Aims/hypothesis: A protective role of sodium–glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP1-ra) in the development of diabetic retinopathy and diabetic macular oedema has been described in some recent studies, which may extend beyond glycaemic control. We aimed to review the clinical impact of SGLT2i and GLP1-ra therapy on the risk of diabetic retinopathy and diabetic macular oedema in individuals with type 2 diabetes taking insulin. Methods: This is a retrospective cohort analysis of approximately two million people with type 2 diabetes receiving insulin across 97 healthcare organisations using a global federated health research network (TriNetX, Cambridge, USA). Two intervention cohorts (SGLT2i + insulin, n=176,409; GLP1-ra + insulin, n=207,034) were compared against a control cohort (insulin with no SGLT2i/GLP1-ra, n=1,922,312). Kaplan–Meier survival analysis was performed and estimated HRs were reported for each outcome. Propensity score was used to 1:1 match for age, sex, ischaemic heart disease, hypertension, microvascular complications, chronic kidney disease, HbA_1c, BMI and use of pioglitazone, lipid modifying agents, antilipemic agents, ACE inhibitors, angiotensin II inhibitors and metformin. A sub-analysis comparing the two intervention cohorts was also performed. Results: SGLT2i with insulin was associated with a reduced HR (95% CI) for diabetic macular oedema compared with the control cohort (0.835; 0.780, 0.893), while GLP1-ra with insulin demonstrated a lack of signal with no statistical significance to the HR (1.013; 0.960, 1.069). SGLT2i with insulin was not associated with a clinically significant increase in the risk of developing diabetic retinopathy (1.076; 1.027, 1.127), while GLP1-ra with insulin increased diabetic retinopathy risk (1.308; 1.261, 1.357). Compared with SGLT2i with insulin, GLP1-ra with insulin was associated with higher risk of diabetic retinopathy (1.205; 1.153, 1.259) and diabetic macular oedema (1.130; 1.056, 1.208). Conclusions/interpretation: Our study suggests that the combination of SGLT2i and insulin is associated with lower risk of developing diabetic macular oedema. However, the use of GLP1-ra was associated with an increased risk of diabetic retinopathy in individuals with type 2 diabetes also taking insulin. A comparative analysis showed favourable outcomes with SGLT2i and insulin in the development of diabetic macular oedema and diabetic retinopathy. RCTs using dedicated retinal imaging are required to determine the causal relationship with these therapies. Graphical

Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are treatments for type 2 diabetes (T2D). Beyond glucose-lowering and cardiorenal protection, these drugs may protect against pneumonia and sepsis. Aims This study assesses the impact of SGLT2i and GLP-1 RAs on the risk of incident pneumonia and severe sepsis. Methods A retrospective cohort study was conducted using anonymised electronic medical records from TriNetX, a global federated database. Two intention-to-treat analyses were performed, each with two cohorts of adult T2D patients. The first analysis compared individuals prescribed SGLT2i, and the second individuals prescribed GLP-1 RAs, with those prescribed dipeptidyl peptidase-4 inhibitors (DPP-4i). An active comparator new user design was used, with outcomes defined as time-to-incident pneumonia and severe sepsis. Propensity score matching (1:1) was applied to control for potential confounders, and patients were followed for 12 months. Secondary analyses compared SGLT2i and GLP-1 RAs against other glucose-lowering therapies. Results After propensity score matching, 352 687 patients were included in the SGLT2i versus DPP-4i comparison. SGLT2i treatment was associated with a risk reduction in incident pneumonia (HR 0.75 (95% CI 0.73, 0.78)) and severe sepsis (0.75 (0.73, 0.77)). In the GLP-1 RA versus DPP-4i comparison, 331 863 patients were included. GLP-1 RA treatment was associated with a risk reduction in incident pneumonia (0.60 (0.58, 0.62)) and severe sepsis (0.61 (0.59, 0.63)). Conclusion SGLT2i and GLP-1 RAs are associated with a reduced risk of incident pneumonia and severe sepsis in patients with T2D. Further research and focused randomised controlled trials are warranted to explore the broader clinical implications of these treatments.

Survival in multiple myeloma has improved significantly in recent years, especially in young patients. We reviewed the evolution of the survival of patients with MM in three groups based on age at MM diagnosis over three time periods between 1999 and 2020 at our 12 de Octubre Hospital institution (H12O). Then, to confirm our results, we used data from TriNetx, a global health research platform that includes patients from Europe to US. Finally, we analysed differences in the patterns of treatment between networks across the world. Kaplan‒Meier analysis was used to estimate survival probabilities, and between-group differences were tested using the log-rank test and hazard ratio. For patients from H12O, the median OS was 35.61, 55.59 and 68.67 months for the 1999–2009, 2010–2014 and 2015–2020 cohorts, respectively (p = 0.0001). Among all patients included in the EMEA network, the median OS was 20.32 months versus 34.75 months from 1999–2009 versus 2010–2014. The median OS from the 2010–2014 versus 2015–2020 time cohorts was 34.75 months versus 54.43 months, respectively. In relation to the US cohort, the median OS from before 2010 versus 2010–2014 was not reached in either time cohort and neither when comparing the 2010–2014 versus 2015–2019 time cohorts. Bortezomib is the most commonly used drug in the EMEA cohort, while lenalidomide is the most commonly used drug in the US cohort. This large-scale study based on real-world data confirms the previous finding that MM patients have increased their survival in the last two decades.

Context: Reports on long-term thyroid dysfunction following COVID-19 vaccination are limited. Understanding the risk of subacute thyroiditis, hyperthyroidism, and hypothyroidism in vaccinated individuals is crucial for postvaccination monitoring. Objective: This study evaluated the risk of thyroid dysfunction in individuals vaccinated against COVID-19 compared to unvaccinated individuals, using a large cohort. Methods: We conducted a retrospective cohort study from January 1, 2022, to December 31, 2023, using the TriNetX database, including 1 166 748 vaccinated and 1 166 748 unvaccinated individuals. Propensity score matching was used to balance baseline characteristics. The primary outcomes were new diagnoses of subacute thyroiditis, hyperthyroidism, and hypothyroidism. Results: The risk of subacute thyroiditis remained unchanged (95% CIs included 1). A significant reduction in hyperthyroidism risk was observed from 3 to 9 months postvaccination (hazard ratios [HRs]: 0.65-0.89, all 95% CIs below 1), but this trend was not significant at 12 months (HR: 0.99; 95% CI: 0.92-1.06). In contrast, the risk of hypothyroidism significantly increased from 6 to 12 months postvaccination (HR: 1.14-1.30, all 95% CIs above 1). Among mRNA vaccine recipients, the risk of both hyperthyroidism and hypothyroidism was significantly elevated at 12 months (HR: 1.16-2.13). Conclusion: COVID-19 vaccination was associated with a reduced risk of hyperthyroidism and an increased risk of hypothyroidism, highlighting the need for ongoing thyroid function monitoring.