Abstract P060: Plasma Osteocalcin And Incident Diabetes Mellitus: The Atherosclerosis Risk In Communities (ARIC) Study

Introduction: Diabetes is a major risk factor for cardiovascular disease. Osteocalcin is a vitamin K-dependent, bone-derived hormone that functions as an endocrine regulator of energy metabolism, male fertility, and cognition. Early studies of endocrine effects of osteocalcin have shown that genomic deletion of osteocalcin in mice resulted in a diabetic phenotype (i.e. glucose intolerance, and insulin resistance). However, results from clinical studies have shown mixed associations between blood levels of osteocalcin and risk of incident type 2 diabetes mellitus. Hypothesis: Lower values of plasma osteocalcin would be associated with an increased risk of diabetes. Methods: A total of 11,557 ARIC participants without diabetes at baseline were followed from ARIC visit 3 (1993-1995) through 2018. Diabetes cases were identified through self-report on annual and semi-annual follow-up phone calls. Plasma osteocalcin data was measured using an aptamer-based proteomic profiling platform (SomaLogic). We used Cox regression to evaluate the association of quintiles of plasma osteocalcin and incident diabetes. The primary model adjusted for age, sex, and race-center. Results: Participants were age 60 ± 5.6 years at visit 3, 56% identified as female, 21% identified as Black. There were 3,031 incident diabetes cases over a median follow-up of 17.9 years. Mean ± SD was 10.053 ± 0.775. When comparing the highest quintile of plasma osteocalcin (values 10.42 to 14.66) to the lowest quintile (values 9.03 to 9.52), there was no association with incident diabetes (HRs [95% CIs]: 0.92 [0.81, 1.02]). There was also no significant trend across the quintiles (p = 0.19). Results were similar when adjusting for additional potential confounders, and when limiting the follow-up time to 10 years. Conclusions: These data do not support the hypothesis that total plasma osteocalcin, as measured by Somalogic proteomic panel, is a biomarker associated with diabetes risk. It is possible that total plasma or serum osteocalcin and/or other isoforms of osteocalcin protein (i.e. gamma carboxylated or uncarboxylated osteocalcin) measured via other validated methodologies may be linked to diabetes.

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Long term perspective with LBBB: role of stress echocardiography

European Heart Journal ◽

10.1093/ehjci/ehaa946.0020 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

S Dedic ◽

N Boskovic ◽

V Giga ◽

M Tesic ◽

S Aleksandric ◽

...

Keyword(s):

Diabetes Mellitus ◽

Myocardial Infarction ◽

Left Bundle Branch Block ◽

Stress Echocardiography ◽

Cox Regression ◽

Survival Curve ◽

Bundle Branch Block ◽

Cox Regression Analysis ◽

Increased Risk

Abstract Background Previous studies have shown that left bundle branch block (LBBB), as a relatively common electrocardiographic (ECG) abnormality, represents the condition with often non benign and sometimes adverse outcome. Purpose The Aim of our study was to determine the predictive value of a stress echocardiography test in patients with LBBB. Methods Our study population included 189 patients (88 male, 46.6%, mean age 63.08±9.65) with diagnosed left bundle branch block who performed stress echocardiography (SECHO) according to Bruce protocol. Median follow-up of the patients was 56 months (IQR 48–71 months) for the occurrence of cardiovascular death and non-fatal myocardial infarction, repeat revascularization (coronary artery bypass grafting-CABG or percutaneous coronary intervention-PCI). Results Out of 189 patients, 32 (16.9%) patients had positive, while 157 (83.1%) patients had negative SECHO test. During the follow up period 28 patients had major adverse cardiac event: 1 nonfatal myocardial infarction, 6 heart failure hospitalizations, 5 CABGs, 8 PCIs, while 8 patients had cardiac death. Using the Cox regression analysis, univariate predictors of adverse cardiac events were diabetes mellitus (HR 4.530 [95% CI 1.355–15.141], p=0.014), PCI (HR 4.288 [95% [95% CI 2.010–9.144], p<0.001) and positive SECHO test (HR 2.289 [95% CI 1.006–5207], p=0.048). In the multivariate analysis only previous PCI remained independent predictor of adverse events (HR 3.650 [95% CI 1.665–8.003], p=0.001). p=0.048). Using the Kaplan-Meier survival curve the patients with negative SECHO had better outcome compared to patients with positive SECHO (140/160; 87,5% vs 21/29; 72.4%, p=0.035) and much longer event-free time (77.4±1.6 months vs 67.1±5.4 months, Log Rank 4.136, p=0.042) Conclusion Patients with LBBB and negative SEHO test have good prognosis. Patients with history of CAD and diabetes mellitus and LBBB are at increased risk for future events and need periodical reassessment. Funding Acknowledgement Type of funding source: None

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Prediction of incident diabetes mellitus by baseline IGF1 levels

Acta Endocrinologica ◽

10.1530/eje-10-0963 ◽

2011 ◽

Vol 164 (2) ◽

pp. 223-229 ◽

Cited By ~ 40

Author(s):

Harald Jörn Schneider ◽

Nele Friedrich ◽

Jens Klotsche ◽

Sabine Schipf ◽

Matthias Nauck ◽

...

Keyword(s):

Diabetes Mellitus ◽

Metabolic Parameters ◽

Incident Diabetes ◽

Large Prospective Study ◽

Prospective Cohort Studies ◽

Hazard Ratios ◽

Increased Risk ◽

Hba1c Levels

ObjectiveIGF1 is associated with metabolic parameters and involved in glucose metabolism. Low-IGF1 has been implicated in the etiology of glucose intolerance and subjects with pathological causes of either low- or high-IGF1 are at risk of diabetes. We hypothesized that both low- and high-IGF1 levels increase the risk of diabetes and aimed to assess the role of IGF1 in the risk of developing diabetes in a large prospective study.DesignAn analysis of two prospective cohort studies, the DETECT study and SHIP.MethodsWe measured IGF1 levels in 7777 nondiabetic subjects and assessed incident diabetes mellitus during follow-up.ResultsThere were 464 cases of incident diabetes during 32 229 person-years (time of follow-up in the DETECT study and SHIP: 4.5 and 5 years respectively). There was no heterogeneity between both studies (P>0.4). The hazard ratios (HRs) of incident diabetes in subjects with IGF1 levels below the 10th or above the 90th age- and sex-specific percentile, compared to subjects with intermediate IGF1 levels, were 1.44 (95% confidence interval (CI) 1.07–1.94) and 1.55 (95% CI 1.06–2.06) respectively, after multiple adjustment. After further adjustment for metabolic parameters, the HR for low-IGF1 became insignificant. Analysis of IGF1 quintiles revealed a U-shaped association of IGF1 with risk of diabetes. Results remained similar after exclusion of patients with onset of new diabetes within 1 year or with borderline glucose or HbA1c levels at baseline.ConclusionsSubjects with low- or high-IGF1 level are at increased risk of developing diabetes.

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Hours lying down per day, as a proxy for sedentary behaviour and risk of diabetes in young and middle-aged adults in Norway: an 11-year follow-up of the HUNT study

BMJ Open ◽

10.1136/bmjopen-2019-035010 ◽

2020 ◽

Vol 10 (3) ◽

pp. e035010

Author(s):

Ernest O Asante ◽

Yi-Qian Sun ◽

Tom Ivar Lund Nilsen ◽

Bjørn Olav Åsvold ◽

Elin Pettersen Sørgjerd ◽

...

Keyword(s):

Physical Activity ◽

Sedentary Behaviour ◽

Leisure Time Physical Activity ◽

Self Report ◽

Incident Diabetes ◽

Middle Aged ◽

Increased Risk ◽

Middle Aged Adults ◽

Lying Down

ObjectiveWe aimed to examine relationship between hours lying down per day, as a proxy for sedentary behaviour and risk of diabetes in young and middle-aged adults, and to assess if leisure-time physical activity and body mass index (BMI) modified this relationship.DesignA population-based prospective cohort study.SettingNord-Trøndelag, Norway.ParticipantsThe cohort included 17 058 diabetes-free adults, at an age of 20–55 years in 1995–1997, who were followed-up to 2006–2008.Primary outcome measuresIncident diabetes was defined by self-report of diabetes or non-fasting glucose levels greater than 11 mmol/L at the follow-up.MethodsMultivariable logistic regression models were used to obtain OR with 95% CI for risk of diabetes by the categories of hours lying down (≤7, 8 and ≥9 hours/day).Results362 individuals (2.1%) developed diabetes during an average of 11-year follow-up. Individuals who reported lying down ≥9 hours/day had an adjusted OR of 1.35 (95% CI 1.01 to 1.80) for incident diabetes compared with those lying down 8 hours/day. Lying down ≤7 hours/day was not associated with the risk of diabetes. In analysis stratified by physical activity, the ORs associated with lying down ≥9 hours/day were 1.41 (95% CI 1.05 to 1.90) and 0.90 (95% CI 0.23 to 3.55), respectively, among the less active and highly active individuals (pinteraction=0.048). There was little evidence that the association differed by BMI status (pinteraction=0.62).ConclusionsProlonged hours lying down per day was associated with an increased risk of diabetes in young and middle-aged adults. The positive association appeared to be modified by physical activity but not by BMI.

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Risk of Diabetes Mellitus in Long-Term Survivors of Hodgkin Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2013.54.4379 ◽

2014 ◽

Vol 32 (29) ◽

pp. 3257-3263 ◽

Cited By ~ 40

Author(s):

Frederika A. van Nimwegen ◽

Michael Schaapveld ◽

Cecile P.M. Janus ◽

Augustinus D.G. Krol ◽

John M.M. Raemaekers ◽

...

Keyword(s):

Diabetes Mellitus ◽

Lymph Nodes ◽

Hodgkin Lymphoma ◽

Cumulative Incidence ◽

Cox Regression ◽

Study Cohort ◽

Increased Risk ◽

Increase Risk ◽

Long Term Survivors

Purpose Recently, an increased risk of diabetes mellitus (DM) was observed after abdominal irradiation for childhood cancer. Because many Hodgkin lymphoma (HL) survivors have also been treated with infradiaphragmatic radiotherapy, we evaluated the association between HL treatment and DM risk. Patients and Methods Our study cohort comprised 2,264 5-year HL survivors, diagnosed before age 51 years and treated between 1965 and 1995. Treatment and follow-up information was collected from medical records and general practitioners. Radiation dosimetry was performed to estimate radiation dose to the pancreas. Cumulative incidence of DM was estimated, and risk factors for DM were evaluated by using Cox regression. Results After a median follow-up of 21.5 years, 157 patients developed DM. Overall cumulative incidence of DM after 30 years was 8.3% (95% CI, 6.9% to 9.8%). After para-aortic radiation with ≥ 36 Gy, the 30-year cumulative incidence of DM was 14.2% (95% CI, 10.7% to 18.3%). Irradiation with ≥ 36 Gy to the para-aortic lymph nodes and spleen was associated with a 2.30-fold increased risk of DM (95% CI, 1.54- to 3.44-fold) whereas para-aortic radiation alone with ≥ 36 Gy was associated with a 1.82-fold increased risk (95% CI, 1.02- to 3.25-fold). Lower doses (10 to 35 Gy) did not significantly increase risk of DM. The risk of DM significantly increased with higher mean radiation doses to the pancreatic tail (P < .001). Conclusion Radiation to the para-aortic lymph nodes increases the risk of developing DM in 5-year HL survivors. Screening for DM should be considered in follow-up guidelines for HL survivors, and treating physicians should be alert to this increased risk.

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Prognostic significance of diabetes mellitus in patients with atrial fibrillation

EP Europace ◽

10.1093/europace/euab116.136 ◽

2021 ◽

Vol 23 (Supplement_3) ◽

Author(s):

A Papazoglou ◽

A Kartas ◽

A Samaras ◽

I Vouloagkas ◽

E Vrana ◽

...

Keyword(s):

Diabetes Mellitus ◽

Atrial Fibrillation ◽

Cox Regression ◽

Survival Rates ◽

Prognostic Significance ◽

Composite Outcome ◽

Increased Risk ◽

All Cause Mortality ◽

Hba1c Levels

Abstract Funding Acknowledgements Type of funding sources: None. Background Despite the plethora of studies on atrial fibrillation (AF) and diabetes mellitus (DM), there is still no sufficient data on the blood glucose regulation as a prognostic modifier in DM patients with AF. Purpose The purpose of this study was to investigate the association of DM and levels of glycated hemoglobin (HbA1c) with outcomes in patients with AF. Methods This retrospective cohort study included patients who were recently hospitalized with a primary or secondary diagnosis of AF from December 2015 through June 2018. Kaplan-Meier curves and Cox-regression adjusted hazard ratios (aHR) were calculated for the primary outcome of all-cause mortality and for the secondary outcomes of cardiovascular (CV) mortality, stroke and the composite outcome of CV death or hospitalization. Spline curve models were fitted to investigate associations of HbA1c values and mortality among patients with AF and DM. Results In total 1140 AF patients were included, of whom 373 (32.7%) had DM. During a median follow-up of 2.6 years, 414 (37.3%) patients died. The presence of DM was associated with a higher risk of all-cause mortality (aHR = 1.44, 95% confidence intervals [CI]: 1.12-1.85), CV mortality (aHR = 1.44, 95% CI: 1.08-1.93), stroke (aHR = 2.62, 95% CI: 1.24-5.53) and the composite outcome of hospitalization or CV death (aHR = 1.28, 95% CI: 1.06-1.54). In AF patients with comorbid DM, the spline curves showed a positive linear association between HbA1c levels and outcomes, with values <6.2% predicting significantly decreased all-cause and CV mortality. Conclusions The presence of DM on top of AF was associated with a 1.5-fold increased risk for all-cause or CV mortality and excess morbidity. HbA1c levels lower than 6.2% were independently related to better survival rates. Follow-up outcomes by presence of DMOutcomeDMNon-DMAdjusted HR(95% CI)p-valueAll-cause death171/373 (45.8%)243/736 (33%)1.44 (1.12-1.85)<0.001CV-death130/373 (34.9%)173/736 (23.5%)1.44 (1.08-1.93)<0.001Major bleeding18/340 (5.3%)29/644 (4.5%)1.53 (0.71-3.28)0.291Stroke24/340 (7.1%)28/645 (4.3%)2.62 (1.24-5.53)0.013AF-related hospitalization59/340 (17.4%)115/645 (17.8%)1.20 (0.78-1.85)0.281HF-related hospitalization35/333 (10.5%)46/640 (7.2%)1.34 (0.83-2.19)0.235Hospitalization or CV-death243/373 (65.1%)399/736(54.2%)1.28 (1.06-1.54)<0.001*Adjusted for: age, gender, smoking, BMI, history of hypertension, eGFR (CKD-EPI) and use of statin, ACEI-ARB, OAC and rate control medication after discharge.DM, diabetes mellitus; HR, hazard ratio; AF, atrial fibrillation; CV, cardiovascular; HF, heart failure.Abstract Figure. Visual overview of the study

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Diabetes mellitus as a risk factor for compression neuropathy: a longitudinal cohort study from southern Sweden

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001298 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001298 ◽

Cited By ~ 1

Author(s):

Mattias Rydberg ◽

Malin Zimmerman ◽

Anders Gottsäter ◽

Peter M Nilsson ◽

Olle Melander ◽

...

Keyword(s):

Diabetes Mellitus ◽

Risk Factor ◽

Plasma Glucose ◽

Regression Models ◽

Cox Regression ◽

Binary Logistic Regression ◽

Population Based ◽

Logistic Regression Models ◽

Increased Risk

IntroductionCompression neuropathies (CN) in the upper extremity, the most common being carpal tunnel syndrome (CTS) and ulnar nerve entrapment (UNE), are frequent among patients with diabetes mellitus (DM). Earlier studies have shown contradicting results regarding DM as a risk factor for CN. Thus, the aim of the present population-based, longitudinal study was to explore potential associations between DM, CTS, and UNE during long-term follow-up.Research design and methodsA total of 30 466 participants aged 46–73 years, included in the population-based Malmö Diet and Cancer Study during 1991–1996, were followed up in Swedish national registries regarding incident CTS and UNE until 2016. Associations between prevalent DM at baseline and incident CTS or UNE were calculated using Cox proportional hazard models, adjusted for baseline confounders, such as sex, age at study entry, smoking, hypertension, use of antihypertensive treatment, alcohol consumption, and body mass index (BMI). HbA1c and fasting plasma glucose levels had been measured at baseline in a subgroup of 5508 participants and were related to incident CTS and UNE in age and sex-adjusted binary logistic regression models.ResultsA total of 1081 participants developed CTS and 223 participants developed UNE during a median follow-up of 21 years. Participants with incident CTS or UNE had higher prevalence of DM and higher BMI at baseline. Using multivariate Cox regression models, prevalent DM at baseline was independently associated with both incident CTS (HR 2.10; 95% CI 1.65 to 2.70, p<0.0001) and incident UNE (HR 2.20; 95% CI 1.30 to 3.74, p=0.003). Higher levels of HbA1c and plasma glucose were associated with an increased risk for CTS, but not for UNE.ConclusionThis study establishes DM as a major risk factor in the development of both CTS and UNE. Furthermore, a higher BMI is associated with both CTS and UNE. Finally, hyperglycemia seems to affect the median and ulnar nerves differently.

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Hypertension and intracerebral hemorrhage recurrence among white, black, and Hispanic individuals

Neurology ◽

10.1212/wnl.0000000000005729 ◽

2018 ◽

Vol 91 (1) ◽

pp. e37-e44 ◽

Cited By ~ 6

Author(s):

Axana Rodriguez-Torres ◽

Meredith Murphy ◽

Christina Kourkoulis ◽

Kristin Schwab ◽

Alison M. Ayres ◽

...

Keyword(s):

Confidence Interval ◽

Intracerebral Hemorrhage ◽

Cox Regression ◽

Recurrence Risk ◽

Hazard Ratio ◽

Self Report ◽

Phone Calls ◽

Hispanic Patients ◽

Race Ethnicity

ObjectiveTo clarify whether recurrence risk for intracerebral hemorrhage (ICH) is higher among black and Hispanic individuals and whether this disparity is attributable to differences in blood pressure (BP) measurements and their variability.MethodsWe analyzed data from survivors of primary ICH enrolled in 2 separate studies: (1) the longitudinal study conducted at Massachusetts General Hospital (n = 759), and (2) the ERICH (Ethnic/Racial Variations of Intracerebral Hemorrhage) study (n = 1,532). Participants underwent structured interview at enrollment (including self-report of race/ethnicity) and were followed longitudinally via phone calls and review of medical records. We captured systolic BP (SBP) and diastolic BP measurements, and quantified variability as SBP and diastolic BP variation coefficients. We used multivariable (Cox regression) survival analysis to identify risk factors for ICH recurrence.ResultsWe followed 2,291 ICH survivors (1,121 white, 529 black, 605 Hispanic, and 36 of other race/ethnicity). Both black and Hispanic patients displayed higher SBP during follow-up (p < 0.05). Black participants also displayed greater SBP variability during follow-up (p = 0.032). In univariable analyses, black and Hispanic patients were at higher ICH recurrence risk (p < 0.05). After adjusting for BP measurements and their variability, both Hispanic (hazard ratio = 1.51, 95% confidence interval 1.14–2.00, p = 0.004) and black (hazard ratio = 1.98, 95% confidence interval 1.36–2.86, p < 0.001) patients remained at higher risk of ICH recurrence.ConclusionBlack and Hispanic patients are at higher risk of ICH recurrence; hypertension severity (average BP and its variability) does not fully account for this finding. Additional studies will be required to further elucidate determinants for this health disparity.

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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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