The objective of this study was to determine whether pre-existing type 2 diabetes is associated with an increased risk of breast cancer-related and all-cause mortality, compared with non-diabetes, and if the risk varies across glycated hemoglobin A1c (HbA1c) categories. Using the Clinical Practice Research Datalink, we assembled a cohort of patients at least 18 years old, newly diagnosed with invasive breast cancer between 1998 and 2020, with follow-up until March 2021. Patients were followed from 3 months after breast cancer diagnosis until one of the study outcomes, end of registration with the general practice, or end of study. Multivariable Cox proportional hazards models, adjusted for 33 confounders, were fitted to estimate the hazard ratios (HRs) and 95

Objective: To estimate the effect of initiating glucagon-like peptide-1 receptor agonists (GLP-1 RAs) versus dipeptidyl peptidase-4 (DPP-4) inhibitors on incident nonarteritic anterior ischemic optic neuropathy (NAION) among adults with type 2 diabetes. Research Design and Methods: This active-comparator, new-user cohort emulated a pragmatic target trial using the Clinical Practice Research Datalink in United Kingdom. Patients aged ≥18 years with a physician diagnosis of type 2 diabetes, who newly initiated a GLP-1 RA or a DPP-4 inhibitor, were included. DPP-4 inhibitors were selected as the comparator because they may be used as second-line treatment, like GLP-1 RAs, and have no established association with NAION. We estimated risks, risk differences (RDs), and risk ratios (RRs) of incident NAION adjusted using propensity score fine stratification weighting. Results: At one year, there were 14 NAION events among 106,858 GLP-1 RA initiators (18.5 per 100,000) and 53 among 416,369 DPP-4 inhibitor initiators (7.2 per 100,000): GLP-1 RAs were associated with an increased risk of NAION compared with DPP-4 inhibitors (RR: 2.56, 95% CI: 1.44-4.86; RD: 11.3 per 100,000). The risk of NAION was higher during the first six months and diminished with longer durations of use, and was higher in patients aged <50 years, men, ever-smokers, and those with ≥ 1% hemoglobin A1c reduction. Conclusions: GLP-1 RAs were associated with an increased one-year risk of NAION compared with DPP-4 inhibitors among adults with type 2 diabetes, particularly in younger patients, men, ever-smokers, and patients with a marked hemoglobin A1c reduction.

Objectives To assess the association between sodium-glucose co-transporter-2 inhibitor (SGLT-2i) use and the risk of incident dementia compared with dipeptidyl peptidase-4 inhibitors (DPP-4i) use among individuals with type 2 diabetes.Design A population-based retrospective cohort study.Setting The Clinical Practice Research Datalink (CPRD) Aurum database from the UK.Participants Individuals with type 2 diabetes, aged 40 years or older, newly prescribed SGLT-2i or DPP-4i on or after 2013–2021, registered in the CPRD Aurum database.Main outcome measure The primary outcome was incident dementia, and the secondary outcome was incident mild cognitive impairment (MCI). Cox proportional hazard models were used to estimate the HR and corresponding 95% CI for the primary and secondary outcomes. Propensity score fine stratification weights were used to adjust for confounding.Results Among a cohort of 118 006 individuals, the incident rate (IR) of dementia was 0.56/1000 person-years over a median follow-up period of 1.54 years among SGLT-2i users compared with 2.67/1000 person-years in DPP-4i users, over a median follow-up period of 1.79 years. The adjusted HR for SGLT-2i use compared with DPP-4i use for dementia was 0.78 (95% CI 0.55 to 1.12), while for MCI was 0.86 (95% CI 0.80 to 0.92). The age-specific stratified analysis demonstrated the adjusted HR for SGLT-2i use compared with DPP-4i use for the risk of incident dementia among elderly, aged ≥65 years, was 0.50 (95% CI 0.31 to 0.80).Conclusion Primary findings did not yield conclusive evidence to infer an association between SGLT-2i use and the risk of incident dementia.

Crude and adjusted hazard ratios of sensitivity analyses for the association between 5-alpha reductase inhibitor use and kidney and bladder cancer compared to alpha blockers

AbstractBackground: Preclinical evidence suggests that 5α-reductase inhibitors (5ARi), commonly used to treat benign prostatic hyperplasia (BPH), are associated with reduced incidence of certain urologic cancers, yet epidemiologic studies are conflicting. This study aimed to determine whether 5ARi's are associated with a reduced risk of kidney and bladder cancers. Methods: We conducted a new-user active-comparator cohort study in the United Kingdom Clinical Practice Research Datalink. From a base cohort of patients with incident BPH, new users of 5ARi's and α-blockers were identified. Patients were followed up until a first ever diagnosis of kidney or bladder cancer, death from any cause, end of registration, or December 31, 2017. Cox proportional hazards models were used to calculate HRs and 95% confidence intervals (CI) for incident kidney and bladder cancer. Results: There were 5,414 and 37,681 new users of 5ARi's and α-blockers, respectively. During a mean follow-up of 6.3 years, we found no association between the use of 5ARi's and kidney (adjusted HR, 1.26; 95% CI, 0.74–2.12; n = 23) or bladder (adjusted HR, 0.89; 95% CI, 0.64–1.23; n = 57) cancer risk compared with α-blockers. Similar results were observed across sensitivity analyses. Conclusions: In this study, we found no association between the use of 5ARi's and kidney or bladder cancer incidence in men with BPH when compared with α-blocker use. Impact: The findings of this study indicate that 5ARi's are unlikely to reduce kidney or bladder cancer risk.

INTRODUCTION:The use of incretin-based drugs may be associated with a decreased risk of endometrial cancer among women with type 2 diabetes. METHODS:Using data from the UK Clinical Practice Research Datalink and linked databases, two new-user active comparator cohorts of women with type 2 diabetes who initiated glucagon-like peptide 1 receptor agonists (GLP-1 RAs) or sulfonylureas (cohort 1) and DPP-4 inhibitors or sulfonylureas (cohort 2) were assembled. Propensity score fine stratification weighted Cox proportional hazards models were fitted to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident endometrial cancer. RESULTS:Cohort 1 included 9239 new users of GLP-1 RAs and 80,086 new users of sulfonylureas. The GLP-1 RAs were not associated with a decreased risk of endometrial cancer when compared with sulfonylureas (HR: 1.11, 95% CI: 0.66-1.88). In a duration-response secondary analysis, use of GLP-1 RAs for more than two years was associated with an increased risk of endometrial cancer (HR: 2.47, 95% CI: 1.37-4.43) when compared to sulfonylureas When analysed by drug type, exenatide was associated with an elevated risk when compared to sulfonylureas (HR: 2.26, 95% CI:1.06-4.82). Cohort 2 included 42,486 new users of DPP-4 inhibitors and 79,353 new users of sulfonylureas. DPP-4 inhibitors were not associated with a decreased risk of endometrial cancer compared with sulfonylureas (HR: 1.00, 95% CI: 0.76-1.32). In a duration-response secondary analysis, use of DPP-4 inhibitors for more than two years was associated with an increased risk of endometrial cancer (HR: 1.63, 95% CI: 1.14-2.33) when compared to sulfonylureas. CONCLUSIONS:In this population-based study, the use of GLP-1 RAs and DPP-4 inhibitors was not associated with a decreased risk of endometrial cancer when compared with the use of sulfonylureas among women with type 2 diabetes.

Baseline Characteristics with standardised differences for propensity Score Analysis using standard mortality ratio weights for kidney cancer cohort

OBJECTIVE To determine whether glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors, separately, compared with dipeptidyl peptidase 4 (DPP-4) inhibitors are associated with a reduced risk of cirrhosis and other adverse liver outcomes among patients with type 2 diabetes.RESEARCH DESIGN AND METHODS With an active comparator, new-user approach, we conducted a cohort study using the U.K. Clinical Practice Research Datalink linked with hospital and national statistics databases. Cox proportional hazards models using propensity score fine stratification weighting were used to calculate hazard ratios (HRs) and 95% CIs for cirrhosis (primary outcome) and decompensated cirrhosis, hepatocellular carcinoma, and liver-related mortality (secondary outcomes).RESULTS In the first cohort comparing 25,516 patients starting GLP-1RAs and 186,752 starting DPP-4 inhibitors, GLP-1RAs were not associated with the incidence of cirrhosis (HR 0.90, 95% CI 0.68-1.19) or the secondary outcomes. In a separate cohort comparing 33,161 patients starting SGLT-2 inhibitors and 124,431 starting DPP-4 inhibitors, SGLT-2 inhibitors were associated with a reduced incidence of cirrhosis (HR 0.64, 95% CI 0.46-0.90), as also decompensated cirrhosis (HR 0.74, 95% CI 0.54-1.00), but not with a lower risk of hepatocellular carcinoma or liver-related mortality.CONCLUSIONS In patients with type 2 diabetes in the U.K., GLP-1RAs were not associated with a lower risk of cirrhosis compared with DPP-4 inhibitors in patients with type 2 diabetes. However, SGLT-2 inhibitors were associated with a lower risk of cirrhosis compared with DPP-4 inhibitors.

Objective To determine whether the use of glucagon-like peptide-1 (GLP-1) receptor agonists is associated with an increased risk of suicidal ideation, self-harm, and suicide among patients with type 2 diabetes compared with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Design Active comparator, new user cohort study. Setting Primary care practices contributing data to the UK Clinical Practice Research Datalink linked to the Hospital Episodes Statistics Admitted Patient Care and Office for National Statistics Death Registration databases. Participants Patients with type 2 diabetes. Exposures Two cohorts were assembled, with the first composed of patients who started and continued on GLP-1 receptor agonists or DPP-4 inhibitors between 1 January 2007 and 31 December 2020 and the second composed of patients who started and continued on GLP-1 receptor agonists or SGLT-2 inhibitors between 1 January 1 2013 and 31 December 2020. Both cohorts were followed until 29 March 2021. Main outcome measures The primary outcome was suicidality, defined as a composite of suicidal ideation, self-harm, and suicide. Secondary outcomes were each of these events considered separately. Propensity score fine stratification weighted Cox proportional hazards models were fitted to estimate hazard ratios and 95% confidence intervals (CIs) to estimate the average treatment effect among the treated patients. Results The first cohort included 36 082 GLP-1 receptor agonist users (median follow-up 1.3 years) and 234 028 DPP-4 inhibitor users (median follow-up 1.7 years). In crude analyses, GLP-1 receptor agonist use was associated with an increased incidence of suicidality compared with DPP-4 inhibitors (crude incidence rates 3.9 v 1.8 per 1000 person years, respectively; hazard ratio 2.08, 95% CI 1.83 to 2.36). This estimate decreased to a null value after confounding factors were accounted for (hazard ratio 1.02, 95% CI 0.85 to 1.23). The second cohort included 32 336 GLP-1 receptor agonist users (median follow-up 1.2 years) and 96 212 SGLT-2 inhibitor users (median follow-up 1.2 years). Similarly, GLP-1 receptor agonist use was associated with an increased risk of suicidality compared with SGLT-2 inhibitors in crude analyses (crude incidence rates 4.3 v 2.7 per 1000 person years; hazard ratio 1.60, 95% CI 1.37 to 1.87) but not after confounding factors were accounted for (0.91, 0.73 to 1.12). Similar findings were observed when suicidal ideation, self-harm, and suicide were analysed separately in both cohorts. Conclusions In this large cohort study, the use of GLP-1 receptor agonists was not associated with an increased risk of suicidality compared with the use of DPP-4 inhibitors or SGLT-2 inhibitors in patients with type 2 diabetes.

BACKGROUND:Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), medications used to treat type 2 diabetes and obesity, are associated with delayed gastric emptying, which is a risk factor for gastroesophageal reflux disease (GERD). However, evidence linking these drugs to GERD is limited. OBJECTIVE:To estimate the effect of GLP-1 RAs compared with sodium-glucose cotransporter-2 (SGLT-2) inhibitors on the risk for GERD and its complications among patients with type 2 diabetes. DESIGN:Active-comparator new-user cohort study emulating a target trial. SETTING:U.K. Clinical Practice Research Datalink. PARTICIPANTS:Adults aged 18 years or older with type 2 diabetes initiating GLP-1 RAs or SGLT-2 inhibitors between 1 January 2013 and 31 December 2021, with follow-up until 31 March 2022. MEASUREMENTS:The primary outcome was incident GERD, and the secondary outcome was its complications. Three-year risk differences (RDs) and risk ratios (RRs) were estimated and weighted using propensity score fine stratification. RESULTS:The study included 24 708 new users of GLP-1 RAs and 89 096 new users of SGLT-2 inhibitors. Over a median follow-up of 3.0 years, the RRs were 1.27 (95% CI, 1.14 to 1.42) for GERD, with an RD of 0.7 per 100 patients, and 1.55 (95% CI, 1.12 to 2.29) for its complications, with an RD of 0.8 per 1000 patients, among GLP-1 RA users compared with SGLT-2 inhibitor users. LIMITATION:Residual confounding due to lack of information on dietary or lifestyle factors. CONCLUSION:The estimated effect of GLP-1 RAs compared with SGLT-2 inhibitors suggested a higher risk for GERD and its complications in patients with type 2 diabetes. Clinicians should be aware of this potential adverse effect to provide timely prevention and treatment strategies. PRIMARY FUNDING SOURCE:Canadian Institutes of Health Research.

Incretin-based drugs, namely glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 (DPP-4) inhibitors, may have neuroprotective effects. Thus, we assessed whether these drugs are associated with a decreased risk of dementia among patients with type 2 diabetes. Using the Clinical Practice Research Datalink from the UK, we formed two new user cohorts of patients at least 50 years of age with type 2 diabetes starting incretin-based drugs or sulfonylureas between 2007 and 2021. Hazard ratios (HRs) and 95

Crude and adjusted hazard ratios for association between 5-alpha reductase inhibitor use and kidney and bladder cancer compared to non-use