Safety and efficacy of new antihyperglycemic agents in type 2 diabetes treatment : systematic reviews and meta-analyzes

A segurança dos novos agentes anti-hiperglicemiantes é uma causa de preocupação maior na prática clínica. Existem perguntas com relação à segurança pancreática das incretinas, tanto inibidores da DPP-4 quanto análogos do GLP-1. Por outro lado, os inibidores da SGLT-2 foram associados com efeitos adversos menores como infecções genitais micóticas e infecções do trato urinário, mas também existem raros relatos de efeitos adversos mais graves. Como tanto análogos do GLP-1 quanto inibidores da SGLT-2 estão associados com redução da mortalidade em pacientes com diabetes melito tipo 2, o que provavelmente provocará aumento no seu uso no futuro, é muito importante definir seu perfil de segurança. Outra pergunta não respondida com relação aos inibidores da SGLT-2 diz respeito aos benefícios clínicos das diferentes doses disponíveis dos agentes e a redução da HbA1c e do peso proporcionada por estas doses. Dado o exposto, os objetivos desta tese são: avaliar a segurança pancreática dos inibidores da DPP-4 com relação à pancreatite aguda e à neoplasia maligna de pâncreas; avaliar a segurança pancreática dos análogos do GLP-1 com relação ao câncer de pâncreas; avaliar os efeitos adversos associados aos inibidores da SGLT-2; e avaliar a eficácia das diferentes doses de inibidores da SGLT-2. O primeiro estudo não achou associação entre inibidores da DPP-4 e câncer de pâncreas, no entanto, um pequeno risco para pancreatite aguda foi encontrado, apesar desse achado não ser definitivo. O segundo estudo analisou a associação entre análogos do GLP-1 e câncer pancreático. Nesse estudo, o TSA confirmou que número suficiente de pacientes foi randomizado e que não há associação desse medicamento e câncer de pâncreas, considerando um NNH de 1000 e o tempo limitado de seguimento dos estudos incluídos (1,7 anos). O último estudo explorou as diferenças entre os inibidores da SGLT-2 em doses diferentes e comparados um com o outro. Nessa análise, canagliflozina 300 mg pareceu o mais potente dos inibidores da SLGT-2 em reduzir a HbA1c e o peso, entretanto as diferenças não parecem ser clinicamente relevantes. Os demais inibidores da SGLT-2 em doses diferentes levaram a reduções similares em ambos os desfechos. Com relação aos efeitos adversos, os inibidores da SGLT-2 foram associados com aumento no risco para infecções genitais. Essa tese reafirma a segurança dos novos agentes anti-hiperglicemiantes. Os resultados também enfatizam a importância de prescrever os medicamentos anti-hiperglicemiantes considerando não apenas efeitos metabólicos e segurança, mas também eventos cardiovasculares e mortalidade.The safety of new antihyperglycemic agents is a major source of concern in clinical practice. There are questions regarding pancreatic safety of incretins, either for DPP-4 inhibitor and GLP-1 agonists. On the other hand, SGLT-2 inhibitors have been associated with minor side effects as genital and urinary infections but reports on rare and more serious outcomes have been published. As GLP-1 agonists and SGLT-2 inhibitors are associated with reduction in the mortality of type 2 diabetic patients, reason why its clinical use is expected to increase in the future, it is very important to clarify their safety profile. Another unsolved question in SGLT-2 inhibitors is the clinical benefits of different commercially available agents and dosages on reduction of HbA1c and body weight. Given that, the objectives of these thesis were: to assess the pancreatic safety of DPP-4 inhibitors regarding acute pancreatitis and pancreatic cancer; to assess the pancreatic safety of GLP-1 inhibitors regarding pancreatic cancer; to assess the adverse events associated with SGLT-2 inhibitors; and to assess the efficacy of different doses of SGLT-2 inhibitors. The first study didn’t find an association between DPP-4 inhibitors and pancreatic cancer, however found a small risk for acute pancreatitis with DPP-4 inhibitors use, even though the latter finding is not definitive. The second study analyzed the relationship between GLP-1 analogues and pancreatic cancer. In this study, TSA confirmed that enough patients were randomized and again no association of the medications and pancreatic cancer was observed considering a NNH of 1000 and the short mean follow-up of the included trials (1.7 years). The last study explored the differences among SGLT-2 inhibitors in different doses and compared one to each other to one. In this analysis, canagliflozin 300 mg seemed to be the most potent SGLT-2 inhibitors in reducing HbA1c and body weight, however the differences don’t look clinically relevant. The remaining SGLT2 inhibitors 15 in different doses lead to statistically similar effects for both outcomes. Regarding side effects, SGLT-2 inhibitors were associated with increased risk for genital infections. This thesis reinforces the safety of the newest antihyperglycemic agents. The results also emphasize the importance of prescribing antihyperglycemic agents after considering not only metabolic effects and safety, but also cardiovascular events and mortality

Glucagon-like peptide-1 receptor agonists and pancreatic cancer : a meta-analysis with trial sequential analysis

We aimed to assess if GLP-1 agonists are associated with pancreatic cancer. Systematic review and meta-analysis of randomized trials with GLP-1 agonists as an intervention was performed. Trial sequential analysis (TSA) was performed to assess if the available information is sufficient to reject this association. Twelve trials met the study criteria, with a total of 36, 397 patients. GLP-1 analogues did not increase the risk for pancreatic cancer when compared to other treatments (OR 1.06; 95% CI 0.67 to 1.67; I2 14%). TSA confirmed that enough patients were randomized and again no association of the medications and pancreatic cancer was observed considering a NNH of 1000 and the short mean follow-up of the included trials (1.7 years). Larger studies with longer duration would be required to exclude a greater NNH and to aside concerns regarding possible influence of study duration and the outcome

Metabolic efects of antihyperglycemic agents and mortality : meta-analysis of randomized controlled trials

The efects of antihyperglycemic medications on cardiovascular events and mortality are heterogeneous and their efects on intermediate factors might explain these diferences. This systematic review explores the relationship between metabolic factors, mechanism of action, and mortality efects of antihyperglycemic medications in type 2 diabetes. Randomized trials assessing the efects of antihyperglycemic medications on all-cause or cardiovascular mortality in type 2 diabetes were included. Myocardial infarction, stroke, and heart failure were secondary outcomes. The efects of medications on HbA1c, severe hypoglycemia (SH), body weight, systolic blood pressure (SBP), and mechanism of action were evaluated. Meta-analyses and meta-regressions were performed grouping studies according to the above-cited factors. All-cause mortality was lower for medications that reduced HbA1c, SH, body weight, and SBP. Decreased cardiovascular mortality was associated with lower HbA1c, SH, SBP. Myocardial infarction and stroke were also associated with favorable metabolic profle. These fndings were not confrmed in meta-regression models. Medications associated with lower SH, body weight and SBP had a lower risk of heart failure. In conclusion, medications with better metabolic profle were associated with reduced all-cause and cardiovascular mortality. These fndings are based on indirect comparisons and must be applied cautiously

Why do men have worse COVID-19-related outcomes? A systematic review and meta-analysis with sex adjusted for age

We aimed to study the mechanism behind worse coronavirus disease-19 (COVID-19) outcomes in men and whether the differences between sexes regarding mortality as well as disease severity are influenced by sex hormones. To do so, we used age as a covariate in the meta-regression and subgroup analyses. This was a systematic search and meta-analysis of observational cohorts reporting COVID-19 outcomes. The PubMed (Medline) and Cochrane Library databases were searched. The primary outcome was COVID-19-associated mortality and the secondary outcome was COVID-19 severity. The study was registered at PROSPERO: 42020182924. For mortality, men had a relative risk of 1.36 (95%CI: 1.17 to 1.59; I² 63%, P for heterogeneity <0.01) compared to women. Age was not a significant covariate in meta-analysis heterogeneity (P=0.393) or subgroup analysis. For disease severity, being male was associated with a relative risk of 1.29 (95%CI: 1.19 to 1.40; I² 48%, P for heterogeneity <0.01) compared to the relative risk of women. Again, age did not influence the outcomes of the metaregression (P=0.914) or subgroup analysis. Men had a higher risk of COVID-19 mortality and severity regardless of age, decreasing the odds of hormonal influences in the described outcomes

Association of quality of life and disease control with cigarette smoking in patients with severe asthma

More information is needed on asthma control and health-related quality of life (HRQoL) in smokers with severe asthma. The main study objective was to characterize the association of HRQoL and disease control with cigarette smoking in individuals with severe asthma. A secondary objective was to analyze subject characteristics according to asthma onset: asthma that developed before smoking initiation versus asthma that developed after smoking initiation. This cross-sectional study included subjects with severe asthma aged 18-65 years. HRQoL was assessed using the Asthma Quality of Life Questionnaire (AQLQ) and asthma control was assessed using the Asthma Control Test (ACT) and Global Initiative for Asthma (GINA) criteria. Of the 87 patients studied, 58 (66.7%) were classified as asthmatics who had never smoked and 29 (33.3%) as asthmatics with smoking exposure. The proportion of subjects with uncontrolled asthma was higher in the asthma and smoking group (GINA criteria: P=0.032 and ACT criteria: P=0.003. There were no between-group differences in overall AQLQ score (P=0.475) or AQLQ domain scores (P>0.05). Fifty-eight subjects (66.7%) were nonsmokers, 20 (23%) had asthma onset before smoking, and 9 (10.3%) had asthma onset after smoking. Asthma onset before smoking was associated with uncontrolled asthma (P=0.013). In subjects with severe asthma, smoking was associated with a higher rate of uncontrolled disease but not with HRQoL scores