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.

SGLT2 inhibitors and kidney outcomes across the spectrum of kidney disease: a systematic review and meta-analysis.

BACKGROUND: SGLT2 inhibitors have shown to reduce clinically meaningful kidney outcomes in individuals with chronic kidney disease at high risk for adverse outcomes. The effect of these agents in preventing clinically meaningful kidney outcomes in populations at lower risk remain uncertain. We aim to evaluate the effect of SGLT2 inhibitors on kidney outcomes across the Kidney Disease: Improving Global Outcomes (KDIGO) classification and urinary albumin-to-creatinine ratio (UACR) levels. METHODS: We have searched MEDLINE (PubMed), EMBASE and the Cochrane Central Register of Controlled Trials from inception up to August 8th, 2023. In pairs, researchers selected large (≥500 subjects per arm) randomized placebo-controlled trials of SGLT2 inhibitors, with a minimum duration of one year. Researchers independently extracted study-level data and assessed within-study risk of bias with the RoB 2.0 tool and quality of evidence with GRADE. RESULTS: We included 10 trials, encompassing 78,184 participants and a median follow-up of 2.7 years. Risk of bias was overall low. We performed meta-analyses summarizing individual study hazard ratios (HR) and 95% confidence intervals (CI) using a random-effects model. SGLT2 inhibitors reduced the composite kidney outcome across all KDIGO (HR [95% CI]: low 0.48 [0.32-0.71], moderate 0.60 [0.39-0.93], high 0.59 [0.47-0.74], very high 0.59 [0.49-0.72]) and UACR (HR [95% CI]: <30 mg/g 0.62 [0.50-0.78], ≥30 ≤300 mg/g 0.80 [0.67-0.96], >300 mg/g 0.61 [0.52-0.73]) groups, without evidence of heterogeneity between groups. LIMITATIONS: Small proportion of subjects without diabetes in low-risk groups and lack of standardization of composite outcomes. CONCLUSIONS: SGLT2 inhibitors consistently reduce kidney outcomes across the spectrum of KDIGO classes and UACR levels.

Cancer Outcomes Among Prediabetes and Type 2 Diabetes Populations With Dietary and Physical Activity-based Lifestyle Interventions.

CONTEXT: People with type 2 diabetes (T2D) have higher risks of cancer incidence and death. OBJECTIVE: We aimed to evaluate the relationship between dietary and physical activity-based lifestyle intervention and cancer outcomes among prediabetes and T2D populations. METHODS: We searched for randomized controlled trials with at least 24 months of lifestyle interventions in prediabetes or T2D populations. Data were extracted by pairs of reviewers and discrepancies were resolved by consensus. Descriptive syntheses were performed, and the risk of bias was assessed. Relative risks (RRs) and 95% CIs were estimated using a pairwise meta-analysis with both a random-effects model and a general linear mixed model (GLMM). Certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation framework, and trial sequential analysis (TSA) was conducted to assess if current information is enough for definitive conclusions. Subgroup analysis was performed by glycemic status. RESULTS: Six clinical trials were included. Among 12 841 participants, the combined RR for cancer mortality comparing lifestyle interventions with usual care was 0.94 (95% CI, 0.81-1.10 using GLMM and 0.82-1.09 using random-effects model). Most studies had a low risk of bias, and the certainty of evidence was moderate. TSA showed that the cumulative Z curve reached futility boundary while total number did not reach detection boundary. CONCLUSION: Based on the limited data available, dietary and physical activity-based lifestyle interventions had no superiority to usual care on reducing cancer risk in populations with prediabetes and T2D. Lifestyle interventions focused on cancer outcomes should be tested to better explore their effects.

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.

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.