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- Graham, Ian, et al.
(författare)
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New strategies for the development of lipid-lowering therapies to reduce cardiovascular risk.
- 2018
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Ingår i: European heart journal. Cardiovascular pharmacotherapy. - : Oxford University Press (OUP). - 2055-6845 .- 2055-6837. ; 4:2, s. 119-127
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Tidskriftsartikel (refereegranskat)abstract
- The very high occurrence of cardiovascular events presents a major public health issue, because treatment remains suboptimal. Lowering LDL cholesterol (LDL-C) with statins or ezetimibe in combination with a statin reduces major adverse cardiovascular events. The cardiovascular risk reduction in relation to the absolute LDL-C reduction is linear for most interventions without evidence of attenuation or increase in risk at low LDL-C levels. Opportunities for innovation in dyslipidaemia treatment should address the substantial risk of lipid-associated cardiovascular events among patients optimally treated per guidelines but who cannot achieve LDL-C goals and who could benefit from additional LDL-C-lowering therapy or experience side effects of statins. Fresh approaches are needed to identify promising drug targets early and develop them efficiently. The Cardiovascular Round Table of the European Society of Cardiology (ESC) convened a workshop to discuss new lipid-lowering strategies for cardiovascular risk reduction. Opportunities to improve treatment approaches and the efficient study of new therapies were explored. Circulating biomarkers may not be fully reliable proxy indicators of the relationship between treatment effect and clinical outcome. Mendelian randomization studies may better inform development strategies and refine treatment targets before Phase 3. Trials should match the drug to appropriate lipid and patient profile, and guidelines may move towards a precision-based approach to individual patient management. Stakeholder collaboration is needed to ensure continued innovation and better international coordination of both regulatory aspects and guidelines. It should be noted that risk may also be addressed through increased attention to other risk factors such as smoking, hypertension, overweight, and inactivity.
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| 2. |
- Ramiro, Sofia, et al.
(författare)
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ASAS-EULAR recommendations for the management of axial spondyloarthritis : 2022 update
- 2022
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 82:1, s. 19-34
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To update the Assessment of SpondyloArthritis international Society (ASAS)-EULAR recommendations for the management of axial spondyloarthritis (axSpA). Methods Following the EULAR Standardised Operating Procedures, two systematic literature reviews were conducted on non-pharmacological and pharmacological treatment of axSpA. In a task force meeting, the evidence was presented, discussed, and overarching principles and recommendations were updated, followed by voting. Results Five overarching principles and 15 recommendations with a focus on personalised medicine were agreed: eight remained unchanged from the previous recommendations; three with minor edits on nomenclature; two with relevant updates (#9, 12); two newly formulated (#10, 11). The first five recommendations focus on treatment target and monitoring, non-pharmacological management and non-steroidal anti-inflammatory drugs (NSAIDs) as first-choice pharmacological treatment. Recommendations 6-8 deal with analgesics and discourage long-term glucocorticoids and conventional synthetic disease-modifying antirheumatic drugs (DMARDs) for pure axial involvement. Recommendation 9 describes the indication of biological DMARDs (bDMARDs, that is, tumour necrosis factor inhibitors (TNFi), interleukin-17 inhibitors (IL-17i)) and targeted synthetic DMARDs (tsDMARDs, ie, Janus kinase inhibitors) for patients who have Ankylosing Spondylitis Disease Activity Score ≥2.1 and failed ≥2 NSAIDs and also have either elevated C reactive protein, MRI inflammation of sacroiliac joints or radiographic sacroiliitis. Current practice is to start a TNFi or IL-17i. Recommendation 10 addresses extramusculoskeletal manifestations with TNF monoclonal antibodies preferred for recurrent uveitis or inflammatory bowel disease, and IL-17i for significant psoriasis. Treatment failure should prompt re-evaluation of the diagnosis and consideration of the presence of comorbidities (#11). If active axSpA is confirmed, switching to another b/tsDMARD is recommended (#12). Tapering, rather than immediate discontinuation of a bDMARD, can be considered in patients in sustained remission (#13). The last recommendations (#14, 15) deal with surgery and spinal fractures. Conclusions The 2022 ASAS-EULAR recommendations provide up-to-date guidance on the management of patients with axSpA.
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| 3. |
- Sjouke, Barbara, et al.
(författare)
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Eprotirome in patients with familial hypercholesterolaemia (the AKKA trial): a randomised, double-blind, placebo-controlled phase 3 study
- 2014
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Ingår i: LANCET DIABETES and ENDOCRINOLOGY. - : Elsevier: Lancet. - 2213-8587 .- 2213-8595. ; 2:6, s. 455-463
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Tidskriftsartikel (refereegranskat)abstract
- Background Eprotirome is a liver-selective thyroid hormone receptor agonist that has been shown to lower plasma LDL cholesterol concentrations in previous phase 1 and 2 studies of patients with dyslipidaemia. We aimed to assess the long-term safety and efficacy of 50 mu g and 100 mu g eprotirome in patients with familial hypercholesterolaemia. Methods For this randomised, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial, we enrolled patients between Oct 3, 2011, and Feb 14, 2012, at 53 sites in 11 countries in Europe, Africa, and south Asia. Patients were eligible for enrolment if they were aged 18 years or older, diagnosed with heterozygous familial hypercholesterolaemia, and had not reached target LDL cholesterol concentrations after at least 8 weeks of statin therapy with or without ezetimibe. We used a computer-generated randomisation sequence to allocate patients to one of three groups: 50 mu g eprotirome, 100 mu g eprotirome, or placebo. This trial was planned for 52-76 weeks, with primary efficacy analysis at 12 weeks, but it was prematurely terminated when another study found that eprotirome causes cartilage damage in dogs. Although it was impossible to meet the predefined study outcomes, we analysed changes in the concentrations of LDL cholesterol and other lipids, liver parameters, thyroid hormone concentrations, and adverse effects of treatment with eprotirome versus placebo at 6 weeks of treatment. Analysis was done in all patients who received 6 weeks of treatment. This study is registered with ClinicalTrials.gov, number NCT01410383. Findings We enrolled 236 patients, randomly allocating 80 to receive placebo, 79 to receive 50 mu g eprotirome, and 77 to receive 100 mu g eprotirome. 69 patients reached the 6 week timepoint (23 given placebo, 24 given 50 mu g eprotirome, and 22 given 100 mu g eprotirome). Mean LDL cholesterol concentrations increased by 9% (95% CI -2 to 20) in the placebo group, decreased by 12% (-28 to 4%; p=0.0677 vs placebo) in the 50 mu g eprotirome group, and decreased by 22% (-32 to -13%; p=0.0045 vs placebo) in the 100 mu g eprotirome group. We noted statistically significant increases between both eprotirome groups and placebo in aspartate aminotransferase (AST; pless than0.0001), alanine aminotransferase (ALT; pless than0.0001), conjugated bilirubin (p=0.0006), and gamma-glutamyltranspeptidase (pless than0.0001). Four patients had to discontinue or interrupt study treatment before trial termination due to AST increases between the upper limit of normal (ULN) and six times ULN, and ALT concentrations between three and seven times ULN. Although we detected no changes in serum concentrations of thyroid-stimulating hormone or free tri-iodothyronine, free tetra-iodothyronine decreased by 19% (23 to 16) in the 50 mu g eprotirome group and 27% (30 to 23) in the 100 mu g eprotirome group (pless than0.0001 vs placebo for both groups). Interpretation Our findings show that eprotirome can lower LDL cholesterol concentrations in patients with familial hypercholesterolaemia when added to conventional statin treatment with or without ezetimibe, but that it has the potential to induce liver injury. These findings, along with findings of cartilage damage in dogs, raise serious doubts about selective thyroid hormone mimetics as a therapeutic approach to lower LDL cholesterol concentrations.
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