1,721,036 research outputs found
Farmacogenetica del fenofibrato: verso una medicina di precisione nella prevenzione delle complicanze micro e macro-vascolari del diabete
No full textDiversi studi hanno dimostrato come il fenofibrato possa ridurre le complicanze cardiovascolari e retiniche del diabete di tipo 2. Tuttavia, i benefici cardiovascolari di questo trattamento appaiono limitati ai pazienti con dislipidemia aterogena, mentre per la retinopatia, a coloro che hanno già questa complicanza. Abbiamo pertanto studiato la possibilità che la variabilità genetica nel gene PPARA, che codifica per il target farmacologico dei fibrati (PPAR-alfa), possa essere utilizzata per migliorare la selezione dei pazienti con diabete che potrebbero trarre beneficio dalla terapia con fenofibrato.
Tra i 3.065 soggetti bianchi trattati con simvastatina e randomizzati a fenofibrato o placebo nello studio sui Action-to-Control-Cardiovascular-Risk-in-Diabetes (ACCORD- Lipid), abbiamo identificato una variante comune nel locus PPARA (rs6008845, C/T) che mostrava un'influenza significativa sull'effetto del fenofibrato sugli eventi cardiovascolari maggiori (MACE). Gli omozigoti T/T (36% dei partecipanti) mostravano una riduzione dei MACE del 51% in risposta al fenofibrato (HR=0,49; IC 95% 0,34-0,72) mentre non si osservava alcun beneficio per gli altri genotipi (p per interazione=3,7x10-4). L'interazione "rs6008845 x fenofibrato" su MACE è stata replicata nei pazienti afroamericani dell’ACCORD (N=585, p=0,02) e in coorti esterne (ACCORD-BP, ORIGIN e TRIUMPH, totale N=3059, p =0,005). Sorprendentemente, gli omozigoti rs6008845 T/T mostravano un beneficio cardiovascolare del fenofibrato anche in assenza di dislipidemia aterogena, e tale effetto non era spiegato da cambiamenti nel profilo lipidico plasmatico.
Un'interazione simile e significativa è stata riscontrata anche sulla progressione della retinopatia diabetica tra i 592 soggetti con anamnesi di retinopatia diabetica (DR) inclusi nel sotto-studio ACCORD-Eye, con gli omozigoti rs6008845 T/T che traevano un beneficio maggiore dal fenofibrato su progressione di DR (OR 0,10, IC 95% 0,02-0,74) rispetto a quella che si osservava nei genotipi T/C e C/C (p per interazione = 0,01). La stessa interazione è stata trovata per la riduzione dell’incidenza di grave riduzione del visus (valutata in 3.650 soggetti dallo studio ACCORD-Lipid, p per interazione = 0,03).
Il ruolo regolatorio di rs6008845 è stato suggerito da analisi bioinformatiche e inoltre i dati Genotype-Tissue Expression hanno rivelato un'associazione tra rs6008845 ed espressione di PPARA in molti tessuti, che è stata confermata in un ampio dataset di eQTL retinici (GtExEye) dove l'allele T si associava a una maggiore espressione di PPARA (P 4x10-38). In linea con questo, i soggetti con un punteggio genetico più elevato per l'espressione di PPARA nella retina hanno avuto una migliore risposta al fenofibrato sulla progressione di DR (P = 0,008). Tra gli omozigoti T/T, il fenofibrato si associava ad un marcato aumento dei livelli di FGF21 (+0,87 SD aumento del valore log2 di FGF21; IC 95% 0,67-1,07, P=10x10-13), che a sua volta si associava a una riduzione del 45% rischio di grave riduzione del visus (HR per SD = 0,55; IC 95% 0,34-0,91, p=0,01) e che spiegava in large parte l'effetto del fenofibrato su questo outcome (90%, p=0,03).
In conclusione questo studio ha permesso di identificare una variante comune di PPARA in grado di influenzare gli effetti cardiovascolari del fenofibrato e che potrebbe essere utilizzata per identificare i pazienti con T2D che trarrebbero un beneficio clinicamente rilevante anche senza dislipidemia aterogena. La stessa variante ha anche identificato soggetti con una migliore risposta al fenofibrato su DR. Inoltre, se da un lato il meccanismo alla base dell'effetto protettivo cardiovascolare è ancora da chiarire, questo studio mostra come l'efficacia sulla DR del fenofibrato sia mediata da un aumento dei livelli di FGF21, una citochina metabolica e antinfiammatoria che potrebbe rappresentare un nuovo bersaglio terapeutico per il trattamento della retinopatia diabetica.Background and aims: Fenofibrate has been shown to have a beneficial effect on cardiovascular and retinal complications of type 2 diabetes. However, for cardiovascular disease, the benefits of this treatment are limited to patients with atherogenic dyslipidemia, and for retinopathy, to those who already have this complication. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-alpha), could be used to improve the selection, and possibly increase the number of patients with type 2 diabetes who may derive a benefit from fenofibrate treatment.
Methods and results: Among 3,065 self-reported White subjects treated with simvastatin and randomized to fenofibrate or placebo in the Action-to-Control-Cardiovascular-Risk-in-Diabetes (ACCORD) Lipid Trial, we identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide-significant influence on the effect of fenofibrate on major cardiovascular events (MACE). T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (HR=0.49; 95%C.I. 0.34-0.72) whereas no benefit was observed for other genotypes (p for interaction=3.7x10-4). The “rs6008845-by-fenofibrate” interaction on MACE was replicated in patients of African-Americans ancestry from ACCORD (N=585, p=0.02) and in external cohorts (ACCORD-Blood-Pressure, ORIGIN, and TRIUMPH, total N=3059, p=0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia and this was not explained by changes in plasma lipid profile.
A similar and significant interaction was also found on progression of diabetic retinopathy among the 592 subjects with prior-history of diabetic retinopathy (DR) included in the ACCORD-Eye sub-study, with rs6008845 T/T homozygotes deriving a larger benefit from fenofibrate on DR progression (OR 0.10, 95% C.I. 0.02-0.74) than that observed in T/C and C/C genotypes (OR 0.47, 95% C.I. 0.17-0.29 and 0.54, 95% C.I. 0.21-1.42, respectively; p for interaction = 0.01). The same interaction was found for severe vision loss (evaluated in 3,650 subjects from the ACCORD-Lipid study, p for interaction=0.03).
The regulatory role of rs6008845 was suggested by bioinformatic analyses and supported by the Genotype-Tissue Expression (GTEx) dataset revealing an association between rs6008845 and PPARA expression in many tissues, that was confirmed also in a large retina-eQTL dataset (GtExEye) showing that T allele was associated with higher PPARA expression in the retina (P 4x10-38). In line with this, subjects with higher genetic score for PPARA expression in the retina had better response to fenofibrate on DR progression (P=0.008). Among the T/T homozygotes, fenofibrate was associated with markedly increase in FGF21 levels (+0.87 S.D. increase in log2-value of FGF21; 95% C.I. 0.67-1.07, P=10x10-13), that was associated with a 45% lower risk of severe vision loss (per S.D. HR=0.55; 95%C.I. 0.34-0.91, p=0.01), and explained most of the effect of fenofibrate on this outcome (90%, p=0.03).
Conclusions: We have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify T2D patients who would derive a clinically relevant benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia. The same variant also identified subjects with better response to fenofibrate on DR. Moreover, while the mechanism underlying the beneficial effect on CVD is still unclear, this study shows that the effectiveness on DR is mediated by an increase in FGF21 levels, a metabolic and anti-inflammatory cytokine that might represents a novel therapeutic target to treat diabetic eye diseases
Cardiovascular risk in special populations: The elderly.
No full textAbstract Age is the main risk factor for cardiovascular disease.
Age increases cardiovascular risk not only because it increases
the exposure time to, the number of, and severity of
other cardiovascular risk factors, but it is also able to change
the system through a CV aging process. Aging per se causes
an alteration of the vascular system, which involves the endothelial
function, the vascular wall, and the related signaling
cascades. These changes provide an important contribution to
cardiovascular risk in the elderly population. At the same time
life expectancy is constantly increasing and the elderly deserve
a good prevention strategy. New algorithms to predict
cardiovascular events are under construction and validation.
These new algorithms are trying to integrate new biomarkers
with the most important cardiovascular risk factors, which
are powerful predictors in adults. In our opinion, at the current
state of knowledge, treatment should be designed taking into
account the characteristics of the patient, without making exceptions
on the criteria of age. Also the goals of treatment
should be similar to those of young adult subjects if the elderly
patient has a good life expectancy, while the goals of
treatment in the frail elderly patient with co-morbidity and reduced
life expectancy should be to avoid complications of
treatment with less stringent targets
Correction to: Physicians’ misperceived cardiovascular risk and therapeutic inertia as determinants of low LDL-cholesterol targets achievement in diabetes
Full text linkGreater efforts are needed to overcome the worldwide reported low achievement of LDL-c targets. This survey aimed to dissect whether and how the physician-based evaluation of patients with diabetes is associated with the achievement of LDL-c targets
Explainable Deep-Learning Model Reveals Past Cardiovascular Disease in Patients with Diabetes Using Free-Form Visit Reports
No full textDeep-learning-based natural-language-processing models to identify cardiovascular disease hospitalisations of patients with diabetes from routine visits' text
Full text link: Writing notes is the most widespread method to report clinical events. Therefore, most of the information about the disease history of a patient remains locked behind free-form text. Natural language processing (NLP) provides a solution to automatically transform free-form text into structured data. In the present work, electronic healthcare records data of patients with diabetes were used to develop deep-learning based NLP models to automatically identify, within free-form text describing routine visits, the occurrence of hospitalisations related to cardiovascular disease (CVDs), an outcome of diabetes. Four possible time windows of increasing level of expected difficulty were considered: infinite, 24 months, 12 months, and 6 months. Model performance was evaluated by means of the area under the precision recall curve, as well as precision, recall, and F1-score after thresholding. Results showed that the proposed NLP approach was successful for both the infinite and 24-month windows, while, as expected, performance deteriorated with shorter time windows. Possible clinical applications of tools based on the proposed NLP approach include the retrospective filling of medical records with respect to a patient's CVD history for epidemiological and research purposes as well as for clinical decision making
Effetto dell’antagonismo farmacologico dei recettori per gli endocannabinoidi sull’equilibrio idrosodico nella cirrosi epatica. Prospettive terapeutiche. [Effect of the pharmacological antagonism of the endocannabinoid receptors on the sodium balance in liver cirrhosis]
No full textGli endocannabinoidi sono sostanze endogene implicate in una molteplicità di processi fisiologici e fisiopatologici del nostro organismo. Recentemente, è stato dimostrato un loro ruolo nella patogenesi della fibrosi epatica e di alcune complicanze della cirrosi. La modulazione farmacologica del sistema degli endocannabinoidi rappresenta un potenziale obiettivo della terapia delle epatopatie.The endocannabinoids are endogenous mediators implicated in many physiologic and pathophysiologic processes. It has been recently shown that they contribute to the pathogenesis of liver fibrosis and hemodynamic alterations of cirrhosis. The pharmacological modulation of the endocannnabinoid system represents a potential target for the treatment of liver diseases
Variants in ANGPTL4 and the Risk of Coronary Artery Disease
Full text linkStitziel et al. report that a common gain-of-function genetic variant in LPL, which encodes lipoprotein lipase, is associated with a reduction in the risk of coronary artery disease. The authors speculate that therapeutic activation of this pathway might reduce the risk of coronary artery disease. test this hypothesis, we analyzed data from 4414 persons involved in the ACCORD Lipid randomized clinical trial to determine whether the cardioprotective effect of fenofibrate (a drug with widespread effects on lipid metabolism, including LPL activation) was influenced by the common gain-of-function LPL variant (p.S447*) described in the article by Stitziel et al. In the ACCORD Lipid trial, patients with type 2 diabetes who were receiving simvastatin and who were at high risk for cardiovascular events were assigned to receive either fenofibrate or placebo. In the overall ACCORD Lipid trial, fenofibrate did not have a significant effect on cardiovascular events. However, consistent with the working hypothesis, a negative interaction (P=0.01) was observed between the use of fenofibrate and p.S447*. Fenofibrate was beneficial in p.S447 homozygotes but not in carriers of the gain-of-function p.447* variant (Figure 1). By showing that there was no association between fenofibrate and protection against risk among persons in whom LPL activity was already elevated, our findings provide some support for the importance of this pathway as a target for cardioprotective interventions
Management of type 2 diabetes with a treat-to-benefit approach improved long-term cardiovascular outcomes under routine care
Full text linkBACKGROUND: Results of cardiovascular outcome trials enabled a shift from “treat-to-target” to “treat-to-benefit” paradigm in the management of type 2 diabetes (T2D). However, studies validating such approach are limited. Here, we examined whether treatment according to international recommendations for the pharmacological management of T2D had an impact on long-term outcomes. METHODS: This was an observational study conducted on outpatient data collected in 2008–2018 (i.e. prior to the “treat-to-benefit” shift). We defined 6 domains of treatment based on the ADA/EASD consensus covering all disease stages: first- and second-line treatment, intensification, use of insulin, cardioprotective, and weight-affecting drugs. At each visit, patients were included in Group 1 if at least one domain deviated from recommendation or in Group 2 if aligned with recommendations. We used Cox proportional hazard models with time-dependent co-variates or Cox marginal structural models (with inverse-probability of treatment weighing evaluated at each visit) to adjust for confounding factors and evaluate three outcomes: major adverse cardiovascular events (MACE), hospitalization for heart failure or cardiovascular mortality (HF-CVM), and all-cause mortality. RESULTS: We included 5419 patients, on average 66-year old, 41% women, with a baseline diabetes duration of 7.6 years. Only 11.7% had pre-existing cardiovascular disease. During a median follow-up of 7.3 years, patients were seen 12 times at the clinic, and we recorded 1325 MACE, 1593 HF-CVM, and 917 deaths. By the end of the study, each patient spent on average 63.6% of time in Group 1. In the fully adjusted model, being always in Group 2 was associated with a 45% lower risk of MACE (HR 0.55; 95% C.I. 0.46–0.66; p < 0.0001) as compared to being in Group 1. The corresponding HF-CVM and mortality risk were similar (HR 0.56; 95%CI 0.47–0.66, p < 0.0001 and HR 0.56; 95% C.I. 0.45–0.70; p < 0.0001. respectively). Sensitivity analyses confirmed these results. No single domain individually explained the better outcome of Group 2, which remained significant in all subgroups. CONCLUSION: Managing patients with T2D according to a “treat-to-benefit” approach based international standards was associated with a lower risk of MACE, heart failure, and mortality. These data provide ex-post validation of the ADA/EASD treatment algorithm. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12933-022-01712-4
- …
