Daily Archives: September 23, 2024
Network Meta-Analysis: Eletriptan, Rizatriptan, Sumatriptan, and Zolmitriptan Most Effective for Acute Migraine Episodes
23 Sep, 2024 | 22:34h | UTCBackground: Migraine, a highly prevalent neurological disorder, is a leading cause of disability, especially among women aged 15 to 49. Effective acute management is critical, with current guidelines recommending non-steroidal anti-inflammatory drugs (NSAIDs) and triptans for moderate to severe episodes. However, the relative efficacy of various drug interventions remains unclear, especially with newer treatments like lasmiditan and gepants entering the market.
Objective: To evaluate and compare the efficacy and tolerability of all licensed oral drugs for the acute treatment of migraine episodes in adults.
Methods: A systematic review and network meta-analysis was conducted, including 137 randomized controlled trials (RCTs) involving 89,445 participants. The study analyzed 17 drug interventions, including NSAIDs, triptans, ditans, and gepants, and compared them with placebo. Primary outcomes included pain freedom at two hours post-dose and sustained pain freedom from two to 24 hours post-dose. Certainty of evidence was assessed using the CINeMA framework, and sensitivity analyses were conducted to confirm the robustness of the findings.
Results: All active interventions outperformed placebo for pain freedom at two hours, with odds ratios ranging from 1.73 (95% CI 1.27 to 2.34) for naratriptan to 5.19 (4.25 to 6.33) for eletriptan. The most effective drugs for sustained pain freedom were eletriptan and ibuprofen. Among head-to-head comparisons, eletriptan was the most effective for pain freedom at two hours, followed by rizatriptan, sumatriptan, and zolmitriptan. Newer drugs like lasmiditan, rimegepant, and ubrogepant were less effective than the triptans and showed adverse effects like dizziness and nausea.
Conclusions: Triptans—specifically eletriptan, rizatriptan, sumatriptan, and zolmitriptan—demonstrated superior efficacy and tolerability profiles compared to newer treatments like lasmiditan and gepants. Given their efficacy, these triptans should be prioritized in acute migraine management. However, triptans are underused, and barriers to access should be addressed to ensure broader utilization. Lasmiditan and gepants may still serve as alternatives for patients contraindicated for triptans due to cardiovascular risks.
Implications for Practice: Clinicians should prioritize triptans, particularly eletriptan, rizatriptan, sumatriptan, and zolmitriptan, in managing acute migraine episodes due to their superior efficacy. Careful consideration is needed when selecting newer drugs like lasmiditan and gepants, as they may be less effective and have higher costs and adverse event risks. Cost-effectiveness and patient cardiovascular profiles should guide decision-making.
Study Strengths and Limitations: Strengths include the comprehensive inclusion of both published and unpublished data, as well as the large sample size and robust methodological framework. Limitations include moderate heterogeneity and low confidence in some comparisons due to reporting biases and imprecise treatment effects in older studies.
Future Research: Future studies should focus on re-evaluating the cardiovascular contraindications of triptans to ensure broader access. Additional research is also needed to assess the cost-effectiveness of newer treatments like lasmiditan and gepants, particularly in patients for whom triptans are unsuitable.
Phase 2 RCT: Ponsegromab Shows Promise for the Treatment of Cancer Cachexia
23 Sep, 2024 | 21:48h | UTCBackground: Cancer cachexia is a multifactorial syndrome characterized by weight loss, muscle wasting, and reduced quality of life. Elevated levels of growth differentiation factor 15 (GDF-15), a cytokine, have been associated with cachexia. Ponsegromab, a monoclonal antibody that inhibits GDF-15, has shown potential in reversing cachexia in early studies by improving weight, appetite, and physical activity. This phase 2, randomized, double-blind trial aimed to assess the efficacy and safety of ponsegromab in patients with cancer cachexia and elevated GDF-15 levels.
Objective: To evaluate the impact of ponsegromab on body weight, cachexia symptoms, appetite, physical activity, and safety in cancer cachexia patients with elevated GDF-15 levels.
Methods: In this 12-week study, 187 patients with non-small-cell lung cancer, pancreatic cancer, or colorectal cancer and elevated GDF-15 levels (≥1500 pg/mL) were randomized into four groups: ponsegromab 100 mg, 200 mg, 400 mg, or placebo, administered subcutaneously every four weeks. The primary endpoint was the change in body weight from baseline to week 12. Secondary outcomes included appetite and cachexia symptoms, physical activity measured via digital devices, and safety. The trial also included exploratory endpoints like changes in skeletal muscle mass.
Results:
At 12 weeks, patients treated with ponsegromab showed significant weight gain compared to placebo. The median weight gain differences were 1.22 kg in the 100-mg group, 1.92 kg in the 200-mg group, and 2.81 kg in the 400-mg group. Significant improvements in appetite and cachexia symptoms were observed in the 400-mg group compared to placebo. Physical activity, measured by nonsedentary time, also increased by 72 minutes per day in the 400-mg group. Adverse events were reported by 70% of ponsegromab patients and 80% of placebo patients. Serious adverse events occurred at similar rates across groups, but none were deemed related to treatment. No significant safety concerns were identified.
Conclusions: Ponsegromab effectively increased body weight and improved cachexia symptoms in patients with cancer cachexia and elevated GDF-15 levels, supporting GDF-15’s role as a key driver of cachexia. The findings suggest that ponsegromab may be a promising therapeutic option for managing cancer cachexia, with a favorable safety profile.
Implications for Practice: Ponsegromab could represent a targeted therapy for cancer cachexia, addressing weight loss, appetite, and physical function. Clinicians may consider its use for patients with advanced cancers experiencing cachexia, particularly those with elevated GDF-15 levels.
Study Strengths and Limitations: Strengths of the study include its randomized, double-blind design and the use of objective measures such as digital physical activity tracking. Limitations include the relatively short trial duration, and missing physical activity data for some patients. Additionally, the efficacy of ponsegromab across different baseline levels of GDF-15 requires further investigation.
Future Research: Larger and longer-term trials are necessary to confirm the therapeutic benefit of ponsegromab in cancer cachexia. Future research should explore its impact on survival and assess whether GDF-15 inhibition benefits other conditions associated with elevated GDF-15, such as heart failure and chronic kidney disease.
Summary of the review “Lipoprotein(a) and Cardiovascular Disease”
23 Sep, 2024 | 21:22h | UTCSummary of the review “Lipoprotein(a) and Cardiovascular Disease“
By Prof Børge G Nordestgaard and Anne Langsted
Key Takeaways for Practicing Physicians:
- Significance of Lipoprotein(a) [Lp(a)]:
- Causal Risk Factor: Elevated Lp(a) is a genetically determined causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis.
- Prevalence: Approximately 1 in 5 individuals globally have high Lp(a) levels, increasing their cardiovascular risk.
- Genetic Determinants and Ethnic Variations:
- Genetic Influence: Over 90% genetically determined with minimal lifestyle impact.
- Ethnic Differences:
- Lowest levels: East Asians, Europeans, Southeast Asians.
- Intermediate levels: South Asians, Middle Easterners, Latin Americans.
- Highest levels: Individuals of African descent.
- Sex Differences: Postmenopausal women have about 17% higher Lp(a) levels than men.
- Clinical Measurement and Interpretation:
- When to Measure:
- Once in a Lifetime: Recommended for all individuals to measure Lp(a) at least once.
- High-Risk Patients: Especially important in those with premature ASCVD, familial hypercholesterolaemia (FH), family history of elevated Lp(a) or early ASCVD.
- Stability of Levels: Lp(a) levels are stable after age two and are unaffected by most lifestyle factors.
- Interpreting Levels:
- Elevated Risk Thresholds:
- >30 mg/dL (≥62 nmol/L): Increased risk begins.
- >50 mg/dL (≥105 nmol/L): Clinically significant high risk.
- >90 mg/dL (≥190 nmol/L): Severe risk, comparable to FH.
- Elevated Risk Thresholds:
- Laboratory Considerations:
- Assay Selection: Use isoform-independent assays with standardized calibration.
- Reporting Units: Preferably in nmol/L; however, mg/dL is acceptable with appropriate conversion.
- When to Measure:
- Impact on Patient Care:
- Risk Stratification:
- Independent Risk Factor: High Lp(a) increases ASCVD risk independent of other lipids.
- Reclassification: Can reclassify patients into higher risk categories, influencing management decisions.
- Management Strategies:
- Current Limitations: No approved therapies specifically targeting Lp(a) reduction.
- Aggressive Risk Factor Control:
- LDL Cholesterol: Intensive lowering with high-intensity statins, ezetimibe, and PCSK9 inhibitors.
- PCSK9 Inhibitors: Lower Lp(a) by ~25% and reduce cardiovascular events.
- Lifestyle Modifications: Emphasize smoking cessation, healthy diet, physical activity, and weight management.
- Blood Pressure and Diabetes Management: Optimize control per guidelines.
- LDL Cholesterol: Intensive lowering with high-intensity statins, ezetimibe, and PCSK9 inhibitors.
- Avoid Unproven Therapies: Niacin is not recommended due to side effects and lack of cardiovascular benefit.
- Risk Stratification:
- Familial Hypercholesterolaemia (FH):
- Dual Risk: Elevated Lp(a) often coexists with FH, compounding cardiovascular risk.
- Screening: Measure Lp(a) in all patients with FH and consider cascade screening in families.
- Emerging Therapies:
- Gene-Silencing Drugs:
- Pelacarsen, Olpasiran, Lepodisiran: Lower Lp(a) levels by 80–98%.
- Administration: Subcutaneous injections, varying from monthly to quarterly.
- Small Molecule Inhibitors:
- Muvalaplin: Oral agent reducing Lp(a) by ~65%.
- Clinical Trials:
- Phase 3 Trials Ongoing: Evaluating cardiovascular outcomes with significant Lp(a) reduction.
- Potential Change in Practice: These therapies may soon provide effective options for patients with high Lp(a).
- Gene-Silencing Drugs:
- Practical Recommendations:
- Include Lp(a) in Lipid Panels: Encourage laboratories to add Lp(a) measurements to standard profiles.
- Patient Communication:
- Educate on Risks: Explain the significance of high Lp(a) and its genetic nature.
- Lifestyle Advice: Reinforce the importance of modifiable risk factor control.
- Family Screening: Consider evaluating first-degree relatives due to genetic inheritance patterns.
- Monitoring and Follow-Up:
- Re-measurement: Generally, one measurement suffices unless a significant event (e.g., menopause) occurs.
- Acute Phase Reactant Consideration: Be cautious interpreting levels during acute illness; recheck once stabilized.
Conclusion:
Elevated Lp(a) is a significant and prevalent cardiovascular risk factor that is largely genetic and stable throughout life. While direct treatments are on the horizon, current management focuses on aggressive modification of other cardiovascular risk factors. Measurement of Lp(a) should become a routine part of cardiovascular risk assessment, guiding more personalized and effective patient care.