Cardiovascular Efficacy Research Articles

Hormone treatments in congestive heart failure.

The common ultimate pathological feature for all cardiovascular diseases, congestive heart failure (CHF), is now considered as one of the main public health burdens that is associated with grave implications. Neurohormonal systems play a critical role in cardiovascular homeostasis, pathophysiology, and cardiovascular diseases. Hormone treatments such as the newly invented dual-acting drug valsartan/sacubitril are promising candidates for CHF, in addition to the conventional medications encompassing beta receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists. Clinical trials also indicate that in CHF patients with low insulin-like growth factor-1 or low thyroid hormone levels, supplemental treatment with growth hormone or thyroid hormone seems to be cardioprotective; and in CHF patients with volume overload the vasopressin antagonists can relieve the symptoms superior to loop diuretics. Furthermore, a combination of selective glucocorticoid receptor agonist and mineralocorticoid receptor antagonist may be used in patients with diuretic resistance. Finally, the potential cardiovascular efficacy and safety of incretin-based therapies, testosterone or estrogen supplementation needs to be prudently evaluated in large-scale clinical studies. In this review, we briefly discuss the therapeutic effects of several key hormones in CHF.

Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis

Glucagon-like peptide-1 (GLP-1) receptor agonists are effective glucose-lowering drugs. Findings from cardiovascular outcome trials showed cardiovascular safety of GLP-1 receptor agonists, but results for cardiovascular efficacy were varied. We aimed to examine overall cardiovascular efficacy for lixisenatide, liraglutide, semaglutide, and extended-release exenatide. In this systematic review and meta-analysis, we analysed data from eligible trials that assessed the safety and efficacy of GLP-1 receptor agonists compared with placebo in adult patients (aged 18 years or older) with type 2 diabetes and had a primary outcome including, but not limited to, cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke. We searched PubMed and MEDLINE without language restrictions up to Sept 18, 2017, for eligible trials. We did a meta-analysis of available trial data using a random-effects model to calculate overall hazard ratios (HRs) for cardiovascular efficacy outcomes and odds ratios for key safety outcomes. Of 12 articles identified in our search and screened for eligibility, four trials of cardiovascular outcomes of GLP-1 receptor agonists were identified: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN 6 (semaglutide), and EXSCEL (extended-release exenatide). Compared with placebo, GLP-1 receptor agonist treatment showed a significant 10% relative risk reduction in the three-point major adverse cardiovascular event primary outcome (cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke; HR 0·90, 95% CI 0·82-0·99; p=0·033), a 13% RRR in cardiovascular mortality (0·87, 0·79-0·96; p=0·007), and a 12% relative risk reduction in all-cause mortality (0·88, 0·81-0·95; p=0·002), with low-to-moderate between-trial statistical heterogeneity. No significant effect of GLP-1 receptor agonists was identified on fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, hospital admission for unstable angina, or hospital admission for heart failure. Overall, no significant differences were seen in severe hypoglycaemia, pancreatitis, pancreatic cancer, or medullary thyroid cancer reported between GLP-1 receptor agonist treatment and placebo. Our findings show cardiovascular safety across all GLP-1 receptor agonist cardiovascular outcome trials and suggest that drugs in this class can reduce three-point major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality risk, albeit to varying degrees for individual drugs, without significant safety concerns. GLP-1 receptor agonists have a favourable risk-benefit balance overall, which should allow the choice of drug to be individualised to each patient's needs. Amylin Pharmaceuticals (AstraZeneca).

Moderate- to high-intensity statins for secondary prevention in patients with type 2 diabetes mellitus on dialysis after acute myocardial infarction

BackgroundEvidences support the benefits of moderate- to high-intensity statins for patients with acute myocardial infarction (AMI) except for those with type 2 diabetes mellitus (T2DM) on dialysis after AMI. This study was aimed to investigate the safety and efficacy of secondary prevention of cardiovascular diseases using moderate- to high-intensity statins in T2DM patients on dialysis after AMI.MethodsA simulated prospective cohort study was conducted between January 1st, 2001 and December 31st, 2013 utilizing data from the Taiwan National Health Insurance Research Database. A total of 882 patients with T2DM on dialysis after AMI were selected as the study cohort. Cardiovascular efficacy and safety of moderate- to high-intensity statins were evaluated by comparing outcomes of 441 subjects receiving statins after AMI to 441 matched subjects not receiving statins after AMI. The primary composite outcome included cardiovascular death, non-fatal myocardial infarction and non-fatal ischemic stroke.ResultsThe Kaplan–Meier event rate for the primary composite outcomes at 8 years was 30.2% (133 patients) in the statin group compared with 25.2% (111 patients) in the non-statin group (hazard ratio [HR], .98; 95% confidence interval [CI] .76–1.27). Significantly lower risks of non-fatal ischemic stroke (HR, .58; 95% CI .35–.98) and all-cause mortality (HR, .70; 95% CI .59–.84) were found in the statin group.ConclusionsIn T2DM patients on dialysis after AMI, the use of moderate- to high-intensity statins has neutral effects on composite cardiovascular events but may reduce risks of non-fatal ischemic stroke and all-cause mortality.

The emerging role of proprotein convertase subtilisin/kexin type-9 inhibition in secondary prevention: from clinical trials to real-world experience.

The recent advent of a highly efficacious class of low-density lipoprotein cholesterol (LDL-C) lowering agents, the proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors, has transformed dyslipidaemia management in patients with cardiovascular disease as well as those with familial hypercholesterolemia. Recent positive results of the landmark Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk cardiovascular outcome trial with evolocumab as an add-on to statin therapy demonstrate further reduction of cardiovascular events. Additional safety outcomes from this large randomized trial, as well as the EBBINGHAUS substudy, allay fears of neurocognitive disorder as an adverse effect of achieving very low LDL-C levels with these agents. Widespread clinical adoption of PCSK9 inhibitors will depend on the results from ongoing and planned cardiovascular efficacy and safety trials with PCSK9 inhibitors. In addition, understanding the practical challenges and barriers to usage of these injectable agents by high cardiovascular risk patients will also affect clinical adoption of this class of agents. Analysis of cost-benefit models, along with anticipated updates to practice guidelines for dyslipidaemia management are likely to strengthen the clinical utility of PCSK9 inhibitors. Importantly, the potency of this new class of agents provides a huge opportunity to extend further the 'lower LDL-C is better' hypothesis in an effort to reduce rates of cardiovascular morbidity and mortality on a population level.

The efficacy of anti-PCSK9 antibodies: Results from recent trials

The serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein (LDL) receptor (LDLR) and directs it to the lysosome for degradation. This results in decreased numbers of LDLR available on the cell surface to bind LDL particles and remove them from the circulation and a subsequent increase in circulating LDL-cholesterol (LDL-C) concentrations. Since the role PCSK9 plays in LDL-C metabolism has been discovered in 2003, there have been major efforts in finding efficient and safe methods to inhibit it. Amongst those the fully human PCSK9 antibodies evolocumab and alirocumab have been studied in a wide range of patients such as in those with statin intolerance, as add-on to statin therapy, as monotherapy and in patients with familial hypercholesterolemia and they have been shown to decrease LDL-C by ∼50 to 70%. Rates of achieving LDL-C goals are up to 87–98% of treated subjects. Multiple phase 3 studies with these drugs are already completed and cardiovascular endpoint trials are expected to be concluded by the end of 2016. Both, alirocumab and evolocumab have been approved in 2015 for the treatment of hypercholesterolemia in the European Union and in the United States. Preliminary meta-analytic data show an improvement in cardiovascular morbidity and mortality by ∼50%. If the large ongoing endpoint trials confirm the cardiovascular efficacy and overall safety of these drugs, PCSK9 antibodies will revolutionarize lipid-lowering therapy.

Anti-PCSK9 Antibodies: A New Era in the Treatment of Dyslipidemia.

The serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein (LDL) receptor (LDLR) and directs it to lysosomal degradation. This results in decreased numbers of LDLR available on the cell surface to bind LDL particles and remove them from the circulation which in turn leads to an increase in circulating LDL-cholesterol (LDL-C) concentrations. Since the role PCSK9 plays in LDLC metabolism has been discovered in 2003 there have been major efforts in finding efficient and safe methods to inhibit it. Amongst those the fully human anti-PCSK9 antibodies alirocumab and evolocumab have been studied in a wide range of patients such as in those with statin intolerance, as add-on to statin therapy, as monotherapy and in patients with familial hypercholesterolemia and have been shown to decrease LDL-C overall by ~50-70%. Rates of achieving LDL-C goals, depending on individual risk, are up to 87 -98% of treated subjects. Multiple phase III studies with these drugs are already completed and cardiovascular endpoint trials are expected to be concluded by the end of 2016 and 2017 for evolocumab and alirocumab, respectively. In 2015 both alirocumab and evolocumab were approved for the treatment of hypercholesterolemia in the European Union and in the US. Preliminary data show an improvement in cardiovascular morbidity and mortality by ~50%. If the large ongoing endpoint trials confirm the cardiovascular efficacy and overall safety of these drugs, PCSK9 antibodies will revolutionarize lipid-lowering therapy.

PCSK9 Inhibition to Reduce Cardiovascular Risk: Tempering Expectations.

> Evolocumab and clinical outcomes in patients with cardiovascular disease > > Sabatine et al > > N Engl J Med . Published online ahead of print March 17, 2017. > Cardiovascular efficacy and safety of bococizumab in high-risk patients > > Ridker et al > > N Engl J Med . 2017;376:1527–1539. The first large clinical outcomes trials of proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors have demonstrated that these drugs, when taken with statins, reduce cardiovascular events by 15% to 20% more than statins alone. However, this event reduction is less than expected for such a large decrease in low-density lipoprotein cholesterol (LDL-C), and the reasons for this disconnect between LDL-C lowering and cardiovascular events remain unclear. Future trials should clarify the degree of clinical benefit to be expected from PCSK9 inhibitors. Two years ago, in these pages, we discussed the results of very early clinical outcome trials of the PCSK9 monoclonal antibodies evolocumab and alirocumab.1 These drugs both reduced LDL-C levels by slightly >60% on top of statin therapy and reduced cardiovascular events by ≈50%.2,3 We noted that although these results engendered great expectations, both of these studies were preliminary, with a small number of end points, short follow-up, and other important limitations.1 As often happens with life in general, our great expectations have been tempered by 2 recent reports. The FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) enrolled 27 564 patients with atherosclerotic cardiovascular disease and LDL-C levels ≥70 mg/dL who were receiving statin therapy.4 Patients were randomly assigned to receive double-blind treatment with evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or placebo as subcutaneous injections. The primary composite end point was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization and the median duration of follow-up …

Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients

BackgroundBococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk.MethodsIn two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow-up was 10 months.ResultsAt 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of −56.0% in the bococizumab group and +2.9% in the placebo group, for a between-group difference of –59.0 percentage points (P<0.001) and a median reduction from baseline of 64.2% (P<0.001). In the lower-risk, shorter-duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P=0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P=0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P=0.08). Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P<0.001).ConclusionsIn two randomized trials comparing the PCSK9 inhibitor bococizumab with placebo, bococizumab had no benefit with respect to major adverse cardiovascular events in the trial involving lower-risk patients but did have a significant benefit in the trial involving higher-risk patients. (Funded by Pfizer; SPIRE-1 and SPIRE-2 ClinicalTrials.gov numbers, NCT01975376 and NCT01975389.)

Acute pancreatitis associated with saxagliptin treatment presented by metabolic acidosis

The DPP-4 inhibitor, saxagliptin, was approved in the US and Europe both as monotherapy and in combination with metformin, sulphonylurea, thiazolidinedione or insulin. An increased risk of acute pancreatitis has been identified for all approved DPP-4 inhibitors. Patients treated with DPP-4 inhibitors should be informed of the characteristic symptoms of acute pancreatitis.1 A causative relationship between DPP-4 inhibitors and pancreatitis has not been established. Diabetes itself is a risk factor for pancreatitis. Other risk factors such as hypercholesterolaemia, hypertriglyceridaemia and obesity were also present in 51% of US cases.2 We present the case of a type 2 diabetes (T2DM) patient who developed acute pancreatitis which was initially thought to be diabetic ketoacidosis (DKA) after Kombiglyze XR (saxagliptin combined with metformin slow release) therapy that reversed to normal after stopping the drug. A 33-year-old man had a known case of T2DM for about five years, along with mild dyslipidaemia and hypertension. He was on regular treatment with metformin 500 mg thrice daily, amlodipine + valsartan 5/160 once daily (od), and fenofibrate 300 mg od; he drinks alcohol occasionally. Saxagliptin (Onglyza) 5 mg od was added in February 2014; the patient was seen in the outpatient clinic a few months later. Subsequently, the treatment was changed to glimepiride and Kombiglyze XR (saxagliptin/metformin 5 mg/1000 mg od). On October 2015, the patient was admitted to hospital with a history of breathlessness, dizziness, vomiting and palpitations. His investigations revealed: high blood glucose 538 mg/dL, mildly elevated urea 9.4 mmol/L and creatinine 141 µmol/L, in addition to elevated CRP 99 mg/L. Arterial blood gases showed pH 7.10, HCO3 4.0, and high ketones in the urine. His last triglycerides checked were 5.54 mmol/L and he was re-started on fenofibrate (having stopped the medication for a period of time). The patient was treated as a case of DKA. However, reviewing the history, the patient admitted he had a history of abdominal pain and vomiting, thinking he had food poisoning prior to hospitalisation. This led to the consideration of acute pancreatitis: he had T2DM and so DKA would be unlikely in his case. Therefore, an abdominal ultrasound scan was done and showed irregular turbid fluid located around the pancreas, raising the possibility of acute pancreatitis. Serum amylase was done on the third day of admission and it was normal (96u/L). Further, his abdominal CT scan with contrast was done and showed signs of acute pancreatitis with evidence of necrotic changes in the tail of the pancreas, with excessive surrounding oedema and fluid extending from the retroperitoneal region around the tail of the pancreas to the anterior intraperitoneal region above the level of the transverse colon. Islet-cell antibodies and glutamate decarboxylase antibodies were negative. Later, he was discharged home in a stable condition on metformin XR 750 twice a day and premixed insulin (NovoMix 30) 18 units am, 16 units pm. Pancreatitis is now included in the product information for all DPP-4 inhibitors as a possible adverse reaction. The reporting rate of pancreatitis appears to be low (ranging between 1/1000 and 1/100 patients receiving the drug), but the precise frequency is unknown as few cases have been reported in clinical trials. In most cases, pancreatitis resolved after discontinuation of treatment. In 21% of the 88 reported cases in the US,2 pancreatitis occurred within 30 days of starting sitagliptin or metformin + sitagliptin. Hospitalisation was required in 66% of the patients. Upon discontinuation of sitagliptin, 53% of the 88 cases resolved. The SAVOR-TIMI 53 trial3 examined the cardiovascular efficacy and safety of saxagliptin vs placebo in patients with or at risk for cardiovascular disease. The investigators reported 35 events of pancreatitis in each treatment arm in 63 patients (33 [0.40%] in the saxagliptin arm and 30 [0.37%] in the control arm), with a hazard ratio (HR) of 1.09 (95% CI 0.66–1.79; p = 0.80). Adjudication confirmed pancreatitis in 24 patients (26 events) in the saxagliptin arm (0.29%) and in 21 patients (25 events) in the placebo arm (0.26%), with an HR of 1.13 (0.63–2.06; p = 0.77). So, the risk for pancreatitis in T2DM patients treated with saxagliptin was low and apparently similar to placebo. However, the trial did not completely resolve the issue. This case shows one needs to be vigilant in the use of DPP-4 inhibitors in high-risk patients who already have a high risk of pancreatitis. Acute pancreatitis should be in differential diagnosis in patients on DPP-4 inhibitors admitted with metabolic acidosis, hyperglycaemia and abdominal pain; even if criteria of diagnosis of DKA are met, consider other causes of metabolic acidosis such as pancreatitis in patients on DPP-4 inhibitors. Further studies are needed to completely resolve the pancreatic safety issues with incretin-based therapy. There are no conflicts of interest declared. References are available in Practical Diabetes online at www.practicaldiabetes.com.

Cardiovascular efficacy of sitagliptin in patients with diabetes at high risk of cardiovascular disease: a 12-month follow-up

BackgroundGliptins should have beneficial effects beyond glycemic control, potentially on the pathophysiology of cardiovascular (CV) diseases, with some basic studies demonstrating this possibility. However, we are yet to answer whether there are any direct CV effects in the clinical setting. We aimed to examine the beneficial effects of sitagliptin in Japanese patients with diabetes and high CV risk for 12 months.MethodsThis was a prospective, multicenter, observational study of 205 patients with type 2 diabetes. All participants had more than one major CV risk factor and were treated with sitagliptin for 12 months. At 3 or 12 months, we examined the effects of treatment on glycemic control, CV function (by electrocardiography, echocardiography, and reactive hyperemia-peripheral arterial tonometry), and CV biomarkers.ResultsPatients were predominantly elderly (68.8 ± 9.9 years) and male (71.5 %) and typically had more than three CV risk factors (79.2 %). Treatment with sitagliptin significantly reduced the hemoglobin A1c (HbA1c) level from 7.09 % ± 0.81 % at baseline to 6.67 % ± 0.69 % at 3 months and 6.68 % ± 0.73 % at 12 months (both P < 0.001). The reduction in HbA1c was also in tandem with the decrease in the level of high-sensitive C-reactive protein throughout the study. Independent of the change in HbA1c, sitagliptin reduced systolic (−7.0 ± 18.9 mmHg) and diastolic blood pressure (−5.1 ± 11.7 mmHg) at 12 months, and this was associated with a decrease in urinary albumin. In contrast, there were no beneficial effects on cardiac and endothelial function or on the levels of serum B-type natriuretic peptide, high-sensitive troponin T, and urinary 8-hydroxy-2′-deoxyguanosine.ConclusionsIn Japanese patients with diabetes and multiple CV risk factors, sitagliptin showed a decrease in blood pressure associated with an improvement in albuminuria in addition to glycemic control.Trial registration: UMIN000005663Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0371-z) contains supplementary material, which is available to authorized users.

Bariatric and Cardiovascular Efficacy of Long-Limb Roux-en-Y Gastric Bypass: Overcoming the Limitations Inherent in Individuals

Background: The failure of the conservative treatment of obesity and its close association with cardiovascular events have lead to a consensus deeming the surgical approach to obesity as a must. The aim of this study is to determine the efficacy and safety of Roux-en-Y Gastric Bypass (RYGB) in obesity and cardiovascular risk (CVR). Methods: A comparative observational retrospective cohort study based on clinical records of patients having undergone RYGB between January 1st, 2011 and January 1st, 2014. Data related to obesity are analyzed at four stages: the consultation during which the patient opts for surgical intervention, immediately before surgery, and at 3 and 9 months following surgery. Furthermore, the risk of cardiovascular event is estimated before RYGB and during the final ninth-month assessment. Results: Rates for immediate complications and quietus complied with safety criteria, being lower in proportion than those reported in recent publications. Effects on body mass index and excess body we...

Cardiovascular safety and efficacy of the combined symptomatic slow-acting drug glucosamine and chondroitin sulfate in patients with gonarthrosis

Objective: to investigate the clinical efficacy and cardiovascular safety of the combined symptomatic slow-acting drug glucosamine and chondroitin sulfate in patients with osteoarthritis (OA) and hypertension. Subjects and methods. The investigation enrolled 44 patients (a female:male ratio of 40:4) aged 54.5±7.4 years with knee OA (duration, 6.4±1.54 years). The patients were blindly randomized into two groups: 1) those who received antihypertensive therapy, teraflex (chondroitin sulfate 400 mg and glucosamine sulfate 500 mg) with/without acetaminophen; 2) those who had antihypertensive therapy and acetaminophen. At baseline and 3 and 6 months after treatment, the investigators assessed a change in the degree of OA by the WOMAC and Lequesne indices, the treatment efficiency evaluated by a physician and a patient using a visual analogue scale, and cardiovascular safety (during the first and last visits) through examination of the antithrombogenic properties of the vascular wall and arterial stiffness. Results. All the patients taking teraflex for 6 months were observed to have a positive effect manifesting as a substantial reduction in WOMAC and Lequesne indices, pain syndrome, and needs for analgesics compared to both the baseline level and parameters in the patients receiving acetaminophen only. Teraflex therapy showed an increase in the fibrinolytic activity of the vascular wall. A more obvious fall in augmentation index and pulse wave velocity was seen in OA and AG patients receiving antihypertensive therapy and teraflex. Conclusion . Group 1 displayed not only reductions in pain syndrome and needs for analgesics, but also no blood pressure destabilization. They also had lower endothelial dysfunction manifesting as enhanced fibrinolytic activity of the vascular wall, decreased brachial and aortic augmentation indices, and lower pulse wave velocity.

Quercetin derivatives as novel antihypertensive agents: Synthesis and physiological characterization

The antihypertensive flavonol quercetin (Q1) is endowed with a cardioprotective effect against myocardial ischemic damage. Q1 inhibits angiotensin converting enzyme activity, improves vascular relaxation, and decreases oxidative stress and gene expression. However, the clinical application of this flavonol is limited by its poor bioavailability and low stability in aqueous medium.In the aim to overcome these drawbacks and preserve the cardioprotective effects of quercetin, the present study reports on the preparation of five different Q1 analogs, in which all OH groups were replaced by hydrophobic functional moieties.Q1 derivatives have been synthesized by optimizing previously reported procedures and analyzed by spectroscopic analysis. The cardiovascular properties of the obtained compounds were also investigated in order to evaluate whether chemical modification affects their biological efficacy. The interaction with β-adrenergic receptors was evaluated by molecular docking and the cardiovascular efficacy was investigated on the ex vivo Langendorff perfused rat heart. Furthermore, the bioavailability and the antihypertensive properties of the most active derivative were evaluated by in vitro studies and in vivo administration (1month) on spontaneously hypertensive rats (SHRs), respectively.Among all studied Q1 derivatives, only the ethyl derivative reduced left ventricular pressure (at 10−8M÷10−6M doses) and improved relaxation and coronary dilation. NOSs inhibition by L-NAME abolished inotropism, lusitropism and coronary effects. Chronic administration of high doses of this compound on SHR reduced systolic and diastolic pressure. Differently, the acetyl derivative induced negative inotropism and lusitropism (at 10−10M and 10−8÷10−6M doses), without affecting coronary pressure. Accordingly, docking studies suggested that these compounds bind both β1/β2-adrenergic receptors.Taking into consideration all the obtained results, the replacement of OH with ethyl groups seems to improve Q1 bioavailability and stability; therefore, the ethyl derivative could represent a good candidate for clinical use in hypertension.

Efficacy and safety of P2Y12 inhibitors according to diabetes, age, gender, body mass index and body weight: Systematic review and meta-analyses of randomized clinical trials

ObjectiveThe efficacy of antiplatelet drugs may differ in specific patient subgroups. We aimed to assess the efficacy and safety of the P2Y12 inhibitors clopidogrel, ticlopidine, prasugrel, ticagrelor, and cangrelor according to diabetes status, age, gender, body mass index, and body weight. MethodsRandomized clinical trials (RCTs) of P2Y12 inhibitors reporting information on cardiovascular disease (defined as myocardial infarction, stroke, or cardiovascular death) and bleeding (defined as any bleeding) events among the subgroups diabetes and non-diabetes, age ≥65 and <65 year-old, men and women, body mass index ≥30 and <30 kg/m2, and body weight ≥60 and <60 kg, were identified in Medline, Embase, Web of Science, and Cochrane Library on August 31st, 2014. For each inhibitor, random-effects meta-analyses were used to estimate the ratio of relative risks (rRR) for cardiovascular and bleeding events among patient subgroups. ResultsTwenty distinct RCTs (233 285 participants, 21 323 cardiovascular and 5183 bleeding events) were identified. Cardiovascular risk reduction with clopidogrel did not significantly differ according to diabetes (rRR: 1.04; 95% CI: 0.95 to 1.13; p = 0.395), age (0.98; 0.88 to 1.09; p = 0.347), gender (0.97; 0.90 to 1.04; p = 0.382), or body mass index (1.11, 0.95 to 1.31; p = 0.191). Results for other inhibitors were comparable, although available data were sparse. Limited data on bleeding events were available. ConclusionData from RCTs did not show a different cardiovascular efficacy of clopidogrel in diabetes mellitus and other clinically relevant subgroups. Limited information was available on the efficacy and safety of other P2Y12 inhibitors in specific subgroups.

DPP4 in cardiometabolic disease: recent insights from the laboratory and clinical trials of DPP4 inhibition.

The discovery of incretin-based medications represents a major therapeutic advance in the pharmacological management of type 2 diabetes mellitus (T2DM), as these agents avoid hypoglycemia, weight gain, and simplify the management of T2DM. Dipeptidyl peptidase-4 (CD26, DPP4) inhibitors are the most widely used incretin-based therapy for the treatment of T2DM globally. DPP4 inhibitors are modestly effective in reducing HbA1c (glycated hemoglobin) (≈0.5%) and while these agents were synthesized with the understanding of the role that DPP4 plays in prolonging the half-life of incretins such as glucagon-like peptide-1 and gastric inhibitory peptide, it is now recognized that incretins are only one of many targets of DPP4. The widespread expression of DPP4 on blood vessels, myocardium, and myeloid cells and the nonenzymatic function of CD26 as a signaling and binding protein, across a wide range of species, suggest a teleological role in cardiovascular regulation and inflammation. Indeed, DPP4 is upregulated in proinflammatory states including obesity, T2DM, and atherosclerosis. Consistent with this maladaptive role, the effects of DPP4 inhibition seem to exert a protective role in cardiovascular disease at least in preclinical animal models. Although 2 large clinical trials suggest a neutral effect on cardiovascular end points, current limitations of performing trials in T2DM over a limited time horizon on top of maximal medical therapy must be acknowledged before rendering judgment on the cardiovascular efficacy of these agents. This review will critically review the science of DPP4 and the effects of DPP4 inhibitors on the cardiovascular system.

Not so critical appraisal of dapagliflozin.

Not so critical appraisal of dapagliflozin.

Synthesis and Characterization of Centhaquin and its Citrate Salt and a Comparative Evaluation of their Cardiovascular Actions

Centhaquin is a compound that produces hypotension and bradycardia in higher doses and resuscitation in lower doses. It is water insoluble, and is unsuitable for intravenous use. We prepared the citrate salt of centhaquin and evaluated its cardiovascular efficacy vs. centhaquin. Centhaquin citrate was prepared and characterized; its purity was determined by HPLC. Mean arterial pressure (MAP), heart rate (HR), pulse pressure (PP), cardiac output (CO), stroke volume (SV) and stroke work (SW) following intravenous administration of centhaquin and the citrate (0.05, 0.15 and 0.45 mg.kg(-1)) were determined in anaesthetized male Sprague-Dawley rats. Centhaquin citrate was 99.8% pure and water soluble. Centhaquin (0.05, 0.15 and 0.45 mg.kg(-1)) produced a maximal decrease in MAP of 15.6, 25.2 and 28.1%, respectively; while centhaquin citrate produced a greater (p<0.001) decrease of 35.7, 47.1 and 54.3%, respectively. The decrease in PP and HR produced by the citrate was greater than centhaquin (p<0.001). At 0.45 mg.kg(-1) centhaquin produced a maximal decrease of 20.9% (p<0.01) in CO, while centhaquin citrate produced a decrease of 42.1% (p<0.001). Reduction in SV (p<0.01) and SW (p<0.001) produced by centhaquin citrate were greater than centhaquin. Centhaquin citrate has greater cardiovascular activity compared to centhaquin.

Sleep Apnea and Cardiovascular Diseases

Obstructive sleep apnea (OSA) is a common respiratory disease characterized by abnormal collapse of the pharyngeal airway during sleep, causing repetitive arousals and falls in the oxygen saturation [1]. This disorder, when not correctly treated, has been associated with higher fatal and nonfatal cardiovascular events [2]. Also, OSA has been related to many cardiovascular diseases (CVD) such as heart failure [3], arrhythmias [4], pulmonary hypertension [5], and coronary artery disease (CAD) [6]. Moreover, in recent years OSA has emerged as a major public health problem due to its profound impact on patients' health. By this reason, we have proposed this special issue about the relationship between sleep disordered breathing (SDB) and CVD. We have suggested different topics such as potential mechanisms linking OSA to CVD, acute cardiovascular effects of OSA, impact of OSA on natural history of CVD, cardiovascular effects of continuous positive airway pressure (CPAP) treatment, and therapeutic cardiovascular efficacy of emerging treatment for OSA and central sleep apnea (CSA). Several mechanisms are involved in the association between OSA and CVD. In fact, enhanced sympathetic activity, oxidative stress, systemic inflammation, and endothelial dysfunction contribute to this association and promote atherogenesis. Moreover, cyclic decreases in blood oxygen saturation during recurrent episodes of apnea produce chronic intermittent hypoxia and contribute to the development of atherosclerosis. Some hypoxia-induced transcription factors as hypoxia-inducible factor-1 and nuclear factor-Kβ are activated during intermittent hypoxia and contribute to the generation of inflammation and expression of proinflammatory cytokines such as tumor necrosis factor-α and interleukin-8. It seems that these mechanisms could have an important impact in the occurrence of ischemic cardiac events. Hence, CAD in OSA patients probably precludes the activation of multiple mechanisms, such as atherosclerosis, hypertension, and endothelial dysfunction. Likewise, OSA may influence outcomes in patients with acute or chronic CAD, but this effect remains controversial as results obtained from studies have yielded discrepant data. In this way, Yumino et al. [7] observed a higher incident of cardiac death, reinfarction, or new revascularization in OSA patients with CAD and compared to subjects without OSA, after a mean follow-up period of 7 months. Nevertheless, Hagenah et al. [8] found that OSA did not increase the risk of mortality and cardiovascular complications in 50 patients with stable CAD after 10 years of follow-up period. Moreover, concerning treatment of OSA patients with CAD, CPAP may have beneficial effects in recurrence of ischemic cardiac disease and necessity of new revascularization procedures but higher-evidence studies are necessary to investigate the effect of CPAP in these subjects. Regarding heart failure, a high prevalence of OSA and CSA in this disorder has been observed. Also, different therapeutic strategies such as oxygen therapy, CPAP, bilevel positive airway pressure (BIPAP), and adaptive servoventilation (ASV) have been proposed to treat OSA in heart failure patients. In this way, in OSA heart failure subjects, CPAP may improve survival, left ventricular ejection fraction, and quality of life [9–11]. Nevertheless, in heart failure CSA patients, CPAP probably is not effective as ASV to abolish the apnea-hypopnea index to <15 events·h−1 [12]. So far, it is evident that SDB treatment has showed consistent improvements in heart function, quality of life, and respiratory events in patients with heart failure. However, it is necessary to evaluate the impact of these respiratory treatments in randomized-controlled, long-term longitudinal studies. Finally, respecting the association between atrial arrhythmia and OSA, it has been described that cardiac remodeling, sympathetic activity, and systemic inflammation may lead to the development of arrhythmias in these patients. Moreover, hypoxemia and hypercapnia have an important role in the pathogenesis of this association. However, it is necessary to investigate the effect of CPAP treatment in atrial arrhythmias of OSA patients. In conclusion, sleep apnea is a high prevalence disease that has an important relationship with cardiovascular disease. In this special issue, we have tried to make an extensive review about mechanisms involved in the association between ischemic cardiac disease, heart failure, and arrhythmias with OSA. Nevertheless, we know that despite multiple reports about OSA and cardiovascular disease, it is yet necessary to perform higher grade evidence studies to explore mechanisms involved in this association and the impact of CPAP treatment in these subjects. Rodolfo Alvarez-Sala Francisco Garcia-Rio Felix del Campo Carlos Zamarron Nikolaus Netzer

Diabetic Dyslipidemia - Role of Saroglitazar

‘Diabetic dyslipidemia’ (combination of raised triglyceride levels, raised small-dense Low-density lipoprotein particles and low high-density lipoprotein cholesterol levels) is the most prominent risk factor of atherosclerosis and cardiovascular disease. Despite statin therapy and LDL-lowering, a high residual risk of cardiovascular events persists. High triglyceride levels and low high-density lipoprotein cholesterol levels singly and collectively increase the risk of cardiovascular events in type 2 diabetes mellitus and guidelines recommend modifying these secondary therapeutic targets to provide additional vascular protection.Addition of a fibrate or niacinareoptions for combination with a statin to reduce atherogenic dyslipidemia and are clearly effective at raising high-density lipoprotein cholesterol levels and lowering triglycerides.Addition of high dose omega-3 fatty acids (2-3 gm/day) with a statin are also effective in lowering triglyceride, but their effects on cardiovascular events remain uncertain and are complicated with safety issues. Saroglitazar is a novel dual Peroxisome Proliferator-Activated Receptors-α/γ agonist and the first glitazar approved in the world for the treatment of diabetic dyslipidemia by Drug Controller General of India in June 2013. Saroglitazar (2 mg and 4 mg) therapy has shown significant (45%) reduction in triglycerides, significant reduction of other atherogenic lipids (Low-density lipoprotein, very-low density lipoprotein, total cholesterol and apolipoprotein-B) and significant improvement of glycemic status, with relatively free from side effects. It has emerged with a hope to further reduce the incidence of cardiovascular disease among statin treated diabetic subjects. However, the trial populations were small and toxicity data may emerge with increasing use of this drug. Moreover, in absence of outcome studies and large multi-center longitudinal follow up data, the clinical cardiovascular efficacy is uncertain till date.

A prediction of the renal and cardiovascular efficacy of aliskiren in ALTITUDE using short-term changes in multiple risk markers

We recently developed and validated in existing trials a novel algorithm (PRE score) to predict long-term drug efficacy based on short-term (month-6) drug-induced changes in multiple risk markers. To show the value of the PRE score for ongoing and planned clinical trials, we here report the predicted long-term cardio-renal efficacy of aliskiren in type 2 diabetes, which was investigated in the ALTITUDE trial, but unknown at the time this study was conducted. We established the relation between multiple risk markers and cardio-renal endpoints (as defined in ALTITUDE) using a background database from past clinical trials. The short-term effect of aliskiren on multiple risk markers was taken from the AVOID trial. A PRE score was developed by multivariate Cox analysis in the background population and was then applied to the baseline and month-6 measurements of the aliskiren treatment arm of the AVOID trial to predict cardio-renal risk. The net risk difference at these time-points, after correction for placebo effects, was taken to indicate the estimated long-term cardio-renal risk change. Based on the PRE score, we predicted that aliskiren treatment in ALTITUDE would confer a relative risk change of -7.9% (95% CI -2.5 to -13.4) for the cardio-renal endpoint, a risk change of -5.1% (-1.2 to -9.0) for the CV endpoint and a non-significant risk change of -19.9% (-42.1 to +2.1) for the renal endpoint. PRE score estimations suggested that aliskiren has only a marginal additive protective effect on cardio-renal endpoints. These predictions were validated by the results of the ALTITUDE trial, confirming the potential of the PRE score to prospectively predict drug efficacy on cardio-renal outcomes.