ABSTRACT
Purpose: Excess body fat, insulin resistance, and abnormal lipid levels signal type 2 diabetes mellitus (DM2). Globally, 536.6 million people suffer from DM2, projected to rise to 783.2 million by 2045. Obesity fuels insulin resistance and DM2 development, with weight loss significantly improving glycemic control. Titrzepatide (TZP), a dual GIP and GLP-1 receptor agonist, proves highly effective in controlling hyperglycemia, stimulating insulin secretion, and promoting weight loss. TZP, holds promise as a treatment for DM2, surpassing insulin and GLP-1. The study aimed to meticulously assess the safety and efficacy of various doses, offering insights into optimal therapeutic strategies for managing DM2. Methods: This study aimed to comprehensively evaluate the safety and efficacy of TZP in treating DM2. The primary focus of the inclusion criteria was on trials comparing TZP with a placebo until November 23, 2023, excluding patients with certain comorbidities. Data extraction included key parameters, and outcomes were assessed for HbA1c levels, weight changes, fasting serum glucose levels, and various adverse events. Quality assessment utilized the Cochrane Collaboration's risk-of-bias tool, and a network meta-analysis explored outcomes across different TZP dosages. Results: This meta-analysis systematically reviewed ten studies on TZP for DM2. Results revealed significant reductions in HbA1c with TZP 10 mg (19%) and TZP 15 mg (31%) compared to TZP 5 mg (MD: -0.19 and MD: -0.32, respectively). Additionally, weight reduction was notable for TZP 10 mg (MD: -1.96) and TZP 15 mg (MD: -3.31). Fasting serum glucose showed improvement with TZP 15 mg (MD:-6.71). Gastrointestinal events increased with higher doses, yet without statistical significance. Death, nausea, diarrhea, vomiting, dyspepsia, decreased appetite, injection site reaction, hypoglycemia, treatment discontinuation, and serious adverse events showed no significant differences across doses. Conclusion: TZP effectively lowers HbA1c and induces weight loss across its three doses for type 2 diabetes management. The higher dose (15 mg) significantly reduces fasting serum glucose, with increased adverse events observed at higher doses. Dose-specific patterns for adverse effects emphasize the need to balance therapeutic benefits and risks. Further research is crucial for refining clinical applications and understanding TZP's role in DM2 management across doses. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-024-01412-8.
ABSTRACT
BACKGROUND: Nivolumab (Nivo) and ipilimumab (Ipi) have revolutionized cancer treatment by targeting different pathways. Their combination shows promising results in various cancers, including melanoma, but not all studies have demonstrated significant benefits. A meta-analysis was performed to assess the effectiveness and safety of Nivo-Ipi compared to Nivo alone in advanced cancer types (excluding melanoma). METHODS: Following PRISMA guidelines, we conducted a meta-analysis up to September 30, 2023, searching databases for randomized controlled trials (RCTs). We focused on advanced solid malignancies (excluding melanoma) with specific Nivo and Ipi dosing. Primary outcomes were overall survival (OS), progression-free survival (PFS), grades 3-4 adverse events (AEs), and treatment-related discontinuations. Secondary outcomes included specific adverse events. Statistical analysis in Review Manager included hazard ratio (HR) and risk ratio (RR), assessing heterogeneity (Higgins I2). RESULTS: Nine RCTs, involving 2152 patients covering various malignancies, were analyzed. The Nivo plus Ipi group exhibited a median OS of 12.3 months and a median PFS of 3.73 months, compared to monotherapy with 11.67 months and 3.98 months, respectively. OS showed no significant difference between Nivo and Ipi combination and Nivo alone (HR = 0.97, 95% CI: 0.88 to 1.08, p = 0.61). PFS had a slight improvement with combination therapy (HR = 0.91, 95% CI: 0.82 to 1.00, p = 0.04). Treatment-related cumulative grades 3-4 adverse events were higher with Nivo and Ipi (RR = 1.52, 95% CI: 1.30 to 1.78, p < 0.00001), as were treatment-related discontinuations (RR = 1.99, 95% CI: 1.46 to 2.70, p < 0.0001). Hepatotoxicity (RR = 2.42, 95% CI: 1.39 to 4.24, p = 0.002), GI toxicity (RR = 2.84, 95% CI: 1.44 to 5.59, p = 0.002), pneumonitis (RR = 2.29, 95% CI: 1.24 to 2.23, p = 0.008), dermatitis (RR = 2.96, 95% CI: 1.08 to 8.14, p = 0.04), and endocrine dysfunction (RR = 6.22, 95% CI: 2.31 to 16.71, p = 0.0003) were more frequent with Nivo and Ipi. CONCLUSIONS: Combining nivolumab and ipilimumab did not significantly improve overall survival compared to nivolumab alone in advanced cancers (except melanoma). However, it did show slightly better PFS at the cost of increased toxicity, particularly grades 3-4 adverse events. Specific AEs occurred more frequently in the combination group. Further trials are needed to fully assess this combination in treating advanced cancers.