The extent of cytochrome P450 3A induction by antiseizure medications: A systematic review and network meta-analysis.

OBJECTIVE: Antiseizure medications (ASMs) are commonly categorized as enzyme-inducers and non-enzyme-inducers based on their propensity to enhance the metabolism of concomitantly administered drugs. This systematic review and network meta-analysis aimed to rank ASMs as cytochrome P450 3A (CYP3A)-inducers based on a comparative assessment of ASM-induced reduction in the concentrations of sensitive substrate drugs. METHODS: The protocol was registered with PROSPERO (International Prospective Register of Systematic Reviews; CRD42022335846), and the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) standards were followed. We searched MEDLINE, Embase, and Cochrane until March 14, 2023 without an initial date restriction. Data were additionally obtained via the US Food and Drug Administration database. Studies had to be prospective, with ASM monotherapy for ≥5 days. The primary parameter was the magnitude of change in the area under the concentration-time curve of CYP3A substrates following treatment with the ASM. The standardized mean difference (SMD) was used as the point estimate for the indirect comparisons between ASMs using the pairwise method. Bias risk was assessed using the PKclin tool. RESULTS: We identified 14 open-label, fixed-sequence studies with 370 participants. The effect size of 600 mg/day carbamazepine did not differ from those of 300 mg/day phenytoin (SMD = -.06, 95% confidence interval [CI] = -.18 to .07) and 200 mg/day cenobamate (SMD = -.11, 95% CI = -.26 to .04). Carbamazepine at 600 mg/day was the strongest CYP3A-inducer (P-score = .88), followed by carbamazepine 400 mg/day (.83), phenytoin 300 mg/day (.79), and cenobamate 200 mg/day (.73). Eslicarbazepine (800 mg/day) ranked higher than cenobamate 100 mg/day and oxcarbazepine 900 mg/day (.60, .39, and .37, respectively). SIGNIFICANCE: Despite the limited number of studies, our network meta-analysis emphasizes that the magnitude of ASM effects on CYP3A substrate metabolism is a dose-dependent continuum. When possible, ASM classification as inducers should apply cutoff values tailored to the outcome. Prescribers should monitor plasma concentrations or clinical effects of CYP3A substrates and consider selecting concomitant medications accordingly.

Long-term Risk for Type 1 Diabetes and Obesity in Early Term Born Offspring: A Systematic Review and Meta-Analysis.

CONTEXT: Prematurity increases the long-term risks for endocrine and metabolic morbidity of offspring, but there is uncertainty regarding the risks for early-term deliveries (370/7-386/7 weeks of gestation). OBJECTIVE: We aim to evaluate whether early-term deliveries increase the long-term risk for type 1 diabetes and obesity of offspring up to the age of 18 years compared with full-term children. PubMed, Medline, and EMBASE were searched. Observational cohort studies addressing the association between early-term delivery and long-term risk for type 1 diabetes and obesity, were included. Two independent reviewers extracted data and assessed risk of bias. Pooled relative risks (RRs) and heterogeneity were determined. Publication bias was assessed by funnel plots with Egger's regression line and contours, and sensitivity analyses were performed. RESULTS: Eleven studies were included following a screen of 7500 abstracts. All studies were scored as high quality according to the Newcastle-Ottawa Quality Assessment Scale. Early-term delivery was significantly associated with an increased risk for type 1 diabetes (RR 1.19, 1.13-1.25), while the association was weaker for overweight and obesity (RR 1.05, 0.97-1.12). It is challenging to determine whether the association between early-term births and long-term morbidity represents a cause and effect relationship or is attributable to confounders. Most of the included studies adjusted for at least some possible confounders. CONCLUSION: Compared with full-term offspring, early-term delivery poses a modest risk for long-term pediatric type 1 diabetes. Our analysis supports that, whenever medically possible, elective delivery should be avoided before 39 completed weeks of gestation.

Hypothyroidism and levothyroxine therapy following bariatric surgery: a systematic review, meta-analysis, network meta-analysis, and meta-regression.

BACKGROUND: Many health benefits of bariatric surgery are known and well-studied, but there is scarce data on the benefits of bariatric surgery on the thyroid function. OBJECTIVE: We aimed to make a meta-analysis regarding the impact of bariatric surgery on thyroid-stimulating hormone (TSH) levels, levothyroxine dose, and the status of subclinical hypothyroidism. SETTING: Systematic review and meta-analysis. METHODS: PubMed, EMBASE, and Cochrane Library were searched up to December 2020 for relevant clinical studies. Random-effects model was used to pool results. Network meta-analysis was performed, incorporating direct and indirect comparisons among different types of bariatric surgery. Meta-regression analysis was performed to evaluate the impact of moderator variables on TSH levels and required levothyroxine dose after surgery. We followed the PRISMA guidelines for data selection and extraction. PROSPERO registry number: CRD42018105739. RESULTS: A total of 28 studies involving 1284 patients were included. There was a statistically significant decrease in TSH levels after bariatric surgery (mean difference = -1.66 mU/L, 95%CI [-2.29, -1.03], P < .0001). In meta-regression analysis, we found that the following moderator variables: length of follow-up, mean age, baseline TSH, and preoperative thyroid function, could explain 1%, 43%, 68%, and 88% of the between-study variance, respectively. Furthermore, subclinical hypothyroidism was completely resolved in 87% of patients following bariatric surgery. In addition, there was a statistically significant decrease of levothyroxine dose in frank hypothyroid patients following bariatric surgery (mean difference = -13.20 mcg/d, 95%CI [-19.69, -6.71]). In network meta-analysis, we found that discontinuing or decreasing levothyroxine dose was significant following Roux-en-Y gastric bypass, 1 anastomosis gastric bypass, and sleeve gastrectomy, (OR = 31.02, 95%CI [10.34, 93.08]), (OR = 41.73, 95%CI [2.04, 854.69]), (OR = 104.03, 95%CI [35.79, 302.38]), respectively. CONCLUSIONS: Based on our meta-analysis, bariatric surgery is associated with the resolution of subclinical hypothyroidism, a decrease in TSH levels, and a decrease in levothyroxine dose.