Does metformin reduce the risk of cancer in obesity and diabetes? A systematic review and meta-analysis.

AIM: To evaluate the effect of metformin on cancer incidence in subjects with overweight/obesity and/or prediabetes/diabetes. MATERIALS AND METHODS: We searched MEDLINE, Embase and CENTRAL for randomized controlled trials (RCTs) in adults with overweight/obesity and/or prediabetes/diabetes that compared metformin to other interventions for ≥24 weeks. Independent reviewers selected and extracted data including population and intervention characteristics and new diagnoses of cancer. We used the RoB 2.0 risk-of-bias tool and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework to assess risk of bias and certainty of evidence. RESULTS: From 14 895 records after removal of duplicates, 27 trials were included, providing a total of 10 717 subjects in the metformin group and 10 003 in the control group, with 170 and 208 new cases of cancer, respectively. Using a random-effects model, the relative risk was 1.07 (95% confidence interval 0.87-1.31), with similar results in subgroup analyses by study duration or effect of control intervention on weight. Risk of bias in most studies was low, and no evidence of publication bias was found. Trial sequential analysis provided evidence that the cumulative sample size was large enough to exclude a significant effect of metformin on cancer incidence. CONCLUSIONS: Metformin did not reduce cancer incidence in RCTs involving subjects with overweight/obesity and/or prediabetes/diabetes.

Sodium-glucose cotransporter-2 inhibitors and cancer outcomes: A systematic review and meta-analysis of randomized controlled trials.

AIMS: Concerns regarding breast and bladder cancer risk with Sodium-glucose cotransporter-2 (SGLT2) inhibitors remain controversial and its effect on cancer mortality is unknown. We aim to evaluate the association between SGLT2 inhibitors and the risk of cancer outcomes. METHODS: We searched PubMed, Embase and CENTRAL up to June 20th, 2022, for randomized controlled trials of SGLT2 inhibitors in adults, with a minimum follow-up of 48 weeks. Researchers extracted study-level data and assessed within-study risk of bias with the RoB 2.0 tool and quality of evidence with GRADE. We performed meta-analyses summarizing the relative risks (RRs) of cancer outcomes. RESULTS: Seventy-six trials encompassing 116,375 participants were selected. Overall risk of bias was low. SGLT2 inhibitors did not reduce/increase the overall risk of cancer (RR, 1.03; 95% confidence interval [CI], 0.96-1.10) and cancer mortality (RR, 0.99; 95% CI, 0.85-1.16). SGLT2 inhibitors likely result in little to no difference in the risk of breast (RR, 1.01; 95% CI 0.77-1.32) and bladder cancers (RR, 0.93; 95% CI 0.71-1.21). Trial sequential analysis provided evidence that the sample size was sufficient to avoid missing alternative results. CONCLUSIONS: SGLT2 inhibitors are not associated with an increased risk of cancer outcomes, providing reassuring data regarding previous safety concerns.

Long-term Effect of Lifestyle Interventions on the Cardiovascular and All-Cause Mortality of Subjects With Prediabetes and Type 2 Diabetes: A Systematic Review and Meta-analysis.

BACKGROUND: Lifestyle interventions improve the metabolic control of individuals with hyperglycemia. PURPOSE: We aimed to determine the effect of lifestyle interventions on cardiovascular and all-cause mortality in this population. DATA SOURCES: Searches were made through MEDLINE, Cochrane CENTRAL, Embase, and Web of Science (no date/language restriction, until 15 May 2022). STUDY SELECTION: We included randomized clinical trials (RCTs) of subjects with prediabetes and type 2 diabetes, comparing intensive lifestyle interventions with usual care, with a minimum of 2 years of active intervention. DATA EXTRACTION: Data from the 11 RCTs selected were extracted in duplicate. A frequentist and arm-based meta-analysis was performed with random-effects models to estimate relative risk (RR) for mortality, and heterogeneity was assessed through I2 metrics. A generalized linear mixed model (GLMM) was used to confirm the findings. DATA SYNTHESIS: Lifestyle interventions were not superior to usual care in reducing cardiovascular (RR 0.99; 95% CI 0.79-1.23) or all-cause (RR 0.93; 95% CI 0.85-1.03) mortality. Subgroup, sensitivity, and meta-regression analyses showed no influence of type of intervention, mean follow-up, age, glycemic status, geographical location, risk of bias, or weight change. All of these results were confirmed with the GLMM. Most studies had a low risk of bias according to the RoB 2.0 tool and the certainty of evidence was moderate for both outcomes. LIMITATIONS: Most studies had a low risk of bias according to the RoB 2.0 tool, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach resulted in moderate certainty of evidence for both outcomes. Differences in lifestyle programs and in usual care between the studies should be considered in the interpretation of our results. CONCLUSIONS: Intensive lifestyle interventions implemented so far did not show superiority to usual care in reducing cardiovascular or all-cause mortality for subjects with prediabetes and type 2 diabetes.

Do GLP-1 Receptor Agonists Increase the Risk of Breast Cancer? A Systematic Review and Meta-analysis.

CONTEXT: Risk of cancer is a major concern in the development of drugs for the treatment of obesity and diabetes. In randomized controlled trials (RCTs) of the Liraglutide Clinical Development Program, subjects treated with a glucagon-like peptide-1 receptor agonist (GLP-1RA) had a higher absolute number of breast cancer events. OBJECTIVE: To assess whether patients treated with GLP-1RAs had a higher risk of breast neoplasms. DATA SOURCES: We searched MEDLINE, Embase, Web of Science, and CENTRAL from July 31, 2019 to February 8, 2020. STUDY SELECTION: Reviewers assessed abstracts and full-text articles for RCTs of GLP-1RAs in adults with excessive weight and/or diabetes and a minimum follow-up of 24 weeks. DATA EXTRACTION: Researchers extracted study-level data and assessed within-study risk of bias with the RoB 2.0 tool and quality of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE). DATA SYNTHESIS: We included 52 trials, of which 50 reported breast cancer events and 11 reported benign breast neoplasms. Overall methodological quality was high. Among 48 267 subjects treated with GLP-1RAs, 130 developed breast cancer compared with 107 of 40 755 controls (relative risk [RR], 0.98; 95% confidence interval [CI], 0.76-1.26). Subset analyses according to follow-up, participant/investigator blinding, and type of GLP-1RA did not reveal any differences. The risk of benign breast neoplasms also did not differ between groups (RR, 0.99; 95% CI, 0.48-2.01). Trial sequential analysis provided evidence that the sample size was sufficient to avoid missing alternative results. CONCLUSIONS: Treatment with GLP-1RAs for obesity and diabetes does not increase the risk of breast neoplasms.