Daily Archives: January 8, 2025
Observational Study Emulation: Denosumab vs. Oral Bisphosphonates in Dialysis-Dependent Patients Shows Reduced Fractures but Possible Elevated Cardiovascular Risk
8 Jan, 2025 | 11:55h | UTCBackground: Patients receiving dialysis have a markedly increased risk of osteoporotic fractures, yet management options in this population remain challenging. Although oral bisphosphonates are the usual first-line treatment for osteoporosis, safety concerns exist for those with severe chronic kidney disease (CKD). Denosumab, which is not cleared via the kidney, offers a potential alternative, but limited data compare its fracture-prevention benefit and cardiovascular (CV) safety against bisphosphonates in dialysis-dependent patients.
Objective: To estimate the risk for major adverse cardiac events (MACE) and the effectiveness in preventing fractures when using denosumab compared with oral bisphosphonates among patients undergoing dialysis.
Methods: This study emulated a target trial using an observational Japanese administrative claims database (April 2014 to October 2022). Adults aged 50 years or older, receiving dialysis and newly prescribed denosumab (60 mg subcutaneously) or oral bisphosphonates (alendronate, risedronate, ibandronate, or minodronate) were included. Exclusions involved recent acute myocardial infarction, stroke, or heart failure. Inverse probability of treatment weighting (IPTW) based on propensity scores was used to balance baseline characteristics. The primary safety outcome was MACE (acute myocardial infarction, stroke, hospitalization for heart failure, or CV death), and the primary effectiveness outcome was all fractures. Three-year risks, risk differences, and risk ratios were estimated.
Results: Among 658 denosumab users and 374 oral bisphosphonate users (mean age, 74.5 years; 62.9% women) followed for up to 3 years, denosumab was associated with a higher weighted risk of MACE (3-year risk ratio, 1.36 [95% CI, 0.99 to 1.87]; risk difference, 8.2% [–0.2% to 16.7%]) compared with oral bisphosphonates. Although the point estimate suggests a notable increase, the 95% CI includes 1.0, indicating that statistical significance was not definitively achieved. Denosumab showed a significantly lower composite fracture risk (3-year risk ratio, 0.55 [0.28 to 0.93]; risk difference, –5.3% [–11.3% to –0.6%]). Individual fracture sites (e.g., hip, vertebral) had imprecise estimates but trended toward fewer nonvertebral fractures with denosumab. Mortality rates did not differ substantially between the groups.
Conclusions: In dialysis-dependent patients with osteoporosis, denosumab may reduce fracture risk while potentially elevating the likelihood of MACE. However, the higher MACE estimate did not surpass the conventional threshold for statistical significance, warranting cautious interpretation. Although these data suggest a clinically meaningful reduction in fractures, the findings regarding cardiovascular outcomes remain imprecise and require further confirmation.
Implications for Practice: Clinicians treating dialysis-dependent patients should weigh denosumab’s fracture-prevention advantage against its possible heightened CV risk. Oral bisphosphonates, though sometimes restricted in severe CKD, may confer lower risk of MACE. Careful monitoring of electrolyte levels, especially calcium, and CV status is essential when administering denosumab in end-stage kidney disease.
Study Strengths and Limitations: Strengths include a large, real-world cohort and the use of target trial emulation with robust propensity score weighting. Limitations involve potential residual confounding, reliance on claims-based definitions of outcomes, and absent lab data (e.g., serum calcium, glomerular filtration rate). Consequently, causality and generalizability should be interpreted with caution, especially outside Japan.
Future Research:
Prospective trials and additional observational studies using detailed clinical data (including renal function parameters and bone mineral density) are needed to clarify the relative net benefits of denosumab versus bisphosphonates in advanced CKD. Investigations into other safety outcomes, such as long-term renal function and hypocalcemia-related complications, would further inform clinical decision-making.
Reference: Masuda S, Fukasawa T, Matsuda S, Kawakami K. “Cardiovascular Safety and Fracture Prevention Effectiveness of Denosumab Versus Oral Bisphosphonates in Patients Receiving Dialysis: A Target Trial Emulation.” Annals of Internal Medicine. DOI:
https://doi.org/10.7326/ANNALS-24-03237
Systematic Review: GLP-1 Receptor Agonists and Co-Agonists Facilitate Significant Weight Loss in Adults Without Diabetes
8 Jan, 2025 | 11:04h | UTCBackground: Obesity is increasingly treated as a chronic disease requiring long-term management. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were originally developed for type 2 diabetes but subsequently demonstrated substantial weight loss benefits in individuals with overweight or obesity. Although several GLP-1 RAs and related dual or triple co-agonists have been assessed in diverse populations, their overall efficacy and safety profile among adults without diabetes had not been thoroughly evaluated.
Objective: To systematically appraise the efficacy and safety of GLP-1 RAs (including single, dual, and triple agonists) for weight loss in otherwise healthy adults with overweight or obesity and without diabetes.
Methods: Investigators searched MEDLINE, Embase, and Cochrane CENTRAL through 4 October 2023 for placebo-controlled randomized controlled trials (RCTs). Eligible studies enrolled adults with body mass index (BMI) ≥27 kg/m^2 (plus one weight-related comorbidity) or ≥30 kg/m^2, in the absence of diabetes or other major diseases. Trials had to last at least 16 weeks and report changes in body weight and safety outcomes. The primary endpoint was percent or absolute change in body weight from baseline. Safety assessments included adverse events (AEs), serious AEs (SAEs), and gastrointestinal (GI) events.
Results: Twenty-six RCTs encompassing 15,491 participants (72% female; mean BMI range, 30–41 kg/m^2; mean age range, 34–57 years) evaluated 12 agents. Three drugs (liraglutide, semaglutide, tirzepatide) are commercially available for weight management; nine are premarket (e.g., retatrutide, orforglipron, mazdutide). Treatment periods ranged from 16 to 104 weeks (median, 43 weeks). Across studies, GLP-1 RAs and co-agonists consistently demonstrated significant weight reductions compared with placebo. Tirzepatide (15 mg weekly) reached up to a 17.8% (95% CI, 16.3% to 19.3%) weight reduction after 72 weeks, whereas semaglutide (2.4 mg weekly) achieved up to 13.9% (95% CI, 11.0% to 16.7%) after 68 weeks. Liraglutide produced more modest losses of up to 5.8% (95% CI, 3.6% to 8.0%) after 26 weeks. Novel agents, particularly the triple agonist retatrutide (12 mg weekly), reported greater average weight losses of up to 22.1% (95% CI, 19.3% to 24.9%) after 48 weeks. Although AEs were often very common (GLP-1 RA vs. placebo: 80%–97% vs. 63%–100%), most were GI-related (47%–84% vs. 13%–63%) and mild or moderate. Importantly, only a smaller proportion of participants (0%–26% vs. 0%–9%) discontinued treatment due to AEs, and SAEs (0%–10% vs. 0%–12%) occurred at relatively lower rates overall. While select SAEs of interest, including severe GI events, biliary disorders, pancreatitis, and psychiatric disorders, were inconsistently reported, they were generally rare (severe GI and biliary disorders, ≤3.5%; pancreatitis, <2%; psychiatric disorders, ≤15% [including less severe events, such as insomnia and mood alterations]).
Conclusions: GLP-1 RAs and co-agonists appear highly efficacious for weight reduction in adults without diabetes, with GI events as the principal safety concern. Among emerging agents, retatrutide in particular has shown even greater efficacy, though further research is needed to clarify comparative effectiveness, costs, and real-world feasibility.
Implications for Practice: Clinicians considering GLP-1 RAs or dual and triple co-agonists for obesity treatment should monitor for GI side effects and counsel patients about long-term use to sustain weight loss. As these newer treatments often come with higher price points and uncertain insurance coverage, cost-effectiveness and sponsor bias should be weighed. Careful patient selection, ongoing monitoring, and discussion of adherence requirements are critical to optimize outcomes in real-world practice.
Study Strengths and Limitations: This review incorporated RCTs with substantial sample sizes and used predefined inclusion criteria focused on healthy adults without diabetes, ensuring a clearer understanding of weight-loss outcomes in this group. However, head-to-head comparisons among agents were lacking, and heterogeneity in trial designs (varying lifestyle interventions, follow-up durations, and dose-escalation approaches) precluded meta-analysis of pooled data. Reporting of specific adverse outcomes was also inconsistent.
Future Research: Larger, longer-term head-to-head RCTs are warranted to evaluate comparative effectiveness, durability of weight loss, and cost implications. Investigations should also explore safety beyond GI events, including rare but serious outcomes such as thyroid disease, gallbladder disorders, or pancreatitis, and determine whether combination therapies (e.g., cagrilintide–semaglutide) confer added benefits.
Reference: Moiz A, Filion KB, Toutounchi H, Tsoukas MA, Yu OHY, Peters TM, Eisenberg MJ. Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes: A Systematic Review of Randomized Controlled Trials. Annals of Internal Medicine. DOI: https://doi.org/10.7326/ANNALS-24-01590
RCT: Sequential Oral Agents Not Noninferior to Insulin for Gestational Diabetes
8 Jan, 2025 | 11:05h | UTCBackground: Gestational diabetes mellitus (GDM) affects a growing number of pregnant individuals worldwide. While insulin has long been the standard pharmacological treatment, oral glucose-lowering agents (metformin and glyburide) have gained traction.
Objective: This trial investigated whether a sequential oral glucose-lowering regimen—beginning with metformin and adding glyburide as needed—was noninferior to an insulin-based strategy in reducing the risk of infants born large for gestational age (LGA).
Methods: This open-label, randomized, noninferiority trial enrolled 820 participants with singleton pregnancies at 16 to 34 weeks of gestation across 25 Dutch centers. Participants were randomized 1:1 to either (1) metformin initiated at 500 mg once daily and increased every three days up to 1000 mg twice daily or the highest tolerated dose with glyburide at 2.5 mg 30-60 minutes before each meal (with a dose increase up to a maximum of 5 mg three times per day) added if needed, and insulin added only if both failed, discontinuing glyburide, or (2) standard insulin therapy. The primary outcome was LGA (>90th percentile for gestational age and sex).
Results: Among those allocated to oral therapy (n=409), 79% achieved glycemic control without insulin. However, 23.9% of infants in the oral-therapy group were LGA vs 19.9% in the insulin group (absolute risk difference 4.0%; 95% CI, −1.7% to 9.8%). This exceeded the predefined 8% absolute risk difference noninferiority margin (P = .09 for noninferiority). Maternal hypoglycemia occurred more often with oral agents (20.9% vs 10.9%; absolute risk difference, 10.0%; 95% CI, 3.7%-21.2%), and neonatal intravenous glucose therapy was administered more frequently to those randomized to oral agents (6.4% vs 3.2%). Exploratory analysis not powered for definitive conclusions of participants requiring only metformin (no glyburide) showed a somewhat lower LGA rate (19.7%).
Conclusions: A sequential oral pharmacotherapy strategy—beginning with metformin and adding glyburide if needed—did not meet noninferiority criteria compared to insulin for preventing LGA births in GDM. While oral agents can reduce the overall need for insulin, the higher rate of maternal hypoglycemia, the higher rate of neonatal hypoglycemia requiring intravenous glucose therapy, and the borderline higher LGA incidence underscore the continued importance of insulin-based strategies, especially considering that the results support a larger body of evidence that glyburide is a suboptimal treatment for gestational diabetes. These results reinforce that insulin remains the preferred first-line pharmacological treatment for GDM, in line with current guidelines. Although patient satisfaction can be higher with oral agents, clinicians should carefully weigh the risks. Further research is needed to clarify the role of metformin-only approaches in GDM management.
Strengths and Limitations: Strengths include a large multicenter design and a clear noninferiority framework. Limitations include the open-label design, which introduces the possibility of bias in treatment allocation and outcome assessment, the reliance on local clinical protocols for insulin adjustments, and variations in diagnostic criteria.
Future Research: Ongoing trials are examining whether metformin alone might match insulin’s efficacy for GDM. Further studies should address long-term offspring outcomes.
Reference:
Rademaker D, de Wit L, Duijnhoven RG, et al. Oral Glucose-Lowering Agents vs Insulin for Gestational Diabetes: A Randomized Clinical Trial. JAMA. Published online January 6, 2025. DOI: http://doi.org/10.1001/jama.2024.23410
Powe CE. For Gestational Diabetes Pharmacotherapy, Insulin Reigns Supreme (Editorial). JAMA. Published online January 6, 2025. DOI: http://doi.org/10.1001/jama.2024.27148
Phase III RCT: Adding Nab-Paclitaxel to Gemcitabine-Cisplatin Fails to Improve Survival in Advanced Biliary Tract Cancers
8 Jan, 2025 | 13:00h | UTCBackground: Biliary tract cancers (BTCs)—including intrahepatic and extrahepatic cholangiocarcinomas and gallbladder carcinoma—are often diagnosed at advanced stages, leaving few curative options. Gemcitabine-cisplatin (GC) has been the longstanding frontline therapy, yielding modest survival benefits. Preclinical research suggested that nab-paclitaxel might enhance drug delivery to desmoplastic tumors, and an encouraging phase II trial (GAP: gemcitabine, nab-paclitaxel, and cisplatin) spurred further investigation.
Objective: SWOG S1815 was designed to determine whether adding nab-paclitaxel (GAP regimen) to standard GC therapy would improve overall survival (OS) for patients newly diagnosed with locally advanced or metastatic BTCs.
Methods: This phase III, randomized, open-label trial enrolled patients with histologically or cytologically confirmed advanced BTC, excluding those with ampullary cancer (no prior systemic therapy for advanced disease). Participants were randomized 2:1 to receive either GAP (gemcitabine 800 mg/m^2, cisplatin 25 mg/m^2, nab-paclitaxel 100 mg/m^2 on days 1 and 8 of a 21-day cycle) or standard GC (gemcitabine 1,000 mg/m^2 plus cisplatin 25 mg/m^2 on days 1 and 8). The primary outcome was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and toxicity. Disease site (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder carcinoma) and stage (locally advanced or metastatic) were key stratification factors.
Results: Among 441 eligible patients, 67% had intrahepatic cholangiocarcinoma, 16% had gallbladder carcinoma, and 17% had extrahepatic cholangiocarcinoma, with 73% presenting metastatic disease. Median OS was 14.0 months (95% confidence interval [CI], 12.4-16.1) in the GAP arm versus 13.6 months (95% CI, 9.7-16.6) in the GC arm (hazard ratio [HR], 0.91; P = .41). Similarly, median PFS did not significantly differ (7.5 months v 6.3 months; HR, 0.89; P = .32). Subset analyses hinted that patients with gallbladder carcinoma and those with locally advanced disease might benefit more from the GAP triplet, but these findings were not statistically conclusive. Although ORR was higher with GAP (31% v 21%; P = .03), this did not translate into improved OS. Treatment-related toxicities were more frequent with the triplet regimen. Grade 3 or higher hematologic adverse events occurred in 60% of GAP patients versus 45% of those on GC (P = .003). Additionally, several grade 3-4 nonhematologic toxicities (such as ALT increase, anorexia, constipation, diarrhea, edema, fatigue, hypomagnesemia, nausea, sepsis, sensory peripheral neuropathy, and vomiting) were significantly more common with GAP. Seven treatment-related deaths occurred in the GAP arm, versus one in the GC arm, underscoring the regimen’s higher toxicity burden.
Conclusions: In this unselected BTC population, adding nab-paclitaxel to standard gemcitabine-cisplatin did not confer an OS advantage. Although higher ORR was observed, the toxicity profile was notably increased. Based on these findings, adding nab-paclitaxel to GC does not improve OS and is associated with increased toxicity. Therefore, GC remains the standard first-line treatment for advanced BTC. However, similar to what was observed in the PRODIGE 38 AMEBICA trial, which compared mFOLFIRINOX to GC, there was no survival advantage with the triplet regimen.
Implications for Practice: From a real-world perspective, the triplet regimen elevates both toxicity and likely treatment costs, without demonstrable survival benefit for the broader BTC population. Clinicians may consider GAP in highly selected subsets (for instance, localized unresectable gallbladder disease) or in research settings. Until further evidence clarifies which patients might benefit, GC remains the standard first-line treatment for advanced BTC.
Study Strengths and Limitations: Strengths include the large, multi-institutional, US-based randomized design and robust accrual (enrollment of a sufficient number of participants).* Limitations involve the heterogeneous nature (diversity) of BTCs and the absence of centralized radiologic review (a process where imaging studies are reviewed by a central group of experts rather than solely by local investigators). Furthermore, the trial did not incorporate cost-effectiveness analyses or routine genomic stratification *(classifying patients based on the genetic characteristics of their tumors), which could have refined patient selection.
Future Research: Ongoing investigations seek to integrate precision oncology—encompassing genetic profiling and circulating tumor DNA—to identify subgroups that may benefit from targeted or intensified cytotoxic strategies. Perioperative or adjuvant approaches with GAP or similar triplets might prove more effective in earlier-stage disease. Studies combining novel immunotherapies or targeted agents with chemotherapy could address the evolving BTC landscape.
Reference: Shroff RT, King G, Colby S, et al. SWOG S1815: A Phase III Randomized Trial of Gemcitabine, Cisplatin, and Nab-Paclitaxel Versus Gemcitabine and Cisplatin in Newly Diagnosed, Advanced Biliary Tract Cancers. Journal of Clinical Oncology.
DOI: https://doi.org/10.1200/JCO-24-01383