor. This retrospective analysis of the SMILE-4 Study sought to compare the efficacy of zofenopril 60 mg plus acetylsalicylic acid (ASA) versus ramipril 10 mg plus ASA 100 mg in patients with acute myocardial infarction (AMI) and heart failure, according to an impaired or preserved LVEF. METHODS: The primary study end point was 1-year combined occurrence of death or hospitalisation for cardiovascular causes. A preserved LVEF was defined by a baseline LVEF >40% and an impaired one by an LVEF ≤40%. RESULTS: 448 patients (63%) had preserved and 262 (37%) had impaired LVEF. The primary end point occurred in 125 patients with preserved (28%) and 106 patients with impaired LVEF (41%, p=0.001). In the first group, the rate of major cardiovascular events was significantly lower under zofenopril than under ramipril (23% vs 33%; OR and 95% CI 0.60, 0.39 to 0.91; p=0.016). This was also the case for patients with impaired LVEF, though between-group difference was not statistically significant (38% zofenopril vs 44% ramipril; OR 0.77, 0.47 to 1.26; p=0.297). LVEF values significantly (p<0.0001) increased during the follow-up in both subsets with no between-treatment differences. However, improvement rates in LVEF (increase ≥5%) were higher in patients with impaired LVEF (72% vs 61%, p=0.006). CONCLUSIONS: In the SMILE-4 Study, the cardiovascular outcome of patients with post-AMI with preserved LVEF was more favourable in the zofenopril than in the ramipril treatment group. TRIAL REGISTRATION NUMBER: EudraCT Number: 2004-001150-88 (http://www.clinicaltrialsregister.eu); Italian Ministry of Health Code: GUIDOTT_III_2004_001 (https://oss-sper-clin.agenziafarmaco.it).

Cost-effectiveness of zofenopril in patients with left ventricular systolic dysfunction after acute myocardial infarction: a post hoc analysis of SMILE-4.

BACKGROUND: In SMILE-4 (the Survival of Myocardial Infarction Long-term Evaluation 4 study), zofenopril + acetylsalicylic acid (ASA) was superior to ramipril + ASA in reducing the occurrence of major cardiovascular events in patients with left ventricular dysfunction following acute myocardial infarction. The present post hoc analysis was performed to compare the cost-effectiveness of zofenopril and ramipril. METHODS: In total, 771 patients with left ventricular dysfunction and acute myocardial infarction were randomized in a double-blind manner to receive zofenopril 60 mg/day (n = 389) or ramipril 10 mg/day (n = 382) + ASA 100 mg/day and were followed up for one year. The primary study endpoint was the one-year combined occurrence of death or hospitalization for cardiovascular causes. The economic analysis was based on evaluation of cost of medications and hospitalizations and was applied to the intention-to-treat population (n = 716). Cost data were drawn from the National Health Service databases of the European countries participating in the study. The incremental cost-effectiveness ratio was used to quantify the cost per event prevented with zofenopril versus ramipril. RESULTS: Zofenopril significantly (P = 0.028) reduced the risk of the primary study endpoint by 30% as compared with ramipril (95% confidence interval, 4%-49%). The number needed to treat to prevent a major cardiovascular event with zofenopril was 13 less than with ramipril. The cost of drug therapies was higher with zofenopril (328.78 Euros per patient per year, n = 365) than with ramipril (165.12 Euros per patient per year, n = 351). The cost related to the occurrence of major cardiovascular events requiring hospitalization averaged 4983.64 Euros for zofenopril and 4850.01 Euros for ramipril. The incremental cost-effectiveness ratio for zofenopril versus ramipril was 2125.45 Euros per event prevented (worst and best case scenario in the sensitivity analysis was 3590.09 and 3243.96 Euros, respectively). CONCLUSION: Zofenopril is a viable and cost-effective treatment for managing patients with left ventricular dysfunction after acute myocardial infarction.

A randomized, double-blind, placebo-controlled trial evaluating sitagliptin action on insulin resistance parameters and ß-cell function.

AIM: To evaluate the impact on glycemic control, insulin secretion and on insulin resistance of a sitagliptin + metformin combination compared to metformin monotherapy in type 2 diabetic, naïve to treatment, patients. MATERIALS AND METHODS: A total of 178 Caucasian type 2 diabetic patients were randomized to take sitagliptin 100 mg once a day or placebo in addition to previously taken metformin, for 12 months. The authors evaluated at 3, 6, 9, and 12 months: body mass index (BMI), glycemic control, fasting plasma insulin (FPI), HOMA-IR, HOMA-ß, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, glucagon, retinol binding protein-4 (RBP-4), visfatin, and chemerin. Before and 12 months after the addition of sitagliptin, patients underwent tests to assess insulin sensitivity and insulin secretion. RESULTS: Sitagliptin + metformin gave a better decrease of glycemic control, HOMA-IR and glucagon levels compared to placebo + metformin; sitagliptin + metformin also better increased HOMA-ß and all ß-cell measurements recorded after the clamp. Regarding adipocytokines, sitagliptin + metformin better reduced RBP-4, visfatin and chemerin levels, compared to placebo + metformin. CONCLUSION: When metformin alone is not enough to reach an adequate glycemic control, sitagliptin can be a valid option, because of its effects in reducing insulin resistance and in preserving ß-cell function.

Tinnitus in elderly patients and prognosis of mild-to-moderate congestive heart failure: a cross-sectional study with a long-term extension of the clinical follow-up.

BACKGROUND: The complex mechanism responsible for tinnitus, a symptom highly prevalent in elderly patients, could involve an impaired control of the microcirculation of the inner ear, particularly in patients with poor blood pressure control and impaired left ventricular (LV) function. METHODS: In order to define the relationship between the presence of tinnitus and the severity and clinical prognosis of mild-to-moderate chronic heart failure (CHF) in a large population of elderly patients (N = 958), a cross-sectional study was conducted with a long-term extension of the clinical follow-up. Blood pressure, echocardiographic parameters, brain natriuretic peptide (BNP), hospitalization, and mortality for CHF were measured. Multivariate logistic regression analysis was used to assess the association between the presence of tinnitus and some of the prognostic determinants of heart failure. RESULTS: The presence of tinnitus was ascertained in 233 patients (24.3%; mean age 74.9 ± 6 years) and was associated with reduced systolic and diastolic blood pressure (123.1 ± 16/67.8 ± 9 vs 125.9 ± 15/69.7 ± 9; P = .027/P = .006), reduced LV ejection fraction (LVEF%; 43.6 ± 15 vs 47.9 ± 14%, P = .001), and increased BNP plasma levels (413.1 ± 480 vs 286.2 ± 357, P = .013) in comparison to patients without symptoms. The distribution of CHF functional class was shifted toward a greater severity of the disease in patients with tinnitus. Combined one-year mortality and hospitalization for CHF (events/year) was 1.43 ± 0.2 in patients with tinnitus and 0.83 ± 0.1 in patients without tinnitus, with an adjusted hazard ratio (HR) of 0.61 (95% confidence interval (CI): 0.37 to 0.93, P <.002). CONCLUSIONS: Our preliminary data indirectly support the hypothesis that tinnitus is associated with a worse CHF control in elderly patients and can have some important clinical implications for the early identification of patients who deserve a more aggressive management of CHF.

Relationship between serum zinc levels, thyroid hormones and thyroid volume following successful iodine supplementation.

OBJECTIVE: Zinc is essential for many biochemical processes and also for cell proliferation. Thyroid hormones influence zinc metabolism by affecting zinc absorption and excretion. Additionally, zinc deficiency affects thyroid function. The aim of the present study was to evaluate a possible association of zinc levels with thyroid volume, thyroid hormones and thyroid autoantibody levels in healthy subjects, patients with autoimmune thyroid disease (AITD) and patients with nodular goitre following successful iodine supplementation. This is a cross-sectional study in which 201 subjects who were not under medical treatment and did not have previous thyroid surgery or radio-iodine treatment were evaluated. Seventy patients had nodular goitre, 67 AITD and 64 had normal thyroid. Thyroid volume was calculated by ultrasonographic measurements. Serum free T4, T3, TSH, anti-thyroglobulin and anti-thyroid peroxidase levels were determined by appropriate methodology. RESULTS: In patients with normal thyroid, zinc levels were significantly positively correlated with free T3 levels (p<0.001). In the nodular goitre group, thyroid volume was negatively correlated with TSH and circulating zinc levels (p=0.014 and p=0.045, respectively). In the AITD group, thyroid autoantibodies and zinc were significantly positively correlated. Multiple regression analysis revealed a significant relationship between thyroid volume and zinc only in the patients with nodular goitre (p=0.043). CONCLUSION: There was significant correlation of serum zinc levels with thyroid volume in nodular goitre patients, with thyroid autoantibodies in AITD and with free T3 in patients with normal thyroid.

Nephroprotective action of glycosaminoglycans: why the pharmacological properties of sulodexide might be reconsidered.

A relatively large body of evidence supports the notion that glomerular capillary wall and mesangial alterations in diabetic nephropathy involve biochemical alterations of glycoproteins in these structures. Evidence in experimental animals rendered diabetic reveals that the administration of heparin and other anionic glycoproteins can effectively prevent the biochemical alterations that promote albuminuria. Moreover, angiotensin II inhibits heparan sulfate synthesis, while heparins modulate angiotensin II signaling in glomerular cells, inhibiting aldosterone synthesis and lowering proteinuria in diabetes patients. Sulodexide, a mixture of heparin and dermatan sulfate, appears to be a promising treatment for diabetic proteinuria partially resistant to renin-angiotensin system blocking agents. Sulodexide prevents heparan sulfate degradation, thus allowing reconstruction of heparan sulfate content and restoration of glomerular basement membrane ionic permselectivity. The antiproteinuric effect appears to be mainly related to the basal proteinuria and consequently to the duration of treatment in a relatively large number of small clinical trials. On the other hand, several sulodexide pharmacodynamic properties could improve the prognosis of chronic kidney disease patients, also independently from its antiproteinuric effect. However, sulodexide development as an antiproteinuric drug needs to be continued, in order to define which kind of patients could better respond to this treatment.