The impact of central obesity on the risk of hospitalization or death due to heart failure in type 1 diabetes: a 16-year cohort study

Abstract Background Obesity and type 2 diabetes are well-known risk factors for heart failure (HF). Although obesity has increased in type 1 diabetes, studies regarding HF in this population are scarce. Therefore, we investigated the impact of body fat distribution on the risk of HF hospitalization or death in adults with type 1 diabetes at different stages of diabetic nephropathy (DN). Methods From 5401 adults with type 1 diabetes in the Finnish Diabetic Nephropathy Study, 4668 were included in this analysis. The outcome was HF hospitalization or death identified from the Finnish Care Register for Health Care or the Causes of Death Register until the end of 2017. DN was based on urinary albumin excretion rate. A body mass index (BMI) ≥ 30 kg/m2 defined general obesity, whilst WHtR ≥ 0.5 central obesity. Multivariable Cox regression was used to explore the associations between central obesity, general obesity and the outcome. Then, subgroup analyses were performed by DN stages. Z statistic was used for ranking the association. Results During a median follow-up of 16.4 (IQR 12.4–18.5) years, 323 incident cases occurred. From 308 hospitalizations due to HF, 35 resulted in death. Further 15 deaths occurred without previous hospitalization. The WHtR showed a stronger association with the outcome [HR 1.51, 95% CI (1.26–1.81), z = 4.40] than BMI [HR 1.05, 95% CI (1.01–1.08), z = 2.71]. HbA1c [HR 1.35, 95% CI (1.24–1.46), z = 7.19] was the most relevant modifiable risk factor for the outcome whereas WHtR was the third. Individuals with microalbuminuria but no central obesity had a similar risk of the outcome as those with normoalbuminuria. General obesity was associated with the outcome only at the macroalbuminuria stage. Conclusions Central obesity associates with an increased risk of heart failure hospitalization or death in adults with type 1 diabetes, and WHtR may be a clinically useful screening tool.

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Myocardial reperfusion reverses the J-curve association of cardiovascular risk and diastolic blood pressure in patients with left ventricular dysfunction and heart failure after myocardial infarction: insights from the EPHESUS trial

European Heart Journal ◽

10.1093/eurheartj/ehaa132 ◽

2020 ◽

Vol 41 (17) ◽

pp. 1673-1683 ◽

Cited By ~ 5

Author(s):

Michael Böhm ◽

João Pedro Ferreira ◽

Felix Mahfoud ◽

Kevin Duarte ◽

Bertram Pitt ◽

...

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Blood Pressure ◽

Diastolic Blood Pressure ◽

Cox Regression ◽

Cardiovascular Death ◽

Left Ventricular ◽

Coronary Perfusion ◽

Increased Risk ◽

The Impact

Abstract Aims The described association of low diastolic blood pressure (DBP) with increased cardiovascular outcomes could be due to reduced coronary perfusion or is simply due to reverse causation. If DBP is physiologically relevant, coronary reperfusion after myocardial infarction (MI) might influence DBP–risk association. Methods and results The relation of achieved DBP with cardiovascular death or cardiovascular hospitalization, cardiovascular death, and all-cause death was explored in 5929 patients after acute myocardial infarction (AMI) with impaired left ventricular function, signs and symptoms of heart failure, or diabetes in the EPHESUS trial according to their reperfusion status. Cox regression models were used to assess the impact of reperfusion status on the association of DBP and systolic blood pressure (SBP) with outcomes in an adjusted fashion. In patients without reperfusion, lower DBP <70 mmHg was associated with increased risk for all-cause death [adjusted hazard ratios (HRs) 1.80, 95% confidence interval (CI) 1.41–2.30; P < 0.001], cardiovascular death (HR 1.70, 95% CI 1.3–3.22; P < 0.001), cardiovascular death or cardiovascular hospitalization (HR 1.54, 95% CI 1.26–1.87; P < 0.001). In patients with reperfusion, the risk increase at low DBP was not observed. At low SBP, risk increased independently of reperfusion. A sensitivity analysis in the subgroup of patients with optimal SBP of 120–130 mmHg showed again risk reduction of reperfusion at low DBP. Adding the treatment allocation to eplerenone or placebo into the models had no effects on the results. Conclusion Patients after AMIs with a low DBP had an increased risk, which was sensitive to reperfusion therapy. Low blood pressure after MI identifies in patients with particular higher risk. These data support the hypothesis that low DBP in patients with stenotic coronary lesions is associated with risk, potentially involving coronary perfusion pressure and the recommendations provided by guidelines suggesting lower DBP boundaries for these high-risk patients.

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Risk Factors for Cardiovascular Disease (CVD) in Adults with Type 1 Diabetes: Findings from Prospective Real-life T1D Exchange Registry

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa015 ◽

2020 ◽

Vol 105 (5) ◽

pp. e2032-e2038 ◽

Cited By ~ 4

Author(s):

Viral N Shah ◽

Ryan Bailey ◽

Mengdi Wu ◽

Nicole C Foster ◽

Rodica Pop-Busui ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Type 1 Diabetes ◽

Diabetic Nephropathy ◽

The United States ◽

Cvd Risk Factors ◽

Cvd Risk ◽

The Impact

Abstract Context Cardiovascular disease (CVD) is a major cause of mortality in adults with type 1 diabetes. Objective We prospectively evaluated CVD risk factors in a large, contemporary cohort of adults with type 1 diabetes living in the United States. Design Observational study of CVD and CVD risk factors over a median of 5.3 years. Setting The T1D Exchange clinic network. Patients Adults (age ≥ 18 years) with type 1 diabetes and without known CVD diagnosed before or at enrollment. Main Outcome Measure Associations between CVD risk factors and incident CVD were assessed by multivariable logistic regression. Results The study included 8,727 participants (53% female, 88% non-Hispanic white, median age 33 years [interquartile ratio {IQR} = 21, 48], type 1 diabetes duration 16 years [IQR = 9, 26]). At enrollment, median HbA1c was 7.6% (66 mmol/mol) (IQR = 6.9 [52], 8.6 [70]), 33% used a statin, and 37% used blood pressure medication. Over a mean follow-up of 4.6 years, 325 (3.7%) participants developed incident CVD. Ischemic heart disease was the most common CVD event. Increasing age, body mass index, HbA1c, presence of hypertension and dyslipidemia, increasing duration of diabetes, and diabetic nephropathy were associated with increased risk for CVD. There were no significant gender differences in CVD risk. Conclusion HbA1c, hypertension, dyslipidemia and diabetic nephropathy are important risk factors for CVD in adults with type 1 diabetes. A longer follow-up is likely required to assess the impact of other traditional CVD risk factors on incident CVD in the current era.

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Biological Activity of c-Peptide in Microvascular Complications of Type 1 Diabetes—Time for Translational Studies or Back to the Basics?

International Journal of Molecular Sciences ◽

10.3390/ijms21249723 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9723

Author(s):

Aleksandra Ryk ◽

Aleksandra Łosiewicz ◽

Arkadiusz Michalak ◽

Wojciech Fendler

Keyword(s):

Type 1 Diabetes ◽

Growth Factor ◽

Transforming Growth Factor ◽

Negative Impact ◽

Current Knowledge ◽

Microvascular Complications ◽

C Peptide ◽

Increased Risk ◽

The Impact

People with type 1 diabetes have an increased risk of developing microvascular complications, which have a negative impact on the quality of life and reduce life expectancy. Numerous studies in animals with experimental diabetes show that c-peptide supplementation exerts beneficial effects on diabetes-induced damage in peripheral nerves and kidneys. There is substantial evidence that c-peptide counteracts the detrimental changes caused by hyperglycemia at the cellular level, such as decreased activation of endothelial nitric oxide synthase and sodium potassium ATPase, and increase in formation of pro-inflammatory molecules mediated by nuclear factor kappa-light-chain-enhancer of activated B cells: cytokines, chemokines, cell adhesion molecules, vascular endothelial growth factor, and transforming growth factor beta. However, despite positive results from cell and animal studies, no successful c-peptide replacement therapies have been developed so far. Therefore, it is important to improve our understanding of the impact of c-peptide on the pathophysiology of microvascular complications to develop novel c-peptide-based treatments. This article aims to review current knowledge on the impact of c-peptide on diabetic neuro- and nephropathy and to evaluate its potential therapeutic role.

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P4989Peripheral neuropathy and diastolic function are associated with adverse cardiovascular outcome in patients with type 1 diabetes mellitus: results from the thousand & 1 study

European Heart Journal ◽

10.1093/eurheartj/ehz746.0167 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

G M Hansen ◽

P G Jorgensen ◽

H U Andersen ◽

P Rossing ◽

M T Jensen

Keyword(s):

Type 1 Diabetes ◽

Heart Disease ◽

Diastolic Function ◽

Cox Regression ◽

Sensory Threshold ◽

Duration Of Diabetes ◽

Increased Risk ◽

Prediction Of Prognosis ◽

Risk Engine

Abstract Background Peripheral neuropathy (PN) is a highly prevalent and feared microvascular complication in patients with type 1 diabetes (T1D). Cardiovascular disease (CVD) is the most common cause of mortality in patients with T1D. PN may act as an early indicator of CVD and can potentially contribute to the propagation of atherosclerosis and cause the disease to remain clinically silent into advanced stages. Therefore, identification of T1D patients at risk of CVD is important in assuring timely prevention and treatment. Purpose The purpose of this study was to evaluate the risk of major adverse cardiovascular events (MACE) associated with measures of PN and diastolic function (DF) in patients with T1D and no known heart disease. Furthermore, we tested the additional prognostic value of including PN and DF both alone and in combination, in the validated Steno T1D Risk Engine. Methods Patients with T1D without known heart disease were included from the Steno Diabetes Center Copenhagen. Echocardiography and quantitative testing for PN using biothesiometry to determine sensory vibration threshold were performed. The patients were divided into three categories according to sensory threshold: <20mV, 20–49 mV, and ≥50mV. DF was divided into three categories of E/e': <8, 8–12, and >12. Endpoints was first occurring MACE. Using multivariable Cox regression models adjusting for age, sex, blood pressure, BMI, HbA1c, smoking, alcohol consumption, family history of CVD, eGFR, albuminuria, and duration of diabetes, the association between PN and/or DF and the risk of MACE was analysed. Improvement in prediction of prognosis was assessed with Harrell's C-statistics and compared to Steno T1D Risk Engine. Results A total of 946 patients (51.5% males) with T1D were included. Mean age was 48.4 (SD 14.4) years and mean duration of diabetes was 25 (SD 14.3) years. In the adjusted analysis, which was mutually adjusted for measures of PN and DF, both PN and DF were associated with increased risk of MACE: Sensory threshold ≥50mV vs. <20mV: Hazard Ratio (HR) 2.18 (95% confidence interval [CI]: 1.02–4.64, p=0.044). Threshold 20–49mV vs. <20mV: HR 1.33 (95% CI: 0.77–2.30, p=0.31). Diastolic measurement E/e' >12 vs. E/e' <8: HR 2.31 (95% CI: 1.16–4.59, p=0.017), and E/e' 8–12 vs. E/e' <8: HR 1.70 (95% CI: 1.03–2.82, p=0.038). In combination, a threshold ≥50mV and E/e' >12 vs. <20mV and E7e' <8 was associated with a marked increased risk of MACE: HR 8.59 (95% CI: 2.60–28.4, p<0.001). The addition of E/e' to the Steno T1D Risk Engine improved the prediction of outcome: C-statistic 0.797, (95% CI: 0.758–0.835) vs. 0.785 (95% CI: 0.744–0.825), p<0.001. Conclusion In patients with T1D without known heart disease and with preserved ejection fraction, PN and DF are independently associated with an increased risk of MACE. However, only measures of DF improved the prediction of prognosis when added to clinical risk factors. Acknowledgement/Funding None

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Evidence of Stage- and Age-Related Heterogeneity of Non-HLA SNPs and Risk of Islet Autoimmunity and Type 1 Diabetes: The Diabetes Autoimmunity Study in the Young

Clinical and Developmental Immunology ◽

10.1155/2013/417657 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 16

Author(s):

Brittni N. Frederiksen ◽

Andrea K. Steck ◽

Miranda Kroehl ◽

Molly M. Lamb ◽

Randall Wong ◽

...

Keyword(s):

Type 1 Diabetes ◽

Cox Regression ◽

Islet Autoimmunity ◽

Candidate Snps ◽

Age Related ◽

Increased Risk ◽

Restricted Cubic Splines ◽

Candidate Loci ◽

Hispanic White

Previously, we examined 20 non-HLA SNPs for association with islet autoimmunity (IA) and/or progression to type 1 diabetes (T1D). Our objective was to investigate fourteen additional non-HLA T1D candidate SNPs for stage- and age-related heterogeneity in the etiology of T1D. Of 1634 non-Hispanic white DAISY children genotyped, 132 developed IA (positive for GAD, insulin, or IA-2 autoantibodies at two or more consecutive visits); 50 IA positive children progressed to T1D. Cox regression was used to analyze risk of IA and progression to T1D in IA positive children. Restricted cubic splines were used to model SNPs when there was evidence that risk was not constant with age.C1QTNF6(rs229541) predicted increased IA risk (HR: 1.57, CI: 1.20–2.05) but not progression to T1D (HR: 1.13, CI: 0.75–1.71). SNP (rs10517086) appears to exhibit an age-related effect on risk of IA, with increased risk before age 2 years (age 2 HR: 1.67, CI: 1.08–2.56) but not older ages (age 4 HR: 0.84, CI: 0.43–1.62).C1QTNF6(rs229541), SNP (rs10517086), andUBASH3A(rs3788013) were associated with development of T1D. This prospective investigation of non-HLA T1D candidate loci shows that some SNPs may exhibit stage- and age-related heterogeneity in the etiology of T1D.

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Resistant hypertension and risk of adverse events in individuals with type 1 diabetes: A nationwide prospective study

10.2337/figshare.12137604.v1 ◽

2020 ◽

Author(s):

Raija Lithovius ◽

Valma Harjutsalo ◽

Stefan Mutter ◽

Daniel Gordin ◽

Carol Forsblom ◽

...

Keyword(s):

Type 1 Diabetes ◽

Diabetic Nephropathy ◽

Prospective Study ◽

Resistant Hypertension ◽

Antihypertensive Drugs ◽

Increased Risk ◽

All Cause Mortality ◽

Nationally Representative ◽

Reduced Kidney Function

Objectives. To estimate the risk of diabetic nephropathy (DN) progression, incident coronary heart disease (CHD) and stroke, and all-cause mortality associated with resistant hypertension (RH) in individuals with type 1 diabetes stratified by stages of DN, renal function and sex. Research Design and Methods This prospective study included a nationally representative cohort of individuals with type 1 diabetes from the Finnish Diabetic Nephropathy Study who had purchases of antihypertensive drugs at (±6 months) baseline visit (1995–2008). Individuals (N=1,103) were divided into three groups: (a) RH, (b) uncontrolled BP, but no RH and (c) controlled BP. DN progression, cardiovascular events and deaths were identified from the individuals’ healthcare records and national registries, until 31 December 2015. Results At baseline 18.7% of the participants had RH, while 23.4% had controlled BP. After full adjustments for clinical confounders, RH was associated with increased risk of DN progression (HR 1.95 [95% CI 1.37, 2.79], p=0.0002), while no differences were observed in those with no RH (1.05 [0.76, 1.44], p=0.8), compared with those who had controlled BP. The risk of incident CHD, incident stroke and all-cause mortality was higher in individuals with RH compared with those who had controlled BP, but not beyond albuminuria and reduced kidney function. Notably, in those with normo- and microalbuminuria the risk of stroke remained higher in the RH compared to controlled BP group (3.49 [81.20, 10.15], p=0.02). Conclusion Our findings highlight importance to identify and provide diagnostic and therapeutic counseling to these very high risk individuals with RH.

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Resistant hypertension and risk of adverse events in individuals with type 1 diabetes: A nationwide prospective study

10.2337/figshare.12137604.v2 ◽

2020 ◽

Author(s):

Raija Lithovius ◽

Valma Harjutsalo ◽

Stefan Mutter ◽

Daniel Gordin ◽

Carol Forsblom ◽

...

Keyword(s):

Type 1 Diabetes ◽

Diabetic Nephropathy ◽

Prospective Study ◽

Resistant Hypertension ◽

Antihypertensive Drugs ◽

Increased Risk ◽

All Cause Mortality ◽

Nationally Representative ◽

Reduced Kidney Function

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1018-P: Chronic Limb-Threatening Ischemia in Individuals with Type 1 Diabetes: The Impact of Diabetic Nephropathy and Severe Diabetic Retinopathy

Diabetes ◽

10.2337/db21-1018-p ◽

2021 ◽

Vol 70 (Supplement 1) ◽

pp. 1018-P

Author(s):

VALMA HARJUTSALO ◽

MILLA KALLIO ◽

CAROL FORSBLOM ◽

PER-HENRIK GROOP ◽

Keyword(s):

Type 1 Diabetes ◽

Diabetic Retinopathy ◽

Diabetic Nephropathy ◽

The Impact

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Abstract P316: Sleep Timing Correlates With Incident Congestive Heart Failure: A Community-based Cohort Study

Circulation ◽

10.1161/circ.141.suppl_1.p316 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Author(s):

Bin Yan ◽

Ruohan Li ◽

Xuting Jin ◽

Ya Gao ◽

Jingjing Zhang ◽

...

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Prospective Study ◽

Sleep Duration ◽

Subgroup Analysis ◽

Cox Regression ◽

Sleep Habits ◽

Sleep Timing ◽

Increased Risk ◽

The Impact

Introduction: Previous studies have suggested that sleep habits were associated with cardiovascular risk factors. However, there is no evidence about the relationship between sleep timing and congestive heart failure (CHF). Hypothesis: We assessed the hypothesis that the bedtime and wake-up time on weekday and weekend may be associated with incident CHF. Methods: From the Sleep Heart Health Study (registration number, NCT00005275), participants without previous heart failure were enrolled in the present prospective study. Sleep timing including bedtime and wake-up time on weekday and weekend was acquired from a self-reported Sleep Habits Questionnaire. Bedtime on weekdays and weekend was divided into >24:00, 23:01 to 24:00, 22:01 to 23:00 and ≤22:00. Wake-up time on weekdays and weekend was classified as >8:00, 7:01 to 8:00, 6:01 to 7:00 and ≤6:00. Further subgroup analysis was conducted according to sleep duration of <6h, 6-8h and >8h. Participants were followed up until the first CHF diagnosed between the date of the completed questionnaire and the final censoring date. Cox regression analysis was used to investigate the association between sleep timing and CHF. Results: A total of 4765 participants including 2207 males and 2558 females with a mean age of 63.6±11.0 years were recruited in the study. During the mean follow-up period of 11 years, 519 participants were diagnosed with CHF. The incidence of CHF in participants with weekday bedtime at >24:00 was 15.6% (69 of 441), which is higher than those with bedtime at 23:01 to 24:00 [12.7% (166 of 1306)], 22:01 to 23:00 [7.0% (128 of 1837)], and ≤22:00 [13.2% (156 of 1181)]. Participants with wake-up time on weekday at > 8:00 also had the highest incidence of CHF [19.7% (45 of 229)] than those with wake-up time at 7:01 to 8:00 [14.2% (89 of 627)], 6:01 to 7:00 [11.5% (171 of 1485)], and ≤6:00 [8.8% (214 of 2424)]. After multivariate Cox regression analyses, individuals with bedtime at >24:00 on weekdays was associated with a higher incidence of CHF (HR 1.559, 95% CI 1.151-2.113, P = 0.004) than those with bedtime at 22:01 to 23:00. And compared with participants with wake-up time at ≤6:00, those with wake-up time at > 8:00 also had an increased risk of incident CHF (HR 1.525, 95% CI 1.074-2.166, P =0.018). After further subgroup analysis, the association between bedtime at >24:00 on weekdays and incident CHF were strengthened in the participants with 6-8 hours’ sleep duration (HR 2.087, 95% CI 1.446-3.013, P <0.001). Conclusion: In conclusion, late bedtime (>24:00) and late wake-up time (>8:00) on weekdays may correlate with an increased risk of CHF. The impact of sleep timing on incident cardiovascular diseases may be worth further prospective study.

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The impact of parental risk factors on the risk of stroke in type 1 diabetes

Acta Diabetologica ◽

10.1007/s00592-021-01694-x ◽

2021 ◽

Author(s):

Anni Ylinen ◽

◽

Stefanie Hägg-Holmberg ◽

Marika I. Eriksson ◽

Carol Forsblom ◽

...

Keyword(s):

Risk Factors ◽

Type 1 Diabetes ◽

Hemorrhagic Stroke ◽

Cox Regression Analysis ◽

Parental Risk Factors ◽

Increased Risk ◽

History Of ◽

The Impact

Abstract Background Individuals with type 1 diabetes have a markedly increased risk of stroke. In the general population, genetic predisposition has been linked to increased risk of stroke, but this has not been assessed in type 1 diabetes. Our aim was, therefore, to study how parental risk factors affect the risk of stroke in individuals with type 1 diabetes. Methods This study represents an observational follow-up of 4011 individuals from the Finnish Diabetic Nephropathy Study, mean age at baseline 37.6 ± 11.9 years. All strokes during follow-up were verified from medical records or death certificates. The strokes were classified as either ischemic or hemorrhagic. All individuals filled out questionnaires concerning their parents’ medical history of hypertension, diabetes, stroke, and/or myocardial infarction. Results During a median follow-up of 12.4 (10.9–14.2) years, 188 individuals (4.6%) were diagnosed with their first ever stroke; 134 were ischemic and 54 hemorrhagic. In Cox regression analysis, a history of maternal stroke increased the risk of hemorrhagic stroke, hazard ratio 2.86 (95% confidence interval 1.27–6.44, p = 0.011) after adjustment for sex, age, BMI, retinal photocoagulation, and diabetic kidney disease. There was, however, no association between maternal stroke and ischemic stroke. No other associations between parental risk factors and ischemic or hemorrhagic stroke were observed. Conclusion A history of maternal stroke increases the risk of hemorrhagic stroke in individuals with type 1 diabetes. Other parental risk factors seem to have limited impact on the risk of stroke.

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