Causes of Excess Mortality in Diabetes Patients Without Coronary Artery Disease: A Cohort Study Revealing Endocrinologic Contributions.

Background: Diabetes mellitus (DM) patients without coronary artery disease (CAD) have a higher all-cause mortality rate than patients with neither DM nor CAD. We examined cause-specific death of DM patients with and without CAD. Methods: We conducted a cohort study of all patients who underwent CAG in Western Denmark between 2003 and 2016. Using Danish health registries, patients were followed for a maximum of 10 years and stratified according to their DM and CAD status. Outcomes included all-cause-, cancer-, circulatory-, and endocrinologic death. Ten-year cumulative risks were computed as well as adjusted and unadjusted hazard ratios (aHR and HR). Results: A total of 132,432 patients (28,524 deaths, median follow-up of 6.2 years) were included. Compared to patients with neither DM nor CAD, DM patients without CAD had a higher 10-year risk of all-cause death (27.9% versus 19.7%, aHR 1.43 [95% CI 1.35-1.52]), cancer death (7.2% versus 5.4%, aHR 1.29 [95% CI 1.15-1.46]), circulatory death (9.1% versus 6.9%, aHR 1.35 [95% CI 1.22-1.49]), and endocrinologic death (3.9% versus 0.3%, aHR 14.02 [95% CI 10.95-17.95]). Among endocrinologic deaths, 87% were due to classical complications of DM, such as diabetic nephropathy and ketoacidosis, in DM patients without CAD. Conclusion: Diabetes patients without CAD exhibit a higher risk of all-cause mortality, driven primarily by elevated rates of cancer, circulatory, and endocrinologic deaths, particularly related to diabetic microvascular complications.

Longitudinal HbA1c patterns before the first treatment of diabetes in routine clinical practice: A latent class trajectory analysis.

AIMS: To examine the longitudinal heterogeneity of HbA1c preceding the initiation of diabetes treatment in clinical practice. METHODS: In this population-based study, we used HbA1c from routine laboratory and healthcare databases. Latent class trajectory analysis was used to classify individuals according to their longitudinal HbA1c patterns before first glucose-lowering drug prescription irrespective of type of diabetes. RESULTS: Among 21,556 individuals initiating diabetes treatment during 2017-2018, 20,733 (96 %) had HbA1c measured (median 4 measurements [IQR 2-7]) in the 5 years preceding treatment initiation. Four classes with distinct HbA1c trajectories were identified, with varying steepness of increase in HbA1c. The largest class (74 % of the individuals) had mean HbA1c above the 48 mmol/mol threshold 9 months before treatment initiation. Mean HbA1c was 52 mmol/mol (95 % CI 52-52) at treatment initiation. In the remaining three classes, mean HbA1c exceeded 48 mmol/mol almost 1.5 years before treatment initiation and reached 79 mmol/mol (95 % CI 78-80), 105 mmol/mol (95 % CI 104-106), and 137 mmol/mol (95 % CI 135-140) before treatment initiation. CONCLUSION: We identified four distinct longitudinal HbA1c patterns before initiation of diabetes treatment in clinical practice. All had mean HbA1c levels exceeding the diagnostic threshold many months before treatment initiation, indicating therapeutic inertia.

Non-HDL cholesterol and residual cardiovascular risk in statin-treated patients with and without diabetes: the Western Denmark Heart Registry.

AIMS: Assessment of residual cardiovascular risk in statin-treated patients with atherosclerotic cardiovascular disease (ASCVD) is pivotal for optimizing secondary preventive therapies. This study investigates if non-high-density lipoprotein cholesterol (non-HDL-C) is associated with residual ASCVD risk in statin-treated ischaemic heart disease (IHD) patients with and without diabetes. METHODS AND RESULTS: Using the Western Denmark Heart Registry, we identified statin-treated patients with IHD examined by coronary angiography (CAG) from 2011 to 2020. Non-HDL-C was assessed within 1 year after CAG. Outcomes were ASCVD (myocardial infarction, ischaemic stroke, and cardiovascular death) and all-cause death. Cox regression analyses obtained hazard ratios (HRs) adjusted for age, sex, smoking, and hypertension. A total of 42 057 patients were included: 8196 patients with diabetes and 33 861 without diabetes. During the median 4.6 years of follow-up, event rates per 1000 person-years of ASCVD were 28.8 (27.1-30.5) and 17.2 (16.5-17.8) among patients with and without diabetes. In patients with diabetes, the adjusted HRs of ASCVD as compared with non-HDL-C < 25th percentile were 1.0 (0.9-1.2), 1.3 (1.1-1.6), and 1.6 (1.2-2.1) for patients in the 25th-74th, 75th-94th, and ≥95th percentiles. In patients without diabetes, the corresponding adjusted HRs were 1.1 (0.9-1.1), 1.2 (1.1-1.4), and 1.7 (1.4-2.0). Results were consistent across sex, age, clinical presentation, and low-density lipoprotein cholesterol strata. CONCLUSION: In statin-treated IHD patients with and without diabetes, non-HDL-C, especially above the 75th percentile, is associated with residual cardiovascular risk. These results have implications for secondary prevention, targeting patients who may benefit most from intensified preventive therapy.

Relevant to individuals, both with and without diabetes, who receive cholesterol-lowering therapy due to ischaemic heart disease, having a high level of non-HDL cholesterol is associated with risk of heart attack, stroke, and death.In individuals with diabetes, having a high compared to a low non-HDL cholesterol level was associated with a 30­60% increased risk of heart attack, stroke, and death. For individuals without diabetes, the high non-HDL cholesterol level was linked to an increased risk by up to 70%.In clinical practice, calculation of non-HDL cholesterol, from the standard lipid profile with no inconvenience to the patient, offers a possibility to identify patients who face a high risk of heart attack, stroke, and death. Patients with high levels of non-HDL cholesterol may benefit from optimized preventive therapy.

Leisure-time physical activity and all-cause mortality and cardiovascular disease in adults with type 2 diabetes: Cross-country comparison of cohort studies.

PURPOSE: This study aimed to quantify the dose-response association and the minimal effective dose of leisure-time physical activity (PA) to prevent mortality and cardiovascular disease in adults with type 2 diabetes. METHODS: Cross-country comparison of 2 prospective cohort studies including 14,913 and 17,457 population-based adults with type 2 diabetes from the UK and China. Baseline leisure-time PA was self-reported and categorized by metabolic equivalent hours per week (MET-h/week) according to World Health Organization recommendations: none, below recommendation (>0-7.49 MET-h/week); at recommended level (7.5-14.9 MET-h/week); above recommendation (≥15 MET-h/week). Mortality and cardiovascular disease data were obtained from national registries. RESULTS: During a median follow-up of 12.4 and 9.7 years, in the UK and China cohorts, repectively, higher levels of leisure-time PA were inversely associated with all-cause (1571 and 2351 events) and cardiovascular mortality (392 and 1060 events), mostly consistent with a linear dose-response relationship. PA below, at, and above recommendations, compared with no activity, yielded all-cause mortality hazard ratios of 0.94 (95% confidence interval (95%CI): 0.79-1.12), 0.90 (95%CI: 0.74-1.10), and 0.85 (95%CI: 0.70-1.02) in British adults and 0.87 (95%CI: 0.68-1.10), 0.88 (95%CI: 0.74-1.03), and 0.77 (95%CI: 0.70-0.85) in Chinese adults. Associations with cardiovascular mortality were more pronounced in British adults (0.80 (95%CI: 0.58-1.11), 0.75 (95%CI: 0.52-1.09), and 0.69 (95%CI: 0.48-0.97)) but less pronounced in Chinese adults (1.06 (95%CI: 0.76-1.47), 1.01 (95%CI: 0.80-1.28), and 0.79 (95%CI: 0.69-0.92)). PA at recommended levels was not associated with lower rates of major adverse cardiovascular events (2345 and 4458 events). CONCLUSION: Leisure-time PA at the recommended levels was not convincingly associated with lower mortality and had no association with risk of major adverse cardiovascular events in British or Chinese adults with type 2 diabetes. Leisure-time PA above current recommendations may be needed to prevent cardiovascular disease and premature mortality in adults with type 2 diabetes.

New Horizons: Epidemiology of Obesity, Diabetes Mellitus, and Cancer Prognosis.

The global prevalence of obesity and diabetes mellitus has increased in parallel with increasing cancer incidence, due to environmental and lifestyle factors and population aging. Metabolic diseases are associated with increased cancer risk, so a growing number of patients with cancer have coexistent obesity and/or diabetes mellitus. In this narrative review, we highlight recent evidence on the clinical impact of obesity and diabetes mellitus on the prognosis of prostate, breast, and colorectal cancer, and provide an overview of the underlying mechanisms. There is evidence that obesity is associated with increased risk of recurrence, and all-cause and cancer-specific mortality among adults with prostate, breast, and colorectal cancer. Diabetes mellitus is associated with increased all-cause and cancer-specific mortality for these 3 cancers, beyond any impact of obesity. Evidence also suggests increased risk of colorectal cancer recurrence in patients with diabetes mellitus. The underlying mechanisms are multifactorial and likely include hormonal imbalances and chronic inflammation that promote cancer cell growth. Obesity and diabetes mellitus are associated with increased risk of complications and side effects of cancer treatment. Associated comorbidities such as impaired kidney function, cardiovascular disease, and neuropathies may preclude the use of guideline cancer treatment and are competing causes of death. Cancer patients with metabolic diseases require a designated clinical program and a multidisciplinary approach involving oncologists, endocrinologists, surgeons, nutritionists, and physiotherapists, to ensure coordinated and optimized patient care.

10-Year Cardiovascular Risk in Patients With Newly Diagnosed Type 2 Diabetes Mellitus.

BACKGROUND: Contemporary data on cardiovascular disease (CVD) risk in patients with newly diagnosed type 2 diabetes mellitus (T2DM) is needed to guide appropriate preventive management. OBJECTIVES: The authors sought to investigate sex- and age-specific 10-year CVD risk in patients with newly diagnosed T2DM compared with the general population. METHODS: A cohort study was conducted of all Danish patients with T2DM diagnosed between 2006 and 2013 (n = 142,587) and sex- and age-matched individuals from the general population (n = 388,410), all without prior atherosclerotic CVD. Ten-year CVD risk (myocardial infarction, stroke, and fatal CVD) was estimated. RESULTS: A total of 52,471 CVD events were recorded. Compared with the general population, the 10-year CVD risks were higher in patients with T2DM in both sexes and across all age groups, especially among younger individuals. For example, patients aged 40 to 49 years had the largest 10-year CVD risk difference (T2DM 6.1% vs general population 3.3%; risk difference: 2.8%, subdistribution HR: 1.91; 95% CI: 1.76-2.07). The age when a given CVD risk was reached differed substantially between the cohorts. Thus, a 10-year CVD risk of 5% was reached at age 43 in men with T2DM compared with 12 years later, at age 55, in men without T2DM. A 10-year CVD risk of 5% was reached at age 51 in women with T2DM and 10 years later, at age 61, in women without T2DM. CONCLUSIONS: Newly diagnosed T2DM increased 10-year CVD risk across both sexes and all age groups, especially among younger patients, with CVD occurring ≤12 years earlier than in general population individuals.

The impact of age and obesity on outcomes among patients hospitalized with COVID-19 in Denmark: A nationwide cohort study.

Purpose: Obesity may alter the severity of infection with Coronavirus disease 2019 (COVID-19). Age may impact the association between body weight and severity of COVID-19 in patients with obesity. The aim of the study was to examine the association between obesity and severity of infection in a Danish cohort hospitalized with COVID-19 in the initial wave of the pandemic. Patients and methods: Based on data from the nationwide, clinical database: COVID-DK, risks of intensive care unit (ICU) admission, invasive mechanical ventilation (IMV), and mortality were compared among patients with and without obesity. Interaction with age was examined and we used Inverse Probability of Treatment Weighting regression for confounder adjustment. Results: Among 524 patients, 142 (27%) were admitted to the ICU, 112 (21%) required IMV, and 109 (21%) died. Compared to COVID-19 patients without obesity, patients with obesity displayed a non-significant increased risk of ICU admission (Relative Risk [RR] 1.19, 95% Confidence Interval [CI] 0.88; 1.60), IMV (RR 1.23, CI 0.86; 1.75) and mortality (RR 1.21, CI 0.84; 1.75). COVID-19 patients with obesity, <60 years had highly increased risk of ICU admission (RR 1.92, CI 1.14; 3.24) and IMV (RR 1.95, CI 1.09; 3.49). Conclusions: In hospitalized COVID-19 patients, obesity conferred an approximately 20% increased risk for ICU admission, IMV, and death, although these relationships did not reach statistical significance. COVID-19 patients with obesity and <60 years had an almost doubled risk of ICU admission and IMV.

Inhaled corticosteroids and adverse outcomes among chronic obstructive pulmonary disease patients with community-acquired pneumonia: a population-based cohort study.

Introduction: While inhaled corticosteroids (ICS) may increase pneumonia risk in patients with chronic obstructive pulmonary disease (COPD), the impact of ICS on pneumonia outcomes is debated. We examined whether ICS use is associated with adverse outcomes among COPD patients with community-acquired pneumonia (CAP). Materials and methods: Population-based cohort study of all COPD patients with an incident hospitalization for CAP between 1997 and 2013 in Northern Denmark. Information on medications, COPD severity, comorbidities, complications, and death was obtained from medical databases. Adjusted risk ratios (aRRs) for pleuropulmonary complications, intensive care unit (ICU) admissions, and 30-day mortality in current and former ICS users were compared with those in non-users, using regression analyzes to handle confounding. Results: Of 11,368 COPD patients with CAP, 6,073 (53.4%) were current ICS users and 1,733 (15.2%) were former users. Current users had a non-significantly decreased risk of pleuropulmonary complications [2.6%; aRR = 0.82 (0.59-1.12)] compared to non-users (3.2%). This was also observed among former users [2.5%; aRR = 0.77 (0.53-1.12)]. Similarly, decreased risks of ICU admission were observed among current users [aRR = 0.77 (0.57-1.04)] and among former users [aRR = 0.81 (0.58-1.13)]. Current ICS users had significantly decreased 30-day mortality [9.1%; aRR = 0.72 (0.62-0.85)] compared to non-users (12.6%), with a stronger association observed among patients with frequent exacerbations [0.58 (0.39-0.86)]. No significant association was observed among former ICS users [0.89 (0.75-1.05)]. Conclusion: Our results suggest a decreased risk of death with ICS use among COPD patients admitted for CAP.

Leisure-Time Physical Activity and Risk of Microvascular Complications in Individuals With Type 2 Diabetes: A UK Biobank Study.

OBJECTIVE: The aim of this study was to determine dose-response associations, including the minimal effective level, between leisure-time physical activity and risk of incident neuropathy, nephropathy, and retinopathy. RESEARCH DESIGN AND METHODS: This cohort study included 18,092 individuals with type 2 diabetes from the UK Biobank. Self-reported leisure-time physical activity was converted into MET-hours per week. Participants were categorized into no physical activity (0 MET-h/week), below recommendations (0-7.49 MET-h/week), at recommendations (7.5-14.9 MET-h/week), and above recommendations (≥15 MET-h/week). Microvascular complications were identified from hospital inpatient records using diagnosis codes. We used Cox proportional hazards regression analysis to calculate adjusted hazard ratios (aHRs) and restricted cubic splines to identify the minimal effective level of physical activity. RESULTS: During a median follow-up of 12.1 years, 672 individuals (3.7%) were diagnosed with neuropathy, 1,839 (10.2%) with nephropathy, and 2,099 (11.7%) with retinopathy. Any level of physical activity was associated with a lower risk of neuropathy and nephropathy but not retinopathy. Compared with those reporting no physical activity, the aHR of neuropathy was 0.71 (95% CI 0.53, 0.90) below recommendations, 0.73 (0.56, 0.96) at recommendations, and 0.67 (0.52, 0.87) above recommendations. Corresponding aHRs for nephropathy were 0.79 (0.68, 0.92), 0.80 (0.67, 0.95), and 0.80 (0.68, 0.95). The association with retinopathy was weaker, with aHRs of 0.91 (0.78, 1.06), 0.91 (0.77, 1.08), and 0.98 (0.84, 1.15), respectively. CONCLUSIONS: Any level of leisure-time physical activity was associated with a lower risk of neuropathy and nephropathy but not retinopathy in individuals with type 2 diabetes. For both neuropathy and nephropathy, the minimal effective physical activity level may correspond to <1.5 h of walking per week.

HbA1c-defined prediabetes and progression to type 2 diabetes in Denmark: A population-based study based on routine clinical care laboratory data.

AIMS: To estimate the prevalence, incidence, mortality, and risk of progression to type 2 diabetes for individuals with HbA1c-defined prediabetes based on Danish nationwide population-based laboratory databases. METHODS: We included all HbA1c measurements from general practice and hospitals during 2012 to 2018. We estimated the cumulative incidence of having at least one HbA1c measurement. The prevalence and incidence rates of prediabetes (HbA1c 42-47 mmol/mol) were examined in the adult Danish population. The 5-year cumulative incidence of progression to type 2 diabetes was estimated with death as competing event. RESULTS: Among 4,979,590 adult Danes, 70.8% (95% CI 70.8-70.9) had at least one HbA1c measurement during 2012 to 2018. The prevalence of prediabetes was 7.1% (95% CI 7.1-7.1) in 2018. The incidence rate was 14.2 (95% CI 14.1-14.3) per 1,000 person-years, with median age 66.9 years (IQR 56.7-75.7) and median HbA1c 43 mmol/mol (IQR 42-44) at prediabetes diagnosis. Within five years, 17.5% (95% CI 17.3-17.7) died and the 5-year cumulative incidence of type 2 diabetes was 21.3% (95% CI 21.1-21.5). CONCLUSIONS: Out of 100 Danish adults, 1.4 develop prediabetes each year and they can be identified at an early stage in laboratory databases. Within five years, one in five individuals with prediabetes progresses to diabetes and one in six dies.

Triglycerides and risk of cardiovascular events in statin-treated patients with newly diagnosed type 2 diabetes: a Danish cohort study.

BACKGROUND: Elevated triglyceride levels are a clinically useful marker of remnant cholesterol. It is unknown whether triglycerides are associated with residual cardiovascular risk in CVD-naïve patients with newly diagnosed type 2 diabetes mellitus (T2DM), who are already on statin therapy. We aimed to assess the association between triglyceride levels and risk of major cardiovascular events (MACE) in statin-treated patients with newly diagnosed T2DM managed in routine clinical care. METHODS: This cohort study included newly diagnosed T2DM patients without a previous diagnosis of cardiovascular disease in Northern Denmark during 2005-2017. Individual triglyceride levels while on statin treatment were assessed within 1 year after T2DM diagnosis. The primary outcome was a composite of myocardial infarction, ischemic stroke, or cardiac death (MACE). Patients were followed from one year after T2DM diagnosis until 30 April 2021, MACE, emigration, or death. We used Cox regression to compute hazard ratios (HRs) controlling for confounding factors. RESULTS: Among 27,080 statin-treated patients with T2DM (median age 63 years; 53% males), triglyceride levels were < 1.0 mmol/L in 17%, 1.0-1.9 mmol/L in 52%, 2.0-2.9 mmol/L in 20%, and ≥ 3.0 mmol/L in 11%. During follow-up, 1,957 incident MACE events occurred (11.0 per 1000 person-years). Compared with triglyceride levels < 1.0 mmol/L, confounder-adjusted HRs for incident MACE were 1.14 (95% CI 1.00-1.29) for levels between 1.0 and 1.9 mmol/L, 1.30 (95% CI 1.12-1.51) for levels between 2.0 and 2.9 mmol/L, and 1.44 (95% CI 1.20-1.73) for levels ≥ 3.0 mmol/L. This association was primarily driven by higher rates of myocardial infarction and cardiac death and attenuated only slightly after additional adjustment for LDL cholesterol. Spline analyses confirmed a linearly increasing risk of MACE with higher triglyceride levels. Stratified analyses showed that the associations between triglyceride levels and MACE were stronger among women. CONCLUSIONS: In statin-treated patients with newly diagnosed T2DM, triglyceride levels are associated with MACE already from 1.0 mmol/L. This suggests that high triglyceride levels are a predictor of residual cardiovascular risk in early T2DM and could be used to guide allocation of additional lipid-lowering therapies for CVD prevention.

The Prevalence of Polyneuropathy in Type 2 Diabetes Subgroups Based on HOMA2 Indices of ß-Cell Function and Insulin Sensitivity.

OBJECTIVE: Metabolic syndrome components may cumulatively increase the risk of diabetic polyneuropathy (DPN) in type 2 diabetes mellitus (T2DM) patients, driven by insulin resistance and hyperinsulinemia. We investigated the prevalence of DPN in three T2DM subgroups based on indices of ß-cell function and insulin sensitivity. RESEARCH DESIGN AND METHODS: We estimated ß-cell function (HOMA2-B) and insulin sensitivity (HOMA2-S) in 4,388 Danish patients with newly diagnosed T2DM. Patients were categorized into subgroups of hyperinsulinemic (high HOMA2-B, low HOMA2-S), classical (low HOMA2-B, low HOMA2-S), and insulinopenic (low HOMA2-B, high HOMA2-S) T2DM. After a median follow-up of 3 years, patients filled the Michigan Neuropathy Screening Instrument questionnaire (MNSIq) to identify DPN (score ≥ 4). We used Poisson regression to calculate adjusted prevalence ratios (PRs) for DPN, and spline models to examine the association with HOMA2-B and HOMA2-S. RESULTS: A total of 3,397 (77%) patients filled in the MNSIq. The prevalence of DPN was 23% among hyperinsulinemic, 16% among classical, and 14% among insulinopenic patients. After adjusting for demographics, diabetes duration and therapy, lifestyle behaviors, and metabolic syndrome components (waist circumference, triglycerides, HDL cholesterol, hypertension, and HbA1c), the PR of DPN was 1.35 (95% CI 1.15-1.57) for the hyperinsulinemic compared with the classical patients. In spline analyses, we observed a linear relation of higher DPN prevalence with increasing HOMA2-B, independent of both metabolic syndrome components and HOMA2-S. CONCLUSIONS: Hyperinsulinemia marked by high HOMA2-B is likely an important risk factor for DPN beyond metabolic syndrome components and insulin resistance. This should be considered when developing interventions to prevent DPN.

CRP, C-Peptide, and Risk of First-Time Cardiovascular Events and Mortality in Early Type 2 Diabetes: A Danish Cohort Study.

OBJECTIVE: We investigated the relationship between hs-CRP, a marker of low-grade inflammation, alone or in combination with C-peptide, a marker of hyperinsulinemia/insulin resistance, and risk for cardiovascular events (CVEs) and mortality in patients recently diagnosed with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: In patients with recent-onset T2D, we measured serum hs-CRP (n = 7,301) and C-peptide (n = 5,765) in the prospective Danish Centre for Strategic Research in Type 2 Diabetes cohort study. Patients with no prior CVE (n = 6,407) were followed until first myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and all patients (n = 7,301) were followed for all-cause mortality. We computed adjusted hazard ratios (aHRs) by Cox regression and tested for the interaction between hs-CRP and C-peptide. RESULTS: During follow-up (median 4.8 years), high (>3 mg/L) versus low (<1 mg/L) hs-CRP was associated with increased CVE risk (aHR 1.45 [95% CI 1.07-1.96]) and with even greater risk of all-cause mortality (2.47 [1.88-3.25]). Compared with patients with low hs-CRP (≤3 mg/L) and low C-peptide (<1,470 pmol/L), those with high levels of both biomarkers had the highest CVE (1.61 [1.10-2.34]) and all-cause mortality risk (2.36 [1.73-3.21]). Among patients with high C-peptide, risk of CVEs did not differ by low or high hs-CRP, whereas risk of all-cause mortality did. CONCLUSIONS: The finding of high hs-CRP as a stronger prognostic biomarker of all-cause mortality than of CVEs may facilitate improved early detection and prevention of deadly diseases besides CVEs. Conversely, elevated C-peptide as a strong CVE biomarker supports the need to target hyperinsulinemia/insulin resistance in T2D CVE prevention.

Increased risk of depression after Guillain-Barré syndrome.

INTRODUCTION/AIMS: Guillain-Barré syndrome (GBS) is a potentially life-threatening disorder, and some patients may develop subsequent depression related to traumatic stress or permanent loss of motor function. We determined the short-term (0 to 2 years) and long-term (>2 years) risk of depression after GBS. METHODS: Individual-level data from nationwide registries were linked in this population-based cohort study of all first-time hospital-diagnosed GBS patients in Denmark between 2005 and 2016 and individuals from the general population. After exclusion of individuals with previous depression, we computed cumulative rates of depression, defined as either antidepressant drug prescription or depression hospital diagnosis. We used Cox regression analyses to calculate adjusted depression hazard ratios (HRs) after GBS. RESULTS: We identified 853 incident GBS patients and recruited 8639 individuals from the general population. Depression within 2 years was observed in 21.3% (95% confidence interval [CI], 18.2% to 25.0%) of GBS patients and in 3.3% (95% CI, 2.9% to 3.7%) of those in the general population, resulting in a HR of 7.6 (95% CI, 6.2 to 9.3). The highest depression HR was observed within the first 3 months after GBS (HR, 20.5; 95% CI, 13.6 to 30.9). After the first 2 years, GBS patients and the general population members had similar long-term depression risks with an HR of 0.8 (95% CI, 0.6 to 1.2). DISCUSSION: During the first 2 years after GBS hospital admission, patients with GBS had a 7.6-fold increased hazard of depression compared with individuals in the general population. Two years after GBS, the risk of depression was similar to that of the background population.

Guillain-Barré syndrome following influenza vaccination: A 15-year nationwide population-based case-control study.

BACKGROUND AND PURPOSE: Influenza vaccination may increase the risk of developing Guillain-Barré syndrome (GBS) due to an elicited immune response, but the exact magnitude and duration of risk is unclear and hence the aim of this study. METHODS: We conducted a retrospective nationwide population-based case-control study of prospectively collected data on all patients with first-time hospital-diagnosed GBS in Denmark between 2002 and 2016 and 10 age-, sex- and index date-matched population controls per case. The primary exposure was incident influenza vaccination 1 month prior to admission with GBS. We used medical registries to ascertain a complete hospital contact history of pre-existing morbidities. To examine duration of GBS risk, we repeated the analysis for five consecutive 1-month risk periods following vaccination. RESULTS: Of the 1295 GBS cases and 12,814 controls, 20 cases (1.5%) and 119 controls (0.9%) had received an influenza vaccination within the last month, yielding a comorbidity-adjusted odds ratio of 1.9 (95% confidence interval 1.1-3.2) for GBS. Stratified analyses by calendar time, gender and age showed similar results. The increased risk of GBS was largely confined to 1 month following influenza vaccination. The population-attributable fraction of GBS from influenza vaccination in Denmark was 0.4%. CONCLUSIONS: Influenza vaccination was associated with a slightly elevated risk of GBS occurrence within 1 month after vaccination. However, only 1.5% of GBS cases in Denmark are associated with recent influenza vaccination. Thus, the benefit of influenza vaccines in preventing influenza infections and associated morbidity and mortality needs to be weighed against the small absolute risk of GBS.

Risk factors associated with mortality among individuals with type 2 diabetes and depression across two cohorts.

Objective: Depression has been linked to excess mortality in individuals with type 2 diabetes, but it remains unclear what drives this association. We examined if the association depends on unhealthy lifestyle and medical comorbidity. Methods: We followed a clinically recruited cohort of Danish people with type 2 diabetes (n = 8175) with fine-grained clinical information and a population-wide register-based cohort of Danish individuals with HbA1c-defined type 2 diabetes (n = 87 500) representing everyday clinical practice. Antidepressant drug use prior to the onset of type 2 diabetes was used as a proxy for preexisting depression. In both cohorts, we first estimated the association between depression and 5-year mortality following type 2 diabetes, using a Cox proportional hazards model, yielding sex- and age-adjusted mortality rate ratios (MRRs). We subsequently examined how further adjustment for markers of unhealthy lifestyle (smoking, physical inactivity, obesity, alcohol abuse, and marital status) and medical comorbidity affected the association. Results: Preexisting depression was associated with an approximately 50% increased age- and sex-adjusted all-cause mortality rate in both the clinically recruited- (5-year MRR: 1.46; 95% CI: 1.12-1.90) and the register-based type 2 diabetes cohort (5-year MRR: 1.51; 95% CI: 1.45-1.57). The excess mortality associated with depression almost disappeared when the analyses were adjusted for unhealthy lifestyle and medical comorbidity in both the clinically recruited- (MRR: 1.05; 95% CI: 0.72-1.52) and the register-based type 2 diabetes cohort (MRR: 1.14, 95% CI: 1.09-1.19). Conclusions: A large fraction of the excess mortality associated with preexisting depression in type 2 diabetes is attributable to the unhealthy lifestyle and medical comorbidity accompanying depression.

Mortality Among Danish Patients with a Hospital Diagnosis of Overweight or Obesity Over a 40-Year Period.

Purpose: Data on long-term mortality among patients with hospital-diagnosed overweight/obesity are limited. Thus, we aim to examine 40-year mortality among patients with hospital-diagnosed overweight/obesity, including cause-specific deaths, secular time trends, and potential effect modification by age, comorbidity, and socioeconomic factors. Patients and Methods: From national registries, we identified all Danes with a first hospital-based overweight/obesity diagnosis (N=331,185), 1979-2018, and constructed an age- and gender-matched general population comparison cohort (N=1,655,925). We computed mortality rates (MRs) per 1000 person-years and adjusted mortality rate ratios (aMRRs) with 95% confidence intervals (CIs), using Cox regression with adjustment for comorbidities and educational level. We performed stratified analyses on age, comorbidities, and socioeconomic factors. Results: The overall aMRR was 1.70 (95% CI: 1.68-1.72) for patients with overweight/obesity, mainly due to diabetes and other endocrine diseases (aMRR=2.68 [95% CI: 2.57-2.81]), cardiovascular (aMRR=1.95 [95% CI: 1.91-1.98]), and respiratory diseases (aMRR=1.83 [95% CI: 1.77-1.89]). The 1-10-year aMRR decreased from 2.06 (95% CI: 2.01-2.11) in 1979-1989 to 1.29 (95% CI: 1.26-1.32) in 2000-2009. We found effect modification by age: age 18 to <30 years: aMRR=2.44 (95% CI: 2.24-2.66) vs age ≥70 years: 1.35 (95% CI: 1.33-1.37); comorbidities: baseline comorbidities: aMRR=1.13 (95% CI: 1.10-1.15) vs no comorbidities: aMRR=1.83 (95% CI: 1.80-1.85); and educational level: high educational level: aMRR=1.81 (95% CI: 1.74-1.88) vs low educational level: aMRR=1.70 (95% CI: 1.67-1.72). Conclusion: Patients with overweight/obesity had a substantially increased long-term mortality, mainly due to diabetes, cardiovascular, and respiratory diseases. The excess mortality decreased during recent decades. Age, comorbidities, and socioeconomic factors modified the association.

Is diabetic neuropathy associated with increased risk of developing mental disorders?

Objective: It is largely unknown whether individuals with diabetic neuropathy face an increased risk of developing mental illness. Therefore, in a population-based cohort study, we aimed to examine whether individuals with diabetic neuropathy are at elevated risk of being diagnosed with a mental disorder compared to diabetes-duration-matched individuals without diabetic neuropathy. Methods: We used the nationwide Danish registers to identify all individuals diagnosed with diabetic neuropathy between January 1, 1996, and January 1, 2019. For each of these individuals, we identified up to five individuals with diabetes, matched on the duration of illness, who were not diagnosed with diabetic neuropathy. We then compared incidence rates of mental disorders between individuals with diabetic neuropathy and the diabetes-duration-matched individuals using a Cox proportional-hazards model. Restults: Individuals with diabetic neuropathy had a substantial and statistically significant increased risk of being diagnosed with any mental disorder (age- and sex-adjusted hazard rate ratio: 1.40, 95% CI: 1.31-1.48) as well as all specific mental disorders (psychotic disorder, bipolar disorder, unipolar depression, and/or anxiety disorder) compared with diabetes-duration-matched individuals without diabetic neuropathy. Conclusions: Diabetic neuropathy appears to be associated with a substantially increased risk of developing a mental disorder. Knowledge of the potential mechanisms underlying this association could inform prevention and treatment and should therefore be pursued further.

Association Between Incident Cancer and Guillain-Barré Syndrome Development: A Nationwide Case-Control Study.

BACKGROUND AND OBJECTIVES: Cancer may increase the risk of developing Guillain-Barré syndrome (GBS) due to molecular mimicry or immunosuppression, but the exact relationship is unclear. We aimed to determine the association between incident cancer and the following risk of GBS development. METHODS: We conducted a nationwide population-based case-control study of all patients with first-time hospital-diagnosed GBS in Denmark between 1987 and 2016 and 10 age-, sex-, and index date-matched population controls per case. We identified incident cancer diagnoses between 6 months before and 2 months after the GBS index date. We used conditional logistic regression to compute odds ratios (ORs) as a measure of relative risk and performed stratified analyses to assess the impact of cancer on GBS risk in strata of calendar periods, sex, and age. In sensitivity analyses, to assess any potential risk of survival bias induced by including cancer diagnoses potentially made after GBS diagnosis, we examined incident cancers in both a broader exposure window (1 year before to 3 months after GBS index date) and a narrower window (6 months to 1 month before the GBS index date). RESULTS: Of the 2,414 patients with GBS and 23,909 controls included, 49 cases (2.0%) and 138 controls (0.6%) had a recent cancer diagnosis, yielding a matched OR of 3.6 (95% CI 2.6-5.1) for GBS associated with cancer. Stratification by calendar time, sex, and age showed robust results for the association between cancer and GBS, with no major variations. Broadening and narrowing the exposure window produced slightly weakened associations of OR of 2.4 (95% CI 1.8-3.3) and 2.5 (95% CI 1.5-4.1), respectively. The GBS ORs were highest for cancers of the lymphatic and hematopoietic tissue (OR 7.2, 95% CI 2.9-18.0), respiratory tract (OR 5.6, 95% CI 2.7-11.9), prostate and other male genital organ (OR 5.0, 95% CI 2.1-11.6), and breast (OR 5.0, 95% CI 1.7-14.5) cancer. DISCUSSION: In this large nationwide epidemiologic study, incident cancer was associated with a markedly increased risk of subsequent GBS development. The results suggest that as-yet unidentified factors present in several types of cancer drive this association.

Increased mortality following Guillain-Barré syndrome: A population-based cohort study.

BACKGROUND AND PURPOSE: Guillain-Barré syndrome (GBS) may be fatal in the acute phase but also affect long-term prognosis due to irreversible sequelae and secondary medical complications. We determined the short-term, intermediate, and long-term mortality of GBS compared to the general population. METHODS: Individual-level data from nationwide registries were linked in this matched cohort study of all first-time hospital-diagnosed GBS patients in Denmark between 1987 and 2016 and 10 individuals from the general population, matched on age, sex, and index date. We used Cox regression analysis to calculate matched mortality hazard ratios (HRs) following GBS, assessing short-term (0-6 months), intermediate (>6 months-4 years), and long-term (>4 years) mortality. RESULTS: We identified 2414 patients with GBS and 23,909 matched individuals from the general population. Short-term mortality was 4.8% (95% confidence interval [CI] = 4.0-5.8) and 0.8% (95% CI = 0.7-0.9) for GBS patients and general population members, respectively, resulting in an HR of 6.6 (95% CI = 4.0-5.8). Intermediate mortality was 7.6% (95% CI = 6.5-8.9), compared with 5.8% (95% CI = 5.5-6.1) for general population members, corresponding to an HR of 1.5 (95% CI = 1.3-1.8). After the first 4 years, long-term mortality showed similar results for GBS patients and general population members (HR = 1.1, 95% CI = 0.9-1.2). CONCLUSIONS: During the first 6 months after GBS hospital admission, GBS was associated with a 6.6-fold increased mortality as compared with the background population of the same age. Mortality remained increased for approximately 4 years following GBS, and then leveled off to a similar long-term mortality rate.