BACKGROUND:We describe changes in HbA1c and body-weight and the relationship between drug adherence and clinical response in a large real-world cohort of patients with type 2 diabetes (T2D) treated with subcutaneous semaglutide for up to three years. METHODS:We included adults with T2D registered at Maccabi Healthcare Services, Israel, who initiated subcutaneous semaglutide (August 2019 - June 2022). Adherence, assessed as Proportion of Days Covered (PDC), was based on drug's dispensation. We assessed the absolute change in HbA1c and the relative change in body-weight from baseline. RESULTS:The 23,442 participants (11,513 women) had a mean age of 62.2 years, HbA1c of 7.6 %, and BMI of 33.7 kg/m2. Compared to baseline, the mean reductions in HbA1c were 0.77 [95 %CI 0.75-0.78], 0.57 [0.53-0.61], and 0.35 [0.27-0.44] %-points at 6 months, 2 years, and 3 years, respectively. The respective body-weight reductions were 4.9 % [4.8-5.0], 5.3% [5.1-5.5], and 4.5 % [3.7-5.2]. Among 6049 patients with ≥2 years of potential follow-up, median PDC between 0-6 months was 83.9 %, and remained relatively stable thereafter, reaching 74.6 % between 18-24 months. Higher PDC was associated with more pronounced HbA1c and body-weight reductions. CONCLUSIONS:Long-term real-world adherence with semaglutide was relatively stable. Semaglutide use was associated with sustained glycemic control and weight reduction in patients with T2D and relatively good baseline glycemic control, especially among those with high adherence, supporting its use for long-term management of T2D.

Background:Chronic kidney disease (CKD) is a global concern that presents significant challenges for disease management. Several factors drive CKD prevalence, including primary risk factors, such as type 2 diabetes and hypertension, and an ageing population. Inside CKD is an international initiative that aims to raise awareness of the substantial burden incurred by CKD. Methods:Using a peer-reviewed microsimulation method, the clinical burden of CKD was estimated from 2022 to 2027. Demographic data from the Americas, Europe, and Asia-Pacific/Middle East were used to generate virtual populations and to project the prevalence of CKD, kidney replacement therapy, associated cardiovascular complications, comorbid conditions, and all-cause mortality in the CKD population over the modelled time frame. Findings:Across the 31 participating countries/regions, the total prevalence of CKD was projected to rise to 436.6 million cases by 2027 (an increase of 5.8% from 2022), with most cases (∼80%) undiagnosed. Inside CKD projected a mean of 8859 cases of heart failure, 10,244 of myocardial infarction, and 7797 of stroke per 100,000 patients with CKD by 2027. Interpretation:The clinical impact of CKD is substantial and likely to increase; the high prevalence of undiagnosed cases and associated complications may benefit from the implementation of health policy interventions that promote screening, earlier diagnosis, and interventions to improve outcomes. Funding:AstraZeneca.

Breast cancer (BC) is associated with type 2 diabetes mellitus (T2DM) and obesity. Glucagon-like peptide (GLP)-1 regulates post-prandial insulin secretion, satiety, and gastric emptying. Several GLP-1 analogs have been FDA-approved for the treatment of T2DM and obesity. Moreover, GLP-1 regulates various metabolic activities across different tissues by activating metabolic signaling pathways like adenosine monophosphate (AMP) activated protein kinase (AMPK), and AKT. Rewiring metabolic pathways is a recognized hallmark of cancer, regulated by several cancer-related pathways, including AKT and AMPK. As GLP-1 regulates AKT and AMPK, we hypothesized that it alters BC cells’ metabolism, thus inhibiting proliferation. The effect of the GLP-1 analogs exendin-4 (Ex4) and liraglutide on viability, AMPK signaling and metabolism of BC cell lines were assessed. Viability of BC cells was evaluated using colony formation and MTT/XTT assays. Activation of AMPK and related signaling effects were evaluated using western blot. Metabolism effects were measured for glucose, lactate and ATP. Exendin-4 and liraglutide activated AMPK in a cAMP-dependent manner. Blocking Ex4-induced activation of AMPK by inhibition of AMPK restored cell viability. Interestingly, Ex4 and liraglutide reduced the levels of glycolytic metabolites and decreased ATP production, suggesting that GLP-1 analogs impair glycolysis. Notably, inhibiting AMPK reversed the decline in ATP levels, highlighting the role of AMPK in this process. These results establish a novel signaling pathway for GLP-1 in BC cells through cAMP and AMPK modulation affecting proliferation and metabolism. This study suggests that GLP-1 analogs should be considered for diabetic patients with BC.

Objective Digital healthcare systems could provide insights into the global prevalence of heart failure (HF). We designed the CardioRenal and Metabolic disease (CaReMe) HF study to estimate the prevalence, key clinical adverse outcomes and costs of HF across 11 countries. Methods Individual level data from a contemporary cohort of 6 29 624 patients with diagnosed HF was obtained from digital healthcare systems in participating countries using a prespecified, common study plan, and summarised using a random effects meta-analysis. A broad definition of HF (any registered HF diagnosis) and a strict definition (history of hospitalisation for HF) were used. Event rates were reported per 100 patient years. Cumulative hospital care costs per patient were calculated for a period of up to 5 years. Results The prevalence of HF was 2.01% (95% CI 1.65 to 2.36) and 1.05% (0.85 to 1.25) according to the broad and strict definitions, respectively. In patients with HF (broad definition), mean age was 75.2 years (95% CI 74.0 to 76.4), 48.8% (40.9–56.8%) had ischaemic heart disease and 34.5% (29.4–39.6%) had diabetes. In 51 442 patients with a recorded ejection fraction (EF), 39.1% (30.3–47.8%) had a reduced, 18.8% (13.5–24.0%) had a mildly reduced and 42.1% (31.5–52.8%) had a preserved left ventricular EF. In 1 69 518 patients with recorded estimated glomerular filtration rate, 49% had chronic kidney disease (CKD) stages III–V. Event rates were highest for cardiorenal disease (HF or CKD) and all cause mortality (19.3 (95% CI 11.3 to 27.1) and 13.1 (11.1 to 15.1), respectively), and lower for myocardial infarction, stroke and peripheral artery disease. Hospital care costs were highest for cardiorenal diseases. Conclusions We estimate that 1–2% of the contemporary adult population has HF. These individuals are at significant risk of adverse outcomes and associated costs, predominantly driven by hospitalisations for HF or CKD. There is considerable public health potential in understanding the contemporary burden of HF and the importance of optimising its management.

Background Studies that have reported lower risk for cardiovascular outcomes in users of Sodium–Glucose Cotransporter-2 Inhibitors (SGLT-2i) are limited by residual cofounding and lack of information on prior cardiovascular disease (CVD). This study compared risk of cardiovascular events in patients within routine care settings in Europe and Asia with type 2 diabetes (T2D) initiating empagliflozin compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) stratified by pre-existing CVD and history of heart failure (HF). Methods and results Adults initiating empagliflozin and DPP-4i in 2014–2018/19 from 11 countries in Europe and Asia were compared using propensity score matching and Cox proportional hazards regression to assess differences in rates of primary outcomes: hospitalisation for heart failure (HHF), myocardial infarction (MI), stroke; and secondary outcomes: cardiovascular mortality (CVM), coronary revascularisation procedure, composite outcome including HHF or CVM, and 3-point major adverse cardiovascular events (MACE: MI, stroke and CVM). Country-specific results were meta-analysed and pooled hazard ratios (HR) with 95% confidence intervals (CI) from random-effects models are presented. In total, 85,244 empagliflozin/DPP4i PS-matched patient pairs were included with overall mean follow-up of 0.7 years. Among those with pre-existing CVD, lower risk was observed for HHF (HR 0.74; 95% CI 0.64–0.86), CVM (HR 0.55; 95% CI 0.38–0.80), HHF or CVM (HR 0.57; 95% CI 0.48–0.67) and stroke (HR 0.79; 95% CI 0.67–0.94) in patients initiating empagliflozin vs DPP-4i. Similar patterns were observed among patients without pre-existing CVD and those with and without pre-existing HF. Conclusion These results from diverse patient populations in routine care settings across Europe and Asia demonstrate that initiation of empagliflozin compared to DPP-4i results in favourable cardioprotective effects regardless of pre-existing CVD or HF status.

BACKGROUND:Contemporary guidelines recommend the use of sodium-glucose cotransporter 2 inhibitors (SGLT2is) independently of glycemic control in patients with type 2 diabetes and those with kidney disease, with heart failure, or at high risk of cardiovascular disease. Using a large Israeli database, we assessed whether long-term use of SGLT2is versus dipeptidyl peptidase 4 inhibitors (DPP4is) is associated with kidney benefits in patients with type 2 diabetes overall and in those without evidence of cardiovascular or kidney disease. METHODS:Patients with type 2 diabetes who initiated SGLT2is or DPP4is between 2015 and 2021 were propensity score-matched (1:1) according to 90 parameters. The kidney-specific composite outcome included confirmed ≥40% decline in eGFR or kidney failure. The kidney-or-death outcome included also all-cause mortality. Risks of outcomes were assessed using Cox proportional hazard regression models. The between-group difference in eGFR slope was also assessed. Analyses were repeated in patients' subgroup lacking evidence of cardiovascular or kidney disease. RESULTS:Overall, 19,648 propensity score-matched patients were included; 10,467 (53%) did not have evidence of cardiovascular or kidney disease. Median follow-up was 38 months (interquartile range, 22-55). The composite kidney-specific outcome occurred at an event rate of 6.9 versus 9.5 events per 1000 patient-years with SGLT2i versus DPP4i. The respective event rates of the kidney-or-death outcome were 17.7 versus 22.1. Compared with DPP4is, initiation of SGLT2is was associated with a lower risk for the kidney-specific (hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.61 to 0.86; P < 0.001) and kidney-or-death (HR, 0.80; 95% CI, 0.71 to 0.89; P < 0.001) outcomes. The respective HRs (95% CI) in those lacking evidence of cardiovascular or kidney disease were 0.67 (0.44 to 1.02) and 0.77 (0.61 to 0.97). Initiation of SGLT2is versus DPP4is was associated with mitigation of the eGFR slope overall and in those lacking evidence of cardiovascular or kidney disease (mean between-group differences 0.49 [95% CI, 0.35 to 0.62] and 0.48 [95% CI, 0.32 to 0.64] ml/min per 1.73 m 2 per year, respectively). CONCLUSIONS:Long-term use of SGLT2is versus DPP4is in a real-world setting was associated with mitigation of eGFR loss in patients with type 2 diabetes, even in those lacking evidence of cardiovascular or kidney disease at baseline.

Binge-eating disorder) BED) is the most common eating disorder in the United-States. Daily, orally administered topiramate has shown BED treatment efficacy, with two major limitations: frequent and severe side effects and slow time-to-effect. SipNose is a novel non-invasive intranasal direct nose-to-brain drug delivery platform that delivers drugs to the central nervous system consistently and rapidly. Herein, we study a SipNose-topiramate combination product, as an acute “as needed” (PRN) solution for BED management. First, SipNose-topiramate’s pharmacokinetics (PK) and safety was evaluated. The second part aimed to demonstrate its PRN-treatment feasibility in terms of usability and potential efficacy in reducing the number of binge-eating events. Twelve BED patients were studied over three time periods; 2-weeks of baseline monitoring [BL], 8-weeks of treatment [TX], and 2-weeks of follow up [FU]. The PK profile showed peak plasma levels at 90 min post-administration, a t1/2 > 24 h and consistent topiramate delivery with no adverse events. In the second part, 251 treatments were self-administered by the patient participants. There was a significant reduction from baseline to treatment periods in mean weekly binge-eating events and binge-eating event days per week. This was maintained during the follow up period. Efficacy was corroborated by improved patient illness severity scales. There were no adverse events associated with any administered treatments. Patients were exposed to less drug when compared with accepted oral dosing. This study introduces a SipNose-topiramate drug-device combination as a potentially safe, effective, and controlled method for BED management. Its findings introduce a potential approach to BED management both as an intranasal and as a PRN therapy for reducing binge-eating events, with a large-scale reduction in patient drug exposure and side effects and with improved patient quality of life. Further studies are needed with larger patient populations to establish SipNose-topiramate as a mainstream treatment for BED. Trial registration: Registration number and date of registration of the clinical studies reported in this article are as follows: 0157-18-HMO, August 15th 2018 and 6814-20-SMC, December 2nd 2020. Binge eating disorder (BED) is a common eating disorder. Daily oral topiramate treatment has shown efficacy in clinical studies and off-label use, with frequent and severe side effects. SipNose is a novel, rapid and consistent direct nose-to-brain drug delivery platform. This study evaluates a SipNose-topiramate combination product, as an innovative acute “as needed” (PRN) BED treatment solution. SipNose-topiramate's pharmacokinetics (PK) and safety demonstrated consistent, dose-dependent topiramate delivery with no adverse events. SipNose-topiramate was studied vis-à-vis its safety and feasibility as a PRN-treatment for reducing the number of binge-eating events. 12 BED patients were studied (2-weeks baseline monitoring, 8-weeks treatment, 2-weeks follow-up). Patients were instructed to self-administer the drug when they feel an urge to binge-eat. Two hundred fifty-one treatments were administered. When compared with daily oral dosing, lower doses were used with no adverse events and minimal side effects. Baseline to treatment periods showed significant reduction in mean weekly binge-eating events and binge-eating event days-per-week. This was maintained during follow-up. Improved illness severity scales corroborated the improved feasibility outcomes. In conclusion, this study introduces SipNose-topiramate as a potential “as needed” intranasal treatment for BED that is safe, effective, and reduces drug exposure and side effects. Additional studies are needed to validate SipNose-topiramate as a BED management therapy.

BACKGROUND:Continued expansion of indications for sodium-glucose cotransporter-2 inhibitors increases importance of evaluating cardiovascular and kidney efficacy and safety of empagliflozin in patients with type 2 diabetes compared to similar therapies. METHODS:The EMPRISE Europe and Asia study is a non-interventional cohort study using data from 2014-2019 in seven European (Denmark, Finland, Germany, Norway, Spain, Sweden, United Kingdom) and four Asian (Israel, Japan, South Korea, Taiwan) countries. Patients with type 2 diabetes initiating empagliflozin were 1:1 propensity score matched to patients initiating dipeptidyl peptidase-4 inhibitors. Primary endpoints included hospitalization for heart failure, all-cause mortality, myocardial infarction and stroke. Other cardiovascular, renal, and safety outcomes were examined. FINDINGS:Among 83,946 matched patient pairs, (0·7 years overall mean follow-up time), initiation of empagliflozin was associated with lower risk of hospitalization for heart failure compared to dipeptidyl peptidase-4 inhibitors (Hazard Ratio 0·70; 95% CI 0.60 to 0.83). Risks of all-cause mortality (0·55; 0·48 to 0·63), stroke (0·82; 0·71 to 0·96), and end-stage renal disease (0·43; 0·30 to 0·63) were lower and risk for myocardial infarction, bone fracture, severe hypoglycemia, and lower-limb amputation were similar between initiators of empagliflozin and dipeptidyl peptidase-4 inhibitors. Initiation of empagliflozin was associated with higher risk for diabetic ketoacidosis (1·97; 1·28 to 3·03) compared to dipeptidyl peptidase-4 inhibitors. Results were consistent across continents and regions. INTERPRETATION:Results from this EMPRISE Europe and Asia study complements previous clinical trials and real-world studies by providing further evidence of the beneficial cardiorenal effects and overall safety of empagliflozin compared to dipeptidyl peptidase-4 inhibitors.

Patients with type 2 diabetes (T2D) have a high incidence of hospitalizations that reduce patients' quality of life and are translated into a significant burden on healthcare systems, accompanied by increased costs.1, 2 Randomized controlled trials (RCTs) showed that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of cardiovascular events, heart failure (HF) hospitalizations, and kidney outcomes in patients with T2D, HF, or chronic kidney disease (CKD).3 In some of these RCTs, SGLT2 inhibitors also modestly reduced the risk for any hospitalization.4-11 However, these studies included patients with T2D and high cardiovascular risk,4-6, 11 or patients with CKD with and without T2D.8, 9 Whether SGLT2 inhibitor use is associated with a lower risk for any hospitalization in a general population of patients with T2D, especially patients without CKD, is unknown. This was an observational, retrospective, cohort study of data from Maccabi Healthcare Services (MHS), Israel's seconds largest Health Maintenance Organization. We assessed the association of long-term, real-world use of SGLT2 inhibitors, versus that of dipeptidyl peptidase-4 (DPP-4) inhibitors, with risk for hospitalization in patients with T2D lacking evidence of CKD. The database includes over 2.2 million patients, and approximately 180 000 are in the diabetes registry, with a 99% yearly retention rate. Patients with T2D, who initiated an SGLT2 inhibitor (empagliflozin or dapagliflozin) in an outpatient setting between August 2015 and December 2020 were propensity-scored matched with patients starting a DPP-4 inhibitor (sitagliptin, linagliptin, vildagliptin or saxagliptin). The presence of T2D was defined by an algorithm combining laboratory measurements (glycated haemoglobin [HbA1c] and fasting plasma glucose), purchased glucose-lowering agents, and diagnoses of diabetes made by expert physicians, as previously described.12 The day of treatment initiation was defined as the index date, and the preceding 12 months were defined as the baseline period. We included only adults with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2. We excluded patients with type 1 diabetes, defined by more than four insulin purchases per year following diabetes diagnosis without an oral glucose-lowering agent, and entry to the diabetes registry at age earlier than 26 years.12 We also excluded patients with urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g, evidence of pregnancy within the prior 9 months, or with a record of SGLT2 inhibitor or DPP-4 inhibitor use in the baseline period in order to limit time-related biases. Comparable groups were created using propensity-score matching according to patients' demographics, medical history, background medications, and socioeconomic status, as previously described.13 A multivariate logistic regression model was used to develop the propensity score, and the dependent binary variable indicated whether the indexed medication was an SGLT2 inhibitor or a DPP-4 inhibitor. Matching was performed by baseline eGFR layers (≥90 or 60 to <90 mL/min/1.73 m2). The complete list of the 95 variables used for matching is presented in Appendix S1. Medical history was collected from validated MHS registries or using International Classification of Diseases-9 or Anatomical Therapeutic Chemical codes (Table S1). Laboratory and clinical values were collected only in outpatient settings to avoid changes in parameters that may occur during acute states. In the intention-to-treat analysis, patients were followed from the index date until September 2021, death, or end of data availability. In the as-treated definition, follow-up was also censored at the end of the last prescription duration with a 90–day grace period added to this, or at the initiation of the comparator study drug without a grace period. The study outcomes were the risks of first any hospitalization or prolonged hospitalization (≥3 nights). Cox proportional hazards regression models were applied to compare outcomes between the groups. We assessed subgroups of patients defined by their sex, age (<60 or ≥60 years), socioeconomic status14 (1-4, 5-7, 8-10), index year of study entry (2015-2016, 2017, 2018, 2019, and 2020), body mass index (<30 or ≥30 kg/m2), HbA1c (<8% or ≥8% [<64 mmol/mol or ≥64 mmol/mol]), history of cardiovascular disease (Appendix S1 and Table S2), history of HF,12 eGFR (≥90 or 60 to <90 mL/min/1.73 m2), urinary albumin (urine albumin below detectable levels or UACR >0 to <30 mg/g), and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use. The models were adjusted to the treatment arm, subgroups, and an interaction term between the treatment arm and the subgroups to assess heterogeneity. Analyses were performed using SAS version 9.4. The study received ethical approval from the institutional review board at MHS. Participants' informed consent was not required by the committee due to the anonymized nature of the dataset. After applying the inclusion and exclusion criteria, 10 090 and 15 238 patients initiated treatment with SGLT2 inhibitors and DPP-4 inhibitors, respectively (Tables S3 and S4; Figure S1). Following propensity-score matching, there were 6477 patients in each arm; 5431 patients (41.9%) were women and the mean (SD) patient age was 59.8 (10.9) years (Table 1). The mean baseline eGFR was 93.4 (14.2) mL/min/1.73 m2, over half of the cohort did not have detectable albumin in urine, and 10 426 (80.5%) had no evidence of cardiovascular disease. Baseline characteristics were balanced between the matched cohorts (Table 1; Tables S3 and S4). During a median (interquartile range) follow-up of 39.2 (21.9-54.9) months (Table S5), 2130 (32.9%) and 2211 (34.1%) of the participants were hospitalized in the SGLT2 inhibitor and DPP-4 inhibitor arms, respectively (13.1 vs. 14.1 hospitalized patients per 100 patient-years; hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.88-0.99). The risk of prolonged (≥3 nights) hospitalization was also lower with SGLT2 inhibitors compared to DPP-4 inhibitors (HR 0.91, 95% CI 0.84-0.98; Figure 1). There was no clear evidence for heterogeneity of the association between initiation of SGLT2 inhibitors versus DPP-4 inhibitors, with risk of any hospitalization by baseline subgroups, although the treatment effect was numerically more pronounced in patients with eGFR 60 to <90 mL/min/1.73 m2 versus eGFR ≥90 mL/min/1.73 m2 (HR 0.87, 95% CI 0.80-0.96 vs. HR 0.98, 95% CI 0.91-1.06, respectively; P-interaction = 0.051), and in those with detectable albumin in urine versus those with urinary albumin below detectable levels (HR 0.88, 95% CI 0.80-0.96 vs. HR 1.00, 95% CI 0.92-1.08, respectively; P-interaction = 0.053 [Figure 1; Table S6]). The association between treatment arms and the risk of prolonged hospitalization was more pronounced in patients with evidence of cardiovascular disease at baseline (P-interaction = 0.012; Figure 1). Similar findings were observed with the as-treated analysis, demonstrating lower risks of first any or prolonged hospitalization with the initiation of SGLT2 inhibitors versus that of DPP-4 inhibitors (Figure S2 and Table S6). Initiation of SGLT2 inhibitors versus DPP-4 inhibitors was associated with a 6% (95% CI 1-12) reduction in the risk of any hospitalization and a 9% (95% CI 2-16) reduction in the risk of prolonged (≥3 nights) hospitalizations. These findings are in line with cumulating data from RCTs.4-10 In the EMPA-REG OUTCOME trial, treatment with empagliflozin compared with placebo resulted in a significant 11% (95% CI 4-19) reduction in the risk of first hospitalization in patients with T2D and previous cardiovascular disease.4 In the CANVAS program, which also included patients with high risk but without established cardiovascular disease, the risk of first all-cause hospitalization was one of the prespecified outcomes. The effect of canagliflozin was marginally significant compared with placebo (HR 0.94, 95% CI 0.88-1.00).6 A post hoc analysis of this trial found a significant 8% reduction in the rate of all (first and subsequent) hospitalizations, mainly driven by a reduction in cardiac-related hospitalizations.5 Post hoc data of the DECLARE-TIMI 58 found a similar 11% reduction in risk of first hospitalizations in 17 160 patients with T2D, with creatinine clearance >60 mL/min, most of them (59.4%) with high risk for but without evidence of cardiovascular disease.11 In the SOLOIST-WHF study involving patients with T2D and recent worsening HF, sotagliflozin increased the number of days alive and out of hospital.10 Analyses from the EMPA-KIDNEY9 and DAPA-CKD8 trials found a lower risk of hospitalizations from any cause with empagliflozin and dapagliflozin, respectively, in patients with CKD with and without T2D. However, all these trials included specific populations with relatively high baseline cardiovascular or kidney risk, compared with the general populations of patients with T2D. Several real-world evidence studies also found an association between SGLT2 inhibitor use and a lower risk of hospitalization.15-18 However, these studies had shorter follow-up duration,15-17 fewer participants,15, 16 or high CV risk.16 The long-term follow-up accompanied by a large number of participants in this analysis enabled us to show that SGLT2 inhibitor use is associated with reduced risk of any-cause hospitalization, even in patients with T2D without evidence of CKD. The diabetes-attributed global annual expenditure rate was 1.3 trillion USD in 2015 and is expected to increase to 2.1 trillion USD in 2030.19 In the United States, hospitalizations and inpatient care are responsible for approximately 30% of medical expenditure in patients with diabetes.2 Thus, even a mild treatment effect on the relative risk of hospitalization may be translated into valuable cost benefits. How SGLT2 inhibitor-mediated reduction of hospitalization risk affects diabetes-related expenditures and patients' quality of life remains to be investigated. This study has several limitations. It is an observational study, and while we used propensity-score matching, the presence of residual bias cannot be excluded, and no causation can be drawn. It is based on one registry, so the external validity remains to be tested, especially in different healthcare systems. We were unable to differentiate elective from non-elective hospitalizations in the dataset; however, we assessed the risk of prolonged (≥3 nights) hospitalizations—events that may have higher clinical relevance. The risk of hospitalization may fluctuate at different seasons and due to pandemics. Finally, although SGLT2 inhibitors in RCTs had varying effects on different causes of hospitalizations,8, 9, 11 we did not assess the risk of specific hospitalization aetiologies, limiting discussion on potential mechanisms. Future studies are needed to evaluate the effect of SGLT2 inhibitors on cause-specific hospitalizations in real-world settings. In conclusion, in a real-world setting, initiation of SGLT2 inhibitors versus DPP-4 inhibitors was associated with lower risks of any or prolonged (≥3 nights) all-cause hospitalization in patients with T2D lacking evidence of CKD. Design: Meir Schechter, Cheli Melzer Cohen, Ilan Yanuv, Aliza Rozenberg, Avraham Karasik, and Ofri Mosenzon. Conduct/data collection: Meir Schechter, Cheli Melzer Cohen, Gabriel Chodick, Avraham Karasik and Ofri Mosenzon. Analysis: Cheli Melzer Cohen, Ilan Yanuv, Aliza Rozenberg and Gabriel Chodick. Writing manuscript: Meir Schechter, Tamir Zelter and Ofri Mosenzon. This was an investigator-initiated project. The study was funded by Boehringer Ingelheim. The funder was involved in study design by means of providing nonbinding scientific expert advice and approved this report. This report was written by the investigators and the decision to submit for publication was made solely by the investigators. Meir Schechter reports travel support from Novo Nordisk and AstraZeneca through Hadassah Medical Center, and lecturing fees from AstraZeneca. Cheli Melzer Cohen, Tamir Zelter and Gabriel Chodick have no conflict of interest to declare. Ilan Yanuv and Aliza Rozenberg receive hourly payment from AstraZeneca through Hadassah Medical Center and from Novo Nordisk. Avraham Karasik has received research grants and speaking honoraria from AstraZeneca, Novo Nordisk and Boehringer Ingelheim. Ofri Mosenzon reports Advisory Board membership for Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca and BOL Pharma, research grant support through Hadassah Hebrew University Hospital from Novo Nordisk and AstraZeneca, and Speaker's Bureau participation for AstraZeneca, Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, and Boehringer Ingelheim. From May 1st, 2023, Ofri Mosenzon has been an employee of Regeneron Pharmaceuticals Inc. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.15172. The data supporting this study's findings are available upon reasonable request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions. Appendix S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

BACKGROUND:In 2019, 1 mg subcutaneous semaglutide was registered for the treatment of diabetes in Israel. Recognition of its effect on weight has led to its use as a treatment for obesity.OBJECTIVES:To explore physicians' pre-therapy considerations, therapy practices, and attitudes regarding subcutaneous semaglutide for weight loss.METHODS:A 22-item questionnaire was disseminated to physicians who prescribed semaglutide 1-mg for weight loss using an authorized off-label path.RESULTS:In total, 127 physicians completed the questionnaire. As for pretreatment requirements, in the absence of diabetes, 30% requested a minimal body mass index of 30 kg/m2. Additional requirements were documented lifestyle-change effort (67%) and prior weight loss medication use (13%). Half of the physicians regarded calorie restriction, and 23% considered physical activity as necessary for weight loss while on therapy. As for dose, most physicians (78%) started with a 0.25-mg weekly injection, 57% doubled the dose monthly, and all others recommended doubling when side effects subsided. Regarding weight loss goal, 43% of the physicians set a personal goal with each patient while 26% limited the goal to 10% of initial weight. Fewer than 50% of physicians discussed treatment duration with their patients, and 52% of patients discontinued therapy in the first 3 months. The main reasons for discontinuation were price, lack of effect, and fear of long-term side effects.CONCLUSIONS:The diverse approaches regarding off-label use of semaglutide for weight reduction highlight the necessity to guide physicians and standardize treatment regimen.

Abstract Background In clinical trials enrolling patients with type 2 diabetes (T2D) at high cardiovascular risk, many glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improved albuminuria status and possibly mitigated kidney function loss. However, limited data are available regarding the effects of GLP-1 RAs on albuminuria status and kidney function in real-world settings, including populations with a lower baseline cardiovascular and kidney risk. We assessed the association of GLP-1 RAs initiation with long-term kidney outcomes in the Maccabi Healthcare Services database, Israel. Methods Adults with T2D treated with ≥ 2 glucose-lowering agents who initiated GLP-1 RAs or basal insulin from 2010 to 2019 were propensity-score matched (1:1) and followed until October 2021 (intention-to-treat [ITT]). In an as-treated (AT) analysis, follow-up was also censored at study-drug discontinuation or comparator-initiation. We assessed the risk of a composite kidney outcome, including confirmed ≥ 40% eGFR loss or end-stage kidney disease, and the risk of new macroalbuminuria. Treatment-effect on eGFR slopes was assessed by fitting a linear regression model per patient, followed by a t-test to compare the slopes between the groups. Results Each propensity-score matched group constituted 3424 patients, 45% women, 21% had a history of cardiovascular disease, and 13.9% were treated with sodium-glucose cotransporter-2 inhibitors at baseline. Mean eGFR was 90.6 mL/min/1.73 m2 (SD 19.3) and median UACR was 14.6 mg/g [IQR 0.0–54.7]. Medians follow-up were 81.1 months (ITT) and 22.3 months (AT). The hazard-ratios [95% CI] of the composite kidney outcome with GLP-1 RAs versus basal insulin were 0.96 [0.82–1.11] (p = 0.566) and 0.71 [0.54–0.95] (p = 0.020) in the ITT and AT analyses, respectively. The respective HRs for first new macroalbuminuria were 0.87 [0.75–0.997] and 0.80 [0.64–0.995]. The use of GLP-1 RA was associated with a less steep eGFR slope compared with basal insulin in the AT analysis (mean annual between-group difference of 0.42 mL/min/1.73 m2/year [95%CI 0.11–0.73]; p = 0.008). Conclusion Initiation of GLP-1 RAs in a real-world setting is associated with a reduced risk of albuminuria progression and possible mitigation of kidney function loss in patients with T2D and mostly preserved kidney function.

Background Iron plays a key role in human immune responses; however, the influence of iron deficiency on the coronavirus disease 2019 (COVID-19) vaccine effectiveness is unclear. Aim To assess the effectiveness of the BNT162b2 messenger RNA COVID-19 vaccine in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19–related hospitalization and death in individuals with or without iron deficiency. Methods This large retrospective, longitudinal cohort study analyzed real-world data from the Maccabi Healthcare Services database (covering 25% of Israeli residents). Eligible adults (aged ≥ 16 years) received a first BNT162b2 vaccine dose between December 19, 2020, and February 28, 2021, followed by a second dose as per approved vaccine label. Individuals were excluded if they had SARS-CoV-2 infection before vaccination, had hemoglobinopathy, received a cancer diagnosis since January 2020, had been treated with immunosuppressants, or were pregnant at the time of vaccination. Vaccine effectiveness was assessed in terms of incidence rates of SARS-CoV-2 infection confirmed by real-time polymerase chain reaction assay, relative risks of COVID-19–related hospitalization, and mortality in individuals with iron deficiency (ferritin <30 ng/mL or transferrin saturation <20%). The two-dose protection period was Days 7 to 28 after the second vaccination. Results Data from 184,171 individuals with (mean [standard deviation; SD] age 46.2 [19.6] years; 81.2% female) versus 1,072,019 without (mean [SD] age 46.9 [18.0] years; 46.2% female) known iron deficiency were analyzed. Vaccine effectiveness in the two-dose protection period was 91.9% (95% confidence interval [CI] 83.7–96.0%) and 92.1% (95% CI 84.2–96.1%) for those with versus without iron deficiency ( P = 0.96). Of patients with versus without iron deficiency, hospitalizations occurred in 28 and 19 per 100,000 during the reference period (Days 1–7 after the first dose), and in 19 and 7 per 100,000 during the two-dose protection period, respectively. Mortality rates were comparable between study groups: 2.2 per 100,000 (4/181,012) in the population with iron deficiency and 1.8 per 100,000 (19/1,055,298) in those without known iron deficiency. Conclusions Results suggest that the BNT162b2 COVID-19 vaccine is >90% effective in preventing SARS-CoV-2 infection in the 3 weeks after the second vaccination, irrespective of iron-deficiency status. These findings support the use of the vaccine in populations with iron deficiency.

Background Digital healthcare systems data could provide insights into the global prevalence of chronic kidney disease (CKD). We designed the CaReMe CKD study to estimate the prevalence, key clinical adverse outcomes and costs of CKD across 11 countries. Methods Individual-level data of a cohort of 2.4 million contemporaneous CKD patients was obtained from digital healthcare systems in participating countries using a pre-specified common protocol; summarized using random effects meta-analysis. CKD and its stages were defined in accordance with current Kidney Disease: Improving Global Outcomes (KDIGO) criteria. CKD was defined by laboratory values or by a diagnosis code. Findings The pooled prevalence of possible CKD was 10.0% (95% confidence interval 8.5-11.4; mean pooled age 75, 53% women, 38% diabetes, 60% using renin-angiotensin-aldosterone system inhibitors). Two out of three CKD patients identified by laboratory criteria did not have a corresponding CKD-specific diagnostic code. Among CKD patients identified by laboratory values, the majority (42%) were in KDIGO stage 3A; and this fraction was fairly consistent across countries. The share with CKD based on urine albumin-creatinine ratio (UACR) alone (KDIGO stages one and two) was 29%, with a substantial heterogeneity between countries. Adverse events were common; 6.5% were hospitalized for CKD or heart failure, and 6.2% died, annually. Costs for renal events and heart failure were consistently higher than costs for atherosclerotic events in CKD patients across all countries. Interpretation We estimate that CKD is present in one out often adults. These individuals experience significant adverse outcomes with associated costs. The prevalence of CKD is underestimated when using diagnostic codes alone. There is considerable public health potential in diagnosing CKD and providing treatments to those currently undiagnosed. (C) 2022 The Author(s). Published by Elsevier Ltd.

Kidney-protective effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) are supported by both randomized control trials and real world evidence in high cardiorenal risk type 2 diabetes mellitus (T2DM) patients. However, long-term efficacy studies of T2DM patients with normal kidney function and low cardiorenal risk are lacking. Using a large Israeli database we studied kidney outcomes in patients with T2DM with low baseline KDIGO risk (eGFR≥60 ml/min/1.73, UACR<30 mg/g) and no cardiovascular history. Patients who initiated empagliflozin or any SGLT2i during 2015-2021 were propensity score matched to DPP4i initiators by 120 baseline characteristics and followed until an event or end of study period. The primary outcome included a composite of ≥40% sustained eGFR decline, end-stage kidney disease (ESKD) , or all cause death. Risk was calculated using cox-proportional hazard models adjusted to baseline eGFR. At baseline, 5195 matched pairs of empagliflozin or DPP4i initiators had a mean age of 60 Y, mean eGFR of 93 mL/min/1.73 m2 and were followed for a median of 35.2 months. Number of events for composite kidney outcomes was 172 (11.0 events per 1000 patient-years [PY]) in the empagliflozin group and 215 (13.7 events per 1000 PY) in the DPP4i group, HR 0.79 (95% CI 0.65-0.97; p=0.02) . Similar trends were observed for composite of ≥40% sustained eGFR decline or ESKD. Comparing all SGLT2 to DPP4i initiators (n= 6477, median FU time 37.6 months) number of events was 2 (9.9 events per 1000 PY) for SGLT2i and 266 (13.0 events per 1000 PY) in DPP4i, HR 0.77 (95% CI 0.64-0.92) . In conclusion the benefits of empagliflozin and any SGLT2 inhibitors on kidney function are observed in T2DM patients with low cardiorenal risk. The finding supports use of empagliflozin independent of glycemic control in low cardiorenal T2DM patients. Disclosure M.Schechter: None. C.Melzer cohen: None. A.Rozenberg: None. I.Yanuv: None. G.Chodick: None. O.Mosenzon: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, BOL Pharma, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, Research Support; AstraZeneca, Novo Nordisk, Speaker's Bureau; AstraZeneca, Bayer AG, Eli Lilly and Company, Novo Nordisk, Sanofi. A.Karasik: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Vifor Pharma Management Ltd., Speaker's Bureau; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Funding Boeheringer Ingelheim

Aim To examine how the development of cardiovascular and renal disease (CVRD) translates to hospital healthcare costs in individuals with type 2 diabetes (T2D) initially free from CVRD. Methods Data were obtained from the digital healthcare systems of 12 nations using a prespecified protocol. A fixed country-specific index date of 1 January was chosen to secure sufficient cohort disease history and maximal follow-up, varying between each nation from 2006 to 2017. At index, all individuals were free from any diagnoses of CVRD (including heart failure [HF], chronic kidney disease [CKD], coronary ischaemic disease, stroke, myocardial infarction [MI], or peripheral artery disease [PAD]). Outcomes during follow-up were hospital visits for CKD, HF, MI, stroke, and PAD. Hospital healthcare costs obtained from six countries, representing 68% of the total study population, were cumulatively summarized for CVRD events occurring during follow-up. Results In total, 1.2 million CVRD-free individuals with T2D were identified and followed for 4.5 years (mean), that is, 4.9 million patient-years. The proportion of individuals indexed before 2010 was 18% (n = 207 137); 2010-2015, 31% (361 175); and after 2015, 52% (609 095). Overall, 184 420 (15.7%) developed CVRD, of which cardiorenal disease was most frequently the first disease to develop (59.7%), consisting of 23.0% HF and 36.7% CKD, and more common than stroke (16.9%), MI (13.7%), and PAD (9.7%). The total cumulative cost for CVRD was US$1 billion, of which 59.0% was attributed to cardiorenal disease, 3-, 5-, and 6-fold times greater than the costs for stroke, MI, and PAD, respectively. Conclusion Across all nations, HF or CKD was the most frequent CVRD manifestation to develop in a low-risk population with T2D, accounting for the highest proportion of hospital healthcare costs. These novel findings highlight the importance of cardiorenal awareness when planning healthcare.

Current literature lacks structured methodologies for analyzing medical technologies' impact from the patient-centered care perspective. This study introduces, applies and validates 'Patient-Centered Care Impact Analysis' (PCIA) as a method for identifying patient-centered care associated demands and expectations for a particular technology and assessing its compliance with these demands. PCIA involves five stages: (1) demand identification, (2) ranking demands' impact magnitude, (3) scoring demand compliance (DC), (4) demand priority (DP) assignment based on impact magnitude and compliance, (5) generating a summative impact priority number (IPN). PCIA was performed as a comparative assessment of two central nervous system (CNS) drug-delivery platforms; SipNose, a novel noninvasive Direct-Nose-to-Brain (DNTB), vs. the standard-of-care invasive intrathecal/intracerebroventricular injection (Invasive I/I). Study participants included a ranking team (RT) without experience with the SipNose technology that based their scoring on experimental data; and a validation team (VT) experienced with the SipNose platform. All had experience with, or knowledge of, InvasiveI/I. Demand identification and impact magnitude were performed by one content and one assessment expert. Each participant assessed each technology's DC. DP scores, IPN's and IPN DNTB:InvasiveI/I ratios were generated for each technology, for each team, based on DC and summative DP scores, respectively. Both teams assigned DNTB higher DC scores, resulting in higher DNTB DP, IPN scores and DNTB:InvasiveI/I IPN ratios. Lack of difference between team assessments of DP and IPN ratio validate PCIA as an assessment tool capable of predicting patient-centered clinical care quality for a new technology. The significant differences between the platforms highlight SipNose's patient-care centered advantages as an effective CNS drug-delivery platform.

Abstract Objectives To characterize and compare glucose-lowering medication use in type 2 diabetes in the US, Sweden, and Israel, including adoption of newer medications and prescribing patterns. Research Design and Methods We used data from the National Health and Nutrition Examination Survey (NHANES) from the US, Stockholm CREAtinine Measurements project (SCREAM) from Sweden, and Maccabi Healthcare Services from Israel. Specific pharmacotherapy for type 2 diabetes between 2007 and 2018 were examined. Results Use of glucose-lowering medications among patients with type 2 diabetes was substantially lower in the US and SCREAM than in Maccabi (66.0% in NHANES, 68.4% in SCREAM, and 88.1% in Maccabi in 2017-2018). Among patients who took at least one glucose-lowering medication in 2017-2018, metformin use was also lower in the US and SCREAM (74.1% in NHANES, 75.9% in SCREAM, and 92.6% in Maccabi) whereas sulfonylureas use was greater in the US (31.5% in NHANES, 16.0% in SCREAM, and 14.9% in Maccabi). Adoption of DPP4i and SGLT2i were slower in the US and SCREAM than Maccabi. History of atherosclerotic cardiovascular disease, heart failure, reduced kidney function, and albuminuria were not consistently associated with greater use of SGLT2i or GLP1RA across the three countries. Conclusions There were substantial differences in real-world use of glucose-lowering medications across the US, Sweden, and Israel, with more optimal pharmacologic management in Israel. Variation in access to care and medication cost across countries may have contributed to these differences. SGLT2i and GLP1RA use in high-risk patients was limited in all three countries during this time period.