Significant Cardiovascular Risk Reduction Research Articles

Effectiveness of a fixed combination of empagliflozin with metformin in reduction of cardiovascular risk in patients with uncontrolled arterial hypertension and decompensated type 2 diabetes mellitus

Objective is to study the effectiveness of a fixed combination of empagliflozin and metformin in reducing cardiovascular risk in patients with uncontrolled arterial hypertension (AH) and decompensated type 2 diabetes mellitus (DM). Materials and methods. 36 patients with uncontrolled AH and decompensated type 2 diabetes mellitus aged 45 to 60 were examined. Before inclusion in the study, all patients received standard antihypertensive (angiotensin‑converting enzyme (ACE) inhibitor or angiotensin‑II receptor blocker (ARB) in combination with a calcium channel blocker and a thiazide‑like diuretic), glucose‑lowering (metformin) and hypolipidemic (atorvastatin) therapy. However, target levels of blood pressure (BP), glycated haemoglobin (HbA1c) and lipids were not achieved. After the initial examination, all patients were prescribed a fixed combination of empagliflozin and metformin at a dose of 12.5 mg/1000 mg 1—2 times a day, and antihypertensive and hypolipidemic therapy was continued. Re‑examination was carried out after 20 weeks. In the work, a statistical analysis of the obtained data was carried out using standard methods using Microsoft Excel 7.0 and SPSS 19.0 application packages. Results. The transfer of the examined patients from previous ineffective hypoglycemic therapy to a fixed combination of empagliflozin with metformin against the background of standard antihypertensive and hypolipidemic therapy made it possible to achieve the target levels of HbA1c in 69% of patients and target BP levels in 64%. The frequency of reaching target BP levels in the subgroup of patients who received ARB was significantly higher than in the subgroup of patients who received ACE inhibitors. The specified therapy contributed to a significant reduction in body weight, reaching the target levels of low‑density lipoprotein cholesterol (LDL‑C) and non‑high‑density lipoprotein cholesterol (Non‑HDL‑C) in more than a third of patients, and reducing the severity of albuminuria in some patients. The tested therapy, in general, led to reduction in cardiovascular risk and did not cause side effects that could lead to discontinuation of treatment. Conclusions. The fixed combination of empagliflozin with metformin against the background of standard antihypertensive and hypolipidemic therapy in patients with uncontrolled hypertension and decompensated type 2 diabetes mellitus contributed to the achievement in the vast majority of patients of the target levels of HbA1c in the blood and BP levels, reduced body weight, positive changes in lipid metabolism and kidney function, and demonstrated the possibility of a significant reduction in cardiovascular risk. A more pronounced decrease in BP was detected in the case of a fixed combination of empagliflozin and metformin with ARB compared to ACE inhibitors in this category of patients.

Rivaroxaban and Dabigatran: prospects for use in the management of heart failure

Scientific articles examine the effectiveness and pharmacokinetics of two oral anticoagulants, dabigatran and rivaroxaban, in the context of treating atrial fibrillation and chronic heart failure. Dabigatran, as a direct thrombin inhibitor, influences the thrombin zone and fibrinogen, preventing fibrin formation. Rivaroxaban, as a selective factor Xa inhibitor, blocks factor X activation. Both medications demonstrate high bioavailability and plasma protein binding. Studies on the efficacy of rivaroxaban in atherosclerosis and low-dose rivaroxaban in chronic heart failure did not reveal statistically significant reductions in cardiovascular risk. The findings emphasize the importance of further research and an individualized approach to selecting anticoagulants for optimal management of patients with diverse cardiovascular conditions.

Prediction of Cardiometabolic Health Through Changes in Plasma Proteins With Intentional Weight Loss in the DiRECT and DIADEM-I Randomized Clinical Trials of Type 2 Diabetes Remission.

To determine the extent to which changes in plasma proteins, previously predictive of cardiometabolic outcomes, predict changes in two diabetes remission trials. We applied SomaSignal predictive tests (each derived from ∼5,000 plasma protein measurements using aptamer-based proteomics assay) to baseline and 1-year samples of trial intervention (Diabetes Remission Clinical Trial [DiRECT], n = 118, and Diabetes Intervention Accentuating Diet and Enhancing Metabolism [DIADEM-I], n = 66) and control (DiRECT, n = 144, DIADEM-I, n = 76) group participants. Mean (SD) weight loss in DiRECT (U.K.) and DIADEM-I (Qatar) was 10.2 (7.4) kg and 12.1 (9.5) kg, respectively, vs. 1.0 (3.7) kg and 4.0 (5.4) kg in control groups. Cardiometabolic SomaSignal test results showed significant improvement (Bonferroni-adjusted P < 0.05) in DiRECT and DIADEM-I (expressed as relative difference, intervention minus control) as follows, respectively: liver fat (-26.4%, -37.3%), glucose tolerance (-36.6%, -37.4%), body fat percentage (-8.6%, -8.7%), resting energy rate (-8.0%, -5.1%), visceral fat (-34.3%, -26.1%), and cardiorespiratory fitness (9.5%, 10.3%). Cardiovascular risk (measured with SomaSignal tests) also improved in intervention groups relative to control, but this was significant only in DiRECT (DiRECT, -44.2%, and DIADEM-I, -9.2%). However, weight loss >10 kg predicted significant reductions in cardiovascular risk, -19.1% (95% CI -33.4 to -4.91) in DiRECT and -33.4% (95% CI -57.3, -9.6) in DIADEM-I. DIADEM-I also demonstrated rapid emergence of metabolic improvements at 3 months. Intentional weight loss in recent-onset type 2 diabetes rapidly induces changes in protein-based risk models consistent with widespread cardiometabolic improvements, including cardiorespiratory fitness. Protein changes with greater (>10 kg) weight loss also predicted lower cardiovascular risk, providing a positive outlook for relevant ongoing trials.

Omega-3 Fatty Acids in Cardiovascular Disease and Diabetes: a Review of Recent Evidence.

Omega-3 fatty acids (n-3 FA) lower triglycerides, have anti-inflammatory properties, and improve metabolism. Clinical evidence of cardiovascular benefit with omega-3 fatty acids is mixed. We discuss mechanisms providing biological plausibility of benefit of omega-3 fatty acids in cardiovascular risk reduction and review clinical trials investigating the benefits of prescription omega-3 fatty acids in dyslipidemia, atherosclerotic cardiovascular disease (ASCVD), and diabetes. Although early trials showed no benefit of omega-3 fatty acids in ASCVD, the REDUCE-IT trial noted significant risk reduction in ASCVD events with highly purifiedEPA (icosapent ethyl) use which has changed the landscape for currently available therapeutic options. However, other large trials like STRENGTH and VITAL, which used different formulations of prescription omega-3 fatty acids, did not note significant cardiovascular risk reduction. Thus the effectiveness of omega-3 fatty acids for cardiovascular disease prevention is an ongoing topic of debate. A relative paucity of studies examining benefits for glycemic outcomes in persons with diabetes exists; however, fewstudies have suggested lack of benefit to date. Significant residual cardiovascular risk exists for individuals with hypertriglyceridemia. Prescription omega-3 fatty acids are more commonly used for CV risk reduction in these patients. Clinical guideline statements now recommend icosapent ethyl use for selected individuals with hypertriglyceridemia to reduce cardiovascular eventsgiven recent evidence from theREDUCE-IT trial. Nonetheless, data from other large scale trials has been mixed, and future research is needed to better understand how different preparations of omega-3 may differ in their cardiovascular and metabolic effects, and the mechanisms for their benefit.

The effect of icosapent ethyl on left atrial and left ventricular morphology.

Atrial fibrillation (AF) is a common arrhythmia associated with poor outcomes. N-3 fatty acids have been shown to provide significant cardiovascular risk reduction, but they may exacerbate the risk of AF. The pathway by which N-3 fatty acids may be arrhythmogenic is unknown. One possible mechanism involves cardiac chamber morphology alteration. The purpose of this study was to investigate the effect of icosapent ethyl (IPE) on left atrial (LA) size and left ventricular (LV) mass. This study used coronary computed tomographic angiography images gathered from the Effect of Icosapent Ethyl on Progression of Coronary Atherosclerosis (EVAPORATE) trial. EVAPORATE was a randomised, double-blind, placebo-controlled study finding a significant reduction in coronary atherosclerosis progression in patients with residually elevated triglycerides despite statin therapy on 4 g IPE daily versus 4 g placebo daily. Computed tomography images were used to measure LA size and LV mass at 0 and 18 months. Of 80 enrolled patients, 68 were included in the final analysis. Baseline demographics and risk factors were similar between IPE and placebo cohorts. LA anterior- posterior diameter measured on axial (p=0.51) and sagittal (p=0.52) orientations were not different over time. Also, there was no difference between groups in the change in LA volume (p=0.84). Change in LV mass was similar between groups (p=0.13). In conclusion, this study did not detect differences in LA size or LV mass over 18 months between patients on 4 g daily IPE versus placebo.

À qui un néphrologue doit-il prescrire un iSGLT2 ? Indications of SGLT2 inhibitors in kidney disease: who, why and when?

Inhibitors of sodium glucose co-transporter type 2 (iSGLT2) constitute a considerable advance in the management of patients with diabetes, heart failure and with chronic kidney disease (CKD). Randomized controlled studies have shown a significant reduction of cardiovascular risk in diabetic type 2 and/or heart failure with reduced ejection fraction patients. These studies observed a risk reduction of worsening nephropathy, leading to randomized controlled studies in CKD patients : CREDENCE, DAPA-CKD and EMPA-KIDNEY. iSGLT2 are associated with a slower progression toward end-stage kidney disease, a lower slope of GFR and a lower rate of albuminuria. In CKD patients with proteinuria either diabetic or not, the DAPA-CKD and the EMPA-KIDNEY studies have demonstrated a nephroprotective effect. This effect has not been found for patients without proteinuria. For the other nephropathies, further studies are required to confirm results obtained in patients without type 2 diabetes and macroalbuminuria. Therefore, the indication of iSGLT2, with appropriate dose of RAS inhibitor, seems undeniable to an optimal nephroprotection in CKD patients with type 2 diabetes and/or albuminuria and/or heart failure. They must be prescribed in addition to conventional nephroprotective and cardioprotective treatments and care. Side effects are limited. However, special education and monitoring concerning risks of genital infection and euglycemic ketoacidosis (diabetic patients) must be taken in mind. The therapeutic arsenal for CKD patients is expanding, leading to consider a personalized care according to the underlying nephropathy. © 2022 Published by Elsevier Masson SAS on behalf of Société francophone de néphrologie, dialyse et transplantation.

Abstract 14842: Concordance Between the Various Cardiovascular Risk Scores: Six Months Results of the Randomised Clinical Trial Evaluating Whole-Body Digital Twin Technology Enabled Precision Nutrition for Remission of Diabetes

Introduction: The Twin Precision Treatment (TPT) intervention uses the Whole-Body Digital Twin Platform, with AI and the Internet of Things, to integrate multi-dimensional data to give precision nutrition and health recommendations via the TPT app and by coaches Methods: We compared the differences between the cardiovascular (CV) risk scores: (ASCVD (atherosclerotic cardiovascular disease) risk score, QRISK, and Framingham risk score (FRS) in the TWIN intervention arm (T) (n=203) and control group (C) (n=80) along with the changes in glycemic and extra glycemic parameters Results: Mean age (years) in T and C was 43.4 (±8.2) and 50.9 (±10.6); respectively. Mean duration of diabetes (years) in T and C was 3.7 (±2.6) and 4.7 (±2.8); respectively. There was a significant reduction in all three risk scores in T arm with glycemic and other extra glycemic parameters (Table). In the intervention arm, the mean difference in the ASCVD score (%) from baseline to 180 days was comparable in the group that achieved remission (AR) (n=170) -5.3 (±5.7, 95% CI -6.2 to -4.4) and the group that did not achieve remission (DAR) (n=33) -3.9 (±4, 95% CI -5.3 to -2.5) (p=019 ns). Similarly, the mean difference in the QRISK score (%) from baseline to 180 days was comparable in AR -3.3 (±5.1, 95% CI -4.1 to -2.5) and DAR -5.1 (±6.7, 95% CI -7.6 to -2.7), (p=0.07 ns). Mean difference in the FRS (%) from baseline to 180 days was comparable in AR -9.2 (±7.4, 95% CI -10.4 to -8.1) and DAR -7.4 (±6.9, 95% CI -9.8 to -4.9), (p=0.18 ns). On day 180 Kappa agreement between ASCVD and QRISK was 0.32, between QRISK and FRS was 0.63, and between ASCVD and FRS was 0.43. Conclusions: The significant reduction in all three CV risk scores at three months was sustained at six months. TPT yields a significant reduction in cardiovascular risk across the three risk scores and is independent of the achievement of remission of diabetes. TPT, apart from achieving diabetes remission, has independent benefits for the reduction of cardiovascular risk.

473 The Effect Of Icosapent Ethyl On Left Atrial And Left Ventricular Morphology

Introduction: Atrial fibrillation (AF) is a common arrhythmia associated with poor outcomes. N-3 fatty acids have been shown to provide significant cardiovascular risk reduction, but they may exacerbate the risk of AF. The pathway by which n-3 fatty acids may be arrhythmogenic is unknown. Both left atrial (LA) size and left ventricular (LV) mass have been cited as risk factors for development of AF. One possible mechanism by which n-three fatty acids may increase AF risk involves cardiac chamber morphology alteration.

Effect of tumor necrosis factor inhibitors on risk of cardiovascular disease in patients with axial spondyloarthritis

BackgroundAxial spondyloarthritis (axSpA) is associated with an increased risk of cardiovascular disease. We aimed to evaluate the effect of tumor necrosis factor inhibitors (TNFis) on the risk of cardiovascular disease in patients with axSpA.MethodsThis retrospective study included 450 patients with axSpA without pre-existing cardiovascular disease. The outcome was incident cardiovascular disease (myocardial infarction or stroke) after the diagnosis of axSpA. The effect of TNFis on cardiovascular risk was analyzed in the total study population and in an inverse probability of treatment weighting (IPTW)-adjusted population. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for cardiovascular disease, according to exposure to TNFis.ResultsOf the 450 patients, 233 (51.8%) and 217 (48.2%) patients were and were not exposed to TNFis, respectively. Twenty cardiovascular diseases occurred during 2868 person-years of follow-up (incidence rate: 6.97/1000 person-years). In the total study population, exposure to TNFis was associated with a reduced cardiovascular risk when adjusted for traditional cardiovascular risk factors (HR 0.30, 95% CI 0.10–0.85, p = 0.024). However, when time-averaged erythrocyte sedimentation rate and C-reactive protein were additionally adjusted, this association was attenuated and lost statistical significance (HR 0.37, 95% CI 0.12–1.12, p = 0.077). Furthermore, in the IPTW-adjusted population, exposure to TNFis showed no significant reduction in cardiovascular risk (HR 0.60, 95% CI 0.23–1.54, p = 0.287).ConclusionsAlthough controlling inflammation through TNFis could be beneficial in cardiovascular risk reduction, our data indicate no TNFi-specific reduction in cardiovascular risk in patients with axSpA.

BENEFICIAL EFFECT OF SODIUM-GLUCOSE CO-TRANSPORTER-2 INHIBITORS ON RIGHT VENTRICULAR SYSTOLIC FUNCTION IN PATIENTS WITH TYPE 2 DIABETES MELLITUS: A PILOT, OBSERVATIONAL STUDY

Objective: Cardiovascular disease remains the leading cause of mortality among patients with type 2 diabetes mellitus (T2DM). Sodium-glucose co-transporter-2 (SGLT-2) inhibitors is a new class of antidiabetics, conferring a significant cardiovascular risk reduction. However, underlying mechanisms are not fully understood. Right ventricular (RV) function is adversely affected early in the course of diabetes. Herein we sought to determine the effect of long-term use of SGLT-2 inhibitors on RV function. Design and method: In this pilot, observational study, we enrolled 20 patients with T2DM and stable antidiabetic and antihypertensive treatment over the last 6 months. Patients were planned to undergo a thorough echocardiographic assessment of RV function twice, before and 6 months after initiation of a SGLT-2 inhibitor. We set as primary efficacy outcome the change in tricuspid annular plane systolic excursion (TAPSE). Results: Mean age of participants was 62.8 ± 7.9 years, with a mean T2DM duration of 8.7 ± 6.1 years. Thirteen subjects were administered dapagliflozin, while the rest 7 were prescribed empagliflozin. Due to special regulations imposed in the context of coronavirus disease-19 (COVID-19) pandemic, mean treatment duration and follow-up period was 9.35 ± 3.4 months. SGLT-2 inhibitors led to a significant increase in TAPSE from 2.01 ± 0.23 to 2.12 ± 0.15 cm (p = 0.022). The result was significant for dapagliflozin (p = 0.015), while administration of empagliflozin resulted in a non-significant increase in TAPSE (p = 0.28). However, no significant difference between the two SGLT-2 inhibitors was shown (p = 0.7). Change in TAPSE was significant in subjects with prior history of cardiovascular disease (p = 0.024), while it was non-significant for subjects without previous cardiovascular disease (p = 0.26). Other parameters of RV function or RV dimensions were unchanged. Conclusions: This is the first study to assess the effect of long-term treatment with SGLT-2 inhibitors on RV function in subjects with T2DM, demonstrating a significant increase in TAPSE.

Exenatide Once Weekly for Management of Type 2 Diabetes: A Review.

Exenatide is one of the exendin-based glucagon-like peptide 1 receptor agonists (GLP-1RAs) and is currently available in two formulations, ie, exenatide twice daily (BID), a short-acting GLP-1RA, and exenatide once weekly (QW), a long-acting GLP-1RA. Clinical efficacy and safety of exenatide 2 mg QW in patients with type 2 diabetes (T2DM) has been demonstrated in the DURATION study program. Exenatide QW has been shown to achieve greater HbA1c reduction compared with exenatide BID, with less injection frequency and greater treatment satisfaction. However, exenatide QW failed to show a significant cardiovascular risk reduction in a cardiovascular outcome trial (CVOT), the EXSCEL trial, while other GLP-1RAs have shown positive CV outcomes. Furthermore, exenatide QW has been shown to be inferior to liraglutide and semaglutide with respect to HbA1c or body weight reduction in the head-to-head trials. Thus, although the long-term efficacy and safety of exenatide QW have been demonstrated, exenatide QW might be selected with lower priority within the class of GLP1-RAs for the management of T2DM, especially for patients at high CV risk. On the other hand, exenatide QW is now expected to be a treatment option for children with T2DM or patients with Parkinson’s disease. This review provides an overview of the current evidence regarding the clinical efficacy and safety of exenatide QW and discusses the current perspectives on exenatide QW for treatment of T2DM.

SUBSTANTIAL CARDIOVASCULAR RISK REDUCTION WITH ICOSAPENT ETHYL REGARDLESS OF DIABETES STATUS OR BMI: REDUCE-IT BMI

BACKGROUND REDUCE-IT, a multinational, double-blind trial, randomized 8179 statin-treated patients with controlled low density lipoprotein cholesterol, elevated triglycerides, and cardiovascular (CV) risk, to icosapent ethyl (IPE) 4 grams daily or placebo. IPE reduced the primary (CV death, myocardial infarction [MI], stroke, coronary revascularization, hospitalization for unstable angina) and key secondary (CV death, MI, stroke) endpoints 25% and 26%, respectively (each p < 0.000001). At baseline, median body mass index (BMI) was 30.8 kg/m2, and 58.5% of REDUCE-IT patients had diabetes mellitus (DM). In patients with DM, the primary and key secondary endpoints were reduced 23% and 30%, respectively (each p≤0.00005). METHODS AND RESULTS We evaluated if BMI modulated CV risk reduction with IPE in patients with or without DM. In the full cohort, similar CV risk reduction was observed across the prespecified endpoint testing hierarchy (interaction p=ns for all), and relative safety between treatment groups was generally consistent. In persons with or without DM, similar reductions in the primary endpoint were observed across BMI categories (Figure), with similar findings in the key secondary endpoint (interaction p=ns for all). CONCLUSION The significant cardiovascular risk reduction provided by IPE 4g/day is consistent across BMI in patients with and without DM. REDUCE-IT, a multinational, double-blind trial, randomized 8179 statin-treated patients with controlled low density lipoprotein cholesterol, elevated triglycerides, and cardiovascular (CV) risk, to icosapent ethyl (IPE) 4 grams daily or placebo. IPE reduced the primary (CV death, myocardial infarction [MI], stroke, coronary revascularization, hospitalization for unstable angina) and key secondary (CV death, MI, stroke) endpoints 25% and 26%, respectively (each p < 0.000001). At baseline, median body mass index (BMI) was 30.8 kg/m2, and 58.5% of REDUCE-IT patients had diabetes mellitus (DM). In patients with DM, the primary and key secondary endpoints were reduced 23% and 30%, respectively (each p≤0.00005). We evaluated if BMI modulated CV risk reduction with IPE in patients with or without DM. In the full cohort, similar CV risk reduction was observed across the prespecified endpoint testing hierarchy (interaction p=ns for all), and relative safety between treatment groups was generally consistent. In persons with or without DM, similar reductions in the primary endpoint were observed across BMI categories (Figure), with similar findings in the key secondary endpoint (interaction p=ns for all). The significant cardiovascular risk reduction provided by IPE 4g/day is consistent across BMI in patients with and without DM.

Evidence born from ASCOT trial – still important after 15 years

The paper presents the overview evolution of hypertension identification and treatment during last 15 years after publication of ASCOT trial (AngloScandinavian Cardiac Outcomes Trial) results. It discusses possible mechanism of more significant cardiovascular risk reduction in amlodipine/ perindopril group comparing with atenolol/diuretic group: central blood pressure, arterial stiffness, asleep blood pressure and BP variability. Innovative approaches in time of ASCOТ trial such as combined antihypertensive therapy from start and RAAS inhibitor as first line now became routine practice in actual guidelines. Importance of early prescribing of fixed antihypertensive combination and choice of safe drugs help to improve adherence and decrease resistant hypertension prevalence. Prevention of new onset of diabetes in metabolic patients needs application of metabolically neutral drugs and including of renin-angiotensin-aldosterone inhibitors in combination therapy. Results of ASCOT-Legacy trial demonstrated long-term protective effect of amlodipine/perindopril combination resulting in decreasing mortality, rate of stroke and coronary events during 20-years follow-up.

Proteomic Analysis of Cardiac Adaptation to Exercise by High Resolution Mass Spectrometry.

Regular exercise has many health benefits, among which is a significant reduction of cardiovascular risk. Although many beneficial effects of exercise are well described, the exact mechanisms by which exercise confers cardiovascular benefits are yet to be fully understood. In the current study, we have used high resolution mass spectrometry to determine the proteomic responses of the heart to exercise training in mice. The impact of exercise-induced oxidative stress on modifications of cardiomyocyte proteins with lipid peroxidation biomarker 4-hydroxynonenal (4-HNE) was examined as well. Fourteen male mice were randomized into the control (sedentary) group and the exercise group that was subjected to a swim exercise training program for 5 days a week for 5 months. Proteins were isolated from the left ventricular tissue, fractionated and digested for shotgun proteomics. Peptides were separated by nanoliquid chromatography and analyzed on an Orbitrap Fusion mass spectrometer using high-energy collision–induced dissociation and electron transfer dissociation fragmentation. We identified distinct ventricular protein signatures established in response to exercise training. Comparative proteomics identified 23 proteins that were upregulated and 37 proteins that were downregulated with exercise, in addition to 65 proteins that were identified only in ventricular tissue samples of exercised mice. Most of the proteins specific to exercised mice are involved in respiratory electron transport and/or implicated in glutathione conjugation. Additionally, 10 proteins were found to be modified with 4-HNE. This study provides new data on the effects of exercise on the cardiac proteome and contributes to our understanding of the molecular mechanisms underlying the beneficial effects of exercise on the heart.

256-OR: Substantial Cardiovascular Risk Reduction with Icosapent Ethyl Regardless of Diabetes Status or BMI: REDUCE-IT BMI

Background: REDUCE-IT, a multinational, double-blind trial, randomized 8179 statin-treated patients with controlled low density lipoprotein cholesterol, elevated triglycerides, and cardiovascular (CV) risk, to icosapent ethyl (IPE) 4 grams daily or placebo. IPE reduced the primary (CV death, myocardial infarction [MI], stroke, coronary revascularization, hospitalization for unstable angina) and key secondary (CV death, MI, stroke) endpoints 25% and 26%, respectively (each p Methods: We evaluated if BMI modulated CV risk reduction with IPE in patients with or without DM. Results: In the full cohort, similar CV risk reduction was observed across the prespecified endpoint testing hierarchy (interaction p=ns for all), and relative safety between treatment groups was generally consistent. In persons with or without DM, similar reductions in the primary endpoint were observed across BMI categories (Figure), with similar findings in the key secondary endpoint (interaction p=ns for all). Conclusion: The significant cardiovascular risk reduction provided by IPE 4g/day is consistent across BMI in patients with and without DM. Disclosure D. L. Bhatt: Research Support; Self; Afimmune Limited, Amarin Corporation plc, Amgen Inc., AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Idorsia Pharmaceuticals Ltd, Lexicon Pharmaceuticals, Inc., PLx Pharma Inc., Sanofi-Aventis. C. M. Ballantyne: Advisory Panel; Self; Amarin Corporation plc, Arrowhead Pharmaceuticals, Inc., Pfizer Inc., Consultant; Self; Amgen Inc., CSL Behring, Intercept Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Regeneron Pharmaceuticals Inc., Research Support; Self; Abbott, Amgen Inc., Ionis Pharmaceuticals, Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals Inc., Roche Diagnostic USA. E. A. Brinton: Consultant; Self; 89bio, Inc., DalCor Pharmaceuticals, Esperion, Novartis AG, Other Relationship; Self; Kowa Pharmaceuticals America, Inc., Speaker’s Bureau; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Amgen Inc., Esperion, Medicure. P. G. Steg: Consultant; Self; Amarin Corporation plc, Amgen Inc., AstraZeneca, Bristol-Myers Squibb Company, Novartis Pharmaceuticals Corporation, Research Support; Self; Bayer AG, Sanofi, Servier Laboratories. S. B. Ketchum: Employee; Self; Amarin Corporation plc, Stock/Shareholder; Self; Amarin Corporation plc. R. A. Juliano: Employee; Self; Amarin Corporation plc, Stock/Shareholder; Self; Amarin Corporation plc. L. Jiao: Employee; Self; Amarin Corporation plc, Stock/Shareholder; Self; Amarin Corporation plc. R. T. Doyle: Employee; Self; Amarin Corporation plc, Stock/Shareholder; Self; Amarin Corporation plc. C. Granowitz: Employee; Self; Amarin Corporation plc. J. Tardif: Other Relationship; Self; Amarin Corporation plc, DalCor Pharmaceuticals, DalCor Pharmaceuticals, Sanofi, Research Support; Self; AstraZeneca, Ceapro, DalCor Pharmaceuticals, Esperion, REGENXBIO Inc., Servier Laboratories.

Dianas terapéuticas en el tratamiento de las dislipemias: de las estatinas a los inhibidores de PCSK9. Necesidades no cubiertas

The use of low-density lipoprotein cholesterol (LDLc)-lowering medications has led to a significant reduction of cardiovascular risk in both primary and secondary prevention. Statins represent the cornerstone of lipid-lowering treatment and substantially decreases cardiovascular morbidity and mortality. However, there are still unmet clinical needs in the management of dyslipidaemia. Indeed, it is difficult to achieve LDLc targets in many patients, particularly in those at high/very high cardiovascular risk and in those with very high baseline LDLc concentrations. Moreover, a considerable proportion of patients are unable to tolerate maximum statin doses, mostly due to muscle-related adverse effects. In the present narrative review, a summary is presented on the current knowledge on the effects of the different cholesterol-lowering drugs, including those recently approved by European and American regulatory agencies, on lipid profile, and on cardiovascular risk. Since difficult-to-treat patients may benefit from new combination therapies as a result of the emergence of new drugs with clinical evidence, updates of the clinical guidelines would be recommended.

Approvals of type 2 diabetes drugs tested in cardiovascular outcome trials: A tripartite comparison.

In 2008, the US Food and Drug Administration (FDA) issued a guidance requiring that cardiovascular outcome trials (CVOTs) be conducted for newer hypoglycaemic drugs for type 2 diabetes (T2D). We aimed to examine the decisions by 3 regulatory authorities in response to identical CVOT data. We surveyed ClinicalTrials.gov to identify CVOTs and examined the revision histories of drug labels in databases from the FDA, the European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency in Japan. We selected 14 drugs and corresponding CVOTs, 12 of which were conducted as postmarketing trials. In the USA and the EU, the pre-CVOT indication on all 14 labels was "improvement in glycaemic control". Six drugs showed significant cardiovascular risk reduction, which led to an additional indication regarding reduction of cardiovascular adverse events in the USA, and a change to the EU indication to specify treatment of adults with T2D. The initial indication in Japan, T2D, remained unchanged. Regarding safety, significant increases in heart failure were observed only in the saxagliptin trial. A warning was added to the saxagliptin labels in the EU and Japan, whereas the FDA required a class effect warning to be added to the labels of all 4 dipeptidyl peptidase-4 inhibitors. Regulatory authorities using identical trial data made substantially different decisions regarding both safety and efficacy of hypoglycaemic drugs. The differences in initial indication wording between Japan and the other authorities suggest that trial data and T2D are interpreted differently in these regions.

Diabetes, Lipids, and CV Risk

Diabetes is often associated with diabetic dyslipidemia. Both hyperglycemia and disorders of lipid metabolism strongly contribute to development of atherosclerosis, the crucial factor of cardiovascular disease. The aim of the manuscript is to summarize possible treatment to reduce cardiovascular risk. Maximal cardiovascular risk reduction is maintained by targeting more pathologic disturbances together. While antihypertensive treatment has not changed much recently, novel PCSK9 inhibitors have significantly improved management of dyslipidemia. Similarly, modern antihyperglycemic agents (SGLT2 inhibitors and GLP-1 receptor agonists) show both significant metabolic effects and cardiovascular benefits. Diabetes treatment is no longer glucocentric. Apart from glucose management, there are effective pharmacologic tools for significant reduction of cardiovascular risk.

A predictive model of pcsk-9 inhibitors eligibility in coronary and dyslipidemic patients

Abstract Purpose Dyslipidemia is a major cardiovascular risk factor and treatment is mostly based on statins and ezetimibe. PCSK-9 inhibitors are monoclonal antibodies that reduce LDL-c levels and have shown significant reduction of cardiovascular risk in high risk patients. Data regarding potential eligibility for PCSK-9, is limited especially when referring to the recent guidelines. Methods Eligibility was calculated using a proprietary adjustable software, which stores data and patient information and thus by using different criteria it can determine potential candidates for PCSK-9 inhibitors. For this purpose, 2000 patients were enrolled prospectively. Our study population was comprised of inpatients diagnosed either with acute coronary syndromes (ACS) or with chronic coronary disease (cCAD) and outpatients from Lipids' Clinic (OLC) (n=407, n=1087, n=506, respectively). In order to test eligibility, three different LDL thresholds were used in our model for high and very high risk groups: a) 70mg/dl and 55mg/dl, respectively, as recommended by the recently updated 2019 ESC/EAS Guidelines for Dyslipidaemia b) 100mg/dl and 70mg/dl, respectively, as recommended by the 2016 ESC/EAS Guidelines for Dyslipidaemias and c) 130mg/dl and 100mg/dl respectively, as mandated by our National Health Care system but also applicable in other countries. Results The eligible percentages for the three thresholds were 18.85%, 9.75% and 2.15%, in the total population (TP) respectively and it varied according to clinical status. Subgroup analysis of eligible population revealed the trends in each group (Figure 1). The increase toward more recent guidelines was mostly attributed to the increasing number of coronary patients who become eligible as our criteria become stricter. Conclusions Our predictive model provides a realistic estimation of PCSK-9 inhibitors potential eligibility in coronary and dyslipidaemic patients and thus it can become a useful tool for the use of PCSK-9 in health care systems. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Amgen Hellas LTD

Dyslipidaemias and Cardiovascular Disease: Focus on the Role of PCSK9 Inhibitors

Genetic, experimental and clinical studies have consistently confirmed that inhibition of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) can result in significant lowering of LDL-C and two fully human PCSK9 monoclonal antibodies have received regulatory approval for use in highrisk patients. Co-administration of PCSK9 with statins has resulted in extremely low LDL-C levels with excellent short-term safety profiles. While results from Phase III clinical trials provided significant evidence about the role of PCSK9 inhibitors in reducing cardiovascular event rates, their impact on mortality remains less clear. PCSK9 inhibitor therapy can be considered for high-risk patients who are likely to experience significant cardiovascular risk reduction.