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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.

BackgroundContinued 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.MethodsThe 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.FindingsAmong 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.InterpretationResults 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. 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.

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.

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 (

Aims Studies in children reported an association between increased body mass index (BMI) and risk for developing type 1 diabetes (T1D), but evidence in late adolescence is limited. We recently investigated the association between adolescent BMI and type 2 diabetes in young adulthood (Diabetes Care 2020, 43(7): 1487-95) and here we studied on the same cohort the association between late adolescent BMI and incident T1D. Methods All Israeli adolescents, ages 16-19, 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 dysglycemia (n=1,462,362; 40% women). Data were linked to information about adult onset of T1D in the Israeli National Diabetes Registry. Weight and height were measured at study entry and BMI was computed and transformed to age- and sex-adjusted BMI percentiles according to US Center for Diseases Control. The definition of T1D was determined based on anti-diabetic drugs and was confirmed for a subpopulation of the cohort to which islet autoantibodies data were available. Cox proportional models were applied, with BMI analyzed both as a categorical and continuous variable. Results There were 777 incident cases of T1D during 15,810,751 person-years (mean age at diagnosis 25.2±3.9 years). The median follow-up period was 11.2 years (IQR 5.8-16.3), with follow-up length shorter for individuals with a higher BMI. The crude diabetes rate showed a consistent graded increase across BMI groups from underweight to obesity; 3.6 to 8.4 cases per 100,000 person-years, respectively. In a multivariable model adjusted for age, sex and socio-demographic variables, the hazard ratios (HRs) for T1D were 1.05 (95% CI 0.87-1.27) for the 50th–74th BMI percentiles, 1.41 (1.11–1.78) for the 75th–84th BMI percentiles, 1.54 (1.23–1.94) for adolescents with overweight (85th–94th percentiles), and 2.05 (1.58–2.66) for adolescents with obesity (BMI≥95th percentile)(reference group, 5th-49th BMI percentile group). One increment in BMI standard deviation was associated with 25% greater risk for incidence of T1D (HR=1.25, 95%CI 1.17-1.32). when the presence of one or multiple (≥2) islet antibodies was added as a criterion for T1D definition, the HRs among those with adolescent obesity were 2.90 (1.80-4.68) and 3.14 (1.68-5.88) respectively. Results were marginally affected by level of adjustment for sociodemographic background, were similar when analysis was stratified by sex, and also persisted when the study population was limited to adolescents with unimpaired health in order to mitigate confounding by coexisting illness. The fraction of type 1 diabetes attributed to adolescent overweight and obesity (Population attributable risk%; PAR%) was 10.1% (95%CI 6.3%-14.2%). Conclusions Adolescent overweight and obesity in apparently healthy adolescents were associated with increased risk for incident type 1 diabetes in early adulthood. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:24 p.m. - 1:30 p.m.

OBJECTIVE To characterize and compare glucose-lowering medication use in type 2 diabetes in the U.S., 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 U.S., the Stockholm CREAtinine Measurements (SCREAM) project from Sweden, and Maccabi Healthcare Services (Maccabi) from Israel. Specific pharmacotherapy for type 2 diabetes between 2007 and 2018 was examined. RESULTS Use of glucose-lowering medications among patients with type 2 diabetes was substantially lower in NHANES 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 NHANES and SCREAM (74.1% in NHANES, 75.9% in SCREAM, and 92.6% in Maccabi) whereas sulfonylureas use was greater in NHANES (31.5% in NHANES, 16.0% in SCREAM, and 14.9% in Maccabi). Adoption of dipeptidyl peptidase 4 inhibitors and sodium–glucose cotransporter 2 inhibitors (SGLT2i) was slower in NHANES and SCREAM than in Maccabi. History of atherosclerotic cardiovascular disease, heart failure, reduced kidney function, or albuminuria was not consistently associated with greater use of SGLT2i or glucagon-like peptide 1 receptor agonists (GLP1RA) across the three countries. CONCLUSIONS There were substantial differences in real-world use of glucose-lowering medications across the U.S., 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 patients at high risk was limited in all three countries during this time period.

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 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

Background: Studies in children reported an association between increased body mass index (BMI) and risk for developing type 1 diabetes (T1D) . We studied the association between adolescent BMI and incident T1D in young adulthood in a nationwide cohort of 1,462,362 adolescents which was recently used to assess the association between adolescent BMI and early-onset type 2 diabetes (Diabetes Care 2020 Jul;43 (7) :1487-1495) . Methods: All Israeli adolescents, ages 16-19, 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 dysglycemia. Data were linked to information about adult onset of T1D in the Israeli National Diabetes Registry. Weight and height were measured at the study entry. Cox proportional models were applied, with BMI analyzed both as a categorical and as a continuous variable. Islet autoantibody data were available for a subpopulation of the cohort. Results: There were 777 incident cases of T1D during 15,810,751 person-years (mean age at diagnosis 25.2±3.9 years) . BMI was associated with incident T1D. In a multivariable model adjusted for age, sex and socio-demographic variables, the hazard ratios (HRs) for T1D were 1. (95% CI 0.87-1.27) for the 50th-74th BMI percentiles, 1.41 (1.11-1.78) for the 75th-84th BMI percentiles, 1.54 (1.23-1.94) for adolescents with overweight (85th-94th percentiles) , and 2. (1.58-2.66) for adolescents with obesity (BMI≥95th percentile) . One increment in BMI standard deviation was associated with 25% greater risk for incidence of T1D (HR=1.25, 95%CI 1.17-1.32) . Association persisted when the definition of T1D included the presence of islet autoantibodies; when the study population was restricted to those with unimpaired health. Conclusions: Excessively high BMI in apparently healthy adolescents is associated with increased risk for incident T1D in early adulthood. Disclosure I.Zucker: None. D.Tzur: None. C.Melzer cohen: None. O.Pinhas-hamiel: Advisory Panel; Novo Nordisk, Speaker's Bureau; Pfizer Inc. G.Chodick: None. I.Raz: None. A.Afek: None. H.C.Gerstein: Advisory Panel; Abbott, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Viatris Inc., Consultant; Kowa Company, Ltd., Other Relationship; DKSH, Eli Lilly and Company, Sanofi, Zuellig Pharma Holdings Pte. Ltd., Research Support; AstraZeneca, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi. A.Tirosh: Advisory Panel; Abbott Diagnostics, AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Novo Nordisk, Sanofi, Consultant; Bayer AG, DreaMed Diabetes, Ltd., Research Support; Medtronic, Speaker's Bureau; Eli Lilly and Company. G.Twig: None. Y.Zloof: None. A.Bardugo: None. A.M.Tsur: None. M.Lutski: None. Y.Cohen: None. T.Cukierman-yaffe: Research Support; European Association for the Study of Diabetes, Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk, Speaker's Bureau; AstraZeneca, Eli Lilly and Company, Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi. N.Minsky: None. E.Derazne: None. Funding This work was partially supported by an internal grant from the Israel Defense Forces Medical Corps.

Background: Cardiovascular outcome trials have shown cardiovascular benefit with sodium-glucose co-transporter-2 (SGLT2) inhibitors in patients with type 2 diabetes, whereas dipeptidyl peptidase-4 (DPP-4) inhibitors have not shown an effect. We aimed to address knowledge gaps regarding the comparative effectiveness of SGLT2 inhibitor use in clinical practice (with DPP-4 inhibitor use as an active comparator) across a range of cardiovascular risks and in diverse geographical settings. Methods: In this comparative cohort study, we used data from clinical practice from 13 countries in the Asia-Pacific, Middle East, European, and North American regions to assess the risk of cardiovascular events and death in adult patients with type 2 diabetes newly initiated on SGLT2 inhibitors compared with those newly initiated on DPP-4 inhibitors. De-identified health records were used to select patients who were initiated on these drug classes between Dec 1, 2012, and May 1, 2016, with follow-up until Dec 31, 2014, to Nov 30, 2017 (full range; dates varied by country). Non-parsimonious propensity scores for SGLT2 inhibitor initiation were developed for each country and patients who were initiated on an SGLT2 inhibitor were matched with those who were initiated on a DPP-4 inhibitor in a 1:1 ratio. Outcomes assessed were hospitalisation for heart failure, all-cause death, myocardial infarction, and stroke. Hazard ratios (HRs) were estimated by country and then pooled in a weighted meta-analysis. Findings: Following propensity score matching, 193 124 new users of SGLT2 inhibitors and 193 124 new users of DPP-4 inhibitors were included in the study population. Participants had a mean age of 58 years (SD 12·2), 170 335 (44·1%) of 386 248 were women, and 111 933 (30·1%) of 372 262 had established cardiovascular disease. Initiation of an SGLT2 inhibitor versus a DPP-4 inhibitor was associated with substantially lower risks of hospitalisation for heart failure (HR 0·69, 95% CI 0·61–0·77; p

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.

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.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.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).Excessively high BMI in otherwise healthy adolescents is associated with increased risk for incident type 1 diabetes in early adulthood.

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.

Summary 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 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.

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

Introduction In both randomized controlled trials and real-world studies, liraglutide has demonstrated glycemic and body weight benefits in patients with type 2 diabetes. However, persistence with diabetes medication can be challenging. This study compared glycated hemoglobin (HbA1c) and other outcomes in patients with type 2 diabetes who continued treatment with liraglutide for over 12 months with those who discontinued treatment earlier, in a real-life setting. Methods This is a retrospective study of adult patients with type 2 diabetes from Maccabi Healthcare Services in Israel, who initiated treatment with liraglutide from 2010 to 2015. Mean HbA1c and body weight change from initiation to after 24 months was compared between patients who received liraglutide for at least 12 months (“continuers”) and those who discontinued within the first year (“discontinuers”). Adjustment for HbA1c, body weight, and other potentially confounding factors was performed using 1:1 propensity score matching. Results The 3580 patients comprised 2695 continuers and 885 discontinuers; 882 patients per group were matched. A significant (p

The EMPRISE study evaluates the effectiveness and safety of empagliflozin (EMPA) in a broader population of patients with T2D in routine clinical care across countries. The study included 67,140 pairs of 1:1 propensity score matched (PSM) patients ≥18 years with T2D newly initiating EMPA or any DPP-4i from large databases/registers in Israel, Finland, Germany, Spain, Sweden, South Korea, Taiwan and Japan. Mostly, PSM used 100+ baseline covariates (Table), and pooled HR with 95% CI were computed using random-effects meta-analysis models. EMPA compared to DPP-4i (Table), was associated with 27-47% lower risk of hospitalization for heart failure (HHF), stroke, all-cause mortality (ACM), and two composite outcomes: HHF & ACM; and myocardial infarction, stroke & ACM. Safety analyses associated EMPA with 46% lower risk of acute kidney injury requiring dialysis. EMPRISE study results showed that EMPA is associated with reduced risk of cardiovascular (CV) disease, incl HHF, in patients with T2D in routine clinical care settings in Israel, Europe and East Asia. These results complement the results from clinical trial EMPA-REG OUTCOME®, and are in line with the ADA/EASD 2019 consensus update to prescribe SGLT-2i for patients with T2D and high-risk, vascular or chronic kidney disease or heart failure to reduce HHF and major adverse CV events/deaths. Disclosure A. Karasik: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk A/S. S. Lanzinger: None. E. C. H. Tan: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc. D. Yabe: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Corporation. Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., MDS Co., Ltd., Novo Nordisk Pharma Ltd. D. Kim: None. W. Sheu: None. C. Melzer Cohen: None. R. W. Holl: None. K. Ha: None. T. Nystrom: Board Member; Self; Abbott, Lilly Diabetes, Sanofi. Research Support; Self; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; AstraZeneca. L. K. Niskanen: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Sanofi-Aventis. Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk. Stock/Shareholder; Self; Boehringer Ingelheim Pharmaceuticals, Inc. M. Linnemann Jensen: Stock/Shareholder; Self; Novo Nordisk A/S. M. H. Kyaw: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. J. Nunez: Advisory Panel; Self; Novo Nordisk Pharma Ltd. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc.

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). Supplementary Information The online version contains supplementary material available at 10.1007/s41669-021-00268-5.

Aim To assess the possible risk of acute kidney injury (AKI) with the use of sodium-glucose co-transporter-2 inhibitors (SGLT2-i) as well as changes in estimated glomerular filtration rate (eGFR), hospitalizations and mortality in a real-world setting. Materials and methods Included in this historical cohort study were patients with type 2 diabetes in a large health organization in Israel who initiated therapy with SGLT2-i or dipeptidyl peptidase-4 inhibitors (DPP-4i) during 1 April 2015 to 30 June 2017. We collected data on serum creatinine measurements taken between 180 days prior to and 24 weeks after therapy initiation. Study endpoints included ≥30% reduction in eGFR, hospitalization with AKI, any hospitalization and all-cause mortality. Results Overall 6418 and 5604 patients initiated SGLT2-i and DPP-4i, respectively. Baseline mean (SD) eGFR was higher among the SGLT2-i group compared with the DPP-4i group (88.3 [17.4] and 82.8 [23.7], respectively) but were similar when stratifying by chronic kidney disease (CKD) stages. The adjusted odds ratio (OR) (95% confidence interval [CI]) for ≥30% reduction in eGFR with SGLT2-i versus DPP4-i was 0.70 (0.49-1.00) and ORs ranged from 1.97 (0.62-6.26) to 0.45 (0.21-0.99) in patients with baseline eGFR 30 to 45 and ≥90 mL/min/1.73 m2 , respectively. Risks of AKI (OR = 0.47, 95% CI 0.27-0.80), hospitalization (OR = 0.66, 95% CI 0.56-0.78) or all-cause mortality (OR = 0.43, 95% CI 0.20-0.95) were lower in patients initiating SGLT2-i versus DPP-4i. Conclusions This real-world data analysis supports reassuring findings from previous randomized clinical trials showing no increased AKI risk among SGLT2-i users. Nevertheless, because of the more prominent decrease in eGFR in patients with moderate CKD, cautious use of SGLT2-i in patients with reduced eGFR is advised.

Background Randomized trials demonstrated a lower risk of cardiovascular (CV) events with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in patients with type 2 diabetes (T2D) at high...

This analysis of real-world data aimed to (a) determine the proportion of Type II diabetes (T2DM) patients treated with metformin or dipeptidyl peptidase-4 inhibitors (DPP-4i) that require dose adjustment or therapy discontinuation due to chronic kidney disease (CKD), and (b) to assess the time required to dose adjustment from the time of worsening of CKD.In this retrospective study, two study populations were defined in a large healthcare organization. In the cross-sectional analysis, the distribution of CKD stages and the appropriate dosage of metformin and DPP-4i in 2013 was examined according to renal function among T2DM patients. In the longitudinal analysis, a cohort was defined to assess the time elapsed from first indication worsening of CKD to dose adjustment, among patients treated with those medications during years 2006-2013.Among patients treated with metformin or DPP-4i, one third of patients with CKD failed to adjust the dosage or to discontinue metformin or DPP-4i as indicated. Median time for dose adjustment or discontinuation was significantly longer for DPP-4i than for metformin (9.8 compared to 16.8 months for metformin and DPP-4i, respectively; p-value.001).This real-world data analysis showed that adjustment of dose or discontinuation of metformin or DPP-4i in patients with worsening CKD occurred less often in DPP-4i users than metformin users and took a longer time.

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.

Introduction Retrospective cohort study evaluating the clinical effectiveness of insulin degludec (IDeg) in insulin-treated patients with type 2 diabetes switching from other insulins to IDeg in a real-world setting. Methods Data were drawn from the Maccabi Health Management Organization in Israel and included patients treated with IDeg between 1 September 2014 and 29 February 2016. Main inclusion criteria were age ≥18 years, diagnosis of type 2 diabetes, and treated with insulin for at least 1 year prior to IDeg initiation. HbA1c, insulin dose, body weight, and body mass index were recorded before and 90 and 180 days post-switch. Results Of 211 eligible patients, 57% were male, mean age ± SD 62.2 ± 12.1 years, and diabetes duration >10 years. Switching to IDeg decreased HbA1c from a mean 8.8 ± 1.5% (73.0 ± 16.4 mmol/mol) baseline by 0.58 ± 1.0% (6.3 ± 10.9 mmol/mol) (p 8.5% (69.0 mmol/mol) and daily insulin dose of ≥50 U were associated with a greater reduction in HbA1c [1.0 ± 1.1% (10.9 ± 12.0 mmol/mol) and 1.2 ± 1.1% (13.1 ± 12.0 mmol/mol), respectively] compared with the total population. At 180 days post-switch, the mean daily basal insulin dose increased by 2 U compared with pre-switch. There was no significant change in body weight post-switch. Conclusions In a real-world setting, switching from another insulin to IDeg significantly improved glycemic control in patients with type 2 diabetes, without significant weight gain and with only a modest increase in insulin dose after IDeg initiation. Funding Novo Nordisk. Electronic supplementary material The online version of this article (doi:10.1007/s13300-017-0297-9) contains supplementary material, which is available to authorized users.

Background Vildagliptin is a dipeptidyl peptidase-4 inhibitor commonly used as a dual oral agent with metformin, thiazolidinediones, or sulfonylurea for the treatment of type 2 diabetes mellitus (T2DM). The efficacy of dual therapy with vildagliptin and metformin has been established in randomized controlled trials, but there is little evidence from observational studies. The aims of the present study were to evaluate the effectiveness of vildagliptin as an add-on therapy to metformin in reducing HbA1c and its affects on body weight and blood lipids in a real-life setting. Methods Included in the present retrospective cohort were T2DM patients (n = 345) who were uncontrolled on metformin monotherapy and intensified treatment with vildagliptin. The efficacy of at least 90 days of dual therapy with vildagliptin and metformin in reducing HbA1c levels, as well as changes in blood lipids and body weight, were evaluated. Results After 180 days (range 90–365 days) from the index date with a mean daily dose of 92 mg vildagliptin, HbA1c was significantly (P < 0.001) reduced by an average of 0.9% (95% confidence interval −1.0%, −0.7%). The absolute reduction in HbA1c was positively associated with baseline HbA1c levels. In addition to HbA1c, a modest but significant (P < 0.05) decrement was also calculated in the patients' body weight and blood lipids. Conclusions The present analysis of real-world data corroborates the results of previous randomized controlled trials indicating that add-on therapy with vildagliptin in uncontrolled patients on metformin monotherapy is associated with a significant improvement in the control of HbA1c.

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 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.

In the past 20 years, significant updates in diabetes management guidelines were performed. In this study we aimed to evaluate long-term trends in the treatment initiation and management of type 2 diabetes mellitus (T2DM). In this retrospective study, a computerized clinical database from Maccabi Healthcare Services, a 2.3 million member in Israel, was used. Included were adults T2DM patients who initiated antihyperglycemic medication between 1999 and 2018 (N=153,168). Fasting plasma glucose (FPG) and HbA1c levels were evaluated at treatment initiation and after 6, 12 and 24 months. In addition, first and second line treatment regimen were examined. Over twenty years of observation, FPG at therapy initiation decreased from 167.3±68.7 mg/dl (mean±SD) in 1999-2002 to 136.1±53.6 mg/dl in 2015-2018 (Figure). The respective decrement in HbA1c was from 7.8±2.1% to 6.8±1.8%. There was a tremendous difference in treatment regimen: In 1999-2002, metformin and sulfonylurea were the leading first line medications (63.5% and 37.0%, respectively) while in 2015-2018, the leading first line medications were metformin and DPP-4i (94.2% and 9.9% of patients, respectively). Study result indicate a clear trend of initiating antidiabetic treatment at lower FPG and HbA1c levels, and the fast disappearance of sulfonylurea from the clinical practice. Disclosure C. Melzer Cohen: None. V. Shalev: None. G. Chodick: None.

Aim To compare the change in urinary albumin to creatinine ratio (UACR) in type 2 diabetes (T2DM) patients with albuminuria who initiate sitagliptin to those who initiate a sulfonylurea (SU) as add-on to metformin monotherapy. Method A cohort of T2DM patients with albuminuria (UACR >30mg/g) who initiated sitagliptin or SU as add-on dual therapy to metformin between 2008 and 2014 was extracted from the computerized medical records of a large managed care organization in Israel. Patients with albuminuria and UACR measurements available at treatment initiation and 120–365days afterwards were included. Propensity scores were calculated based on 17 factors, including demography, comorbidities, baseline levels of HbA1c, UACR, BMI, eGFR, and ACE/ARB use, and patients were matched in a 1:1 ratio. Changes in UACR were compared between the matched pairs using generalized estimating equations. Results A total of 282 eligible pairs (sitagliptin:SU) were identified. During a mean follow-up of 9months, median UACR changes were −35% (IQR=−73% to 5%) and −31% (IQR=−72% to 21%) in the sitagliptin and SU groups, respectively. Mean absolute HbA1c reductions among sitagliptin and SU groups were 0.9% and 1.0%, respectively. The magnitude of UACR reduction generally increased with greater magnitude of HbA1c reduction in both treatment groups. However, after controlling for HbA1c reduction and the interaction between HbA1c reduction and UACR reduction, sitagliptin users demonstrated a trend toward an increased likelihood of UACR reduction compared to SU users (odds ratio=1.20; 95% confidence interval: 0.99–1.47, P =0.063). Conclusion Our results suggest that both sitagliptin and SU reduce albuminuria as an add-on therapy to metformin, but that sitagliptin may provide greater reductions in albuminuria independent of glycemic control when compared to SU. Larger population studies are required to further explore this.

Objective: In both randomized, controlled trials and real-world studies, liraglutide (Victoza®) has demonstrated glycemic and body weight benefits in patients with type 2 diabetes mellitus (T2DM). To achieve long-term beneficial outcomes, persistence with treatment is important; however, this can be challenging with injectable drugs. In this study, we examined the association of long-term adherence to liraglutide and metabolic changes. Methods: A retrospective analysis of patients with T2DM (≥18 years old) from Maccabi Healthcare Services, Israel, who initiated liraglutide from 2010-2015 and had HbA1c measurements at treatment initiation and after 24 months. Mean change in HbA1c and body weight from initiation to 24 months was compared between patients who received liraglutide regularly for at least 12 months (’continuers’) and those who discontinued liraglutide before 12 months (’discontinuers’). Patients who were treated with another GLP-1 receptor agonist, or who underwent bariatric surgery, were excluded. Adjustment for potential confounding factors (sex, age, years in diabetes registry, HbA1c, body mass index, and insulin use at treatment start) was performed using propensity score matching (1:1 [n=882 in each group]). Results: Significant reductions in HbA1c were seen in continuers compared with discontinuers (0.80% vs. 0.32%, p Conclusion: In a real-world setting, persistent use of liraglutide was associated with good glycemic and body weight control. Disclosure C. Melzer Cohen: None. G. Chodick: None. L.N. Husemoen: Employee; Self; Novo Nordisk A/S. N. Rhee: Employee; Self; Novo Nordisk A/S. V. Shalev: None. A. Karasik: Stock/Shareholder; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S, AstraZeneca. Research Support; Self; AstraZeneca. Consultant; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Merck & Co., Inc., GlucoMe.

Supplemental Digital Content is available in the text, The aim of the study was to define whether anxiety itself or only the treatment with anxiolytic medication is risk factor for hyponatremia and overhydration. A case–control study of patients with a diagnosis of anxiety who received a selective serotonin reuptake inhibitor (SSRI). Serum sodium, urea to creatinine ratio, and odds ratio (OR) of hyponatremia and overhydration before initiation of treatment were compared to those of a control group of participants. Laboratory tests were also examined for changes following treatment with an SSRI. All blood tests were conducted from January 1, 2001 until December 31, 2017. Subjects were selected from a large electronic database, insuring 2 million Israelis. A total of 7211 patients with a diagnosis of anxiety who have received a prescription for an SSRI were identified; 3634 were excluded mostly due to other conditions that could cause hyponatremia, and 3520 participants were included in the case group. The control group consisted of 6985 age and gender matched participants who did not have a diagnosis of anxiety or any other exclusion criteria. Mean serum sodium levels were elevated in cases before the initiation of SSRIs; sodium: case 139.3 (137.3–141.3), control 139.2 (137.06–141.26) mmol/L (P = .01). The OR of hyponatremia was 0.89 for the case group (P = .004). Treatment with SSRIs decreased mean serum sodium (139.3–139.1 mmol/L; P = .0001) and increased by 50% the rate of hyponatremia (2.6–3.9% P = .024). It is the use of SSRIs and not anxiety itself that causes hyponatremia among anxious patients.

Vildagliptin is a dipeptidyl peptidase-4 inhibitor commonly used as a dual oral agent with metformin, thiazolidinediones, or sulfonylurea for the treatment of type 2 diabetes mellitus (T2DM). The efficacy of dual therapy with vildagliptin and metformin has been established in randomized controlled trials, but there is little evidence from observational studies. The aims of the present study were to evaluate the effectiveness of vildagliptin as an add-on therapy to metformin in reducing HbA1c and its affects on body weight and blood lipids in a real-life setting.Included in the present retrospective cohort were T2DM patients (n = 345) who were uncontrolled on metformin monotherapy and intensified treatment with vildagliptin. The efficacy of at least 90 days of dual therapy with vildagliptin and metformin in reducing HbA1c levels, as well as changes in blood lipids and body weight, were evaluated.After 180 days (range 90-365 days) from the index date with a mean daily dose of 92 mg vildagliptin, HbA1c was significantly (P0.001) reduced by an average of 0.9% (95% confidence interval -1.0%, -0.7%). The absolute reduction in HbA1c was positively associated with baseline HbA1c levels. In addition to HbA1c, a modest but significant (P0.05) decrement was also calculated in the patients' body weight and blood lipids.The present analysis of real-world data corroborates the results of previous randomized controlled trials indicating that add-on therapy with vildagliptin in uncontrolled patients on metformin monotherapy is associated with a significant improvement in the control of HbA1c.