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| 2. |
- Ferreira, J. P., et al.
(författare)
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Impact of Insulin Treatment on the Effect of Eplerenone: Insights From the EMPHASIS-HF Trial
- 2021
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Ingår i: Circulation-Heart Failure. - : Ovid Technologies (Wolters Kluwer Health). - 1941-3289 .- 1941-3297. ; 14:6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with heart failure with reduced ejection fraction (HFrEF) and insulin-treated diabetes have a high risk of cardiovascular complications. Mineralocorticoid receptor antagonists may mitigate this risk. We aim to explore the effect of eplerenone on cardiovascular outcomes and all-cause mortality in HFrEF patients with diabetes, including those treated with insulin in the EMPHASIS-HF trial (Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms). METHODS: The primary outcome was the composite of heart failure hospitalization or cardiovascular death. Cox models with treatment-by-diabetes subgroup interaction terms were used. RESULTS: The median follow-up was 21 (10-33) months. Of the 2737 patients included, 623 (23%) had non-insulin-treated diabetes, 236 (9%) had insulin-treated diabetes and 1878 did not have diabetes. Patients with insulin-treated diabetes were younger, more often women, with higher body mass index, waist circumference, more frequent ischemic heart failure cause, impaired kidney function, and longer diabetes duration. Compared with patients without diabetes, those with insulintreated diabetes had a 2-fold higher risk of having a primary outcome event. The hazard ratio (95% CI) for the effect of eplerenone, compared with placebo, on the primary outcome was 0.31 (0.19-0.50) in insulin-treated diabetes, 0.69 (0.500.93) in non-insulin-treated diabetes, and 0.72 (0.58-0.88) in patients without diabetes; interaction P=0.007. The annualized number needed-to-treat-to-benefit with regards to the primary outcome was 3 (95% CI, 3-4) in patients with insulin-treated diabetes, 16 (13-19) in patients with diabetes not receiving insulin, and 26 (24-28) in patients without diabetes. CONCLUSIONS: Patients with insulin-treated diabetes experienced a greater benefit from eplerenone than those with diabetes not treated with insulin and people without diabetes.
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- Monzo, L., et al.
(författare)
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Time to clinical benefit of eplerenone among patients with heart failure and reduced ejection fraction: a subgroups analysis from the EMPHASIS-HF trial
- 2023
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Ingår i: European Journal of Heart Failure. - 1388-9842. ; 25:8, s. 1444-1449
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Tidskriftsartikel (refereegranskat)abstract
- AimEplerenone reduces the risk of cardiovascular death or first hospitalization for heart failure (HF) in patients with HF and a reduced ejection fraction (HFrEF), but it is still frequently underused in routine practice. We evaluated the time course of benefits of eplerenone after its initiation in HFrEF patients from the EMPHASIS-HF trial. Methods and resultsThe EMPHASIS-HF trial was a double-blind randomized clinical trial assessing the effect of eplerenone in patients (n = 2737, mean age 68.6 & PLUSMN; 7.6 years, 22.3% women) with HFrEF and mild symptoms. The time trajectories for the effect of eplerenone versus placebo on the primary composite endpoint (cardiovascular death or first hospitalization for HF) were investigated using Cox proportional hazards models with truncated data at each day post-randomization. A significant reduction in the primary composite endpoint was observed 26 days after randomization (hazard ratio 0.58; 95% confidence interval, 0.34-1.00, p = 0.049). Eplerenone was first associated with a significant reduction in the primary endpoint in 35 days or less in most subgroups, including patients with HF history & GE;18 months (day 24), estimated glomerular filtration rate <60 ml/min (day 12), ischaemic HF aetiology (day 28), age & GE;65 years (day 28), narrow QRS (day 30), higher MAGGIC score (day 35), lower potassium (day 30), left ventricular ejection fraction & GE;30% (day 28) or already treated with beta-blockers (day 25). ConclusionsEplerenone provides statistically significant and clinically meaningful benefits shortly after treatment initiation in most patients, irrespective of clinical profile. This result reinforces the need for an early initiation of eplerenone in HFrEF, as part of rapidly instituting guideline-directed medical therapy.
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- Matsumoto, Shingo, et al.
(författare)
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Underutilization of Mineralocorticoid Antagonists in Patients With Heart Failure With Reduced Ejection Fraction
- 2023
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Ingår i: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY. - 0735-1097 .- 1558-3597. ; 82:11, s. 1080-1091
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND It is unknown how the efficacy and safety of mineralocorticoid receptor antagonists vary according to duration of heart failure with reduced ejection fraction (HFrEF).OBJECTIVES In this study, we sought to evaluate the safety and efficacy of eplerenone according to duration of HFrEF. METHODS In the EMPHASIS-HF trial, 3 patient groups were created according to HFrEF duration: <1 year, 1 to <5 years, and >= 5 years. The primary outcome was the composite of heart failure (HF) hospitalization or cardiovascular death. Outcomes were adjusted for prespecified prognostic variables and examined with the use of Cox regression models.RESULTS The numbers of patients in each group were: 975, <1 year; 769, 1 to <5 years; and 988, >= 5 years. Patients with longer-standing HF were older and more frequently had cardiovascular and noncardiovascular comorbidities. The rate of the primary outcome (per 100 person-years) increased with HFrEF duration: 9.8 (95% CI: 8.4-11.4) for <1 year, 13.5 (95% CI: 11.6-15.7) for 1 to <5 years, and 17.6 (95% CI: 15.6-19.8) for >= 5 years. The benefits of eplerenone were consistent across HF duration: HRs for the primary outcome were 0.57 (95% CI: 0.42-0.79) for <1 year, 0.81 (95% CI: 0.60-1.10) for 1 to <5 years, and 0.61 (95% CI: 0.48-0.78) for >= 5 years; Pinteraction 1/4 0.24. The absolute benefit was greatest in the longest-duration group: the number needed to treat for the primary outcome was 14 for <1 year, 13 for 1 to <5 years, and 10 for >= 5 years duration. CONCLUSIONS Patients with longer-standing HFrEF had worse clinical status and a higher rate of events, but the benefit of eplerenone was consistent regardless of HFrEF duration. (A Comparison of Outcomes in Patients in NYHA Class II Heart Failure When Treated With Eplerenone or Placebo in Addition to Standard Heart Failure Medicines [EMPHASIS-HF]; NCT00232180) (J Am Coll Cardiol 2023;82:1080-1091)
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- Rossignol, P., et al.
(författare)
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Cardiovascular risk associated with serum potassium in the context of mineralocorticoid receptor antagonist use in patients with heart failure and left ventricular dysfunction
- 2020
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 22:8, s. 1402-1411
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Tidskriftsartikel (refereegranskat)abstract
- Background To assess the prognostic value of mineralocorticoid receptor antagonist (MRA) initiation and change in serum potassium (K+) during follow-up in patients post-acute myocardial infarction with left ventricular dysfunction or chronic heart failure (HF) and reduced ejection fraction (HFrEF). Methods and results Risk scores for predicting cardiovascular death (primary outcome), hospitalization for HF and all-cause death were developed. K+ and other relevant time-updated clinical and biological variables were added to conventional prognostic factors when constructing these new models. EPHESUS (n = 6632) was the derivation cohort, while EMPHASIS-HF (chronic HF, n = 2737) was used as external validation cohort. The final cardiovascular death risk score included medical history, clinical and biological parameters (e.g. K+, below or above the normal range of 4-5 mmol/L, estimated glomerular filtration rate, and anaemia), as well as aspects of treatment (any diuretic usage, MRA use or discontinuation, and beta-blocker use). The risk score performed well in both the derivation and validation cohorts and outperformed the MAGGIC score. A web-based calculator was created to allow easy determination of the risk score (). Conclusion Adding time-updated variables, including K+ and MRA treatment, improved risk prediction of cardiovascular death (on top of the MAGGIC score) in patients with HF eligible for renin-angiotensin system inhibitors and MRA therapy. This new risk score including MRA usage and K+ may be of value in helping physicians to better use MRAs, avoid unnecessary and potentially detrimental permanent discontinuations, and therefore improving cardiovascular outcomes in patients with chronic HFrEF or HF after acute myocardial infarction with left ventricular dysfunction.
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- Felipe-Lucia, María R., et al.
(författare)
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Conceptualizing ecosystem services using social–ecological networks
- 2022
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Ingår i: Trends in Ecology & Evolution. - : Elsevier BV. - 0169-5347 .- 1872-8383. ; 37:3, s. 211-222
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Tidskriftsartikel (refereegranskat)abstract
- Social–ecological networks (SENs) represent the complex relationships between ecological and social systems and are a useful tool for analyzing and managing ecosystem services. However, mainstreaming the application of SENs in ecosystem service research has been hindered by a lack of clarity about how to match research questions to ecosystem service conceptualizations in SEN (i.e., as nodes, links, attributes, or emergent properties). Building from different disciplines, we propose a typology to represent ecosystem service in SENs and identify opportunities and challenges of using SENs in ecosystem service research. Our typology provides guidance for this growing field to improve research design and increase the breadth of questions that can be addressed with SEN to understand human–nature interdependencies in a changing world.
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| 10. |
- Mallach, A., et al.
(författare)
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Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons
- 2021
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:11
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Tidskriftsartikel (refereegranskat)abstract
- Microglial exosomes are an emerging communication pathway, implicated in fulfilling homeostatic microglial functions and transmitting neurodegenerative signals. Gene variants of triggering receptor expressed on myeloid cells-2 (TREM2) are associated with an increased risk of developing dementia. We investigated the influence of the TREM2 Alzheimer's disease risk variant, R47H(het), on the microglial exosomal proteome consisting of 3019 proteins secreted from human iPS-derived microglia (iPS-Mg). Exosomal protein content changed according to how the iPS-Mg were stimulated. Thus lipopolysaccharide (LPS) induced microglial exosomes to contain more inflammatory signals, whilst stimulation with the TREM2 ligand phosphatidylserine (PS+) increased metabolic signals within the microglial exosomes. We tested the effect of these exosomes on neurons and found that the exosomal protein changes were functionally relevant and influenced downstream functions in both neurons and microglia. Exosomes from R47H(het) iPS-Mg contained disease-associated microglial (DAM) signature proteins and were less able to promote the outgrowth of neuronal processes and increase mitochondrial metabolism in neurons compared with exosomes from the common TREM2 variant iPS-Mg. Taken together, these data highlight the importance of microglial exosomes in fulfilling microglial functions. Additionally, variations in the exosomal proteome influenced by the R47H(het) TREM2 variant may underlie the increased risk of Alzheimer's disease associated with this variant.
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| 11. |
- Mallach, A., et al.
(författare)
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The influence of the R47H triggering receptor expressed on myeloid cells 2 variant on microglial exosome profiles
- 2021
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Ingår i: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 3:2
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Tidskriftsartikel (refereegranskat)abstract
- Variants in the triggering receptor expressed on myeloid cells 2 gene are linked with an increased risk of dementia, in particular the R47H(het) triggering receptor expressed on myeloid cells 2 variant is linked to late-onset Alzheimer's disease. Using human induced pluripotent stem cells-derived microglia, we assessed whether variations in the dynamics of exosome secretion, including their components, from these cells might underlie some of this risk. We found exosome size was not altered between common variant controls and R47H(het) variants, but the amount and constitution of exosomes secreted were different. Exosome quantities were rescued by incubation with an ATP donor or with lipids via a phosphatidylserine triggering receptor expressed on myeloid cells 2 ligand. Following a lipopolysaccharide or phagocytic cell stimulus, exosomes from common variant and R47H(het) microglia were found to contain cytokines, chemokines, APOE and triggering receptor expressed on myeloid cells 2. Differences were observed in the expression of CCL22, IL-1 beta and triggering receptor expressed on myeloid cells 2 between common variant and R47H(h)(et) derived exosomes. Furthermore unlike common variant-derived exosomes, R47H(h)(et) exosomes contained additional proteins linked to negative regulation of transcription and metabolic processes. Subsequent addition of exosomes to stressed neurones showed R47H(het)-derived exosomes to be less protective. These data have ramifications for the responses of microglia in Alzheimer's disease and may point to further targets for therapeutic intervention.
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- Khunti, K, et al.
(författare)
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Metformin discontinuation in patients beginning second-line glucose-lowering therapy: results from the global observational DISCOVER study programme
- 2020
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 10:8, s. e034613-
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Tidskriftsartikel (refereegranskat)abstract
- To evaluate the extent to which patients with type 2 diabetes discontinue metformin therapy when initiating second-line treatment and factors associated with metformin discontinuation, using baseline data from the DISCOVER study programme.DesignDISCOVER is a 3-year, prospective, observational study programme including data from 38 countries across 6 continents from 2014 to 2019.SettingPrimary and secondary healthcare centres, hospitals and specialist diabetes centres in both urban and rural locations.ParticipantsA total of 15 992 patients with type 2 diabetes initiating second-line glucose-lowering therapy.Primary and secondary outcome measuresThe proportion of patients who discontinued metformin as a second-line therapy and the factors associated with this treatment change.ResultsOf the 14 668 patients (from 37 countries) with valid treatment data, 11 837 (80.7%) received metformin as first-line glucose-lowering therapy; 8488 (71.7%) received metformin monotherapy and 3349 (28.3%) received metformin as part of a combination therapy. Overall, treatment with metformin was discontinued in 15.1% (1782) of patients who received first-line metformin (14.1% (1194) and 17.6% (588) in those who received metformin as monotherapy and as part of a combination, respectively); this proportion varied across regions from 6.9% (54) in Africa to 20.6% (628) in South-East Asia. On metformin discontinuation, 73.6% (1311) of patients received a non-insulin monotherapy at second line. Factors associated with an increased odds of metformin discontinuation were older age (≥75 years) and having a history of chronic kidney disease. The probability of metformin monotherapy discontinuation was lower in patients from Africa than in those from Europe.ConclusionsA substantial number of patients discontinued taking metformin when beginning second-line therapy. Most of these patients subsequently received a non-insulin monotherapy at second line, in contradiction to international guidelines and potentially leaving them at an increased risk of hyperglycaemia and associated adverse outcomes.Trial registration numbersNCT02322762 and NCT02226822.
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