Efficacy and Safety of Setmelanotide, a Melanocortin-4 Receptor Agonist, for Obese Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: A malfunction in the melanocortin-4 receptor (MC4R) is associated with obesity in rare genetic syndromes; setmelanotide is a new drug that activates this receptor and is being used to treat severe obesity. This meta-analysis evaluated the efficacy and safety of setmelanotide for weight loss in severe obesity linked to human MC4R deficiency. METHODS: We searched PubMed, Embase, and Cochrane for randomized and nonrandomized clinical trials using setmelanotide. We considered a p-value ≤ 0.05 statistically significant. RESULTS: We included 376 patients, of whom 328 (87.2%) received setmelanotide for a mean follow-up of 52 weeks. The mean age was 32.8 (14.67) years. Weight loss was significant (MD -3.52; 95% CI -3.98, -3.05; p = 0.01; I2 = 92%), with an average proportion of -6.91% weight loss during treatment. Changes in BMI showed an MD of -10.55 kg/m2 in patients > 18 years and -0.61 kg/m2 in patients < 18 years (BMI score). However, the drug was associated with a higher risk of skin hyperpigmentation (OR 0.69; 95% CI 0.55, 0.80; p = 0.08). CONCLUSIONS: Our results support the use of setmelanotide in treating severe obesity.

Epidemiological-molecular profile of variants associated with type 2 diabetes mellitus in indigenous populations from the Brazilian Amazon.

AIMS: While lifestyle factors are strongly associated with Type 2 diabetes (T2DM), genetic characteristics also play a role. However, much of the research on T2DM genetics focuses on European and Asian populations, leaving underrepresented groups, such as indigenous populations with high diabetes prevalence, understudied. METHODS: We characterized the molecular profile of 10 genes involved in T2DM risk through complete exome sequencing of 64 indigenous individuals belonging to 12 different Amazonian ethnic groups. RESULTS: The analysis revealed 157 variants, including four exclusive variants in the indigenous population located in the NOTCH2 and WFS1 genes with a modifier or moderate impact on protein effectiveness. Furthermore, a high impact variant in NOTCH2 was also found. Additionally, the frequency of 10 variants in the indigenous group showed significant differences when compared to other global populations that were evaluated. CONCLUSION: Our study identified 4 novel variants associated with T2DM in the NOTCH2 and WFS1 genes in the Amazonian indigenous populations we studied. In addition, a variant with a high predicted impact in NOTCH2 was also observed. These findings represent a valuable starting point for conducting further association and functional studies, which could help to improve our understanding of the unique characteristics of this population.

Association between the TPMT*3C (rs1142345) Polymorphism and the Risk of Death in the Treatment of Acute Lymphoblastic Leukemia in Children from the Brazilian Amazon Region.

Acute lymphoblastic leukemia (ALL) is the leading cause of death from pediatric cancer worldwide. However, marked ethnic disparities are found in the treatment of childhood ALL with less effective results and higher mortality rates being obtained in populations with a high level of Native American ancestry. Genetic variations of the patient can affect resistance to ALL chemotherapy and potentially play an important role in this disparity. In the present study, we investigated the association of 16 genetic polymorphisms with the cell and metabolic pathways of the chemotherapeutic agents used in the treatment of ALL with the risk of death in treating childhood ALL in patients with a high contribution of Amerindian ancestry, coming from the Brazilian Amazon. The study included 121 patients with B-cell ALL treated with the BFM-2002 protocol. We are the first to identify the association between the TPMT gene rs1142345 polymorphism and the high risk of death in treating childhood ALL. Patients with the CC genotype had an approximately 25.5 times higher risk of dying during treatment of the disease than patients with other genotypes (p = 0.019). These results may help elucidate how the patient's genetic characteristics contribute to the mortality disparity in populations with a high contribution of Native American ancestry. The rs1142345 variant of the TPMT gene could be used as a potential marker to early stratify patients at high risk of death in treating childhood ALL in the investigated population.