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Alexandra Simbrich,1 Jasmine Thibaut,1 Laura Khil,1,2 Klaus Berger,1 Oliver Riedel,3 Niklas Schmedt3,41Institute of Epidemiology and Social Medicine, University of Münster, 48149 Münster, Germany; 2Cancer Registry North Rhine-Westphalia, 44801, Bochum, Germany; 3Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology – BIPS, 28359 Bremen, Germany; 4InGef – Institute for Applied Health Research Berlin GmbH, 10117 Berlin, GermanyPurpose: To describe drug-use patterns in patients with multiple sclerosis (MS) using disease-modifying drugs (DMDs) and to estimate the incidence of severe adverse events (SAEs) of treatment.Methods: We conducted a cohort study within the German Pharmacoepidemiological Research Database between January 1, 2006 and December 31, 2013. MS patients on DMDs were described in terms of clinical characteristics and drug-use patterns. Next, we assessed the incidence of AEs in new users of fingolimod, natalizumab, glatiramer acetate, and IFNβ1a.Results: Among approximately 11 million insured members of German Statutory Health Insurance, the DMD-user cohort comprised 15,377 patients with MS, with a mean age of 39.6 years and 68% females. Nearly half of all DMD users had a diagnosis of depression, with prevalence ranging from 40.1% for IFNβ1a to 62.3% for immunoglobulins. The overall rate of MS relapses per patient and year was 0.34 (95% CI 0.33–0.34). During an average follow-up of 1,650 days, the majority (42.4%) of MS patients were adherent to DMD treatment (“continuous single users”), followed by patients interrupting treatment (39.5%, “interrupters”). Switch of DMD treatment (11.9%) was less frequent, and only 5.6% discontinued treatment. Treatment discontinuation was most common in users of natalizumab (7.5%) and IFNβ1b (7.0%). The most frequent SAE was hospitalization for depression, followed by any infectious disease and any malignancy. The incidence rate of all adverse events did not significantly differ across different DMDs.Conclusion: Treatment discontinuation with DMDs and treatment switch were rare. Causes of rather frequent DMD-treatment interruption have to be evaluated in further studies based on primary data collection. Active safety monitoring of new DMDs based on claims data requires large data sets to detect rare AEs and availability of up-to-date data.Keywords: multiple sclerosis, drug-use patterns, adverse events, claims data, disease-modifying drugs

Importance: Empagliflozin might lower the risk of diabetic retinopathy (DR) by preventing retinal pericyte loss. However, the role of empagliflozin with respect to DR in patients with type 2 diabetes (T2D) remains unclear., Objective: To compare the risk of incident nonproliferative DR (NPDR) and DR progression in patients with T2D initiating empagliflozin vs a dipeptidyl peptidase 4 inhibitor (DPP4i)., Design, Setting, and Participants: A new-user active-comparator cohort study was conducted using US nationwide insurance claims data from 2 commercial insurers and Medicare from August 2014 to September 2019. Adults with T2D initiating study drugs without prior diagnosis or treatment for proliferative DR or other advanced retinal diseases were included. To assess incident NPDR, patients with a history of NPDR were additionally excluded, while for the DR progression outcome, patients were required to have a history of NPDR. Data were analyzed from August 2022 to May 2024., Exposures: Initiation of empagliflozin or a DPP4i., Main Outcomes and Measures: Incident NPDR was defined using diagnostic codes for mild, moderate, or severe NPDR. The DR progression outcome was defined as a composite of incident proliferative DR, vitreous hemorrhage, initiation of intravitreal anti-vascular endothelial growth factor injection, or panretinal photocoagulation. Incidence rates, hazard ratios (HRs), and rate differences (RDs) with 95% CIs were estimated., Results: A total of 34 239 pairs of propensity-score matched adults were identified in the incident NPDR cohort and 7831 pairs in the DR progression cohort. In the incident NPDR cohort, 35 867 patients (52.4%) were male, and the mean (SD) age was 65.6 (10.3) years. In the DR progression cohort, 8229 patients (52.5%) were male, and the mean (SD) age was 67.0 (10.0) years. Over a mean (SD) follow-up period of 8 (7.5) months receiving treatment, the risk of incident NPDR was not different across groups (HR, 1.04; 95% CI, 0.94 to 1.15; RD, 1.30; 95% CI, -1.83 to 4.44), while the risk of DR progression was lower among individuals who initiated empagliflozin compared with those who began DPP4i therapy (HR, 0.78; 95% CI, 0.63 to 0.96; RD, -9.44; 95% CI, -16.90 to -1.98). Results were consistent across multiple subgroups and sensitivity analyses., Conclusions and Relevance: Compared with initiation of a DPP4i, empagliflozin initiation was not associated with incident NPDR, although it may be associated with a lower risk of DR progression. Although residual confounding cannot be entirely ruled out due to the observational nature of our study, these findings may be helpful when weighing the risks and benefits of various glucose-lowering agents in adults with T2D.

Objective: We compared health care resource utilization (HCRU) and costs for inpatient and outpatient services and dispensed medications in older adults with type 2 diabetes initiating empagliflozin versus dipeptidyl peptidase 4 inhibitors (DPP-4is)., Research Design and Methods: The study population included U.S. Medicare fee-for-service beneficiaries with diabetes (age ≥65 years) initiating empagliflozin or DPP-4is (August 2014 to September 2018). We estimated rate ratios (RRs) for HCRU outcomes using zero-inflated negative binomial regression and per-member per-year (PMPY) cost differences using generalized linear model with gamma distributions, overall and stratified by baseline cardiovascular disease (CVD), after adjusting for 143 baseline covariates using 1:1 propensity score matching., Results: We identified 23,335 matched pairs (mean age 72 years, 51% with baseline CVD). HCRU rates were lower in empagliflozin versus DPP-4i initiators (number of inpatient days, RR 0.89 [95% CI 0.82, 0.97]; number of emergency department [ED] visits, 0.86 [0.82, 0.91]; number of hospitalizations, 0.86 [0.79, 0.93]; number of office visits, 0.96 [0.95, 0.98]). Inpatient cost (-$713 PMPY [95% CI -847, -579), outpatient cost (-$198 PMPY [-272, -124]), and total cost of care (-$1,109 PMPY [-1,478, -739]) were lower for empagliflozin versus DPP-4is, although diabetes medication cost was higher in empagliflozin initiators ($454 PMPY [95% CI 284, 567]). In the CVD subgroup, total cost was lower for empagliflozin initiators (-$2,005 PMPY [-2,451, -1,337]), while the difference was attenuated in the non-CVD subgroup (-$296 PMPY [-740, 148])., Conclusions: Among older adults with diabetes, empagliflozin was associated with a lower number of inpatient days, hospitalizations, ED visits, and office visits and with lower costs of care compared with DPP-4is, especially in those with history of CVD., (© 2024 by the American Diabetes Association.)

Background: Hyperuricemia is frequently observed in patients with type 2 diabetes (T2D) and is associated with increased risk of gout and cardiovascular disease (CVD). Empagliflozin lowers serum urate levels by enhancing its urinary excretion., Objective: To compare initiators of empagliflozin vs dipeptidyl peptidase-4 inhibitor (DPP4i) and initiators of empagliflozin vs glucagon-like peptide-1 receptor agonist (GLP-1RA) with respect to the risk of incident gout events., Design and Participants: Using three claims-based datasets from 08/2014 to 09/2019, we generated two cohorts (cohort 1: empagliflozin vs DPP4i; cohort 2: empagliflozin vs GLP-1RA) of adult patients with T2D and without prior history of gout or gout-specific medication dispensing separately in each dataset. To assess the risk of incident gout, we estimated hazard ratios (HR) and rate differences (RD) per 1000 person-years (PY) with their 95% confidence intervals (CI) before and after 1:1 propensity score (PS) matching adjusting for 141 baseline covariates., Key Results: We identified 102,262 pairs of 1:1 propensity score-matched adults in cohort 1 and 131,216 pairs in cohort 2. Over a mean follow-up period of 8 months on treatment, the risk of gout was lower in patients initiating empagliflozin compared to DPP4i (HR = 0.69: 95% CI (0.60-0.79); RD =  - 2.27: 95% CI (- 3.08, 1.46)) or GLP-1RA (HR = 0.83: 95% CI (0.73-0.94); RD =  - 0.99: 95% CI (- 1.66, - 0.32)). Results were consistent across subgroups (sex, age, body mass index, chronic kidney disease, heart failure, cardiovascular disease, and concurrent diuretic use) and sensitivity analyses., Conclusions: Among adults with T2D, the initiation of empagliflozin vs a DPP4i or GLP-1RA was associated with lower risk of incident gout, complementing results from a post hoc analysis of the EMPA-REG OUTCOME trial and previously published observational research focusing on the sodium-glucose co-transporter-2 inhibitor class in more narrowly defined study populations., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Aims/hypothesis: Limited evidence exists on the comparative safety and effectiveness of empagliflozin against alternative glucose-lowering medications in individuals with type 2 diabetes with the broad spectrum of cardiovascular risk. The EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) cohort study was designed to monitor the safety and effectiveness of empagliflozin periodically for a period of 5 years with data collection from electronic healthcare databases., Methods: We identified individuals ≥18 years old with type 2 diabetes who initiated empagliflozin or dipeptidyl peptidase-4 inhibitors (DPP-4i) from 2014 to 2019 using US Medicare and commercial claims databases. After 1:1 propensity score matching using 143 baseline characteristics, we identified four a priori-defined effectiveness outcomes: (1) myocardial infarction (MI) or stroke; (2) hospitalisation for heart failure (HHF); (3) major adverse cardiovascular events (MACE); and (4) cardiovascular mortality or HHF. Safety outcomes included lower-limb amputations, non-vertebral fractures, diabetic ketoacidosis (DKA), acute kidney injury (AKI), severe hypoglycaemia, retinopathy progression, and short-term kidney and bladder cancers. We estimated HRs and rate differences (RDs) per 1000 person-years, overall and stratified by age, sex, baseline atherosclerotic cardiovascular disease (ASCVD) and heart failure., Results: We identified 115,116 matched pairs. Compared with DPP-4i, empagliflozin was associated with lower risks of MI/stroke (HR 0.88 [95% CI 0.81, 0.96]; RD -2.08 [95% CI (-3.26, -0.90]), HHF (HR 0.50 [0.44, 0.56]; RD -5.35 [-6.22, -4.49]), MACE (HR 0.73 [0.62, 0.86]; RD -6.37 [-8.98, -3.77]) and cardiovascular mortality/HHF (HR 0.57 [0.47, 0.69]; RD -10.36 [-12.63, -8.12]). Absolute benefits were larger in older individuals and in those with ASCVD/heart failure. Empagliflozin was associated with an increased risk of DKA (HR 1.78 [1.44, 2.19]; RD 1.59 [1.08, 2.09]); decreased risks of AKI (HR 0.62 [0.54, 0.72]; RD -2.39 [-3.08, -1.71]), hypoglycaemia (HR 0.75 [0.67, 0.84]; RD -2.46 [-3.32, -1.60]) and retinopathy progression (HR 0.78 [0.63, 0.96)]; RD -9.49 [-16.97, -2.10]); and similar risks of other safety events., Conclusions/interpretation: Empagliflozin relative to DPP-4i was associated with risk reductions of MI or stroke, HHF, MACE and the composite of cardiovascular mortality or HHF. Absolute risk reductions were larger in older individuals and in those who had history of ASCVD or heart failure. Regarding the safety outcomes, empagliflozin was associated with an increased risk of DKA and lower risks of AKI, hypoglycaemia and progression to proliferative retinopathy, with no difference in the short-term risks of lower-extremity amputation, non-vertebral fractures, kidney and renal pelvis cancer, and bladder cancer., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Non-vitamin K antagonist oral anticoagulants (NOACs) have largely supplanted vitamin K antagonists (VKAs) for oral anticoagulation in non-valvular atrial fibrillation (NVAF). However, data on the real-world effectiveness of NOACs vs. phenprocoumon, a VKA widely used in Germany, are limited. The RELOADED study aimed to compare effectiveness of factor Xa NOACs and phenprocoumon in NVAF in clinical practice., Methods: Patients who started on a factor Xa NOAC or phenprocoumon for NVAF during the study period were enrolled from the Institute for Applied Healthcare Research Berlin. Patients were followed from first prescription until the end of exposure or available data. Primary outcomes were analyzed by Cox proportional hazard regression models and included ischemic stroke and systemic embolism for effectiveness, and intracranial hemorrhage (ICH) for safety. Subgroups of interest were patients with diabetes and patients with renal impairment., Results: The total study population was 64,920; 36.3% of patients initiated phenprocoumon, 34.4% initiated rivaroxaban, 25.0% apixaban, and 4.4% edoxaban. Treatment with phenprocoumon is associated with a similar risk of ischemic stroke/systemic embolism as treatment with rivaroxaban or apixaban; while rivaroxaban (adjusted hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.43-0.75) and apixaban (adjusted HR 0.43, 95% CI 0.31-0.6) were associated with a lower risk of ICH compared to phenprocoumon in NVAF patients. The use of rivaroxaban and apixaban was associated with a lower risk of developing kidney failure in patients with diabetes or renal impairment in comparison to those treated with phenprocoumon., Conclusion: The factor Xa NOACs rivaroxaban and apixaban demonstrated similar effectiveness and lower rates of ICH compared with phenprocoumon in this study., Competing Interests: Declaration of competing interest RK reports support for research by Bayer, honoraria for lectures from Bayer, Berlin-Chemie/Menarini, Daiichi Sankyo, Ferrer, Merck, Sanofi and Servier. SK was an employee of Bayer AG during the development of this study and manuscript. DE is employed by InGef, which acted as subcontractor and received funding from WIG2 for the execution of the study. KA is an employee of Bayer AG. DH has received grants or contracts from Bristol-Myers Squibb GmbH & Co KGaA and Pfizer Pharma GmbH. NS left InGef and joined Bayer AG after the conduct of the study. Except for the manuscript, all work for this study by NS was performed under InGef affiliation. HB reports no conflicts of interest. The study was funded by Bayer AG., (Copyright © 2024. Published by Elsevier B.V.)

Background: No randomized clinical trials have directly compared the cardiorenal effectiveness of empagliflozin and GLP-1RA agents with demonstrated cardioprotective effects in patients with a broad spectrum of cardiovascular risk. We reported the final-year results of the EMPRISE study, a monitoring program designed to evaluate the cardiorenal effectiveness of empagliflozin across broad patient subgroups., Methods: We identified patients ≥ 18 years old with type 2 diabetes who initiated empagliflozin or GLP-1RA from 2014 to 2019 using US Medicare and commercial claims databases. After 1:1 propensity score matching using 143 baseline characteristics, we evaluated risks of outcomes including myocardial infarction (MI) or stroke, hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE - MI, stroke, or cardiovascular mortality), a composite of HHF or cardiovascular mortality, and progression to end-stage kidney disease (ESKD) (in patients with chronic kidney disease stages 3-4). We estimated hazard ratios (HR) and rate differences (RD) per 1,000 person-years, overall and within subgroups of age, sex, baseline atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF)., Results: We identified 141,541 matched pairs. Compared with GLP-1RA, empagliflozin was associated with similar risks of MI or stroke [HR: 0.99 (0.92, 1.07); RD: -0.23 (-1.25, 0.79)], and lower risks of HHF [HR: 0.50 (0.44, 0.56); RD: -2.28 (-2.98, -1.59)], MACE [HR: 0.90 (0.82, 0.99); RD: -2.54 (-4.76, -0.32)], cardiovascular mortality or HHF [HR: 0.77 (0.69, 0.86); RD: -4.11 (-5.95, -2.29)], and ESKD [0.75 (0.60, 0.94); RD: -6.77 (-11.97, -1.61)]. Absolute risk reductions were larger in older patients and in those with baseline ASCVD/HF. They did not differ by sex., Conclusions: The cardiovascular benefits of empagliflozin vs. cardioprotective GLP-1RA agents were larger in older patients and in patients with history of ASCVD or HF, while they did not differ by sex. In patients with advanced CKD, empagliflozin was associated with risk reductions of progression to ESKD., (© 2024. The Author(s).)

Background: Mineralocorticoid receptor antagonists (MRAs) were shown to delay chronic kidney disease (CKD) progression in patients with hypertension and/or heart failure (HF) and proteinuria., Objective: We conducted a systematic literature review on real-world evidence to identify the literature gaps related to the efficacy and safety outcomes of MRAs administered to CKD patients., Results: A total of 751 records were identified of which, 23 studies (26 publications) were analyzed. Studies included heterogeneous populations, including the overall CKD, CKD and diabetes, CKD and HF, and CKD and a history of cardiovascular disease. Most of the studies were small and non-rigorous, resulting in a notable lack of evidence in these populations. In the overall CKD population, steroidal MRAs resulted in a significant or sustained eGFR reduction but no efficacy in delaying progression to end-stage kidney disease. No cardiovascular protection was found. Results for all-cause mortality and hospitalization for HF were inconsistent; however, the longest follow-up studies indicate similar or lower incidence for spironolactone non-users. Most results consistently reported a higher incidence of hyperkalemia among patients on steroidal MRAs in all CKD stages, and side effects led to high discontinuation rates in the real-world setting., Conclusions: Despite the limited availability of evidence on the effectiveness and safety of steroidal MRAs in CKD patients and subgroups with diabetes, HF or history of cardiovascular disease, MRAs were shown to have a limited effect on renal and cardiovascular outcomes. Gaps in the evidence regarding the efficacy and safety of MRAs are particularly relevant in diabetic CKD patients; therefore, further research is warranted., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objectives: To describe prevalence of chronic kidney disease (CKD), demographic and clinical characteristics, treatment patterns and rates of cardiovascular and renal complications for patients with type 2 diabetes (T2D) treated in routine clinical care., Design: Repeat cross-sectional study (6 monthly cross-sections) and cohort study from 1 January 2017 to 31 December 2019., Setting: Primary care data from English practices contributing to the UK Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office for National Statistics mortality data., Participants: Patients with T2D aged >18 years, at least one year of registration data., Primary and Secondary Outcomes: Primary outcome was prevalence of CKD defined as chronic kidney disease epidemiology collaboration (CKD-EPI) estimated glomerular filtration rate <60 mL/min/1.73 m 2 , and/or urinary albumin creatinine ratio ≥3 mg/mmol in the past 24 months. Secondary outcomes were prescriptions of medications of interest and clinical and demographic characteristics in the past 3 months.In the cohort study rates of renal and cardiovascular complications, all-cause mortality and hospitalisations over the study period were compared among those with and without CKD., Results: There were 574 190 eligible patients with T2D as of 1 January 2017 and 664 296 as of 31 December 2019. Estimated prevalence of CKD across the study period was stable at approximately 30%. Medication use was stable over time in people with CKD and T2D, with low use of steroidal mineralocorticoid receptor antagonists (approximately 4.5% across all time points) and a low use but steady increase in use of sodium-glucose co-transporter-2 inhibitors (from 2.6% to 6.2%). Rates of all complications were higher in those with CKD at the start of the study period, with increasing rates, with increased severity of CKD, heart failure and albuminuria., Conclusions: The burden of CKD in patients with T2D is high and associated with substantially increased rates of complications particularly in those with comorbid heart failure., Competing Interests: Competing interests: JB is an employee of Bayer, UK. NS is now an employee at Boehringer Ingelheim International. All of his work for this project was done while an employee for Bayer AG. Imperial College London received funding on behalf of JKQ, and SC for the work. PK and LAT received funding from Bayer AG for their contributions to this project., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Chronic kidney disease (CKD), a serious complication of type 2 diabetes (T2D) increases the comorbid risk of cardiovascular disease (CVD) and end-stage kidney disease(ESKD). Treatment guidelines recommend renin-angiotensin blockade and antihyperglycemic treatment with metformin and sodium-glucose cotransporter 2 inhibitors (SGLT2is) as first-line treatment. We evaluated treatment initiation and discontinuation overall and in subgroups of T2D patients with incident CKD (incident cohort) and rates of clinical and economic outcomes in patients with T2D and any CKD (prevalent cohort)., Methods: In this retrospective study of administrative claims in the USA between 1 January 2007 and 31 March 2019, we evaluated the proportion of patients with concomitant, newly initiated and discontinued use of antihypertensive [angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blockers (ARBs), steroidal mineralocorticoid receptor antagonists (sMRAs)] and antidiabetic [SGLT2is, dipeptidyl peptidase-4 inhibitors (DPP4is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), insulin and sulfonylureas] medications, rates of clinical outcomes per 1000 person-years and mean total healthcare costs., Results: We identified 63 127 and 326 763 patients in the incident and prevalent CKD cohorts, respectively. Low initiation and high discontinuation rates were observed with 17.8% and 56.0% for ACEi/ARBs, 1.3% and 66.0% for sMRAs, 2.5% and 65.0% for SGLT2is, 3.7% and 66.8% for DPP4is, 2.31% and 69.0% for GLP-1 RAs, 4% and 75.7% for insulin and 5.5% and 56.9% for sulfonylureas. Similar results were seen by subgroups. Rates of clinical outcomes ranged from 35.07 per 1000 person-years for all-cause mortality to 104.19 for ESKD, with rates of hospitalization ranging from 36.61 for kidney hospitalizations to 283.14 for all-cause hospitalizations. Among patients with comorbidities, higher clinical and economic outcomes were found., Conclusion: Our results highlight high unmet needs of CKD and T2D, particularly subgroups of patients with multimorbid CVD, high-risk CKD (low estimated glomerular filtration rate or high urinary albumin:creatinine ratio) or rapidly progressing CKD. Low initiation and high discontinuation of recommended treatments suggest that adherence to guidelines for halting CKD progression is suboptimal. These high-risk patients may benefit from further treatment options to improve morbidity and mortality and reduce the economic burden., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)