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In-silico simulated prototype-patients using TPMS technology to study a potential adverse effect of sacubitril and valsartan.

ABSTRACT: Unveiling the mechanism of action of a drug is key to understand the benefits and adverse reactions of a medication in an organism. However, in complex diseases such as heart diseases there is not a unique mechanism of action but a wide range of different responses depending on the patient. Exploring this collection of mechanisms is one of the clues for a future personalized medicine. The Therapeutic Performance Mapping System (TPMS) is a Systems Biology approach that generates multiple models of the mechanism of action of a drug. Each molecular mechanism generated could be associated to particular individuals, here defined as prototype-patients, hence the generation of models using TPMS technology may be used for detecting adverse effects to specific patients. TPMS operates by (1) modelling the responses in humans with an accurate description of a protein network and (2) applying a Multilayer Perceptron-like and sampling strategy to find all plausible solutions. In the present study, TPMS is applied to explore the diversity of mechanisms of action of the drug combination sacubitril/valsartan. We use TPMS to generate a wide range of models explaining the relationship between sacubitril/valsartan and heart failure (the indication), as well as evaluating their association with macular degeneration (a potential adverse effect). Among the models generated, we identify a set of mechanisms of action associated to a better response in terms of heart failure treatment, which could also be associated to macular degeneration development. Finally, a set of 30 potential biomarkers are proposed to identify mechanisms (or prototype-patients) more prone of suffering macular degeneration when presenting good heart failure response. All prototype-patients models generated are completely theoretical and therefore they do not necessarily involve clinical effects in real patients. Data and accession to software are available at http://sbi.upf.edu/data/tpms/.

SUBMITTER: Jorba G

PROVIDER: S-EPMC7018085 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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In-silico simulated prototype-patients using TPMS technology to study a potential adverse effect of sacubitril and valsartan.

Jorba Guillem G Aguirre-Plans Joaquim J Junet Valentin V Segú-Vergés Cristina C Ruiz José Luis JL Pujol Albert A Fernández-Fuentes Narcís N Mas José Manuel JM Oliva Baldo B

PloS one 20200213 2

Unveiling the mechanism of action of a drug is key to understand the benefits and adverse reactions of a medication in an organism. However, in complex diseases such as heart diseases there is not a unique mechanism of action but a wide range of different responses depending on the patient. Exploring this collection of mechanisms is one of the clues for a future personalized medicine. The Therapeutic Performance Mapping System (TPMS) is a Systems Biology approach that generates multiple models o ...[more]

PMID: 32053711

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Project description:Heart failure (HF) and diabetes mellitus (DM) frequently coexist, with a prevalence of DM of 35-40% in patients with HF, independent of the level of impairment of the ejection fraction (EF). Furthermore, DM is considered a strong independent risk factor for the progression of HF with either preserved or reduced EF and is associated with poor prognosis. The ability of neprilysin inhibitors to elevate levels of biologically active natriuretic peptides has made them a potential therapeutic approach in HF. In the Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, a dual-acting angiotensin-receptor-neprilysin inhibitor, sacubitril/valsartan was superior to enalapril in reducing the risks of death and HF hospitalization in patients with HF with reduced EF. In addition, in a post-hoc analysis of this trial, among patients with DM, treatment with sacubitril/valsartan resulted in improved glycemic control compared with enalapril. Also, there are additional studies suggesting beneficial metabolic effects of this class of drugs. In this review we discuss potential mechanisms of sacubitril/valsartan effect on glycemic control. Sacubitril/valsartan concomitantly blocks the renin-angiotensin system and inhibits neprilysin, a ubiquitous enzyme responsible for the breakdown of more than 50 vasoactive peptides, including the biologically active natriuretic peptides, bradykinin, angiotensin I and II, endothelin 1, glucagon, glucagon-like peptide-1, insulin-B chain, and others. There are a number of potential mechanisms by which inhibition of neprilysin may lead to improvement in glycemic control, with most evidence suggesting modulation of neprilysin circulating substrates. Although there is some evidence suggesting the improvement of glucose metabolism by renin-angiotensin system inhibition, this effect is most likely modest. As these mechanisms are not fully understood, detailed mechanistic studies, as well as large randomized clinical trials in patients with DM, are needed to further clarify beneficial metabolic properties of sacubitril/valsartan.

Project description:ObjectiveTo evaluate the impact of sacubitril/valsartan on blood pressure (BP), ventricular structure, and myocardial fibrosis compared with valsartan in perimenopausal hypertensive women.MethodsThis prospective, randomized, actively controlled, open-label study included 292 women with perimenopausal hypertension. They were randomly divided into two groups: sacubitril/valsartan 200 mg once daily and valsartan 160 mg once daily for 24 weeks. The relevant indicators of ambulatory BP, echocardiography, and myocardial fibrosis regulation were assessed at baseline and at 24 weeks.ResultsThe 24-h mean SBP after 24 weeks of treatment was 120.08 ± 10.47 mmHg in the sacubitril/valsartan group versus 121.00 ± 9.76 mmHg in the valsartan group ( P = 0.457). After 24 weeks of treatment, there was no difference in central SBP between the sacubitril/valsartan and valsartan groups (117.17 ± 11.63 versus 116.38 ± 11.58, P = 0.568). LVMI in the sacubitril/valsartan group was lower than that in the valsartan group at week 24 ( P = 0.009). LVMI decreased by 7.23 g/m 2 from the baseline in the sacubitril/valsartan group and 3.70 g/m 2 in the valsartan group at 24 weeks ( P = 0.000 versus 0.017). A statistically significant difference in LVMI between the two groups was observed at 24 weeks after adjusting for the baseline LVMI ( P = 0.001). The levels of α-smooth muscle actin (α-SMA), connective tissue growth factor (CT-GF) and transforming growth factor-β (TGF-β) were reduced in the sacubitril/valsartan group compared with the baseline ( P = 0.000, 0.005, and 0.000). LVMI between the two groups was statistically significant at 24 weeks after correcting for confounding factors 24-h mean SBP and 24-h mean DBP ( P = 0.005). The LVMI, serum TGF-β, α-SMA, and CT-GF remained statistically significant between the two groups after further correcting the factors of age, BMI, and sex hormone levels ( P < 0.05).ConclusionSacubitril/valsartan could reverse ventricular remodeling more effectively than valsartan. The different effects of these two therapies on ventricular remodeling in perimenopausal hypertensive women might be because of their different effects on the down-regulation of fibrosis-related factors.

Project description:Randomized clinical trials have shown that sacubitril-valsartan reduces the risks of mortality and hospitalization in patients with heart failure with reduced ejection fraction (HFrEF), but patients with kidney failure requiring dialysis were excluded. To investigate the comparative effectiveness of sacubitril-valsartan vs angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs or ARBs) in patients with HFrEF requiring hemodialysis. This retrospective, 1:1 propensity score-matched comparative effectiveness study included patients who were 18 years or older with HFrEF, enrolled in Medicare Parts A, B, and D, and survived at least 90 days receiving in-center hemodialysis from July 8, 2015, to December 31, 2020. Patients were excluded for less than 180 days of continuous Medicare Parts A, B, and D primary payer coverage or prior dispensing of sacubitril-valsartan. Data analysis was conducted from September 23, 2023, to June 25, 2024. New use of sacubitril-valsartan vs new or continued use of ACEIs or ARBs. The associations between initiation of sacubitril-valsartan therapy and all-cause mortality, cardiovascular mortality, all-cause hospitalization, and HF hospitalization were assessed using Cox proportional hazards regression models in a propensity score-matched sample. Participants included 1:1 matched pairs of 1434 sacubitril-valsartan users and 1434 ACEI or ARB users (mean [SD] age, 64 [13] years). Of the 2868 matched participants, 996 (65%) were male; 987 (34%) were Black or African American and 1677 (58%) were White; and median dialysis vintage was 3.8 (IQR, 1.8-6.3) years. The median follow-up was 0.9 (IQR, 0.4-1.7) years. Sacubitril-valsartan (vs ACEI or ARB) therapy was associated with a reduction in all-cause mortality (hazard ratio [HR], 0.82 [95% CI, 0.73-0.92]) and all-cause hospitalization (HR, 0.86 [95% CI, 0.79-0.93]) but not cardiovascular mortality (HR, 1.01 [95% CI, 0.86-1.19]) or HF hospitalization (HR, 0.91 [95% CI, 0.82-1.02]). There was a decrease in hyperkalemia (HR, 0.71 [95% CI, 0.62-0.81]) and no difference in hypotension (HR, 0.99 [95% CI, 0.83-1.19]). Only 195 participants (14%) ever received the maximum combination dose of sacubitril (97 mg twice daily) and valsartan (103 mg twice daily). In this comparative effectiveness study of patients with HFrEF requiring hemodialysis, sacubitril-valsartan therapy was associated with beneficial effects in all-cause mortality and all-cause hospitalization.

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In-silico simulated prototype-patients using TPMS technology to study a potential adverse effect of sacubitril and valsartan.

Publications

In-silico simulated prototype-patients using TPMS technology to study a potential adverse effect of sacubitril and valsartan.

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