Pub Date : 2024-11-01DOI: 10.1016/j.clinthera.2024.08.009
Ismail A. Ibrahim , Rem Ehab Abdelkader , Ahmed Hosney Nada , Siham Younes , George Hanen , Ghena Shahwan , Mohammad Hamad , Mostafa Meshref , Abdulqadir J. Nashwan
Purpose
This study addresses the effectiveness of oral everolimus in treating various malignancies associated with Neurofibromatosis Type 1 (NF1). The purpose is to determine whether everolimus reduces lesion size in NF1 patients, considering the controversial findings from previous clinical trials. The scientific hypotheses and questions involve evaluating the impact of everolimus on NF1-associated lesions and understanding the variability in treatment outcomes.
Methods
A systematic review and meta-analysis were conducted following PRISMA and Cochrane Collaboration guidelines. The study included four-phase II, single-arm, nonrandomized trials investigating the effect of oral everolimus on NF1-associated lesion size. The search covered multiple databases, and data extraction involved evaluating studies for inclusion criteria and assessing quality using the Cochrane Collaboration's Risk of Bias in Nonrandomized Studies tool. Statistical analysis utilized Open Meta(Analyst).
Findings
The search yielded 388 studies, with 10 selected for full-text review and four included in the final analysis. The quality of the studies ranged from low to moderate. The meta-analysis indicated no observed heterogeneity (I^2 = 0%), and the overall estimate suggested no significant reduction in NF1-associated lesion size with everolimus (P = 0.069).
Implications
The findings reveal a varied and inconsistent picture of everolimus efficacy in NF1 treatment. The study highlights the need for personalized approaches, considering individual genetic and clinical differences. The limitations, including small sample sizes and nonrandomized trials, call for larger, more standardized research efforts. The study emphasizes ongoing trials and the importance of future research in understanding predictors of everolimus response and optimizing treatment strategies for NF1 patients.
Conclusion
While everolimus shows promise in reducing lesion size in a subset of NF1 patients, the study cannot draw conclusive results due to limitations in the included studies. Ongoing, adequately powered trials are crucial for advancing the evidence base and informing the potential role of everolimus in NF1 treatment.
Others
There was no funding for this review and no conflicts of interest.
{"title":"Effect of Everolimus on Prognosis of Neurofibromatosis Type 1 Lesions: A Systematic Review and Meta Analysis","authors":"Ismail A. Ibrahim , Rem Ehab Abdelkader , Ahmed Hosney Nada , Siham Younes , George Hanen , Ghena Shahwan , Mohammad Hamad , Mostafa Meshref , Abdulqadir J. Nashwan","doi":"10.1016/j.clinthera.2024.08.009","DOIUrl":"10.1016/j.clinthera.2024.08.009","url":null,"abstract":"<div><h3>Purpose</h3><div>This study addresses the effectiveness of oral everolimus in treating various malignancies associated with Neurofibromatosis Type 1 (NF1). The purpose is to determine whether everolimus reduces lesion size in NF1 patients, considering the controversial findings from previous clinical trials. The scientific hypotheses and questions involve evaluating the impact of everolimus on NF1-associated lesions and understanding the variability in treatment outcomes.</div></div><div><h3>Methods</h3><div>A systematic review and meta-analysis were conducted following PRISMA and Cochrane Collaboration guidelines. The study included four-phase II, single-arm, nonrandomized trials investigating the effect of oral everolimus on NF1-associated lesion size. The search covered multiple databases, and data extraction involved evaluating studies for inclusion criteria and assessing quality using the Cochrane Collaboration's Risk of Bias in Nonrandomized Studies tool. Statistical analysis utilized Open Meta(Analyst).</div></div><div><h3>Findings</h3><div>The search yielded 388 studies, with 10 selected for full-text review and four included in the final analysis. The quality of the studies ranged from low to moderate. The meta-analysis indicated no observed heterogeneity (I^2 = 0%), and the overall estimate suggested no significant reduction in NF1-associated lesion size with everolimus (<em>P</em> = 0.069).</div></div><div><h3>Implications</h3><div>The findings reveal a varied and inconsistent picture of everolimus efficacy in NF1 treatment. The study highlights the need for personalized approaches, considering individual genetic and clinical differences. The limitations, including small sample sizes and nonrandomized trials, call for larger, more standardized research efforts. The study emphasizes ongoing trials and the importance of future research in understanding predictors of everolimus response and optimizing treatment strategies for NF1 patients.</div></div><div><h3>Conclusion</h3><div>While everolimus shows promise in reducing lesion size in a subset of NF1 patients, the study cannot draw conclusive results due to limitations in the included studies. Ongoing, adequately powered trials are crucial for advancing the evidence base and informing the potential role of everolimus in NF1 treatment.</div></div><div><h3>Others</h3><div>There was no funding for this review and no conflicts of interest.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 11","pages":"Pages 865-869"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.clinthera.2024.04.013
Aihua Wang , Weilong Shi , Ning Zhang , Huilin Tang , Xin Feng
Purpose
Previous studies have shown that newer glucose-lowering drugs (GLDs), such as sodium-glucose transport protein 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase 4 (DPP-4) inhibitors, may decrease the risk of gout, however, the evidence remains inconclusive. This study aimed to assess the association between newer GLDs and risk of gout.
Methods
We systematically searched electronic databases up to August 2023 to include randomized, placebo-controlled outcome trials that reported gout-related outcomes in participants with and without type 2 diabetes. A random effects network meta-analysis was conducted to estimate the risk ratio (RR) with 95% confidence interval (CI) to compare the effects of SGLT2 inhibitors, GLP-1RAs, and DPP-4 inhibitors on risk of gout.
Findings
This study included 22 trials involving 173,498 patients. Compared with placebo, SGLT2 inhibitors were significantly associated with decreased risk of gout (RR, 0.51; 95% CI, 0.29–0.91) while both GLP-1RAs and DPP-4 inhibitors have no significant effects on gout risk. There were no significant differences between SGLT2 inhibitors and GLP-1RAs (RR, 0.75; 95%CI, 0.31–1.82) and between GLP-1RAs and DPP-4 inhibitors (RR, 0.39; 95%CI, 0.14–1.10).
Implications
SGLT2 inhibitors may potentially prevent the risk of gout, however, both GLP-1RAs and DPP-4 inhibitors have neutral effects.
{"title":"Newer Glucose-Lowering Drugs and Risk of Gout: A Network Meta-Analysis of Randomized Outcomes Trials","authors":"Aihua Wang , Weilong Shi , Ning Zhang , Huilin Tang , Xin Feng","doi":"10.1016/j.clinthera.2024.04.013","DOIUrl":"10.1016/j.clinthera.2024.04.013","url":null,"abstract":"<div><h3>Purpose</h3><div>Previous studies have shown that newer glucose-lowering drugs (GLDs), such as sodium-glucose transport protein 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase 4 (DPP-4) inhibitors, may decrease the risk of gout, however, the evidence remains inconclusive. This study aimed to assess the association between newer GLDs and risk of gout.</div></div><div><h3>Methods</h3><div>We systematically searched electronic databases up to August 2023 to include randomized, placebo-controlled outcome trials that reported gout-related outcomes in participants with and without type 2 diabetes. A random effects network meta-analysis was conducted to estimate the risk ratio (RR) with 95% confidence interval (CI) to compare the effects of SGLT2 inhibitors, GLP-1RAs, and DPP-4 inhibitors on risk of gout.</div></div><div><h3>Findings</h3><div>This study included 22 trials involving 173,498 patients. Compared with placebo, SGLT2 inhibitors were significantly associated with decreased risk of gout (RR, 0.51; 95% CI, 0.29–0.91) while both GLP-1RAs and DPP-4 inhibitors have no significant effects on gout risk. There were no significant differences between SGLT2 inhibitors and GLP-1RAs (RR, 0.75; 95%CI, 0.31–1.82) and between GLP-1RAs and DPP-4 inhibitors (RR, 0.39; 95%CI, 0.14–1.10).</div></div><div><h3>Implications</h3><div>SGLT2 inhibitors may potentially prevent the risk of gout, however, both GLP-1RAs and DPP-4 inhibitors have neutral effects.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 11","pages":"Pages 851-854"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141129979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acute ischemic stroke (AIS) is a life-threatening condition demanding prompt reperfusion to salvage brain tissue. Thrombolytic drugs, like tenecteplase (TNK), offer clot dissolution, but time constraints and contraindications limit their use. Mechanical thrombectomy (MT) revolutionized AIS treatment, especially for large vessel occlusions (LVO). Recent evidence suggests that administering TNK before MT improves recanalization and outcomes, challenging the dominance of alteplase.
Methods
Relevant articles focusing on TNK before MT were retrieved from PubMed, Scopus, and Web of Science, looking for randomized controlled trials (RCT), clinical trials, and meta-analyses in humans until 2024.
Findings
TNK, a genetically engineered thrombolytic, exhibits superior fibrin specificity and a longer half-life than alteplase. Clinical trials comparing TNK and alteplase before MT showcase enhanced recanalization, functional outcomes, and safety with TNK. Advanced neuroimaging aids patient selection, though its cost-effectiveness warrants consideration. Dosing studies favor a 0.25 mg/kg dose for efficacy and reduced complications. Clinical guidelines from various associations acknowledge TNK's potential as an alteplase alternative for AIS treatment, particularly for LVOs eligible for thrombectomy.
Implications
In conclusion, TNK emerges as a promising option for bridging therapy in AIS, displaying efficacy and safety benefits, especially when administered before MT. Its fibrin specificity, longer half-life, and potential for improved outcomes position TNK as a viable alternative to alteplase, potentially transforming the landscape of AIS treatment strategies. While limitations like small sample sizes and variations in protocols exist, future research should focus on large-scale RCT, subgroup analyses, and cost-effectiveness evaluations to further elucidate TNK's role in optimizing AIS management.
{"title":"Optimizing Acute Ischemic Stroke Outcomes: The Role of Tenecteplase Before Mechanical Thrombectomy","authors":"Arsh Haj Mohamad Ebrahim Ketabforoush M.D. , Ali Hosseinpour M.D. , Mohamad Amin Habibi M.D. , Armin Ariaei , Maedeh Farajollahi , Rojin Chegini M.D. , Zahra Mirzaasgari M.D.","doi":"10.1016/j.clinthera.2024.08.014","DOIUrl":"10.1016/j.clinthera.2024.08.014","url":null,"abstract":"<div><h3>Purpose</h3><div>Acute ischemic stroke (AIS) is a life-threatening condition demanding prompt reperfusion to salvage brain tissue. Thrombolytic drugs, like tenecteplase (TNK), offer clot dissolution, but time constraints and contraindications limit their use. Mechanical thrombectomy (MT) revolutionized AIS treatment, especially for large vessel occlusions (LVO). Recent evidence suggests that administering TNK before MT improves recanalization and outcomes, challenging the dominance of alteplase.</div></div><div><h3>Methods</h3><div>Relevant articles focusing on TNK before MT were retrieved from PubMed, Scopus, and Web of Science, looking for randomized controlled trials (RCT), clinical trials, and meta-analyses in humans until 2024.</div></div><div><h3>Findings</h3><div>TNK, a genetically engineered thrombolytic, exhibits superior fibrin specificity and a longer half-life than alteplase. Clinical trials comparing TNK and alteplase before MT showcase enhanced recanalization, functional outcomes, and safety with TNK. Advanced neuroimaging aids patient selection, though its cost-effectiveness warrants consideration. Dosing studies favor a 0.25 mg/kg dose for efficacy and reduced complications. Clinical guidelines from various associations acknowledge TNK's potential as an alteplase alternative for AIS treatment, particularly for LVOs eligible for thrombectomy.</div></div><div><h3>Implications</h3><div>In conclusion, TNK emerges as a promising option for bridging therapy in AIS, displaying efficacy and safety benefits, especially when administered before MT. Its fibrin specificity, longer half-life, and potential for improved outcomes position TNK as a viable alternative to alteplase, potentially transforming the landscape of AIS treatment strategies. While limitations like small sample sizes and variations in protocols exist, future research should focus on large-scale RCT, subgroup analyses, and cost-effectiveness evaluations to further elucidate TNK's role in optimizing AIS management.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 11","pages":"Pages e10-e20"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.clinthera.2024.08.017
Xiaoxia Wu MD , Chenpeng Xie MD , Weiting Peng DD , Jie Zhao DD , Lin Shu MD , Manjie Guo MD , Qiquan Wan DD
<div><h3>Purpose</h3><div>Infections caused by <em>Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa</em>, and <em>Enterobacter</em> spp (ESKAPE) plus <em>Escherichia coli</em> (E<sub>2</sub>SKAPE), in particular multidrug-resistant (MDR) E<sub>2</sub>SKAPE infections, occur frequently and pose a life-threatening to liver transplant (LT) recipients. To prevent E<sub>2</sub>SKAPE infections and improve the prognosis of LT recipients, the identification of risk factors for E<sub>2</sub>SKAPE infections and mortality is necessary.</div></div><div><h3>Methods</h3><div>E<sub>2</sub>SKAPE pathogens were isolated and identified from clinical samples following standard microbiological procedures. All episodes of E<sub>2</sub>SKAPE infections and mortality documented among LT recipients were analyzed.</div></div><div><h3>Findings</h3><div>A total of 83 episodes of E<sub>2</sub>SKAPE infections, including 75 (90.4%) episodes of MDR-E<sub>2</sub>SKAPE infections, occurred in 23.1% (53/229) of LT recipients. <em>E. faecium</em> was the dominant causative bacterium (37/83; 44.6%). The most common site of infections was the urinary tract (14/53; 26.4%). Sixteen (7%) patients died within 2 months after LT, and 7 deaths were E<sub>2</sub>SKAPE infections-related. Multivariate logistic regression analysis revealed that female sex [odds ratio (OR) = 3.665, 95% confidence interval (CI): 1.614–8.321, <em>P</em> = 0.002], duration of surgery ≥ 400 min [OR = 2.328, 95%CI: 1.151–4.707, <em>P</em> = 0.019], intraoperative red blood cell (RBC) transfusion ≥ 12U [OR = 2.542, 95%CI: 1.218–5.306, <em>P</em> = 0.013] and indwelling urethral catheter use ≥ 3 days [OR = 3.96, 95%CI: 1.309–11.981, <em>P</em> = 0.015] were independent risk factors for E<sub>2</sub>SKAPE infections after LT, and that only exposure to more than 2 intravenous antibiotics post-LT [OR = 0.318, 95%CI: 0.15–0.674, <em>P</em> = 0.003] was negatively associated with acquisition of E<sub>2</sub>SKAPE infections. The predictors of crude mortality included female sex [OR = 4.822, 95%CI: 1.299–17.904, <em>P</em> = 0.019], creatinine on day 3 post-LT > 1.5 mg/dL [OR = 11.014, 95%CI: 2.985–40.637, <em>P</em> < 0.001], mechanical ventilation post-LT [OR = 10.724, 95%CI: 2.695–42.676, <em>P</em> = 0.001] and recipients with E<sub>2</sub>SKAPE infections [OR = 4.112, 95%CI: 1.169-14.47, <em>P</em> = 0.028].</div></div><div><h3>Implications</h3><div>A high incidence of E<sub>2</sub>SKAPE infections was noted in the early post-LT period. The most common infection site was the urinary tract, and the dominant pathogenic bacterium was <em>E. faecium</em>. Female sex, prolonged surgery time, massive RBC transfusion, or delayed urethral catheter removal were associated with E<sub>2</sub>SKAPE infections. Only exposure to more than 2 intravenous antibiotics post-LT was negatively related to the acquisition of E<sub>2</sub>SKAPE infections. The predic
{"title":"Risk Factors for E2SKAPE Infections and Mortality Among Liver Transplant Recipients","authors":"Xiaoxia Wu MD , Chenpeng Xie MD , Weiting Peng DD , Jie Zhao DD , Lin Shu MD , Manjie Guo MD , Qiquan Wan DD","doi":"10.1016/j.clinthera.2024.08.017","DOIUrl":"10.1016/j.clinthera.2024.08.017","url":null,"abstract":"<div><h3>Purpose</h3><div>Infections caused by <em>Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa</em>, and <em>Enterobacter</em> spp (ESKAPE) plus <em>Escherichia coli</em> (E<sub>2</sub>SKAPE), in particular multidrug-resistant (MDR) E<sub>2</sub>SKAPE infections, occur frequently and pose a life-threatening to liver transplant (LT) recipients. To prevent E<sub>2</sub>SKAPE infections and improve the prognosis of LT recipients, the identification of risk factors for E<sub>2</sub>SKAPE infections and mortality is necessary.</div></div><div><h3>Methods</h3><div>E<sub>2</sub>SKAPE pathogens were isolated and identified from clinical samples following standard microbiological procedures. All episodes of E<sub>2</sub>SKAPE infections and mortality documented among LT recipients were analyzed.</div></div><div><h3>Findings</h3><div>A total of 83 episodes of E<sub>2</sub>SKAPE infections, including 75 (90.4%) episodes of MDR-E<sub>2</sub>SKAPE infections, occurred in 23.1% (53/229) of LT recipients. <em>E. faecium</em> was the dominant causative bacterium (37/83; 44.6%). The most common site of infections was the urinary tract (14/53; 26.4%). Sixteen (7%) patients died within 2 months after LT, and 7 deaths were E<sub>2</sub>SKAPE infections-related. Multivariate logistic regression analysis revealed that female sex [odds ratio (OR) = 3.665, 95% confidence interval (CI): 1.614–8.321, <em>P</em> = 0.002], duration of surgery ≥ 400 min [OR = 2.328, 95%CI: 1.151–4.707, <em>P</em> = 0.019], intraoperative red blood cell (RBC) transfusion ≥ 12U [OR = 2.542, 95%CI: 1.218–5.306, <em>P</em> = 0.013] and indwelling urethral catheter use ≥ 3 days [OR = 3.96, 95%CI: 1.309–11.981, <em>P</em> = 0.015] were independent risk factors for E<sub>2</sub>SKAPE infections after LT, and that only exposure to more than 2 intravenous antibiotics post-LT [OR = 0.318, 95%CI: 0.15–0.674, <em>P</em> = 0.003] was negatively associated with acquisition of E<sub>2</sub>SKAPE infections. The predictors of crude mortality included female sex [OR = 4.822, 95%CI: 1.299–17.904, <em>P</em> = 0.019], creatinine on day 3 post-LT > 1.5 mg/dL [OR = 11.014, 95%CI: 2.985–40.637, <em>P</em> < 0.001], mechanical ventilation post-LT [OR = 10.724, 95%CI: 2.695–42.676, <em>P</em> = 0.001] and recipients with E<sub>2</sub>SKAPE infections [OR = 4.112, 95%CI: 1.169-14.47, <em>P</em> = 0.028].</div></div><div><h3>Implications</h3><div>A high incidence of E<sub>2</sub>SKAPE infections was noted in the early post-LT period. The most common infection site was the urinary tract, and the dominant pathogenic bacterium was <em>E. faecium</em>. Female sex, prolonged surgery time, massive RBC transfusion, or delayed urethral catheter removal were associated with E<sub>2</sub>SKAPE infections. Only exposure to more than 2 intravenous antibiotics post-LT was negatively related to the acquisition of E<sub>2</sub>SKAPE infections. The predic","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 11","pages":"Pages 883-890"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The modern oncology drug development landscape has shifted away from traditional cytotoxic chemotherapies. Following their initial approvals, many oncology drugs have been approved in subsequent indications either as monotherapy or in combination to benefit a broader patient population. To date, dose selection strategies for subsequent indications have not been systematically reviewed. This review examines how approved dosing regimens were selected in subsequent indications for FDA-approved oncology drugs.
Methods
The Drugs@FDA database was used to identify FDA-approved new molecular entities (NMEs) between 2010 and 2023. NMEs with more than 1 approved indication were included in the analysis. In total, the dosing regimens for 67 novel oncology drugs that obtained FDA approvals for multiple indications were evaluated.
Findings
Overall, in subsequent indications, 72% of NMEs used the same or clinically equivalent alternative dosing regimens to those approved in the initial indications. Amongst the 28% of NMEs that used different dosing regimens, safety/tolerability was the leading cause of a dosing regimen changes in both monotherapy and combination therapy settings. Other factors leading to changes in dosing regimens include differences in tumor biology, disease burden, pharmacokinetics, and overall benefit-risk profiles obtained from dose-finding studies.
Implications
Our analysis highlighted the importance of selecting a safe, tolerable, and yet efficacious dosing regimen for the initial indication as a suboptimal initially approved regimen could lead to dosing regimen changes in later indications. Preclinical and clinical data could be leveraged to understand the pharmacology, pharmacokinetic, and pharmacodynamic differences between indications and thus support dose selection in subsequent indications.
目的：现代肿瘤药物的开发已从传统的细胞毒性化学疗法转变而来。许多肿瘤药物在首次获批后，又被批准用于后续适应症，无论是单药治疗还是联合用药，以造福更广泛的患者群体。迄今为止，尚未对后续适应症的剂量选择策略进行过系统回顾。本综述研究了 FDA 批准的肿瘤药物在后续适应症中如何选择已获批准的给药方案：方法：使用Drugs@FDA数据库识别2010年至2023年期间FDA批准的新分子实体（NMEs）。具有一个以上批准适应症的新分子实体被纳入分析。总共对 67 种获得 FDA 批准用于多个适应症的新型肿瘤药物的给药方案进行了评估：总体而言，在后续适应症中，72%的 NMEs 采用了与最初适应症所批准的相同或临床效果相当的替代给药方案。在使用不同给药方案的 28% 的 NMEs 中，安全性/耐受性是导致单一疗法和联合疗法给药方案改变的主要原因。导致改变给药方案的其他因素包括肿瘤生物学差异、疾病负担、药代动力学以及从剂量试验研究中获得的总体获益-风险概况：我们的分析强调了为最初适应症选择安全、可耐受且有效的给药方案的重要性，因为最初批准的次优方案可能会导致以后适应症的给药方案改变。可以利用临床前和临床数据来了解不同适应症的药理学、药动学和药效学差异，从而为后续适应症的剂量选择提供支持。
{"title":"Oncology Dose Selection in Subsequent Indications: What Can We Learn From FDA-approved Oncology Drugs?","authors":"Huy X. Ngo PharmD, PhD, Elise Oh PharmD, Chunze Li PhD, Jiajie Yu PhD","doi":"10.1016/j.clinthera.2024.08.020","DOIUrl":"10.1016/j.clinthera.2024.08.020","url":null,"abstract":"<div><h3>Purpose</h3><div>The modern oncology drug development landscape has shifted away from traditional cytotoxic chemotherapies. Following their initial approvals, many oncology drugs have been approved in subsequent indications either as monotherapy or in combination to benefit a broader patient population. To date, dose selection strategies for subsequent indications have not been systematically reviewed. This review examines how approved dosing regimens were selected in subsequent indications for FDA-approved oncology drugs.</div></div><div><h3>Methods</h3><div>The Drugs@FDA database was used to identify FDA-approved new molecular entities (NMEs) between 2010 and 2023. NMEs with more than 1 approved indication were included in the analysis. In total, the dosing regimens for 67 novel oncology drugs that obtained FDA approvals for multiple indications were evaluated.</div></div><div><h3>Findings</h3><div>Overall, in subsequent indications, 72% of NMEs used the same or clinically equivalent alternative dosing regimens to those approved in the initial indications. Amongst the 28% of NMEs that used different dosing regimens, safety/tolerability was the leading cause of a dosing regimen changes in both monotherapy and combination therapy settings. Other factors leading to changes in dosing regimens include differences in tumor biology, disease burden, pharmacokinetics, and overall benefit-risk profiles obtained from dose-finding studies.</div></div><div><h3>Implications</h3><div>Our analysis highlighted the importance of selecting a safe, tolerable, and yet efficacious dosing regimen for the initial indication as a suboptimal initially approved regimen could lead to dosing regimen changes in later indications. Preclinical and clinical data could be leveraged to understand the pharmacology, pharmacokinetic, and pharmacodynamic differences between indications and thus support dose selection in subsequent indications.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 11","pages":"Pages 927-937"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.clinthera.2024.08.007
Barbara Vogg PhD , Johann Poetzl PhD , Arnd Schwebig MD , Susmit Sekhar MD , Alan Kivitz MD , Natalia Krivtsova MSc , Oliver Renner PhD , Jean-Jacques Body MD, PhD , Richard Eastell MD, FRCP, FRCPath, FMedSci
Purpose
Sandoz biosimilar denosumab (GP2411 [SDZ-deno]; Jubbonti/Wyost) is approved by the US FDA, EMA and Health Canada for all indications of reference denosumab (REF-deno; Prolia/Xgeva), a fully human IgG2κ monoclonal antibody that binds with high affinity and specificity to receptor activator of nuclear factor kappa-B ligand (RANKL). Denosumab blocks RANKL, preventing bone resorption and loss of bone density/architecture in conditions characterized by excessive bone loss such as osteoporosis in postmenopausal women and metastatic bone disease, among others.
Methods
This narrative review summarizes the totality of evidence (ToE) for SDZ-deno that supported its approval as Jubbonti/Wyost in the EU and US.
Findings
Analytical evaluation indicated that SDZ-deno has high purity and structural homology with REF-deno. SDZ-deno also demonstrated similar binding affinities, size and charge variants, and disulfide isoforms to REF-deno, and did not trigger clinically meaningful antibody-dependent cellular cytotoxicity. In clinical evaluation, SDZ-deno was similar to REF-deno in pharmacokinetics (PK) and pharmacodynamics (PD) in a 39-week Phase I study in 502 healthy male participants, and to REF-deno in a 72-week Phase III study in 527 postmenopausal women with osteoporosis. In both studies, the 90% and 95% confidence intervals (for PK and PD endpoints, respectively) of the geometric mean ratios for AUCinf, Cmax (and AUClast in the Phase I study; PK endpoints), and area under the effect versus time curve of percent change from baseline in serum carboxy-terminal crosslinked telopeptide of type I collagen (PD endpoint), were fully contained within the prespecified equivalence margins (0.80, 1.25). The Phase III study also demonstrated SDZ-deno is similar in efficacy to REF-deno in postmenopausal women with osteoporosis, as the difference in percent change from baseline in lumbar spine bone mineral density at week 52 between REF-deno and SDZ-deno was fully contained within the prespecified equivalence margins (−1.45, 1.45). SDZ-deno was well tolerated in both studies. As the ToE has established biosimilarity of SDZ-deno and REF-deno, extrapolation to all indications is justified based on the common mechanism of action and the comparable PK, safety, and immunogenicity across all indications.
Implications
The ToE for SDZ-deno suggests it will be an effective biosimilar to REF-deno, and its lower unit price is anticipated to increase the number of appropriate patients who will benefit.
{"title":"The Totality of Evidence for SDZ-deno: A Biosimilar to Reference Denosumab","authors":"Barbara Vogg PhD , Johann Poetzl PhD , Arnd Schwebig MD , Susmit Sekhar MD , Alan Kivitz MD , Natalia Krivtsova MSc , Oliver Renner PhD , Jean-Jacques Body MD, PhD , Richard Eastell MD, FRCP, FRCPath, FMedSci","doi":"10.1016/j.clinthera.2024.08.007","DOIUrl":"10.1016/j.clinthera.2024.08.007","url":null,"abstract":"<div><h3>Purpose</h3><div>Sandoz biosimilar denosumab (GP2411 [SDZ-deno]; Jubbonti/Wyost) is approved by the US FDA, EMA and Health Canada for all indications of reference denosumab (REF-deno; Prolia/Xgeva), a fully human IgG2κ monoclonal antibody that binds with high affinity and specificity to receptor activator of nuclear factor kappa-B ligand (RANKL). Denosumab blocks RANKL, preventing bone resorption and loss of bone density/architecture in conditions characterized by excessive bone loss such as osteoporosis in postmenopausal women and metastatic bone disease, among others.</div></div><div><h3>Methods</h3><div>This narrative review summarizes the totality of evidence (ToE) for SDZ-deno that supported its approval as Jubbonti/Wyost in the EU and US.</div></div><div><h3>Findings</h3><div>Analytical evaluation indicated that SDZ-deno has high purity and structural homology with REF-deno. SDZ-deno also demonstrated similar binding affinities, size and charge variants, and disulfide isoforms to REF-deno, and did not trigger clinically meaningful antibody-dependent cellular cytotoxicity. In clinical evaluation, SDZ-deno was similar to REF-deno in pharmacokinetics (PK) and pharmacodynamics (PD) in a 39-week Phase I study in 502 healthy male participants, and to REF-deno in a 72-week Phase III study in 527 postmenopausal women with osteoporosis. In both studies, the 90% and 95% confidence intervals (for PK and PD endpoints, respectively) of the geometric mean ratios for AUC<sub>inf</sub>, C<sub>max</sub> (and AUC<sub>last</sub> in the Phase I study; PK endpoints), and area under the effect versus time curve of percent change from baseline in serum carboxy-terminal crosslinked telopeptide of type I collagen (PD endpoint), were fully contained within the prespecified equivalence margins (0.80, 1.25). The Phase III study also demonstrated SDZ-deno is similar in efficacy to REF-deno in postmenopausal women with osteoporosis, as the difference in percent change from baseline in lumbar spine bone mineral density at week 52 between REF-deno and SDZ-deno was fully contained within the prespecified equivalence margins (−1.45, 1.45). SDZ-deno was well tolerated in both studies. As the ToE has established biosimilarity of SDZ-deno and REF-deno, extrapolation to all indications is justified based on the common mechanism of action and the comparable PK, safety, and immunogenicity across all indications.</div></div><div><h3>Implications</h3><div>The ToE for SDZ-deno suggests it will be an effective biosimilar to REF-deno, and its lower unit price is anticipated to increase the number of appropriate patients who will benefit.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 11","pages":"Pages 916-926"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.clinthera.2024.08.006
Yoonjin Kim MD , Sungyeun Bae MD , Inseung Jeon PhD , Jihoon Kwon MS , Sung Hee Hong MS , Na Young Kim MS , Kyung-Sang Yu MD, PhD , In-Jin Jang MD, PhD , SeungHwan Lee MD, PhD
Purpose
A fixed-dose combination (FDC) of proton pump inhibitors (PPIs) and antacid salts enables rapid acid suppression through the neutralizing effect of the antacid salt and the rapid absorption of PPIs. This study aimed to compare the pharmacokinetics (PKs) and pharmacodynamics (PDs) of a recently formulated FDC of esomeprazole and magnesium hydroxide to the enteric-coated esomeprazole in healthy subjects.
Methods
A randomized, open-label, multiple-dose, two-treatment, two-way crossover design was conducted in healthy subjects. Forty-nine subjects were randomized to one of the two treatment sequences and received either the test drug (esomeprazole/magnesium hydroxide 40/350 mg) or reference drug (enteric-coated esomeprazole 40 mg) for 7 days in the first period and the alternative in the second period with a 14-day washout period. Blood samples were collected for up to 24 hours for PK assessment, and 24-hour gastric pH monitoring was conducted for PD assessment both before and after a single administration, as well as at a steady state after seven consecutive days of administration. The PK and PD parameters were compared between the two drugs.
Findings
After multiple administrations, the median value of time to reach maximum concentration was faster in the test drug than in the reference drug, with a difference of 1.68 hours. The overall systemic exposure of the test drug was similar to that of the reference drug, and the PK parameter fell within the equivalence criteria. The test drug demonstrated a shorter time to reach gastric pH ≥ 4 compared to the reference drug (P = 0.0463). A decrease from baseline in integrated gastric acidity over 24 hours, which represents the degree of inhibition of gastric acid secretion, was equivalent between the two drugs.
Implications
The fixed-dose combination of esomeprazole and magnesium hydroxide showed rapid absorption and quicker gastric acid suppression than enteric-coated esomeprazole with comparable PK and PD properties. ClinicalTrials.gov identifier: NCT04324905 (https://classic.clinicaltrials.gov/ct2/show/NCT04324905).
{"title":"Pharmacokinetics and Pharmacodynamics of a Fixed-Dose Combination of Esomeprazole and Magnesium Hydroxide Compared to the Enteric-Coated Esomeprazole","authors":"Yoonjin Kim MD , Sungyeun Bae MD , Inseung Jeon PhD , Jihoon Kwon MS , Sung Hee Hong MS , Na Young Kim MS , Kyung-Sang Yu MD, PhD , In-Jin Jang MD, PhD , SeungHwan Lee MD, PhD","doi":"10.1016/j.clinthera.2024.08.006","DOIUrl":"10.1016/j.clinthera.2024.08.006","url":null,"abstract":"<div><h3>Purpose</h3><div>A fixed-dose combination (FDC) of proton pump inhibitors (PPIs) and antacid salts enables rapid acid suppression through the neutralizing effect of the antacid salt and the rapid absorption of PPIs. This study aimed to compare the pharmacokinetics (PKs) and pharmacodynamics (PDs) of a recently formulated FDC of esomeprazole and magnesium hydroxide to the enteric-coated esomeprazole in healthy subjects.</div></div><div><h3>Methods</h3><div>A randomized, open-label, multiple-dose, two-treatment, two-way crossover design was conducted in healthy subjects. Forty-nine subjects were randomized to one of the two treatment sequences and received either the test drug (esomeprazole/magnesium hydroxide 40/350 mg) or reference drug (enteric-coated esomeprazole 40 mg) for 7 days in the first period and the alternative in the second period with a 14-day washout period. Blood samples were collected for up to 24 hours for PK assessment, and 24-hour gastric pH monitoring was conducted for PD assessment both before and after a single administration, as well as at a steady state after seven consecutive days of administration. The PK and PD parameters were compared between the two drugs.</div></div><div><h3>Findings</h3><div>After multiple administrations, the median value of time to reach maximum concentration was faster in the test drug than in the reference drug, with a difference of 1.68 hours. The overall systemic exposure of the test drug was similar to that of the reference drug, and the PK parameter fell within the equivalence criteria. The test drug demonstrated a shorter time to reach gastric pH ≥ 4 compared to the reference drug (<em>P</em> = 0.0463). A decrease from baseline in integrated gastric acidity over 24 hours, which represents the degree of inhibition of gastric acid secretion, was equivalent between the two drugs.</div></div><div><h3>Implications</h3><div>The fixed-dose combination of esomeprazole and magnesium hydroxide showed rapid absorption and quicker gastric acid suppression than enteric-coated esomeprazole with comparable PK and PD properties. ClinicalTrials.gov identifier: NCT04324905 (<span><span>https://classic.clinicaltrials.gov/ct2/show/NCT04324905</span><svg><path></path></svg></span>).</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 11","pages":"Pages 870-876"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.clinthera.2024.08.016
Jing Nie PhD , Lihui Liu MD , Huina Wu MD , Shan Yuan MD , Ke Tang BS , Jiyong Wu PhD
Purpose
Zanubrutinib, a potent and specific irreversible Bruton's tyrosine kinase inhibitor, has proven to be effective in untreated chronic lymphocytic leukemia (CLL), whether used alone or in combination with other therapies. Here, we compared the cost-effectiveness of zanubrutinib with bendamustine-rituximab (R-bendamustine) to determine its effectiveness as the first-line treatment for Chinese patients with untreated CLL.
Methods
The evaluation utilized a partitioned survival model, constructed using TreeAge Pro 2011 software, incorporating data from SEQUOIA trial (NCT03336333). Transition probabilities were estimated from the reported survival probabilities in trials using parametric survival modeling. In this analysis, the quality-adjusted life years (QALYs), incremental cost-effectiveness ratio, and lifetime cost were calculated from the Chinese health care system perspective. Sensitivity analyses, including 1-way analysis and probabilistic sensitivity analysis, were carried out to explore the uncertainty of the modeling results. Additionally, several scenario analyses, including different zanubrutinib price calculation and 20-year time horizon, were evaluated.
Findings
The findings revealed that zanubrutinib had an incremental cost-effectiveness ratio of $58,258.18 per additional QALYs gained compared with bendamustine-rituximab, with zanubrutinib being cost-effective only if its price was reduced by more than 30%. Research indicated that zanubrutinib achieved at least a 3.70% probability of cost-effectiveness at the threshold of $38,223.34/QALY. One-way sensitivity analysis revealed that the results were sensitive to the utility of progressed disease.
Implications
The study highlighted the importance of considering the cost-effectiveness of zanubrutinib at its current price point for patients with untreated CLL in China, emphasizing the need for further assessment and potential pricing adjustments to enhance its economic viability in clinical practice.
目的：扎鲁替尼是一种强效、特异性不可逆的布鲁顿酪氨酸激酶抑制剂，已被证明对未经治疗的慢性淋巴细胞白血病（CLL）有效，无论是单独使用还是与其他疗法联合使用。在此，我们比较了扎努鲁替尼与苯达莫司汀-利妥昔单抗（R-苯达莫司汀）的成本效益，以确定其作为中国未治疗的慢性淋巴细胞白血病患者一线治疗的有效性：评估采用了TreeAge Pro 2011软件构建的分区生存模型，并纳入了SEQUOIA试验（NCT03336333）的数据。根据试验报告的生存概率，利用参数生存模型估算过渡概率。在本分析中，质量调整生命年（QALYs）、增量成本效益比和终生成本均从中国医疗保健系统的角度进行计算。为了探索建模结果的不确定性，我们进行了敏感性分析，包括单向分析和概率敏感性分析。此外，还评估了几种情景分析，包括不同的扎鲁替尼价格计算方法和 20 年的时间跨度：研究结果显示，与苯达莫司汀-利妥昔单抗相比，扎努布替尼每增加一个QALYs的增量成本效益比为58,258.18美元，只有当扎努布替尼的价格下降30%以上时才具有成本效益。研究表明，在 38,223.34 美元/QALY 的临界值下，扎努布替尼至少有 3.70% 的概率具有成本效益。单向敏感性分析显示，结果对疾病进展的效用很敏感：该研究强调了考虑扎鲁替尼在当前价位对中国未经治疗的CLL患者的成本效益的重要性，强调了进一步评估和潜在定价调整的必要性，以提高其在临床实践中的经济可行性。
{"title":"Cost-Effectiveness of Zanubrutinib Versus Bendamustine and Rituximab in Patients With Untreated Chronic Lymphocytic Leukemia","authors":"Jing Nie PhD , Lihui Liu MD , Huina Wu MD , Shan Yuan MD , Ke Tang BS , Jiyong Wu PhD","doi":"10.1016/j.clinthera.2024.08.016","DOIUrl":"10.1016/j.clinthera.2024.08.016","url":null,"abstract":"<div><h3>Purpose</h3><div>Zanubrutinib, a potent and specific irreversible Bruton's tyrosine kinase inhibitor, has proven to be effective in untreated chronic lymphocytic leukemia (CLL), whether used alone or in combination with other therapies. Here, we compared the cost-effectiveness of zanubrutinib with bendamustine-rituximab (R-bendamustine) to determine its effectiveness as the first-line treatment for Chinese patients with untreated CLL.</div></div><div><h3>Methods</h3><div>The evaluation utilized a partitioned survival model, constructed using TreeAge Pro 2011 software, incorporating data from SEQUOIA trial (NCT03336333). Transition probabilities were estimated from the reported survival probabilities in trials using parametric survival modeling. In this analysis, the quality-adjusted life years (QALYs), incremental cost-effectiveness ratio, and lifetime cost were calculated from the Chinese health care system perspective. Sensitivity analyses, including 1-way analysis and probabilistic sensitivity analysis, were carried out to explore the uncertainty of the modeling results. Additionally, several scenario analyses, including different zanubrutinib price calculation and 20-year time horizon, were evaluated.</div></div><div><h3>Findings</h3><div>The findings revealed that zanubrutinib had an incremental cost-effectiveness ratio of $58,258.18 per additional QALYs gained compared with bendamustine-rituximab, with zanubrutinib being cost-effective only if its price was reduced by more than 30%. Research indicated that zanubrutinib achieved at least a 3.70% probability of cost-effectiveness at the threshold of $38,223.34/QALY. One-way sensitivity analysis revealed that the results were sensitive to the utility of progressed disease.</div></div><div><h3>Implications</h3><div>The study highlighted the importance of considering the cost-effectiveness of zanubrutinib at its current price point for patients with untreated CLL in China, emphasizing the need for further assessment and potential pricing adjustments to enhance its economic viability in clinical practice.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 11","pages":"Pages 877-882"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.clinthera.2024.06.021
Frank G. Preston , Matthew Anson , David R. Riley , Gema H. Ibarburu , Alexander Henney , Gregory Y.H. Lip , Daniel J. Cuthbertson , Uazman Alam , Sizheng S. Zhao
Purpose
This study aimed to evaluate the relative association between sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1Ra) with the incidence of gout in patients with type 2 diabetes (T2D) using real-world data.
Methods
We conducted a cohort study using data from TriNetX (an international federated database). We included patients commenced on metformin or insulin, either alone or with an SGLT2i or GLP-1Ra, at least 2 years prior to date of analysis. We propensity score matched (PSM) (1:1) for 26 relevant characteristics. Time to event analysis was performed to assess the incidence of gout, all-cause mortality (positive control), and herpes zoster infection (negative control) at 5 years following drug initiation.
Findings
Prior to PSM, the cohort numbers were as follows: metformin control, 1,111,449; SGLT2i with metformin, 101,706; GLP-1Ra with metformin, 110,180, insulin control, 1,398,066; SGLT2i with insulin, 68,697; and GLP-1Ra with insulin, 99,693. SGLT2i with metformin demonstrated a statistically significant decreased incidence of gout at 5 years compared to the metformin control cohort (HR 0.75 [95% CI 0.69-0.82], P < 0.0001). Similarly, SGLT2i with insulin demonstrated a statistically significant decreased incidence of gout at 5 years compared to the insulin control cohort (HR 0.83 [95% CI 0.74–0.92], P < 0.0001). Conversely, no significant disparity in gout incidence was observed between the use of GLP-1Ra and matched controls. Subgroup analysis showed an associated reduced incidence of gout with SGLT2i use compared to GLP-1Ra, in groups using metformin (HR 0.77 [95% CI 0.70-0.86], P < 0.0001) or insulin (HR 0.82 [95% CI 0.73-0.91)], P < 0.0001).
Implications
In this large-scale real-world study, SGLT2i use was associated with a lower incidence of gout in patients with T2D compared to both insulin and metformin controls. These findings suggest the potential of SGLT2i as a promising therapeutic option for treating gout in this population.
{"title":"SGLT2 Inhibitors, but Not GLP-1 Receptor Agonists, Reduce Incidence of Gout in People Living With Type 2 Diabetes Across the Therapeutic Spectrum","authors":"Frank G. Preston , Matthew Anson , David R. Riley , Gema H. Ibarburu , Alexander Henney , Gregory Y.H. Lip , Daniel J. Cuthbertson , Uazman Alam , Sizheng S. Zhao","doi":"10.1016/j.clinthera.2024.06.021","DOIUrl":"10.1016/j.clinthera.2024.06.021","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aimed to evaluate the relative association between sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1Ra) with the incidence of gout in patients with type 2 diabetes (T2D) using real-world data.</div></div><div><h3>Methods</h3><div>We conducted a cohort study using data from TriNetX (an international federated database). We included patients commenced on metformin or insulin, either alone or with an SGLT2i or GLP-1Ra, at least 2 years prior to date of analysis. We propensity score matched (PSM) (1:1) for 26 relevant characteristics. Time to event analysis was performed to assess the incidence of gout, all-cause mortality (positive control), and herpes zoster infection (negative control) at 5 years following drug initiation.</div></div><div><h3>Findings</h3><div>Prior to PSM, the cohort numbers were as follows: metformin control, 1,111,449; SGLT2i with metformin, 101,706; GLP-1Ra with metformin, 110,180, insulin control, 1,398,066; SGLT2i with insulin, 68,697; and GLP-1Ra with insulin, 99,693. SGLT2i with metformin demonstrated a statistically significant decreased incidence of gout at 5 years compared to the metformin control cohort (HR 0.75 [95% CI 0.69-0.82], <em>P <</em> 0<em>.</em>0001). Similarly, SGLT2i with insulin demonstrated a statistically significant decreased incidence of gout at 5 years compared to the insulin control cohort (HR 0.83 [95% CI 0.74–0.92], <em>P</em> < 0.0001). Conversely, no significant disparity in gout incidence was observed between the use of GLP-1Ra and matched controls. Subgroup analysis showed an associated reduced incidence of gout with SGLT2i use compared to GLP-1Ra, in groups using metformin (HR 0.77 [95% CI 0.70-0.86], <em>P</em> < 0.0001) or insulin (HR 0.82 [95% CI 0.73-0.91)], <em>P</em> < 0.0001).</div></div><div><h3>Implications</h3><div>In this large-scale real-world study, SGLT2i use was associated with a lower incidence of gout in patients with T2D compared to both insulin and metformin controls. These findings suggest the potential of SGLT2i as a promising therapeutic option for treating gout in this population.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 11","pages":"Pages 835-840"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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