Real-world effectiveness of sodium-glucose cotransporter-2 inhibitors on the progression of chronic kidney disease in patients without diabetes, with and without albuminuria.

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 m2, 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 m2. The mean body mass index was 29.1 ± 5.4 kg/m2. During the year before index date, 146 participants (41%) had a urinary albumin to creatinine ratio (UACR) <30 mg/g, 81 (23%) had a UACR of 30-300 mg/g, 74 (21%) had a 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 m2 per year at baseline, which improved to -1.7 ± 6.8 mL/min/1.73 m2 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.

Pharmaceutical Agents as Potential Drivers in the Development of Early-Onset Colorectal Cancer: Case-Control Study.

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.

Estimated Glomerular Filtration Rate, Albuminuria, and Adverse Outcomes: An Individual-Participant Data Meta-Analysis.

Importance: Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. Objective: To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. Design, Setting, and Participants: Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. Exposures: The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). Main Outcomes and Measures: The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. Results: Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]). Conclusions and Relevance: In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.

Empagliflozin is associated with lower cardiovascular risk compared with dipeptidyl peptidase-4 inhibitors in adults with and without cardiovascular disease: EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study results from Europe and Asia.

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.

Long-Term, Real-World Kidney Outcomes with SGLT2i versus DPP4i in Type 2 Diabetes without Cardiovascular or Kidney Disease.

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.

Kidney function loss and albuminuria progression with GLP-1 receptor agonists versus basal insulin in patients with type 2 diabetes: real-world evidence.

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.

Real-World Use of Alirocumab: Experience from a Large Healthcare Provider.

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.

Empagliflozin cardiovascular and renal effectiveness and safety compared to dipeptidyl peptidase-4 inhibitors across 11 countries in Europe and Asia: Results from the EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study.

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.

Obesity in late adolescence and incident type 1 diabetes in young adulthood.

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.

Epidemiology of the diabetes-cardio-renal spectrum: a cross-sectional report of 1.4 million adults.

BACKGROUND: Type-2 diabetes (T2D), chronic kidney disease, and heart failure (HF) share epidemiological and pathophysiological features. Although their prevalence was described, there is limited contemporary, high-resolution, epidemiological data regarding the overlap among them. We aimed to describe the epidemiological intersections between T2D, HF, and kidney dysfunction in an entire database, overall and by age and sex. METHODS: This is a cross-sectional analysis of adults ≥ 25 years, registered in 2019 at Maccabi Healthcare Services, a large healthcare maintenance organization in Israel. Collected data included sex, age, presence of T2D or HF, and last estimated glomerular filtration rate (eGFR) in the past two years. Subjects with T2D, HF, or eGFR < 60 mL/min/1.73 m2 were defined as within the diabetes-cardio-renal (DCR) spectrum. RESULTS: Overall, 1,389,604 subjects (52.2% females) were included; 445,477 (32.1%) were 25- < 40 years, 468,273 (33.7%) were 40- < 55 years, and 475,854 (34.2%) were ≥ 55 years old. eGFR measurements were available in 74.7% of the participants and in over 97% of those with T2D or HF. eGFR availability increased in older age groups. There were 140,636 (10.1%) patients with T2D, 54,187 (3.9%) with eGFR < 60 mL/min/1.73m2, and 11,605 (0.84%) with HF. Overall, 12.6% had at least one condition within the DCR spectrum, 2.0% had at least two, and 0.23% had all three. Cardiorenal syndrome (both HF and eGFR < 60 mL/min/1.73m2) was prevalent in 0.40% of the entire population and in 2.3% of those with T2D. In patients with both HF and T2D, 55.2% had eGFR < 60 mL/min/1.73m2 and 15.8% had eGFR < 30 mL/min/1.73m2. Amongst those within the DCR spectrum, T2D was prominent in younger participants, but was gradually replaced by HF and eGFR < 60 mL/min/1.73m2 with increasing age. The congruence between all three conditions increased with age. CONCLUSIONS: This large, broad-based study provides a contemporary, high-resolution prevalence of the DCR spectrum and its components. The results highlight differences in dominance and degree of congruence between T2D, HF, and kidney dysfunction across ages.

Validating the UK prospective diabetes study outcome model 2 using data of 94,946 Israeli patients with type 2 diabetes.

AIMS: To externally validate the United Kingdom Prospective Diabetes Study (UKPDS) Outcome Model 2 (OM2) in contemporary Israeli patient populations. METHODS: De-identified patient data on demographics, time-varying risk factors, and clinical events of newly diagnosed type 2 diabetes patients were extracted from the Maccabi Healthcare Services (MHS) diabetes registry over years 2000-2013. Depending on the baseline risk, patients were categorized into low-risk and intermediate-risk groups. In addition to assessing discriminatory performance, the predicted and observed 15-year cumulative incidences of diabetes complications and death were compared among all patients and for the two risk-groups. RESULTS: The discriminatory capability of OM2 was moderate to good, C-statistic ranging 0.71-0.95. The model overpredicted the risk for MI, blindness and death (Predicted/Observed events (P/O: 1.32-2.31)), and underpredicted the risk of IHD (P/O: 0.5). In patients with a low baseline risk, overpredictions were even more pronounced. OM2 performed well in predicting renal failure and ulcer risk in patients with a low risk but predicted well the risk of death, stroke, CHF, and amputation in patients with an intermediate risk. CONCLUSION: OM2 demonstrated good to moderate discrimination capability for predicting diabetes complications and mortality risks in Israeli diabetes population. The prediction performance differed between patients with different baseline risks.

Cardiorenal outcomes with sodium/glucose cotransporter-2 inhibitors in patients with type 2 diabetes and low kidney risk: real world evidence.

BACKGROUND: Randomized controlled trials showed that sodium/glucose cotransporter-2 inhibitors (SGLT2i) protect the heart and kidney in an array of populations with type 2 diabetes (T2D) and increased cardiorenal risk. However, the extent of these benefits also in lower kidney-risk T2D populations needs further investigation. METHODS: Members of Maccabi Healthcare Systems listed in their T2D registry who initiated new glucose lowering agents (GLA), were divided into SGLT2i initiators and other GLAs (oGLAs). Groups were propensity score-matched by baseline demographic and medical characteristics. Two composite cardiovascular outcomes were defined: all-cause mortality (ACM) or hospitalization for heart failure (hHF); and ACM, myocardial infraction (MI) or stroke. The cardiorenal outcome was: ACM, new end-stage kidney disease (ESKD) or ≥ 40% reduction from baseline estimated glomerular filtration rate (eGFR). Renal-specific outcome was new ESKD or ≥ 40% eGFR reduction. Single components of cardiovascular and kidney outcomes were also assessed. Three subgroup definitions of low baseline kidney-risk were used: eGFR > 90 ml/min/1.73 m2; urinary albumin below detectable levels; and low risk according to Kidney Disease: Improving Global Outcomes (KDIGO) classification. Analyses were performed utilizing an unadjusted model, and a model adjusted to baseline eGFR and urinary albumin-to-creatinine ratio. RESULTS: Between April 1, 2015 and June 30, 2018; 68,187 patients initiated new GLAs - 11,321 SGLT2i initiators and 42,077 oGLAs initiators were eligible. Propensity score-matching yielded two comparable cohorts; each included 9219 participants. Median follow-up was 1.7 years. Compared to oGLAs, SGLT2i initiators had lower incidence of ACM or hHF [HR95%CI = 0.62(0.51-0.75)]; ACM, MI or stroke [0.67(0.57-0.80)]; the cardiorenal outcome [0.65(0.56-0.76)]; and the renal-specific outcome [0.70(0.57-0.85)]. SGLT2i initiators also had lower risk for ACM, hHF and ≥ 30%, ≥ 40%, ≥ 50%, ≥ 57% eGFR reduction. No difference between groups was observed for MI or stroke. In the low baseline kidney-risk subgroups, SGLT2i initiation was generally associated with lower risk of the cardiovascular and cardiorenal outcomes, driven mainly by lower ACM incidence. CONCLUSIONS: Our findings in the general population of patients with T2D demonstrates lower risk of cardiorenal outcomes associated with initiation of SGLT2i compared with oGLAs, including specifically in patients with low baseline kidney-risk.

Short-Term Excess Healthcare Costs Associated with Cardiovascular Events Among Adults with Type 2 Diabetes in Israel: A Retrospective Cohort Study.

OBJECTIVE: The aim was to characterise the short-term (up to 12 months) direct economic burden of new cardiovascular (CV) events among adults with type 2 diabetes (T2D) in Israel. METHODS: In this retrospective cohort study utilising the electronic health records of the Maccabi Healthcare Services, adults aged ≥ 21 years with T2D who experienced their first CV event (2013-2016) were identified via adjudicated enrolment in a CV registry. Wilcoxon rank-sum test estimated excess healthcare resource utilisation in three periods after the CV event: immediate (1 month; for all patients), acute (3 months; for survivors of 1 month of follow-up) and short-term (12 months; for survivors of 3 months of follow-up). Direct healthcare expenditure (2018 United States dollars [USD]) was estimated from unit costs from the State of Israel Ministry of Health price list. RESULTS: In total, 5133 adults experienced a qualifying CV event, with a mean (standard deviation [SD]) age of 67.4 (11.8) years, diabetes duration of 17.7 (11.1) years and glycated haemoglobin of 7.4% (1.6%); 38.0% were female. In USD per patient, mean (SD) immediate costs were $10,741 ($11,707) compared with $2820 ($5661) at baseline (cost ratio [CR] 3.81), acute costs were $14,586 ($15,410) compared with $5202 ($8971) at baseline (CR 2.80) and short-term costs were $23,847 ($25,227) compared with $11,123 ($15,990) at baseline (CR 2.14). A sensitivity analysis of survivors only was consistent with the main analysis. CONCLUSIONS: Our results indicate that CV complications of T2D place a substantial excess economic burden on Israel's healthcare system over the short term (up to 12 months).

Association of sodium-glucose cotransporter-2 inhibitors with outcomes in type 2 diabetes with reduced and preserved left ventricular ejection fraction: Analysis from the CVD-REAL 2 study.

This study of real-world data from the Maccabi database in Israel compared the risk of heart failure hospitalization (HHF) or death in patients with type 2 diabetes (T2D) initiating sodium-glucose cotransporter-2 (SGLT2) inhibitors versus other glucose-lowering drugs (OGLDs) according to baseline left ventricular (LV) ejection fraction (EF). After propensity-matching patients by baseline EF there were 10 614 episodes of treatment initiation; 57% had diabetes for >10 years, the mean glycated haemoglobin level was 66 mmol/mol (8.2%), ∼43% had cardiovascular disease, ∼7% had heart failure and ∼ 20% had chronic kidney disease. A total of 2876 patients (∼9%) had reduced EF (<50%). Over a mean follow-up of 1.5 years there were 371 HHFs or deaths, 88 (23.7%) in patients with reduced EF. Initiation of SGLT2 inhibitors versus OGLDs was associated with lower risk of HHF or death overall (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.46-0.70]; P < 0.001) and in patients with both reduced EF (HR 0.61, 95% CI 0.40-0.93) and preserved EF (HR 0.55, 95% CI 0.43-0.70), with no significant heterogeneity (Pinteraction = 0.72). Our findings from real-world clinical practice show that the lower risk of HHF and death associated with use of SGLT2 inhibitors versus OGLDs is consistent in T2D patients with both reduced and preserved EF.

Elevated Costs and Healthcare Resource Utilization in Patients With Type 2 Diabetes and Established Cardiovascular Disease in Israel.

OBJECTIVES: To evaluate excess healthcare resource utilization (HRU) and costs among patients with both type 2 diabetes (T2D) and established cardiovascular disease (CVD) relative to those with T2D only, in Israel. METHODS: A retrospective, observational, cohort study of adult patients with T2D from the Maccabi Healthcare Services in Israel who enrolled in a cardiovascular registry between 2013 and 2016 (pre-index date period). Patients with established CVD between 2013 and 2016 were propensity matched 1:2 to control patients without established CVD. HRU and medical costs (2018 US Dollars [USD]) were extracted for a 2-year observation period (January 1, 2017, to December 31, 2018) and analyzed using generalized linear models. RESULTS: Overall, 4,582 patients with established CVD were matched 1:2 to 9151 controls (including 13 patients matched to a single control). HRU and costs were significantly higher in patients with established CVD versus controls across a wide range of resources. In total, annual costs per patient (USD) were 10 011.8 (95% confidence interval 9,502.2; 10 548) and 7206.8 (95% confidence interval 6631.8; 7831.7) in patients with established CVD and controls, respectively. Hospitalizations, primary care visits, and medications for any condition were the main cost drivers, with greater utilization and higher costs in the established CVD group versus controls (P < .001 for all) in the postevent period. CONCLUSIONS: In a real-world setting, HRU and costs were significantly higher in patients with T2D and established CVD compared with controls across the vast majority of resource types. These up-to-date cost estimates of CVD improve our understanding of the financial implications of established CVD beyond the direct expenses.

The effectiveness of insulin glargine 300 U/mL among type 2 diabetes patients: Analysis of a real-world data in Israel.

AIMS: Randomized controlled trials have shown that insulin glargine 300 U/mL (Gla-300) has a more stable and prolonged glucose lowering effect among patients with type 2 diabetes (T2DM) compared to insulin glargine 100 U/mL (Gla-100), resulting in a reduced risk of hypoglycaemia while maintaining a similar efficacy of lowering HbA1c. We aimed to investigate if the effectiveness of Gla-300 is reproducible in real-world settings. MATERIAL AND METHODS: In this retrospective cohort study, data from a large state-mandated health organization were used to identify adult T2DM patients who were previously on insulin and initiated Gla-300 therapy between 6/ 2016 and 12/2017. Changes in HbA1c levels, body weight and insulin dose were calculated from baseline period and over a follow-up period of 180 days. Documented hypoglycaemia events were also explored. RESULTS: A total of 1797 patients were included in this study with a mean age of 64.2 (SD = ±11.0y), baseline HbA1c was 8.7 ± 1.6% and 42.5% were females. Among all patients with HbA1c measurement during follow-up (n = 1508), HbA1c was significantly reduced by -0.6% (95% CI -0.6,-0.5; P < .001) from baseline, with a significant reduction in body weight (-0.4 kg; P = <.001).Additionally, a significant (P = .04) reduction of 40.5% in patients with hypoglycaemia events was recorded during follow-up period, from 2.1% (n = 37) at the baseline period to 1.2% (n = 22). CONCLUSIONS: This real-world study supports evidence from RCTs regarding the effectiveness of Gla-300 among T2DM patients by improving glycaemic control.

Very Low Birth Weight Preterm Infants have Decreased Celiac Disease Autoimmunity During Childhood and Adolescence.

Little is known about the effect of prematurity on later development of celiac disease (CD). We conducted a retrospective analysis of real-world data examining the association between very low birth weight (VLBW) prematurity and later development of CD autoimmunity (CDA) in 3580 infants born between years 2000 and 2012 and their matched controls. At a median of 12 years, VLBW prematurity was negatively associated with later development of CDA with a cumulative prevalence of 5.9 per 1000 versus 10.3 per 1000 (P = 0.02), though more former VLBW premature infants were ever tested for CDA (48.5% vs 37.4%, P < 0.001). The odds ratio for developing CDA among children born preterm at VLBW was 0.57 (95% confidence interval (CI) 0.35-0.92) as compared with matched controls. There was no difference in clinical characteristics of CDA between both groups. In conclusion, VLBW preterm infants present a decreased risk for the development of CDA during childhood and adolescence.

Kidney outcomes associated with use of SGLT2 inhibitors in real-world clinical practice (CVD-REAL 3): a multinational observational cohort study.

BACKGROUND: Cardiovascular and kidney outcome trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors slow progression of chronic kidney disease in patients with type 2 diabetes with or without chronic kidney disease. The aim of this study was to assess whether these benefits extend to patients with type 2 diabetes treated in routine clinical practice. METHODS: CVD-REAL 3 was a multinational observational cohort study in which new users of SGLT2 inhibitors and other glucose-lowering drugs with measurements of estimated glomerular filtration rate (eGFR) before and after (within 180 days) initiation were identified via claims, medical records, and national registries in Israel, Italy, Japan, Taiwan, and the UK. Propensity scores for SGLT2 inhibitor initiation were developed in each country, with 1:1 matching with initiators of other glucose-lowering drugs. Propensity score included (in addition to other clinical and demographic variables) baseline eGFR and eGFR slope before SGLT2 inhibitor or other glucose-lowering drug initiation. The main outcome measure was rate of eGFR decline (slope) calculated with a linear mixed regression model. Differences in eGFR slope between SGLT2 inhibitors and other glucose-lowering drugs were calculated and pooled. We also assessed a composite outcome of 50% eGFR decline or end-stage kidney disease. FINDINGS: After propensity matching, there were 35 561 episodes of treatment initiation in each group, from 65 231 individual patients. Dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, and luseogliflozin accounted for 57·9%, 34·1%, 5·7%, 1·4%, 0·5%, and 0·4% of SGLT2 inhibitor initiation episodes, respectively. At baseline, 29 363 (41·3%) of 71 122 initiations were in women, mean age was 61·3 years, mean HbA1c was 72 mmol/mol (8·71%), and mean eGFR was 90·7 mL/min per 1·73 m2. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs other glucose-lowering drugs 1·53 mL/min per 1·73 m2 per year, 95% CI 1·34-1·72, p<0·0001). During a mean follow-up of 14·9 months, 351 composite kidney outcomes occurred: 114 (3·0 events per 10 000 patient-years) among initiators of SGLT2 inhibitors and 237 (6·3 events per 10 000 patient-years) among initiators of other glucose-lowering drugs (hazard ratio 0·49, 95% CI 0·35-0·67; p<0·0001). These findings were consistent across countries (pheterogeneity 0·10) and prespecified subgroups. INTERPRETATION: In this large, international, real-world study of patients with type 2 diabetes, initiation of SGLT2 inhibitor therapy was associated with a slower rate of kidney function decline and lower risk of major kidney events compared with initiation of other glucose-lowering drugs. These data suggest that the benefits of SGLT2 inhibitors on kidney function identified in clinical trials seem to be largely generalisable to clinical practice. FUNDING: AstraZeneca.

Metabolic Control and Adherence to Therapy in Type 2 Diabetes Mellitus Patients Using IDegLira in a Real-World Setting.

INTRODUCTION: Insulin degludec/liraglutide (IDegLira) is a fixed-ratio combination (FRC) of basal insulin and glucagon-like protein-1 receptor agonist (GLP-1 RA) that has demonstrated glycemic and metabolic benefits in patients with type 2 diabetes mellitus (T2DM) in both randomized controlled trials and real-world studies. The impact of adherence to this medication and its effect on patients with T2DM who switch from loose-dose combination therapy to a FRC of insulin and GLP-1RA have not yet been reported. We have examined the metabolic effects and adherence to this medication in a real-life setting, in T2DM patients who initiated IDegLira therapy after being treated with other glucose-lowering drugs. METHODS: This is a retrospective observational study of adult T2DM patients managed by the Maccabi Healthcare Services (Israel) who initiated IDegLira and persisted with therapy for 180 days between July 2017 and August 2018. Mean glycated hemoglobin (HbA1c), body weight change, metabolic parameters, dose and proportion of days covered (PDC) by IDegLira were recorded from initiation to after 180 days of therapy. RESULTS: A total of 413 patients who persisted with IDegLira therapy for at least 180 days were evaluated as a per protocol group. A significant mean reduction in HbA1c of 0.65% (95% confidence limits [CL] - 0.78, - 0.52; P < 0.001) was observed at 180 days compared with baseline. IDegLira therapy led to a significant reduction in HbA1c in patients previously treated with different background combinations of glucose-lowering drugs before being started on IDegLira. The largest group (n = 247) comprised those who switched from a loose-dose combination therapy of insulin and GLP-1 RA as injectable components given alone to the IDegLira FRC. In this group, HbA1c was reduced by 0.42% (95% CL - 0.57, - 0.27; P < 0.001) and in parallel the PDC of insulin and GLP-1 RA increased from a median of 60% (interquartile range [IQR] 34.4-79.4) in the 180 days prior to IDegLira initiation to 77.8% (IQR 65.6-90.0) in the 180 days after initiation. CONCLUSION: In a real-world setting, the use of IDegLira was associated with improved glycemic control and adherence to therapy.