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Purpose To investigate the association between stuttering in adolescence and incident type 2 diabetes in young adulthood. Methods This nationwide population-based study included 2 193 855 adolescents of age 16 to 20 years who were assessed for military service between 1980 and 2013. Diagnoses of stuttering in adolescence were confirmed by a speech-language pathologist. Diabetes status for each individual as of December 31, 2016, was determined by linkage to the Israeli National Diabetes Registry. Relationships were analyzed using regression models adjusted for socioeconomic variables, cognitive performance, coexisting morbidities, and adolescent body mass index. Results Analysis was stratified by sex (Pinteraction = 0.035). Of the 4443 (0.4%) adolescent men with stuttering, 162 (3.7%) developed type 2 diabetes, compared with 25 678 (2.1%) men without stuttering (adjusted odds ratio [OR] 1.3; 95% CI, 1.1-1.6). This relationship persisted when unaffected brothers of men with stuttering were used as the reference group (adjusted OR = 1.5; 95% CI, 1.01-2.2), or when the analysis included only adolescents with unimpaired health at baseline (adjusted OR = 1.4; 95% CI, 1.1-1.7). The association was stronger in later birth cohorts, with an adjusted OR of 2.4 (1.4-4.1) for cases of type 2 diabetes before age 40. Of the 503 (0.1%) adolescent women with stuttering 7 (1.4%) developed type 2 diabetes, compared with 10 139 (1.1%) women without stuttering (OR = 2.03; 95% CI, 0.48-2.20). Conclusions Adolescent stuttering is associated with an increased risk for early-onset type 2 diabetes among men.

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.

Context The long-term risk of type 2 diabetes in adolescents with nonalcoholic fatty liver disease (NAFLD) is unclear. Objective To assess type 2 diabetes risk among adolescents with NAFLD. Design and Setting A nationwide, population-based study of Israeli adolescents who were examined before military service during 1997–2011 and were followed until December 31, 2016. Participants A total of 1 025 796 normoglycemic adolescents were included. Interventions Biopsy or radiographic tests were prerequisite for NAFLD diagnosis. Data were linked to the Israeli National Diabetes Registry. Main Outcome Measures Type 2 diabetes incidence. Results During a mean follow-up of 13.3 years, 12 of 633 adolescents with NAFLD (1.9%; all with high body mass index [BMI] at baseline) were diagnosed with type 2 diabetes compared with 2917 (0.3%) adolescents without NAFLD. The hazard ratio (HR) for type 2 diabetes was 2.59 (95% confidence interval [CI], 1.47–4.58) for the NAFLD vs. the non-NAFLD group after adjustment for BMI and sociodemographic confounders. The elevated risk persisted in several sensitivity analyses. These included an analysis of persons without other metabolic comorbidities (adjusted HR, 2.75 [95% CI, 1.48-5.14]) and of persons with high BMI; and an analysis whose outcome was type 2 diabetes by age 30 years (adjusted HR, 2.14 [95% CI, 1.02-4.52]). The results remained significant when a sex-, birth year-, and BMI-matched control group was the reference (adjusted HR, 2.98 [95% CI, 1.54-5.74]). Conclusions Among normoglycemic adolescents, NAFLD was associated with an increased adjusted risk for type 2 diabetes, which may be apparent before age 30 years.

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.

Context A correlation between myopia and insulin resistance has been suggested. Objective We investigated the association between myopia in adolescence and type 2 diabetes (T2D) incidence in young adulthood. Methods This population-based, retrospective, cohort study comprised 1 329 705 adolescents (579 543 women, 43.6%) aged 16 to 19 years, who were medically examined before mandatory military service during 1993 to 2012, and whose data were linked to the Israel National Diabetes Registry. Myopia was defined based on right-eye refractive data. Cox proportional models were applied, separately for women and men, to estimate hazard ratios (HRs) for T2D incidence per person-years of follow-up. Results There was an interaction between myopia and sex with T2D (P Conclusion For women, myopia in adolescence was associated with a significantly increased risk for incident T2D in young adulthood, in a severity-dependent manner. This finding may support the role of insulin resistance in myopia pathogenesis.

The association of long-term HbA1c variability with mortality has been previously suggested. However, the significance of HbA1c variability and trends in different age and HbA1c categories is unclear.Data on patients with diabetes listed in the Israeli National Diabetes Registry during years 2012-2016 (observation period) were collected. Patients with4 HbA1c measurements, type 1 diabetes, eGFR 30mg/ml/min, persistent HbA1c 6% or malignancy were excluded. Utilizing machine learning methods, patients were classified into clusters according to their HbA1c trend (increasing, stable, decreasing). Mortality risk during 2017-2019 was calculated in subgroups defined by age (35-54, 55-69, 70-89 years) and last HbA1c (≤7% and7%) at end of observation period. Models were adjusted for demographic, clinical and laboratory measurements including HbA1c, standard deviation (SD) of HbA1c and HbA1c trend.This historical cohort study included 293,314 patients. Increased HbA1c variability (high SD) during the observation period was an independent predictor of mortality in patients aged more than 55 years (p 0.01). The HbA1c trend was another independent predictor of mortality. Patients with a decreasing versus stable HbA1c trend had a greater mortality risk; this association persisted in all age groups in patients with HbA1c 7% at the end of the observation period (p = 0.02 in age 35-54; p 0.01 in aged55). Patients with an increasing versus stable HbA1c trend had a greater mortality risk only in the elderly group (70), yet in both HbA1c categories (p 0.01).HbA1c variability and trend are important determinants of mortality risk and should be considered when adjusting glycaemic targets.

The incidence of adolescent hypertension is growing worldwide, mostly in conjunction with the growing obesity prevalence (1,2). Adolescent hypertension was shown to be a risk factor for cardiovascular and renal outcomes later in life, thus promoting current guidelines to screen all pediatric and adolescent population for hypertension (1,3). Here, we elucidate the association of adolescent hypertension and early-onset type 2 diabetes in a nationwide cohort of adolescents. In this population-based, retrospective cohort study we linked the Israeli Defense Forces conscription center database with the Israeli National Diabetes Registry (INDR). One year prior to mandatory military service at age 17 years, Israeli adolescents undergo comprehensive medical evaluation based on their medical history, an interview and physical examination that includes measurements of height, weight, and blood pressure. Included were adolescents who were examined between 1 January 1993 and 31 December 2016. Excluded were those with prior diagnosis of dysglycemia and those with missing baseline height or weight data (3.8% in total). Essential hypertension diagnosis was confirmed by a board-specified nephrologist based on a preexisting diagnosis or screening for hypertension as described previously (1). Briefly, adolescents with blood pressure measurement during the screening assessment of >140/90 mmHg were referred for further investigation. The final diagnosis was made when the average of 10 additional outpatient blood pressure measurements was >140/90 mmHg, when at least 50% of the measurements were above this level, and after exclusion of secondary hypertension. The primary outcome was incident type 2 diabetes as documented by the INDR, which captures all cases of diabetes in Israel with a sensitivity of 95.1% (2). Cox models were applied. Follow-up started at the day of the first medical examination and ended at the date of diabetes diagnosis, 31 December 2016, or death—whichever came first. Due to the previously described …

Aim: We investigated the relationship between midlife C-reactive protein (CRP) levels in men with coronary heart disease (CHD) and depressive symptoms at old age. CRP levels were measured in a subs...

OBJECTIVE The relationship between acute pancreatitis and incident diabetes is unclear. We assessed whether a resolved single event of acute pancreatitis in childhood was associated with incident diabetes in adulthood. RESEARCH DESIGN AND METHODS A nationwide, population-based study of 1,802,110 Israeli adolescents (mean age 17.4 years [range 16–20]) who were examined before compulsory military service between 1979 and 2008 and whose data were linked to the Israeli National Diabetes Registry (INDR). Resolved pancreatitis was defined as a history of a single event of acute pancreatitis with normal pancreatic function at enrollment. Logistic regression analysis was applied. RESULTS Incident diabetes developed in 4.6% of subjects with resolved pancreatitis (13 of 281; none of these cases were identified as type 1 diabetes) and 2.5% among the unexposed group (44,463 of 1,801,716). Resolved acute pancreatitis was associated with incident diabetes with an odds ratio (OR) of 2.23 (95% CI 1.25–3.98) with adjustment for age, sex, and birth year. Findings persisted after further adjustments for baseline BMI and sociodemographic confounders (OR 2.10 [95% CI 1.15–3.84]). Childhood pancreatitis was associated with a diagnosis of diabetes at a younger age, with 92% of diabetes case subjects diagnosed before 40 years of age compared with 47% in the unexposed group (P = 0.002). The association accentuated when the study sample was limited to individuals of unimpaired health or normal BMI at baseline. CONCLUSIONS A history of acute pancreatitis in childhood with normal pancreatic function in late adolescence is a risk factor for incident type 2 diabetes, especially at young adulthood.

OBJECTIVE We investigated the association between severity of angina pectoris (AP) and subsequent late-life frailty among men with cardiovascular disease (CVD). METHOD A subset of 351 men (mean age at baseline 56.7 ± 6.5 years) who previously participated in the Bezafibrate Infarction Prevention, BIP trial (1990-1997) underwent a neurovascular evaluation as part of the BIP Neurocognitive study 15.0 ± 3.0 years after baseline (T1) and a frailty evaluation according to Fried 19.9 ± 1.0 years after baseline (T2). Severity of AP was assessed at baseline of the BIP trial using the Canadian Cardiovascular Society angina classification. We assessed the odds of being in the advanced rank of frailty status (robust, pre-frail, and frail) using ordered logistic regression. RESULTS Among 351 participants, 134 (38.2%) were classified as pre-frail and 100 (28.5%) as frail. Frailty was found among 42% participants in the AP class ≥2 and among 26% participants in the AP class

BACKGROUND Lipid levels are associated with an increased risk of cardiovascular disease. OBJECTIVE We investigated the association between plasma lipids, apolipoproteins levels, apolipoprotein B/low-density lipoprotein cholesterol (Apo-B/LDL-C), and Apo-B/Apo-A ratios and rate of cognitive decline two decades later in men with coronary heart disease (CHD). METHODS A subset of 337 men (mean age at baseline 56.6±6.4 years) who previously participated in the Bezafibrate Infarction Prevention (BIP) trial (1990-1997) underwent cognitive evaluations 15±3 years (T1) and 19.9±1 years after baseline (T2) as part of the BIP Neurocognitive study. Lipid and apolipoprotein fractions were measured at baseline. Cognitive function for memory, executive function, visual spatial, attention domains, and composite score were assessed using the NeuroTrax Computerized Battery at T1 and T2 evaluations. Linear mixed models were used to assess change in cognitive function between the two cognitive evaluations. RESULTS Controlling for confounders, the decline in composite cognitive score (β= -0.161±0.06; p = 0.013) as well as in memory (β= -0.269±0.10; p = 0.009) and visual spatial function (β= -0.304±0.12; p = 0.010) was greater among patients in the upper (≥105 mg/dL) Apo-B tertile as compared to counterparts with

Context Thyroid hormones play a key role in systemic metabolism, yet the relationship between thyroid dysfunction and risk for type 2 diabetes is unclear. Objective To assess type 2 diabetes risk in adulthood among adolescents with thyroid disorders. Design and Setting A nationwide, population-based study of Israeli adolescents who were examined before military recruitment during 1988 to 2007 and were followed until December 31, 2016. Participants 1 382 560 adolescents (mean age 17.3 years). Interventions The diagnosis of thyroid disorders was based on recent thyroid function tests. Data were linked to the Israeli National Diabetes Registry. Cox proportional hazard models were applied. Main Outcome Measures Type 2 diabetes incidence. Results During a mean follow-up of 18.5 years, 1.12% (69 of 6,152) of adolescents with thyroid disorders were diagnosed with type 2 diabetes vs 0.77% of adolescents without thyroid disorders. The hazard ratio (HR) for type 2 diabetes was 2.3 (95% CI, 1.8-2.9) among those with thyroid disorders, after adjustment for sex, birth-year, body mass index, and sociodemographic confounders. The increased diabetes risk was observed in both men and women, with the presence or absence of obesity, and in the absence of other health conditions and was associated with different types of thyroid disorders. It was also similar when the outcome was defined as type 2 diabetes diagnosed at or before the age of 30 years (HR 2.3, 95% CI, 1.5-3.5). Conclusions Thyroid disorders diagnosed in adolescence are a risk factor for early-onset type 2 diabetes in both men and women.

Background The prevalence of both asthma and early-onset diabetes is on the rise; however, the association between them remains unclear. We examined a possible association of asthma at adolescence with type 2 diabetes in young adulthood. Methods This is a nationwide, population-based study of 1 718 541 Israeli adolescents (57% males; mean age 17.3 years; range 16-19 years), examined before compulsory military service between 1992 and 2016, with data linked to the Israeli National Diabetes Registry. Asthma diagnosis and severity were determined by a board-certified pulmonologist and based on spirometry tests. Results Type 2 diabetes developed in 58/9090 (0.64%), 507/97 059 (0.52%), 114/23 332 (0.49%), and 7095/1 589 060 (0.44%) persons with moderate-to-severe, mild, inactive, and no history of asthma, respectively, during a mean follow-up >13 years. The respective odds ratios (ORs) were 1.33 (95% CI, 1.02-1.74), 1.17 (1.06-1.28), and 1.09 (0.9-1.31), considering those without asthma history as the reference, in a model adjusted for birth year, sex, body mass index, and other sociodemographic variables. The association persisted when the analysis accounted for coexisting morbidities, and when persons without asthma, individually matched by age, sex, birth year, and body mass index were the reference. Both mild and moderate-to-severe asthma were associated with type 2 diabetes before age 35 years: ORs 1.18 (1.05-1.34) and 1.44 (1.05-2.00), respectively. The strength of the association was accentuated over time. The effect was unchanged when adjusted for oral and inhaled glucocorticoid use. Conclusion Adolescents with active asthma have higher risk to develop type 2 diabetes. This seems related to disease severity, independent of adolescent obesity status, apparent before age 35 years, and more pronounced in recent years.

Introduction Little is known about the association between obesity and sarcopenia — age-related loss of muscle mass and function — among patients with cardiovascular disease. We investigated the association between overweight, obesity, and sarcopenia among community-dwelling men in Israel with cardiovascular disease. Methods A subset of 337 men (mean age at baseline 56.7 [SD, 6.5]) who previously (1990–1997) participated in the Bezafibrate Infarction Prevention trial underwent a neurovascular evaluation as part of the Bezafibrate Infarction Prevention Neurocognitive Study 15.0 (SD, 3.0) years after baseline and a sarcopenia evaluation 19.9 (SD, 1.0) years after baseline. We applied a multinomial logistic model to estimate odds ratios and 95% CIs for 3 categories of sarcopenia: no evidence of sarcopenia (ie, robust), probable sarcopenia, and sarcopenia. Results We found sarcopenia among 54.3% of participants with obesity (body mass index [BMI, in kg/m2] ≥30.0), 37.0% of participants who were overweight (25.0 ≤ BMI ≤29.9), and 24.8% of participants with normal weight (BMI 18.5 to 24.9). In a comparison of BMI ≥25.0 and BMI

Background We assessed in a nationwide cohort the association between adolescent BMI and early-onset ( Methods Normoglycemic adolescents (range 16–20 years old), including 93,806 native Israelis (≥ 3rd generation in Israel) and 27,684 Israelis of Ethiopian origin, were medically assessed for military service between 1996 and 2011. Weight and height were measured. Data were linked to the Israeli National Diabetes Registry. Incident type 2 diabetes by December 31, 2016 was the outcome. Cox regression models stratified by sex and BMI categories were applied. Results 226 (0.29%) men and 79 (0.18%) women developed diabetes during 992,980 and 530,814 person-years follow-up, respectively, at a mean age of 30.4 and 27.4 years, respectively. Among native Israeli men with normal and high (overweight and obese) BMI, diabetes incidence was 9.5 and 62.0 (per 105 person-years), respectively. The respective incidences were 46.9 and 112.3 among men of Ethiopian origin. After adjustment for sociodemographic confounders, the hazard ratios for type 2 diabetes among Ethiopian men with normal and high BMI were 3.4 (2.3–5.1) and 15.8 (8.3–30.3) respectively, compared to third-generation Israelis with normal BMI. When this analysis was limited to Israeli-born Ethiopian men, the hazard ratios were 4.4 (1.7–11.4) and 29.1 (12.9–70.6), respectively. Results persisted when immigrants of other white Caucasian origin were the reference; and among women with normal, but not high, BMI. Conclusions Ethiopian origin is a risk factor for early-onset type 2 diabetes among young men at any BMI, and may require selective interventions.

OBJECTIVE Type 2 diabetes (T2D) is increasingly diagnosed at younger ages. We investigated the association of adolescent obesity with incident T2D at early adulthood. RESEARCH DESIGN AND METHODS A nationwide, population-based study evaluated 1,462,362 adolescents (59% men, mean age 17.4 years) during 1996–2016. Data were linked to the Israeli National Diabetes Registry. Weight and height were measured at study entry. Cox proportional models were applied. RESULTS During 15,810,751 person-years, 2,177 people (69% men) developed T2D (mean age at diagnosis 27 years). There was an interaction among BMI, sex, and incident T2D (Pinteraction = 0.023). In a model adjusted for sociodemographic variables, the hazard ratios for diabetes diagnosis were 1.7 (95% CI 1.4–2.0), 2.8 (2.3–3.5), 5.8 (4.9–6.9), 13.4 (11.5–15.7), and 25.8 (21.0–31.6) among men in the 50th–74th percentile, 75th–84th percentile, overweight, mild obesity, and severe obesity groups, respectively, and 2.2 (1.6–2.9), 3.4 (2.5–4.6), 10.6 (8.3–13.6), 21.1 (16.0–27.8), and 44.7 (32.4–61.5), respectively, in women. An inverse graded relationship was observed between baseline BMI and mean age of T2D diagnosis: 27.8 and 25.9 years among men and women with severe obesity, respectively, and 29.5 and 28.5 years among low-normal BMI (5th–49th percentile; reference), respectively. The projected fractions of adult-onset T2D that were attributed to high BMI (≥85th percentile) at adolescence were 56.9% (53.8–59.9%) and 61.1% (56.8–65.2%) in men and women, respectively. CONCLUSIONS Severe obesity significantly increases the risk for incidence of T2D in early adulthood in both sexes. The rise in adolescent severe obesity is likely to increase diabetes incidence in young adults in coming decades.

Background Recent studies suggest that impaired cerebrovascular reactivity (CVR), a marker of cerebral microvascular damage, is associated with a higher risk of stroke, cognitive decline, and mortality. We tested whether abnormal cerebrovascular status is associated with late-life frailty among men with pre-existing cardiovascular disease. Methods A subset of 327 men (mean age at baseline 56.7 ± 6.5 years) who previously participated in the Bezafibrate Infarction Prevention (BIP) trial (1990-1997) and then in the BIP Neurocognitive Study underwent a neurovascular evaluation 14.6 ± 1.9 years after baseline (T1) and were evaluated for frailty 19.9 ± 1.0 years after baseline (T2). CVR was measured at T1 using the breath-holding index and carotid large-vessel disease using ultrasound. Frailty status was measured at T2 according to the physical phenotype developed by Fried. Patients were categorized into CVR tertiles with cutoff points at ≤0.57, 0.58-0.94, and ≥0.95 and also as normal or impaired (

Background The role of insulin resistance (IR) in the pathogenesis of cognitive performance is not yet clear. Objective To examine the associations between IR and cognitive performance and change in cognitive functions two decades later in individuals with cardiovascular disease with and without diabetes. Methods A subset of 489 surviving patients (mean age at baseline 57.7±6.5 y) with coronary heart disease who previously participated in the secondary prevention Bezafibrate Infarction Prevention (BIP trial; 1990-1997), were included in the current neurocognitive study. Biochemical parameters including IR (using the homeostasis model of assessment; HOMA-IR) were measured at baseline. During 2004-2008, computerized cognitive assessment and atherosclerosis parameters were measured (T1; n = 558; mean age 72.6±6.4 years). A second cognitive assessment was performed during 2011-2013 (T2; n = 351; mean age 77.2±6.4 years). Cognitive function, overall and in specific domains, was assessed. We used linear regression models and linear mixed models to evaluate the differences in cognitive performance and decline, respectively. Results Controlling for potential confounders, IR (top HOMA-IR quartile versus others) was associated with subsequent poorer cognitive performance overall (β= -4.45±Standard Error (SE) 1.54; p = 0.004) and on tests of memory and executive function among non-diabetic patients (β= -7.16±2.38; p = 0.003 and β= -3.33±1.84; p = 0.073, respectively). Moreover, among non-diabetic patients, IR was related to a greater decline overall (β= -0.17±0.06; p = 0.008), and in memory (β= -0.22±0.10; p = 0.024) and executive function (β= -0.19±0.08; p = 0.012). The observed associations did not differ after excluding subjects with prevalent stroke or dementia. Conclusion IR is related to subsequent poorer cognitive performance and greater cognitive decline among patients with cardiovascular disease with and without diabetes.

Background: Autonomic imbalance is linked with multiple health conditions, yet its associations with frailty were rarely studied. We assessed the relationship of resting heart rate (RHR) and visit-to-visit heart rate variability (HRV) with future frailty among elderly men with coronary heart disease (CHD). Methods: Three-hundred-six community-dwelling men with CHD who participated in the Bezafibrate Infarction Prevention (BIP) trial (1990-1998; mean age 56.6 ± 6.5 years) underwent assessment of physical frailty in 2011-2013 (mean age 77.0 ± 6.4 years). Mean RHR and visit-to-visit HRV were calculated from electrocardiogram as indicators of autonomic imbalance. Nominal logistic and linear regression models were used to assess the relationships of RHR and HRV with frailty status and its components (i.e. gait speed, grip strength, weight loss, exhaustion and activity), respectively. Adjustments were made for various demographic, clinical and metabolic covariates. Results: Of the 306 men, 81 (26%) were frail and 117 (38%) were prefrail. After controlling for potential confounders, RHR, but not visit-to-visit HRV, was associated with higher odds of being prefrail [OR = 1.44 (95%CI 1.15, 1.79)] and frail [OR = 1.35 (95%CI 1.03, 1.77)]. Each 5-bpm increase in RHR was associated with weaker grip (β= -1.12 ± 0.32 kg; p-value < .001) and slower gait speed (β = 0.19 ± 0.08s/m; p-value = .022). Conclusions: Midlife RHR may be associated with late-life frailty in men with CHD.

Cardiovascular health (CVH) factors are associated with lower risk of cardiovascular disease, stroke, and mortality. We investigated the association between a modified CVH metrics score and change in cognitive functions 2 decades later in patients with pre-existing coronary artery disease. A subset of 200 men (mean age at baseline 57.3 ± 6.3 years) who previously participated in a secondary prevention trial (1990 to 1997) underwent cognitive evaluation 14.6 ± 1.9 years after baseline (mean age 72.3 ± 6.2 years, T1 evaluation), and were re-evaluated for cognitive performance 19.9 ± 1.0 years after baseline (mean age 77.2 ± 6.4 years, T2 evaluation). A CVH metrics score at baseline was calculated, including 3 health parameters and 4 health behaviors. We have scored each of these CVH metrics into best (2 points), intermediate (1 point), and poor (0 points) levels. Cognitive function was assessed using the NeuroTrax Computerized Battery. A linear mixed model was used to assess change in cognitive functions between T1 and T2 cognitive evaluations. Among the 200 patients, 68 (34.0 %) had ≤7 (bottom group), 85 (42.5%) had 8 to 9 (middle group), and 47 (23.5%) had ≥10 (top group) CVH metrics points. After adjustments, the top group of CVH score versus others was associated with slower decline in the overall cognitive performance composite z-score (0.23 ± 0.09, p = 0.009) and on tests of executive and visual spatial functions (0.23 ± 0.11, p = 0.047, and 0.49 ± 0.17, p = 0.004, respectively). In conclusion, an inverse association was observed between the score of best CVH metrics and cognitive decline. Lifestyle factors are important predictors of late-life decline in cognitive function among high-risk patients.