Combining familial hypercholesterolemia and statin genetic studies as a strategy for the implementation of pharmacogenomics. A multidisciplinary approach.

The diagnostic process of familial hypercholesterolemia frequently involves the use of genetic studies. Patients are treated with lipid-lowering drugs, frequently statins. Although pharmacogenomic clinical practice guidelines focusing on genotype-based statin prescription have been published, their use in routine clinical practice remains very modest.We have implemented a new NGS strategy that combines a panel of genes related to familial hypercholesterolemia with genomic regions related to the pharmacogenomics of lipid-lowering drugs described in clinical practice guidelines and in EMA and FDA drug labels. A multidisciplinary team of doctors, biologists, and pharmacists creates a clinical report that provides diagnostic and therapeutic findings using a knowledge management and clinical decision support system, as well as an algorithm for treatment selection.For 12 months, a total of 483 genetic diagnostic studies for familial hypercholesterolemia were carried out, of which 221 (45.8%) requested a complementary pharmacogenomic test. Of these 221 patients, 66.5% were carriers of actionable variants in any of the studied pharmacogenomic pathways: 46.6% of patients in one pathway, 19.0% in two pathways, and 0.9% in three pathways. 45.7% of patients could have a response to atorvastatin different from that of the reference population, 45.7% for simvastatin and lovastatin, 29.0% for fluvastatin, and 6.7% patients for pitavastatin.This implementation approach facilitates the incorporation of pharmacogenomic studies in clinical care practice, it does not add complexity nor additional steps to laboratory processes, and improves the pharmacotherapeutic process of patients.

Clinical and economic impact of current ALK rearrangement testing in Spain compared with a hypothetical no-testing scenario.

BACKGROUND: Currently biomarkers play an essential role in diagnosis, treatment, and management of cancer. In non-small cell lung cancer (NSCLC) determination of biomarkers such as ALK, EGFR, ROS1 or PD-L1 is mandatory for an adequate treatment decision. The aim of this study is to determine the clinical and economic impact of current anaplastic lymphoma kinase testing scenario in Spain. METHODS: A joint model, composed by decision-tree and Markov models, was developed to estimate the long-term health outcomes and costs of NSCLC patients, by comparing the current testing scenario for ALK in Spain vs a hypothetical no-testing. The current distribution of testing strategies for ALK determination and their sensitivity and specificity data were obtained from the literature. Treatment allocation based on the molecular testing result were defined by a panel of Spanish experts. To assess long-term effects of each treatment, 3-states Markov models were developed, where progression-free survival and overall survival curves were extrapolated using exponential models. Medical direct costs (expressed in €, 2019) were included. A lifetime horizon was used and a discount rate of 3% was applied for both costs and health effects. Several sensitivity analyses, both deterministic and probabilistic, were performed in order test the robustness of the analysis. RESULTS: We estimated a target population of 7628 NSCLC patients, including those with non-squamous histology and those with squamous carcinomas who were never smokers. Over the lifetime horizon, the current ALK testing scenario produced additional 5060 and 3906 life-years and quality-adjusted life-years (QALY), respectively, compared with the no-testing scenario. Total direct costs were increased up to € 51,319,053 for testing scenario. The incremental cost-effectiveness ratio was 10,142 €/QALY. The sensitivity analyses carried out confirmed the robustness of the base-case results, being the treatment allocation and the test accuracy (sensitivity and specificity data) the key drivers of the model. CONCLUSIONS: ALK testing in advanced NSCLC patients, non-squamous and never-smoker squamous, provides more than 3000 QALYs in Spain over a lifetime horizon. Comparing this gain in health outcomes with the incremental costs, the resulting incremental cost-effectiveness ratio reinforces that testing non-squamous and never-smoker squamous NSCLC is a cost-effective strategy in Spain.

Thigh and buttock exertional pain for the diagnosis of peripheral arterial disease.

OBJECTIVES: To evaluate the prevalence of both non-calf intermittent claudication (IC) and classic IC in patients with no known atherosclerotic disease, and their accuracy to detect peripheral arterial disease (PAD). DESIGN: Cross sectional, observational study conducted at 96 internal medicine services. MATERIALS AND METHODS: 1487 outpatients with no known atherosclerotic disease, and either diabetes or a SCORE risk estimation of at least 3% were enrolled. IC was assessed using the Edinburgh Claudication Questionnaire and PAD was confirmed by an ankle-brachial index (ABI) <0.9. RESULTS: Overall, 7.2% met criteria of classic and 5.8% of non-calf IC. PAD was diagnosed in 393 cases (26.4%). In these PAD patients, 17.8% exhibited classic and 13.2% non-calf IC. Both calf and non-calf IC had similar overall accuracy for detecting PAD. Considering both categories as a whole, the sensitivity of IC to predict a low ABI was 31% and the specificity 93%. CONCLUSIONS: Non-calf IC is comparable to classic IC for the diagnosis of PAD in patients with no known arterial disease. The systematic implementation of Edinburgh Claudication Questionnaire could be a valuable call-to-action to improve clinical evaluation of PAD, bearing in mind that PAD detected by either non-calf or classic IC must be confirmed by ABI testing.

Systemic and local effects of angiotensin II blockade in experimental diabetic nephropathy.

INTRODUCTION: Our objective was to evaluate the effect of blocking the renin-angiotensin system (RAS) on the expression of transforming growth factor-beta 1 (TGF-beta1), platelet derived growth factor-B (PDGF-B), tumour necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor (VEGF) in diabetic kidney glomeruli. MATERIALS AND METHOD: 1) Uninephrectomised streptozotocin induced diabetic rats were treated during eight months with vehicle (CD) or irbesartan (ID). Uninephrectomised non-diabetic rats were used as control group (ND). Protein urinary excretion and morphological renal damage were analysed. Glomerular expression of TGF-beta1, PDGF-B, VEGF and TNF-alpha were evaluated by Western blot and Immunohistochemistry. 2) Isolated glomeruli of diabetic rats were incubated 24-hours in the presence of different doses of irbesartan. Glomerular expression of TGF-beta1, PDGF-B, TNF-alpha and VEGF were determined by Western blot. RESULTS: ND and ID presented lower renal injury and proteinuria than CD (p<0.05). Glomerular expression of TGF-beta1, PDGF-B, TNF-alpha and VEGF were similar in ND and ID, but lower than in CD (p<0.05). In addition, in isolated diabetic rat glomeruli, irbesartan reduced the content of all these factors. CONCLUSION: Systemic and local administration of irbesartan lowers glomerular expression of TGF-beta1, PDGF-B, VEGF and TNF-alpha. These data suggest that part of the effect of lowering the expression of these growth factors and cytokines is due to a direct blockade of glomerular RAS.

Role of systolic blood pressureon the progression of kidney damage in an experimental model of type 2 diabetes mellitus, obesity, and hypertension (Zucker rats).

BACKGROUND: Hypertension is the main risk factor for the progression of kidney damage in diabetes mellitus. The aim of the present work is to compare the effect of the treatment with irbesartan (IRBE) and omapatrilat (OMA), in obese Zucker rats (OZR). METHODS: A group of 45 OZR were uninephrectomized to accelerate renal damage, and divided into three groups: two experimental groups (IRBE and OMA) treated with 50 and 40 mg/kg/d, respectively; and the control group (CG). At the end of the 8-month follow-up period, animals were killed and the remnant kidney was removed for histologic study and to evaluate the transforming growth factor-beta1 (TGF-beta1) expression. RESULTS: Both therapies reduced blood pressure (BP) versus CG (P <.001). Moreover, systolic BP was significantly lower in the OMA group than in the IRBE group (P <.001). Also, both treatments significantly lowered the urinary albumin excretion (P <.001). The OMA treatment exhibited lower values than the IRBE treatment (P <.05). The kidney TGF-beta1 expression was reduced by both treatments to a similar level. The correlation between systolic BP and glomerulosclerosis (GS) is very high (r = 0.90; P <.0001). Also, a high correlation was observed between GS and proteinuria (r = 0.79, P <.0001). The correlation between systolic BP and proteinuria was weaker (r = 0.69; P <.01). CONCLUSIONS: These data suggest that both therapies are effective in ameliorating the progression of renal damage in this experimental model. Omapatrilat affords greater long-term renoprotection than irbesartan, mainly due to its potent effect in reducing systolic BP.