This phase 3 trial evaluated the safety and efficacy of inclisiran, a small interfering RNA that inhibits hepatic PCSK9 synthesis, in 482 adults with heterozygous familial hypercholesterolemia, who ...received subcutaneous injections of inclisiran or placebo on days 1, 90, 270, and 450. Changes in cholesterol were assessed up to day 540.
Abstract Since the publication of the 2012 guidelines new literature has emerged to inform decision-making. The 2016 guidelines primary panel selected a number of clinically relevant questions and ...has produced updated recommendations, on the basis of important new findings. In subjects with clinical atherosclerosis, abdominal aortic aneurysm, most subjects with diabetes or chronic kidney disease, and those with low-density lipoprotein cholesterol ≥ 5 mmol/L, statin therapy is recommended. For all others, there is an emphasis on risk assessment linked to lipid determination to optimize decision-making. We have recommended nonfasting lipid determination as a suitable alternative to fasting levels. Risk assessment and lipid determination should be considered in individuals older than 40 years of age or in those at increased risk regardless of age. Pharmacotherapy is generally not indicated for those at low Framingham Risk Score (FRS; <10%). A wider range of patients are now eligible for statin therapy in the FRS intermediate risk category (10%-19%) and in those with a high FRS (> 20%). Despite the controversy, we continue to advocate for low-density lipoprotein cholesterol targets for subjects who start therapy. Detailed recommendations are also presented for health behaviour modification that is indicated in all subjects. Finally, recommendation for the use of nonstatin medications is provided. Shared decision-making is vital because there are many areas in which clinical trials do not fully inform practice. The guidelines are meant to be a platform for meaningful conversation between patient and care provider so that individual decisions can be made for risk screening, assessment, and treatment.
The magnitude of effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on specific cardiovascular and renal outcomes and whether heterogeneity is based on key baseline characteristics remains ...undefined.
We did a systematic review and meta-analysis of randomised, placebo-controlled, cardiovascular outcome trials of SGLT2i in patients with type 2 diabetes. We searched PubMed and Embase for trials published up to Sept 24, 2018. Data search and extraction were completed with a standardised data form and any discrepancies were resolved by consensus. Efficacy outcomes included major adverse cardiovascular events (myocardial infarction, stroke, or cardiovascular death), the composite of cardiovascular death or hospitalisation for heart failure, and progression of renal disease. Hazard ratios (HRs) with 95% CIs were pooled across trials, and efficacy outcomes were stratified by baseline presence of atherosclerotic cardiovascular disease, heart failure, and degree of renal function.
We included data from three identified trials and 34 322 patients (60·2% with established atherosclerotic cardiovascular disease), with 3342 major adverse cardiovascular events, 2028 cardiovascular deaths or hospitalisation sfor heart failure events, and 766 renal composite outcomes. SGLT2i reduced major adverse cardiovascular events by 11% (HR 0·89 95% CI 0·83–0·96, p=0·0014), with benefit only seen in patients with atherosclerotic cardiovascular disease (0·86 0·80–0·93) and not in those without (1·00 0·87–1·16, p for interaction=0·0501). SGLT2i reduced the risk of cardiovascular death or hospitalisation for heart failure by 23% (0·77 0·71–0·84, p<0·0001), with a similar benefit in patients with and without atherosclerotic cardiovascular disease and with and without a history of heart failure. SGLT2i reduced the risk of progression of renal disease by 45% (0·55 0·48–0·64, p<0·0001), with a similar benefit in those with and without atherosclerotic cardiovascular disease. The magnitude of benefit of SGLT2i varied with baseline renal function, with greater reductions in hospitalisations for heart failure (p for interaction=0·0073) and lesser reductions in progression of renal disease (p for interaction=0·0258) in patients with more severe kidney disease at baseline.
SGLT2i have moderate benefits on atherosclerotic major adverse cardiovascular events that seem confined to patients with established atherosclerotic cardiovascular disease. However, they have robust benefits on reducing hospitalisation for heart failure and progression of renal disease regardless of existing atherosclerotic cardiovascular disease or a history of heart failure.
None.
Abstract
Aims
To objectively appraise evidence for possible adverse effects of long-term statin therapy on glucose homeostasis, cognitive, renal and hepatic function, and risk for haemorrhagic stroke ...or cataract.
Methods and results
A literature search covering 2000–2017 was performed. The Panel critically appraised the data and agreed by consensus on the categorization of reported adverse effects. Randomized controlled trials (RCTs) and genetic studies show that statin therapy is associated with a modest increase in the risk of new-onset diabetes mellitus (about one per thousand patient-years), generally defined by laboratory findings (glycated haemoglobin ≥6.5); this risk is significantly higher in the metabolic syndrome or prediabetes. Statin treatment does not adversely affect cognitive function, even at very low levels of low-density lipoprotein cholesterol and is not associated with clinically significant deterioration of renal function, or development of cataract. Transient increases in liver enzymes occur in 0.5–2% of patients taking statins but are not clinically relevant; idiosyncratic liver injury due to statins is very rare and causality difficult to prove. The evidence base does not support an increased risk of haemorrhagic stroke in individuals without cerebrovascular disease; a small increase in risk was suggested by the Stroke Prevention by Aggressive Reduction of Cholesterol Levels study in subjects with prior stroke but has not been confirmed in the substantive evidence base of RCTs, cohort studies and case–control studies.
Conclusion
Long-term statin treatment is remarkably safe with a low risk of clinically relevant adverse effects as defined above; statin-associated muscle symptoms were discussed in a previous Consensus Statement. Importantly, the established cardiovascular benefits of statin therapy far outweigh the risk of adverse effects.
Type 2 diabetes and obesity are pro-inflammatory states associated with increased risk of cardiovascular disease. Canagliflozin, an SGLT2 inhibitor, demonstrated superiority in lowering HbA1c versus ...glimepiride with less hypoglycemia and greater weight reduction via loss of fat mass in a 52-week trial of type 2 diabetes patients. This post hoc, exploratory analysis assessed the effects of canagliflozin versus glimepiride on select adipokines, inflammatory biomarkers, and chemokines.
Changes from baseline to Week 52 in serum leptin, adiponectin, IL-6, TNFα, CRP, PAI-1, VCAM-1, and MCP-1 were measured in a randomly selected subset of type 2 diabetes patients on metformin receiving canagliflozin 300 mg (n = 100) or glimepiride (n = 100) in the overall study. Correlations between change in biomarkers and change in select metabolic and anthropometric variables were assessed.
At Week 52, canagliflozin decreased median serum leptin by 25% (95% CI: −34%, −15%) and increased median serum adiponectin by 17% (95% CI: 11%, 23%) compared with glimepiride. There was a 22% reduction in median serum IL-6 (95% CI: −34%, −10%) and a 7% increase in median serum TNFα (95% CI: 1%, 12%) with canagliflozin versus glimepiride. No between-group differences were observed with the other biomarkers. The decrease in serum leptin with canagliflozin was correlated with change in weight (r ≥ 0.3) only; the increase in adiponectin and decrease in IL-6 with canagliflozin occurred independently of changes in HbA1c, weight, or lipids.
These results indicate that canagliflozin may improve adipose tissue function and induce changes in serum leptin, adiponectin, and IL-6 that favorably impact insulin sensitivity and cardiovascular disease risk.
•Canagliflozin reduced HbA1c and provided greater weight loss vs glimepiride.•Canagliflozin decreased serum leptin and increased serum adiponectin vs glimepiride.•Canagliflozin also decreased serum IL-6 and increased TNFα vs glimepiride.•No meaningful changes in biomarkers were seen with glimepiride.•Canagliflozin may improve adipose tissue function and cardiometabolic health.
The 2021 guidelines primary panel selected clinically relevant questions and produced updated recommendations, on the basis of important new findings that have emerged since the 2016 guidelines. In ...patients with clinical atherosclerosis, abdominal aortic aneurysm, most patients with diabetes or chronic kidney disease, and those with low-density lipoprotein cholesterol ≥ 5 mmol/L, statin therapy continues to be recommended. We have introduced the concept of lipid/lipoprotein treatment thresholds for intensifying lipid-lowering therapy with nonstatin agents, and have identified the secondary prevention patients who have been shown to derive the largest benefit from intensification of therapy with these agents. For all other patients, we emphasize risk assessment linked to lipid/lipoprotein evaluation to optimize clinical decision-making. Lipoprotein(a) measurement is now recommended once in a patient's lifetime, as part of initial lipid screening to assess cardiovascular risk. For any patient with triglycerides ˃ 1.5 mmol/L, either non-high-density lipoprotein cholesterol or apolipoprotein B are the preferred lipid parameter for screening, rather than low-density lipoprotein cholesterol. We provide updated recommendations regarding the role of coronary artery calcium scoring as a clinical decision tool to aid the decision to initiate statin therapy. There are new recommendations on the preventative care of women with hypertensive disorders of pregnancy. Health behaviour modification, including regular exercise and a heart-healthy diet, remain the cornerstone of cardiovascular disease prevention. These guidelines are intended to provide a platform for meaningful conversation and shared-decision making between patient and care provider, so that individual decisions can be made for risk screening, assessment, and treatment.
Le panel principal responsable des lignes directrices 2021 a sélectionné des éléments cliniquement pertinents et a soumis des recommandations actualisées, basées sur de nouvelles découvertes d'importance apparues depuis les lignes directrices de 2016. Ainsi, le traitement par statine reste recommandé pour les patients atteints d'athérosclérose clinique, d'anévrisme de l'aorte abdominale, pour la plupart des patients diabétiques ou atteints d'insuffisance rénale chronique, et chez ceux dont le cholestérol à lipoprotéines de basse densité est ≥ 5 mmol/l. Nous avons introduit la notion de seuils pour le traitement des lipides/lipoprotéines afin d'intensifier le traitement hypolipidémiant avec des agents non-statiniques, et nous avons identifié les patients en prévention secondaire distingués comme ayant tirer le plus grand bénéfice de l'intensification du traitement avec ces agents. Pour tous les autres patients, nous mettons l'accent sur l'appréciation du risque par le biais de l'évaluation des lipides/lipoprotéines afin d'optimiser la prise de décision clinique. Le dosage de la lipoprotéine (a) est maintenant recommandé une fois dans la vie d'un patient, dans le cadre du dépistage initial des lipides pour évaluer le risque cardiovasculaire. Pour tout patient présentant des taux de triglycérides ˃ 1,5 mmol/l, l'apolipoprotéine B ou le cholestérol lié aux lipoprotéines autres que celles de haute densité sont les indices lipidiques à privilégier pour le dépistage, plutôt que le cholestérol à lipoprotéines de basse densité. Nous proposons des recommandations actualisées concernant le rôle du score calcique des artères coronaires en tant qu'outil de décision clinique pour aider à la décision d'administrer un traitement par statine. Il existe de nouvelles recommandations concernant les soins préventifs des femmes souffrant de troubles hypertensifs de la grossesse. Le changement de comportement en matière de santé, incluant l'exercice physique régulier et une alimentation saine pour le coeur, reste la pierre angulaire de la prévention des maladies cardiovasculaires. Ces lignes directrices visent à fournir une plateforme pour une discussion constructive et une prise de décision partagée entre le patient et le prestataire de soins, afin que des décisions individuelles puissent être prises pour le dépistage, l'évaluation et le traitement des risques.
Summary Background Sodium–glucose cotransporter 2 (SGLT2) inhibitors improve glycaemia in patients with type 2 diabetes by enhancing urinary glucose excretion. We compared the efficacy and safety of ...canagliflozin, an SGLT2 inhibitor, with glimepiride in patients with type 2 diabetes inadequately controlled with metformin. Methods We undertook this 52 week, randomised, double-blind, active-controlled, phase 3 non-inferiority trial at 157 centres in 19 countries between Aug 28, 2009, and Dec 21, 2011. Patients aged 18–80 years with type 2 diabetes and glycated haemoglobin A1c (HbA1c ) of 7·0–9·5% on stable metformin were randomly assigned (1:1:1) by computer-generated random sequence via an interactive voice or web response system to receive canagliflozin 100 mg or 300 mg, or glimepiride (up-titrated to 6 mg or 8 mg per day) orally once daily. Patients, study investigators, and local sponsor personnel were masked to treatment. The primary endpoint was change in HbA1c from baseline to week 52, with a non-inferiority margin of 0·3% for the comparison of each canagliflozin dose with glimepiride. If non-inferiority was shown, we assessed superiority on the basis of an upper bound of the 95% CI for the difference of each canagliflozin dose versus glimepiride of less than 0·0%. Analysis was done in a modified intention-to-treat population, including all randomised patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov , number NCT00968812. Findings 1450 of 1452 randomised patients received at least one dose of glimepiride (n=482), canagliflozin 100 mg (n=483), or canagliflozin 300 mg (n=485). For lowering of HbA1c at 52 weeks, canagliflozin 100 mg was non-inferior to glimepiride (least-squares mean difference −0·01% 95% CI −0·11 to 0·09), and canagliflozin 300 mg was superior to glimepiride (–0·12% –0·22 to −0·02). 39 (8%) patients had serious adverse events in the glimepiride group versus 24 (5%) in the canagliflozin 100 mg group and 26 (5%) in the 300 mg group. In the canagliflozin 100 mg and 300 mg groups versus the glimepiride group, we recorded a greater number of genital mycotic infections (women: 26 11% and 34 14% vs five 2%; men: 17 7% and 20 8% vs three 1%), urinary tract infections (31 6% for both canagliflozin doses vs 22 5%), and osmotic diuresis-related events (pollakiuria: 12 3% for both doses vs one <1%; polyuria: four <1% for both doses vs two <1%). Interpretation Canagliflozin provides greater HbA1c reduction than does glimepiride, and is well tolerated in patients with type 2 diabetes receiving metformin. These findings support the use of canagliflozin as a viable treatment option for patients who do not achieve sufficient glycaemic control with metformin therapy. Funding Janssen Research & Development, LLC.
BACKGROUND:In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the ...composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown.
METHODS:In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of cardiovascular death/HHF, its components, and all-cause mortality.
RESULTS:Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio HR, 0.62 95% CI, 0.45–0.86) than in those without HFrEF (HR, 0.88 95% CI, 0.76–1.02; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 95% CI, 0.66–1.17) and those without HF (HR, 0.88 95% CI, 0.74–1.03). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 95% CI, 0.43–0.95) and in those without HFrEF (HR, 0.76 95% CI, 0.62–0.92), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 95% CI, 0.34–0.90) but not in those without HFrEF (HR, 1.08 95% CI, 0.89–1.31; P for interaction=0.012). Likewise, dapagliflozin reduced all-cause mortality in patients with HFrEF (HR, 0.59 95% CI, 0.40–0.88;) but not in those without HFrEF (HR, 0.97 95% CI, 0.86–1.10; P for interaction=0.016).
CONCLUSIONS:In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT01730534.
In this cardiovascular safety trial, lorcaserin facilitated sustained weight loss without a higher risk of major adverse cardiovascular events than that with placebo in a high-risk population of ...overweight or obese patients.
Patients with diabetes and recent worsening heart failure that had led to hospitalization were randomly assigned to receive sotagliflozin or placebo. At a median of 9 months, the total number of ...deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure was significantly lower with sotagliflozin than with placebo.
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