U-Shaped Association of Plasma Testosterone, and no Association of Plasma Estradiol, with Incidence of Fractures in Men

Abstract Purpose Whether androgens, distinct from estrogen, maintain bone health during male aging has implications for understanding osteoporosis. We assessed associations of different sex hormones with incidence of any bone fracture or hip fracture in older men. Participants and methods Analysis of 3307 community-dwelling men aged 76.8 ± 3.5 years, median follow-up period of 10.6 years. Plasma testosterone (T), dihydrotestosterone (DHT), and estradiol (E2) assayed by mass spectrometry, sex hormone-binding globulin (SHBG), and luteinizing hormone (LH) using immunoassay. Incident fractures determined via data linkage. We analyzed probability of fracture and performed Cox regression adjusted for age, medical comorbidities, and frailty. Results Incident fractures occurred in 330 men, including 144 hip fractures. Probability plots suggested nonlinear relationships between hormones and risk of any fracture and hip fracture, with higher risk at lower and higher plasma T, lower E2, higher SHBG, and higher LH. In fully adjusted models, there was a U-shaped association of plasma T with incidence of any fracture (Quartile 2 [Q2] versus Q1: fully adjusted hazard ratio [HR] = 0.69, 95% confidence interval [CI] 0.51–0.94, P = .020; Q3: HR 0.59, 95% CI 0.42–0.83, P = .002) and hip fracture (Q2 versus Q1: HR 0.60, 95% CI 0.37–0.93, P = .043; Q3: HR 0.52, 95% CI 0.31–0.88, P = .015). DHT, E2, and LH were not associated with fracture. Higher SHBG was associated with hip fracture (Q4 versus Q1: HR 1.76, 95% CI 1.05–2.96, P = .033). Conclusions Midrange plasma T was associated with lower incidence of any fracture and hip fracture, and higher SHBG with increased risk of hip fracture. Circulating androgen rather than estrogen represents a biomarker for hormone effects on bone driving fracture risk.

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SAT-033 U-Shaped Association of Plasma Testosterone, and No Association of Plasma Estradiol, with Incidence of Any Fracture and Hip Fracture in Older Men

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.985 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Bu Beng Yeap ◽

Helman Alfonso ◽

Paul Chubb ◽

Jacqueline Center ◽

Jonathan Beilin ◽

...

Keyword(s):

Hip Fracture ◽

Fracture Risk ◽

Older Men ◽

Hazard Ratio ◽

Community Dwelling ◽

Sex Hormone ◽

Plasma Testosterone ◽

Increased Risk ◽

Non Linear

Abstract Osteoporosis resulting in bone fractures is a major cause of morbidity in older men. Previous studies implicated reduced exposure to estradiol (E2) with increased fracture risk in men. The extent to which circulating androgens contribute to maintenance of bone health is uncertain. We examined associations of different sex hormones with incidence of any bone fracture or hip fracture in older men. We analysed 3,307 community-dwelling men aged 76.8±3.5 years, median follow-up period of 10.6 years. Medical information was collected by questionnaire. Frailty was assessed using the FRAIL scale (1). Early morning plasma testosterone (T), dihydrotestosterone (DHT) and E2 were assayed by mass spectrometry, sex hormone-binding globulin (SHBG) and luteinising hormone (LH) by immunoassay. Incidence of any fracture and hip fracture were determined via data linkage to emergency department presentations and hospital admissions. Risk of fracture according to sex hormone concentrations was analysed. Hazard ratio of fracture according to sex hormone quartiles (Q1-4) was assessed using Cox regression models adjusted for age, medical comorbidities and frailty. In 30,355 participant-years of follow-up, the incidence of any fracture was 1.1% and hip fracture 0.5% per participant per year. Incident fractures occurred in 330 men, including 144 hip fractures. Probability plots suggested non-linear relationships between hormones and risk of any fracture and hip fracture, with higher risk at lower and higher concentrations of plasma T, lower E2, higher SHBG and higher LH. In fully-adjusted models, there was a U-shaped association of plasma T with incidence of any fracture (Q1: reference group, Q2: fully-adjusted hazard ratio [HR]=0.69, 95% confidence interval [CI]=0.51-0.94, p=0.020; Q3: HR=0.59, CI=0.42-0.83, p=0.002; Q4: 0.85, CI=0.62-1.18, p=0.335). A similar U-shaped association of T was found with incidence of hip fracture (Q1: HR=1.0; Q2: HR=0.60, CI=0.37-0.93, p=0.043; Q3: HR=0.52, CI=0.31-0.88, p=0.015; Q4: HR=1.04, CI=0.65-1.68, p=0.866). DHT, E2 and LH were not associated with incidence of any fracture or hip fracture (all p>0.050). SHBG was not associated with incidence of any fracture, but was associated with hip fracture (Q4 vs Q1: HR=1.76, CI=1.05-2.96, p=0.033). In conclusion, we found a non-linear or U-shaped association of T with fracture risk, with no association of E2. Mid-range plasma T was associated with lower incidence of any fracture and hip fracture, and higher SHBG with increased risk of hip fracture. Circulating androgen rather than estrogen may be a biomarker for hormone effects on bone driving fracture risk. A randomised controlled trial of T therapy powered for the outcome of fracture may be warranted and should recruit men with baseline T in the lowest quartile of values. Reference: (1) Hyde Z, et al. J Clin Endocrinol Metab 2010; 95: 3165-3172.

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Trimethyllysine Predicts All-Cause and Cardiovascular Mortality in Community-Dwelling Adults and Patients With Coronary Heart Disease

European Heart Journal Open ◽

10.1093/ehjopen/oeab007 ◽

2021 ◽

Author(s):

Espen Ø Bjørnestad ◽

Indu Dhar ◽

Gard F T Svingen ◽

Eva R Pedersen ◽

Mads M Svenningsson ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Cardiovascular Mortality ◽

Cox Regression ◽

Community Dwelling ◽

Health Study ◽

Community Based ◽

Increased Risk ◽

Established Coronary Heart Disease

Abstract Aims Trimethyllysine (TML) is involved in carnitine synthesis, serves as a precursor of trimethylamine N-oxide (TMAO) and is associated with cardiovascular events in patients with established coronary heart disease (CHD). We prospectively examined circulating TML as a predictor of all-cause and cardiovascular mortality in community-dwelling adults and patients with CHD. Methods and Results By Cox regression modelling, risk associations were examined in 6393 subjects in the community-based Hordaland Health Study (HUSK). A replication study was conducted among 4117 patients with suspected stable angina pectoris in the Western Norway Coronary Angiography Cohort (WECAC). During a mean follow-up of 10.5 years in the HUSK-cohort, 884 (13.8%) subjects died, of whom 287 from cardiovascular causes. After multivariable adjustments for traditional cardiovascular risk factors, the hazard ratio (HR) (95% CI) for all-cause mortality comparing the 4th vs. 1st TML-quartile was 1.66 (1.31-2.10, p < 0.001). Particularly strong associations were observed for cardiovascular mortality (HR [95% CI] 2.04 [1.32-3.15, p = 0.001]). Corresponding risk-estimates in the WECAC (mean follow-up of 9.8 years) were 1.35 [1.10-1.66, p = 0.004] for all-cause and 1.45 [1.06-1.98, p = 0.02] for cardiovascular mortality. Significant correlations between plasma TML and TMAO were observed in both cohorts (rs≥0.42, p < 0.001); however, additional adjustments for TMAO did not materially influence the risk associations, and no effect modification by TMAO was found. Conclusion Elevated TML-levels were associated with increased risk of all-cause and cardiovascular mortality both in subjects with and without established CHD.

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Apathy is associated with incident dementia in community-dwelling older people

Neurology ◽

10.1212/wnl.0000000000004767 ◽

2017 ◽

Vol 90 (1) ◽

pp. e82-e89 ◽

Cited By ~ 12

Author(s):

Jan Willem van Dalen ◽

Lennard L. Van Wanrooij ◽

Eric P. Moll van Charante ◽

Edo Richard ◽

Willem A. van Gool

Keyword(s):

Depressive Symptoms ◽

Older People ◽

Cox Regression ◽

Depression Scale ◽

Community Dwelling ◽

Memory Complaints ◽

Incident Dementia ◽

Increased Risk ◽

Community Dwelling Older People

ObjectiveTo assess whether apathy and depressive symptoms are independently associated with incident dementia during 6-year follow-up in a prospective observational population-based cohort study.MethodsParticipants were community-dwelling older people in the Prevention of Dementia by Intensive Vascular Care trial, aged 70–78 years, without dementia at baseline. Apathy and depressive symptoms were measured using the 15-item Geriatric Depression Scale (GDS-15). Dementia during follow-up was established by clinical diagnosis confirmed by an independent outcome adjudication committee. Hazard ratios (HRs) were calculated using Cox regression analyses. Given its potentially strong relation with incipient dementia, the GDS item referring to memory complaints was assessed separately.ResultsDementia occurred in 232/3,427 (6.8%) participants. Apathy symptoms were associated with dementia (HR 1.28, 95% confidence interval [CI] 1.12–1.45; p < 0.001), also after adjustment for age, sex, Mini-Mental State Examination score, disability, and history of stroke or cardiovascular disease (HR 1.21, 95% CI 1.06–1.40; p = 0.007), and in participants without depressive symptoms (HR 1.26, 95% CI 1.06–1.49; p = 0.01). Depressive symptoms were associated with dementia (HR 1.12, 95% CI 1.05–1.19), also without apathy symptoms (HR 1.16, 95% CI 1.03–1.31; p = 0.015), but not after full adjustment or after removing the GDS item on memory complaints.ConclusionsApathy and depressive symptoms are independently associated with incident dementia in community-dwelling older people. Subjective memory complaints may play an important role in the association between depressive symptoms and dementia. Our findings suggest apathy symptoms may be prodromal to dementia and might be used in general practice to identify individuals without cognitive impairment at increased risk of dementia.

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Associations Between Sex Steroids and the Development of Metabolic Syndrome: A Longitudinal Study in European Men

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2014-4184 ◽

2015 ◽

Vol 100 (4) ◽

pp. 1396-1404 ◽

Cited By ~ 59

Author(s):

Leen Antonio ◽

Frederick C. W. Wu ◽

Terence W. O'Neill ◽

Stephen R. Pye ◽

Emma L. Carter ◽

...

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Sex Steroids ◽

Community Dwelling ◽

Sex Hormone Binding Globulin ◽

Gas Chromatography Mass Spectrometry ◽

Model Assessment ◽

Lower Baseline ◽

Increased Risk

Context: Low testosterone (T) has been associated with incident metabolic syndrome (MetS), but it remains unclear if this association is independent of sex hormone binding globulin (SHBG). Estradiol (E2) may also be associated with MetS, but few studies have investigated this. Objective: To study the association between baseline sex steroids and the development of incident MetS and to investigate the influence of SHBG, body mass index (BMI) and insulin resistance on this risk. Methods: Three thousand three hundred sixty nine community-dwelling men aged 40–79 years were recruited for participation in EMAS. MetS was defined by the updated NCEP ATP III criteria. Testosterone and E2 levels were measured by liquid and gas chromatography/mass spectrometry, respectively. Logistic regression was used to assess the association between sex steroids and incident MetS. Results: One thousand six hundred fifty one men without MetS at baseline were identified. During follow-up, 289 men developed incident MetS, while 1362 men did not develop MetS. Men with lower baseline total T levels were at higher risk for developing MetS [odds ratio (OR) = 1.72, P < .001), even after adjustment for SHBG (OR = 1.43, P = .001), BMI (OR = 1.44, P < .001) or homeostasis model assessment of insulin resistance (HOMA-IR) (OR = 1.64, P < .001). E2 was not associated with development of MetS (OR = 1.04; P = .56). However, a lower E2/T ratio was associated with a lower risk of incident MetS (OR = 0.38; P < .001), even after adjustment for SHBG (OR = 0.48; P < .001), BMI (OR = 0.60; P = .001) or HOMA-IR (OR = 0.41; P < .001). Conclusions: In men, lower T levels, but not E2, are linked with an increased risk of developing MetS, independent of SHBG, BMI or insulin resistance. A lower E2/T ratio may be protective against developing MetS.

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The Association of the Brief Dementia Risk Index and Incident Dementia among Finnish 70-Year-Olds: A 5-Year Follow-Up Study

Gerontology ◽

10.1159/000513964 ◽

2021 ◽

pp. 1-4

Author(s):

Jenni Vire ◽

Marika Salminen ◽

Paula Viikari ◽

Tero Vahlberg ◽

Seija Arve ◽

...

Keyword(s):

Prediction Models ◽

Cox Regression ◽

Risk Index ◽

Community Dwelling ◽

Older Individuals ◽

Accurate Identification ◽

Dementia Risk ◽

Incident Dementia ◽

Increased Risk

Background: An accurate identification of older individuals at increased risk of developing dementia is very important. Various dementia risk prediction models have been developed, but not all models are applicable among older population. Objectives: To examine the association of the Brief Dementia Risk Index (BDRI) and incidence of dementia among community-dwelling Finnish older adults. Methods: Participants were community-dwelling nondemented 70-year-olds examined in 2011 (n = 943). Cox regression model with death as a competing risk was used to analyze the association of BDRI and incident dementia (ICD-10 codes F00-03 and G30) during the 5-year follow-up (n = 883). Results: The rate of dementia incidence was 4.9% during the follow-up. Having at least moderate risk according to BDRI significantly predicted incident dementia (hazard ratio 3.18, 95% confidence interval: 1.71–5.92, p < 0.001), also after adjustment with education level (2.93, 1.52–5.64, p = 0.001). No interaction between gender and BDRI was found. Conclusion: BDRI could be an applicable tool for identification of older individuals at increased risk of developing dementia in clinical settings.

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Fear of falling and all-cause mortality among young-old community-dwelling adults: a 6-year prospective study

European Journal of Ageing ◽

10.1007/s10433-021-00635-5 ◽

2021 ◽

Author(s):

Giulia Belloni ◽

Christophe Büla ◽

Brigitte Santos-Eggimann ◽

Yves Henchoz ◽

Sarah Fustinoni ◽

...

Keyword(s):

Cox Regression ◽

Fear Of Falling ◽

Community Dwelling ◽

Activity Restriction ◽

Personalized Care ◽

Hazard Ratios ◽

Increased Risk ◽

All Cause Mortality ◽

Young Old

AbstractThis study investigated whether fear of falling (FOF) measured by two different instruments, the Falls Efficacy Scale-International (FES-I) and the single question on FOF and activity restriction (SQ-FAR), is associated with mortality at 6-year follow-up. Participants (n = 1359, 58.6% women) were community-dwelling persons enrolled in the Lausanne cohort 65 + , aged 66 to 71 years at baseline. Covariables assessed at baseline included demographic, cognitive, affective, functional and health status, while date of death was obtained from the office in charge for population registration. Unadjusted Kaplan Meyer curves were performed to show the survival probability for all-cause mortality according to the degree of FOF reported with FES-I and SQ-FAR, respectively. Bivariable and multivariable Cox regression analyses were performed to assess hazard ratios, using time-in-study as the time scale variable and adjusting for variables significantly associated in bivariable analyses. During the 6-year follow-up, 102 (7.5%) participants died. Reporting the highest level of fear at FES-I (crude HR 3.86, 95% CI 2.37–6.29, P < .001) or “FOF with activity restriction” with SQ-FAR (crude HR 2.42, 95% CI 1.44-4.09, P = .001) were both associated with increased hazard of death but these associations did not remain significant once adjusting for gender, cognitive, affective and functional status. As a conclusion, although high FOF and related activity restriction, assessed with FES-I and SQ-FAR, identifies young-old community-dwelling people at increased risk of 6-year mortality, this association disappears when adjusting for potential confounders. As a marker of negative health outcomes, FOF should be screened for in order to provide personalized care and reduce subsequent risks.

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Incident Use of a Potentially Inappropriate Medication and Hip Fracture in Community-Dwelling Older Persons With Alzheimer’s Disease

Annals of Pharmacotherapy ◽

10.1177/1060028017708394 ◽

2017 ◽

Vol 51 (9) ◽

pp. 725-734 ◽

Cited By ~ 2

Author(s):

Virva Hyttinen ◽

Heidi Taipale ◽

Anna-Maija Tolppanen ◽

Antti Tanskanen ◽

Jari Tiihonen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Hip Fracture ◽

Hip Fractures ◽

Service Use ◽

Health Care Service ◽

Community Dwelling ◽

Potentially Inappropriate Medications ◽

Increased Risk

Background: Potentially inappropriate medications (PIMs) increase the risk of adverse drug reactions and events and have been associated with greater health care service use, such as an increased risk of hospitalization. Objective: The aim of this study is to evaluate the association between PIM use and hip fractures in a nationwide cohort of community-dwelling persons ≥65 years old with Alzheimer’s disease (AD). Methods: The study, which is based on the Finnish nationwide MEDALZ cohort, included all persons diagnosed with AD between 2005 and 2011 (n = 70 718). After a 1-year washout period for PIM use and exclusion of persons with previous hip fracture before AD diagnosis or those who had been hospitalized, we included 47 850 persons ≥65 years old with AD. PIM use was identified using Finnish criteria. Associations between PIM use and hip fracture were analyzed with Cox proportional hazards regression. Results: Of the study population, 12.3% (n = 5895) initiated PIMs during the follow-up (maximum follow-up 2921 days and total number of person-years 139 538.7). Of those, 103 (1.7%) persons had hip fractures during the PIM use period. The results suggest that PIM use was only associated with an increased risk of hip fracture with incident PIM use (adjusted hazard ratio = 1.31; 95% CI = 1.06-1.63; P = 0.014). Conclusions: PIM use is associated with increased risk of hip fracture when a person uses PIMs for the first time. However, the association between PIM use and hip fracture should be investigated more comprehensively in future studies.

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Risk of infective endocarditis among patients with tetralogy of fallot

European Heart Journal ◽

10.1093/ehjci/ehaa946.2171 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

E Havers-Borgersen ◽

J.H Butt ◽

M Groening ◽

M Smerup ◽

G.H Gislason ◽

...

Keyword(s):

Infective Endocarditis ◽

Tetralogy Of Fallot ◽

Valve Replacement ◽

Pulmonary Valve ◽

Cox Regression ◽

Pulmonary Valve Replacement ◽

Varying Coefficients ◽

Background Population ◽

Increased Risk

Abstract Introduction Patients with tetralogy of Fallot (ToF) are considered at high risk of infective endocarditis (IE) as a result of altered hemodynamics and multiple surgical and interventional procedures including pulmonary valve replacement (PVR). The overall survival of patients with ToF has increased in recent years. However, data on the risk of adverse outcomes including IE are sparse. Purpose To investigate the risk of IE in patients with ToF compared with controls from the background population. Methods In this nationwide observational cohort study, all patients with ToF born in 1977–2017 were identified using Danish nationwide registries and followed from date of birth until occurrence of an outcome of interest (i.e. first-time IE), death, or end of study (July 31, 2017). The comparative risk of IE among ToF patients versus age- and sex-matched controls from the background population was assessed. Results A total of 1,156 patients with ToF were identified and matched with 4,624 controls from the background population. Among patients with ToF, 266 (23.0%) underwent PVR during follow-up. During a median follow-up time of 20.4 years, 38 (3.3%) patients and 1 (0.03%) control were admitted with IE. The median time from date of birth to IE was 10.8 years (25th-75th percentile 2.8–20.9 years). The incidence rates of IE per 1,000 person-years were 2.2 (95% confidence interval (CI) 1.6–3.0) and 0.01 (95% CI 0.0001–0.1) among patients and controls, respectively. In multivariable Cox regression models, in which age, sex, pulmonary valve replacement, and relevant comorbidities (i.e. chronic renal failure, diabetes mellitus, presence of cardiac implantable electronic devices, other valve surgeries), were included as time-varying coefficients, the risk of IE was significantly higher among patients compared with controls (HR 171.5, 95% CI 23.2–1266.7). Moreover, PVR was associated with an increased risk of IE (HR 3.4, 95% CI 1.4–8.2). Conclusions Patients with ToF have a substantial risk of IE and the risk is significantly higher compared with the background population. In particular, PVR was associated with an increased risk of IE. With an increasing life-expectancy of these patients, intensified awareness, preventive measures, and surveillance of this patient group are advisable. Figure 1. Cumulative incidence of IE Funding Acknowledgement Type of funding source: None

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Urinary Carnosinase-1 Excretion is Associated with Urinary Carnosine Depletion and Risk of Graft Failure in Kidney Transplant Recipients: Results of the TransplantLines Cohort Study

Antioxidants ◽

10.3390/antiox10071102 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1102

Author(s):

Angelica Rodriguez-Niño ◽

Diego O. Pastene ◽

Adrian Post ◽

M. Yusof Said ◽

Antonio W. Gomes-Neto ◽

...

Keyword(s):

Kidney Transplant ◽

Graft Failure ◽

Cox Regression ◽

Carbonyl Stress ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Increased Risk ◽

High Concentrations ◽

Kidney Function Decline

Carnosine affords protection against oxidative and carbonyl stress, yet high concentrations of the carnosinase-1 enzyme may limit this. We recently reported that high urinary carnosinase-1 is associated with kidney function decline and albuminuria in patients with chronic kidney disease. We prospectively investigated whether urinary carnosinase-1 is associated with a high risk for development of late graft failure in kidney transplant recipients (KTRs). Carnosine and carnosinase-1 were measured in 24 h urine in a longitudinal cohort of 703 stable KTRs and 257 healthy controls. Cox regression was used to analyze the prospective data. Urinary carnosine excretions were significantly decreased in KTRs (26.5 [IQR 21.4–33.3] µmol/24 h versus 34.8 [IQR 25.6–46.8] µmol/24 h; p < 0.001). In KTRs, high urinary carnosinase-1 concentrations were associated with increased risk of undetectable urinary carnosine (OR 1.24, 95%CI [1.06–1.45]; p = 0.007). During median follow-up for 5.3 [4.5–6.0] years, 84 (12%) KTRs developed graft failure. In Cox regression analyses, high urinary carnosinase-1 excretions were associated with increased risk of graft failure (HR 1.73, 95%CI [1.44–2.08]; p < 0.001) independent of potential confounders. Since urinary carnosine is depleted and urinary carnosinase-1 imparts a higher risk for graft failure in KTRs, future studies determining the potential of carnosine supplementation in these patients are warranted.

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Use of incretin-based drugs and risk of cholangiocarcinoma: Scandinavian cohort study

Diabetologia ◽

10.1007/s00125-021-05508-1 ◽

2021 ◽

Author(s):

Peter Ueda ◽

Viktor Wintzell ◽

Mads Melbye ◽

Björn Eliasson ◽

Ann-Marie Svensson ◽

...

Keyword(s):

Incidence Rate ◽

Cox Regression ◽

Absolute Rate ◽

Dipeptidyl Peptidase 4 ◽

Rate Difference ◽

Receptor Agonists ◽

Dpp4 Inhibitors ◽

Increased Risk ◽

Increase In Risk

Abstract Aims/hypothesis Concerns have been raised regarding a potential association of use of the incretin-based drugs dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1)-receptor agonists with risk of cholangiocarcinoma. We examined this association in nationwide data from three countries. Methods We used data from nationwide registers in Sweden, Denmark and Norway, 2007–2018, to conduct two cohort studies, one for DPP4 inhibitors and one for GLP-1-receptor agonists, to investigate the risk of incident cholangiocarcinoma compared with an active-comparator drug class (sulfonylureas). The cohorts included patients initiating treatment episodes with DPP4 inhibitors vs sulfonylureas, and GLP-1-receptor agonists vs sulfonylureas. We used Cox regression models, adjusted for potential confounders, to estimate hazard ratios from day 366 after treatment initiation to account for cancer latency. Results The main analyses of DPP4 inhibitors included 1,414,144 person-years of follow-up from 222,577 patients receiving DPP4 inhibitors (median [IQR] follow-up time, 4.5 [2.6–7.0] years) and 123,908 patients receiving sulfonylureas (median [IQR] follow-up time, 5.1 [2.9–7.8] years) during which 350 cholangiocarcinoma events occurred. Use of DPP4 inhibitors, compared with sulfonylureas, was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.15 [95% CI 0.90, 1.46]; absolute rate difference 3 [95% CI -3, 10] events per 100,000 person-years). The main analyses of GLP-1-receptor agonists included 1,036,587 person-years of follow-up from 96,813 patients receiving GLP-1-receptor agonists (median [IQR] follow-up time, 4.4 [2.4–6.9] years) and 142,578 patients receiving sulfonylureas (median [IQR] follow-up time, 5.5 [3.2–8.1] years) during which 249 cholangiocarcinoma events occurred. Use of GLP-1-receptor agonists was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.25 [95% CI 0.89, 1.76]; absolute rate difference 3 [95% CI -5, 13] events per 100,000 patient-years). Conclusions/interpretation In this analysis using nationwide data from three countries, use of DPP4 inhibitors and GLP-1-receptor agonists, compared with sulfonylureas, was not associated with a significantly increased risk of cholangiocarcinoma. Graphical abstract

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