Cheli Melzer Cohen

Aims: The global prevalence of obesity has more than doubled between 1990 and 2022, making it a significant public health concern. Obesity is associated with an increased risk of various complications, including cardiovascular diseases, type 2 diabetes, as well as increased risk for all‐cause mortality. Existing research also indicates that higher BMI is linked to increased healthcare costs, but most evidence comes from cross‐sectional studies and older populations. The present study aims to estimate the direct healthcare cost of obesity from late adolescence through mid‐adulthood. Materials and Methods: The study included a national cohort of 496 404 conscripts for mandatory military service that underwent medical evaluation at age 17. Study participants were retrospectively followed for hospitalization days and total healthcare costs at ages 35, 45 and 55 using data from a large national healthcare provider. Direct medical costs were standardized using gross domestic product (GDP) inflation rates and purchasing power parity. Analyses were adjusted for sex and socioeconomic status. Results: Higher BMI categories in adolescence were associated with increased hospitalization rates and total healthcare costs across all follow‐up ages. At age 45, individuals with obesity class I and class II/III had 1.65‐fold and 1.62‐fold higher costs, respectively, compared to those with normal BMI. This association was stronger among males. Conclusions: The correlation between obesity in adolescence and higher medical costs is evident already in early‐and‐mid‐adulthood. The study underscores the need for comprehensive approaches targeting adolescents to reduce long‐term healthcare costs and improve population health outcomes.

Background: Armed conflicts and large-scale population displacement pose major challenges to healthcare systems, even in high-income countries with universal health coverage. On October 7, 2023, the “Iron Swords” war led to the internal displacement of tens of thousands of civilians in Israel, creating a unique opportunity to examine continuity of preventive and chronic care during a prolonged national emergency. Objectives: To assess changes in preventive healthcare utilization, mental health medication use, and chronic disease management among populations evacuated from their homes during the Iron Swords war, and to compare trends between evacuees and non-evacuated district residents. Methods: This retrospective population-based study used de-identified electronic health record data from Maccabi Healthcare Services, Israel’s second-largest health maintenance organization. Adults aged ≥ 21 years with continuous enrollment prior to October 7, 2023, were included. Evacuees from northern and southern regions were compared with non-evacuated district residents across two post-war periods and corresponding pre-war periods. Outcomes included screening tests, incidence of chronic diseases, monitoring of chronic conditions, and dispensation of medications for mental health and sleep disorders. Results: Following the outbreak of war, evacuees experienced a marked decline in preventive screening, including diabetes, hypertension, and cancer screening, particularly during the first six months. Partial or full compensation occurred in some measures during later periods, but annual rates remained lower for breast and colorectal cancer screening. Use of antidepressant and anxiolytic medications increased substantially, especially among southern evacuees, with up to a 90% annual increase compared with pre-war levels. Modest worsening in glycemic and blood pressure control was observed in certain subgroups, while the incidence of major chronic diseases remained largely unchanged. Conclusions: Internal displacement during the ‘Iron Swords’ war was associated with substantial disruptions in preventive care and increased mental-health–related medication use among evacuees. Despite these challenges, Israel’s strong, integrated health system enabled rapid restoration of many services and supported continuity not only in chronic disease management but also in ongoing evaluation of preventive care patterns even during a national crisis. This capacity provides important insights for strengthening preparedness and response strategies and underscores the value of robust health information systems and coordinated primary care in managing large-scale civilian displacement.

Aim: To examine the renal effects of sodium‐glucose cotransporter‐2 (SGLT2) inhibition among non‐diabetic individuals with chronic kidney disease (CKD) in a real‐world setting. Methods: We collected de‐identified data on adults without diabetes and with an estimated glomerular filtration rate (eGFR) of 25–60 mL/min/1.73 m ² , who initiated the SGLT2 inhibitors dapagliflozin or empagliflozin between September 2020 and November 2022 at Maccabi Healthcare Services, an Israeli health maintenance organization. We assessed the effects of SGLT2 inhibitors on renal function (changes in eGFR slope/time). Index date was defined as the date of the first dispensing of SGLT2 inhibitors. Annual baseline slope was calculated using all eGFR measurements during the 2 years prior to index date (median = 7 measurements), while annual follow‐up slope was calculated from all evaluations during 90–900 days post index date, along with baseline measurement at index date (median = 6 measurements). Paired t tests were used to compare differences between baseline and follow‐up annual slopes. Results: Of a total of 354 participants with CKD, without diabetes, who received SGLT2 inhibitors and were followed for a median of 527 days, the mean age was 72.8 ± 11.8 years, 26% were female, and 91% used renin‐angiotensin system blockade. The mean eGFR was 45.4 ± 9.5 mL/min/1.73 m ² . The mean body mass index was 29.1 ± 5.4 kg/m ² . During the year before index date, 146 participants (41%) had a urinary albumin to creatinine ratio (UACR) 300 mg/g, and 53 (15%) had no UACR evaluation. The mean eGFR slope over time was −5.6 ± 7.7 mL/min/1.73 m ² per year at baseline, which improved to −1.7 ± 6.8 mL/min/1.73 m ² per year after SGLT2 inhibitor administration ( p <0.001). This effect was independent of UACR. Conclusion: In a real‐world study of primarily older non‐diabetic adults with CKD, SGLT2 inhibition was associated with a slower rate of kidney function decline, regardless of baseline UACR level.

Background: The incidence of early-onset colorectal cancer (EOCRC) rose abruptly in the mid 1990s, is continuing to increase, and has now been noted in many countries. By 2030, 25% of American patients diagnosed with rectal cancer will be 49 years or younger. The large majority of EOCRC cases are not found in patients with germline cancer susceptibility mutations (eg, Lynch syndrome) or inflammatory bowel disease. Thus, environmental or lifestyle factors are suspected drivers. Obesity, sedentary lifestyle, diabetes mellitus, smoking, alcohol, or antibiotics affecting the gut microbiome have been proposed. However, these factors, which have been present since the 1950s, have not yet been conclusively linked to the abrupt increase in EOCRC. The sharp increase suggests the introduction of a new risk factor for young people. We hypothesized that the driver may be an off-target effect of a pharmaceutical agent (ie, one requiring regulatory approval before its use in the general population or an off-label use of a previously approved agent) in a genetically susceptible subgroup of young adults. If a pharmaceutical agent is an EOCRC driving factor, regulatory risk mitigation strategies could be used. Objective: We aimed to evaluate the possibility that pharmaceutical agents serve as risk factors for EOCRC. Methods: We conducted a case-control study. Data including demographics, comorbidities, and complete medication dispensing history were obtained from the electronic medical records database of Maccabi Healthcare Services, a state-mandated health provider covering 26% of the Israeli population. The participants included 941 patients with EOCRC (≤50 years of age) diagnosed during 2001-2019 who were density matched at a ratio of 1:10 with 9410 control patients. Patients with inflammatory bowel disease and those with a known inherited cancer susceptibility syndrome were excluded. An advanced machine learning algorithm based on gradient boosted decision trees coupled with Bayesian model optimization and repeated data sampling was used to sort through the very high-dimensional drug dispensing data to identify specific medication groups that were consistently linked with EOCRC while allowing for synergistic or antagonistic interactions between medications. Odds ratios for the identified medication classes were obtained from a conditional logistic regression model. Results: Out of more than 800 medication classes, we identified several classes that were consistently associated with EOCRC risk across independently trained models. Interactions between medication groups did not seem to substantially affect the risk. In our analysis, drug groups that were consistently positively associated with EOCRC included beta blockers and valerian (Valeriana officinalis). Antibiotics were not consistently associated with EOCRC risk. Conclusions: Our analysis suggests that the development of EOCRC may be correlated with prior use of specific medications. Additional analyses should be used to validate the results. The mechanism of action inducing EOCRC by candidate pharmaceutical agents will then need to be determined.

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 m² 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.

BACKGROUND The incidence of early-onset colorectal cancer (EOCRC) rose abruptly in the mid 1990s, is continuing to increase, and has now been noted in many countries. By 2030, 25% of American patients diagnosed with rectal cancer will be 49 years or younger. The large majority of EOCRC cases are not found in patients with germline cancer susceptibility mutations (eg, Lynch syndrome) or inflammatory bowel disease. Thus, environmental or lifestyle factors are suspected drivers. Obesity, sedentary lifestyle, diabetes mellitus, smoking, alcohol, or antibiotics affecting the gut microbiome have been proposed. However, these factors, which have been present since the 1950s, have not yet been conclusively linked to the abrupt increase in EOCRC. The sharp increase suggests the introduction of a new risk factor for young people. We hypothesized that the driver may be an off-target effect of a pharmaceutical agent (ie, one requiring regulatory approval before its use in the general population or an off-label use of a previously approved agent) in a genetically susceptible subgroup of young adults. If a pharmaceutical agent is an EOCRC driving factor, regulatory risk mitigation strategies could be used. OBJECTIVE We aimed to evaluate the possibility that pharmaceutical agents serve as risk factors for EOCRC. METHODS We conducted a case-control study. Data including demographics, comorbidities, and complete medication dispensing history were obtained from the electronic medical records database of Maccabi Healthcare Services, a state-mandated health provider covering 26% of the Israeli population. The participants included 941 patients with EOCRC (≤50 years of age) diagnosed during 2001-2019 who were density matched at a ratio of 1:10 with 9410 control patients. Patients with inflammatory bowel disease and those with a known inherited cancer susceptibility syndrome were excluded. An advanced machine learning algorithm based on gradient boosted decision trees coupled with Bayesian model optimization and repeated data sampling was used to sort through the very high-dimensional drug dispensing data to identify specific medication groups that were consistently linked with EOCRC while allowing for synergistic or antagonistic interactions between medications. Odds ratios for the identified medication classes were obtained from a conditional logistic regression model. RESULTS Out of more than 800 medication classes, we identified several classes that were consistently associated with EOCRC risk across independently trained models. Interactions between medication groups did not seem to substantially affect the risk. In our analysis, drug groups that were consistently positively associated with EOCRC included beta blockers and valerian (Valeriana officinalis). Antibiotics were not consistently associated with EOCRC risk. CONCLUSIONS Our analysis suggests that the development of EOCRC may be correlated with prior use of specific medications. Additional analyses should be used to validate the results. The mechanism of action inducing EOCRC by candidate pharmaceutical agents will then need to be determined.

With the emerging use of anti-PCSK9 monoclonal antibodies for lowering low-density lipoprotein cholesterol (LDL-C) levels, real-world evidence (RWE) is needed to evaluate drug effectiveness. This study aimed to characterize new users of alirocumab and evaluate its effectiveness in achieving LDL-C target levels. Included were patients initiating treatment with alirocumab from 1 August 2016 to 1 May 2020, with blood lipids evaluations during baseline (180 days prior to therapy initiation) and after 120 (±60) days of follow-up. Patients with treatment intensification during the follow-up period were excluded. LDL-C change from baseline and reaching LDL-C target levels, according to 2019 ESC/EAS guidelines, were evaluated. Among 623 included patients, 50.2% were men, the mean age was 65 years (±9 y), 62% were classified as very-high risk, and 76% had statin intolerance. During the follow-up, 65% (n = 407) were treated only with alirocumab. In 90% the initiation dose was 75 mg, and 21% were up-titrated. Alirocumab was associated with a 31.7% reduction in LDL-C, with 20.5% of patients reaching target levels. In this RWE study, alirocumab was used primarily as a single agent for eligible patients. Suboptimal use and adherence to therapy may have led to a lower LDL-C reduction compared to previous RCTs and most reported real-world studies.

Aims/hypothesis Studies in children have reported an association between increased BMI and risk for developing type 1 diabetes, but evidence in late adolescence is limited. We studied the association between BMI in late adolescence and incident type 1 diabetes in young adulthood. Methods All Israeli adolescents, ages 16–19 years, undergoing medical evaluation in preparation for mandatory military conscription between January 1996 and December 2016 were included for analysis unless they had a history of dysglycaemia. Data were linked with information about adult onset of type 1 diabetes in the Israeli National Diabetes Registry. Weight and height were measured at study entry. Cox proportional models were applied, with BMI being analysed both as a categorical and as a continuous variable. Results There were 777 incident cases of type 1 diabetes during 15,819,750 person-years (mean age at diagnosis 25.2±3.9 years). BMI was associated with incident type 1 diabetes. In a multivariable model adjusted for age, sex and sociodemographic variables, the HRs for type 1 diabetes were 1.05 (95% CI 0.87, 1.27) for the 50th–74th BMI percentiles, 1.41 (95% CI 1.11, 1.78) for the 75th–84th BMI percentiles, 1.54 (95% CI 1.23, 1.94) for adolescents who were overweight (85th–94th percentiles), and 2.05 (95% CI 1.58, 2.66) for adolescents with obesity (≥95th percentile) (reference group: 5th–49th BMI percentiles). One increment in BMI SD was associated with a 25% greater risk for incidence of type 1 diabetes (HR 1.25, 95% CI 1.17, 1.32). Conclusions Excessively high BMI in otherwise healthy adolescents is associated with increased risk for incident type 1 diabetes in early adulthood. Graphical abstract