Effects of gender-affirming hormone therapy on cardiovascular risk factors focusing on glucose metabolism in an Austrian transgender cohort.

Objective: We aimed to investigate the effect of gender-affirming hormone therapy (GAHT) on cardiovascular disease risk factors focusing on glucose tolerance. Patients and Methods: This primarily translational study enrolled 16 transgender persons assigned female at birth (AFAB), 22 assigned male at birth (AMAB), and 33 age- and BMI-matched cisgender controls at the Medical University of Vienna from 2013 to 2020. A 3-Tesla MRI scan to measure intramyocardial, pancreatic, hepatic fat content and subcutaneous-to-visceral adipose tissue ratio (SAT/VAT-ratio), an oral glucose tolerance test (oGTT), bloodwork including brain natriuretic peptide (pro-BNP), sex hormones and two glucose-metabolism related biomarkers (adiponectin, betatrophin) were performed. Results: Estrogen intake was associated with higher fasting insulin (p = 0.034) and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (p = 0.037), however, lower HbA1c levels (p = 0.031) in AMAB than cisgender males. Adiponectin (p = 0.001) and betatrophin (p = 0.034) levels were higher in AMAB than cisgender males, but similar to cisgender females. Compared to cisgender females, AFAB displayed no differences in glucose metabolism or SAT/VAT-ratio. AFAB had lower pro-BNP levels (p = 0.014), higher liver enzymes (AST: p = 0.011; ALT: p = 0.012) and lower HDL levels (p = 0.017) than cisgender females, but comparable levels to cisgender males. AMAB showed an increased heart rate (p < 0.001) and pro-BNP (p = 0.002) levels, but a more favorable SAT/VAT-ratio (p = 0.013) and lower creatine kinase (CK) (p = 0.001) than cisgender males. There were no relevant differences in organ fat content between transgender persons and their respective cisgender controls. Conclusion: In AMAB, most investigated parameters adapted to levels seen in cisgender females except for parameters related to fasted insulin resistance. AMAB should be monitored with respect to the development of insulin resistance.

Gremlin-1 in pregnancy and postpartum: relation to the fatty liver index, markers of bone health, glucose metabolism and gestational diabetes mellitus status.

INTRODUCTION: Gremlin-1 is a peptide that functions as an antagonist to bone morphogenic proteins and is overexpressed in obesity and type 2 diabetes mellitus. Gremlin-1 has not yet been investigated in pregnancy, pregnancy-related insulin resistance or gestational diabetes mellitus (GDM). PATIENTS AND METHODS: Gremlin-1 levels were measured throughout the pregnancy of 58 women at high risk for GDM at the Medical University of Vienna. Furthermore, an oral glucose tolerance test, fasting insulin, fasting glucose, sex hormones, blood lipids, liver and renal parameters, and markers of bone development were evaluated at two points during pregnancy (< 20 weeks of gestation (GW), GW 24-28) and 12-14 weeks postpartum. RESULTS: Gremlin-1 levels decreased from < 20 GW (mean = 9.2 pg/ml, SD = 8.4 pg/ml) to GW 24-28 (mean = 6.7 pg/ml, SD = 5.7 pg/ml, p = 0.033) and increased again postpartum, albeit not significantly (mean = 10.7 pg/ml, SD = 13.1 pg/ml, p = 0.339). During pregnancy, Gremlin-1 levels correlated negatively with osteocalcin and procollagen type I aminoterminal propeptide (P1NP), markers of bone health. Concerning glucose metabolism, Gremlin-1 levels were inversely related to the Insulinogenic Index at GW < 20. However, Gremlin-1 levels were not significantly different between women with normal glucose tolerance and GDM during pregnancy. Postpartum, Gremlin-1 was associated with the fatty liver index, osteocalcin levels, diastolic blood pressure and weight. CONCLUSION: Gremlin-1 levels decreased significantly during pregnancy. The biomarker is not related to GDM status, but correlates negatively with the Insulinogenic Index, an index related to beta cell function. Trial Registry Number ACTRN12616000924459.

Diabetes mellitus is associated with a higher relative risk for venous thromboembolism in females than in males.

AIMS: The risk for developing venous thromboembolism (VTE) is about equal in both sexes. Research suggests diabetes mellitus (DM) is a risk factor for pulmonary embolism and deep vein thrombosis, both forms of VTE. We aimed at investigating the sex-specific impact of DM on VTE risk. MATERIALS AND METHODS: Medical claims data were analyzed in a retrospective, population-level cohort study in Austria between 1997 and 2014. 180,034 patients with DM were extracted and compared to 540,102 sex and age-matched controls without DM in terms of VTE risk and whether specific DM medications might modulate VTE risk. RESULTS: The risk to develop VTE was 1.4 times higher amongst patients with DM than controls (95% CI 1.36-1.43, p < 0.001). The association of DM with newly diagnosed VTE was significantly greater in females (OR = 1.52, 95% CI 1.46-1.58, p < 0.001) resulting in a relative risk increase of 1.17 (95% CI 1.11-1.23) across all age groups with a peak of 1.65 (95% CI 1.43-1.89) between 50 and 59 years. Dipeptidyl peptidase 4 inhibitors were associated with a higher risk for VTE amongst female DM patients (OR = 2.3, 95% CI 1.3-4.3, p = 0.0096). CONCLUSION: Amongst DM patients, females appear to be associated with a higher relative risk increase in VTE than males, especially during perimenopause.

Women With Cerebral Infarction Feature Worse Clinical Profiles at Admission but Comparable Success to Men During Long-Term Inpatient Neurorehabilitation.

Objective: Little is known about possible sex and gender differences in post-stroke neurorehabilitation outcomes. We aimed to analyze if functional performance, prevalence and impact of comorbidities at admission, and success of inpatient stroke-neurorehabilitation differ between men and women. Methods: Retrospective cohort analysis of 1,437 men and 907 women with prior cerebral infarction treated at a neurorehabilitation clinic between 2012 and 2017; multiple linear regression was used to examine the influence of sex/gender as well as multiple confounders on health and functional outcomes. The main outcome measures were Barthel index (BI) at admission and its change during 4 weeks inpatient neurorehabilitation. Results: Men had been diagnosed with osteoporosis less frequently than women but more often with type 2 diabetes mellitus, coronary artery or chronic kidney disease (p ≤ 0.01). Although twice as many women presented with pre-stroke depression compared to men, the risk of post-stroke depression detected during rehabilitation was comparable. Men were more likely to have less than 30 days between diagnosis and neurorehabilitation start than women (p < 0.03). At admission, women exhibited less autonomy, a lower BI, a higher pain score and worse 2-min walk test (2'WT) compared to men (p < 0.001). Among males osteoporosis and peripheral artery disease independently predicted BI at admission, in women it was pre-stroke depression, dementia, and arterial fibrillation. During neurorehabilitation, both sexes improved regarding BI, pain and walk tests (p < 0.001). Despite comparable rehabilitation effectiveness, women still had worse functional outcomes than males at discharge. Time after stroke to start of neurorehabilitation and length of the stay but, most strongly, the simple 2'WT at admission, and in women, pain intensity independently predicted post-stroke functional status and recovery. Conclusion: Women presented with worse functional status at admission to neurorehabilitation. Although men and women showed similar rehabilitation effectiveness, women still displayed worse clinical outcome measures and higher levels of pain at discharge. Early access and gender-sensitive, personalized post-stroke care with more focus on different comorbidities and psychosocial factors like pain levels and management, could further improve neurorehabilitation outcomes.

Glypican-4 in pregnancy and its relation to glucose metabolism, insulin resistance and gestational diabetes mellitus status.

Glypican-4 (GPC-4) is an adipokine that enhances insulin receptor signaling. Plasma concentrations were found to be elevated in patients with prediabetes but reduced in type 2 diabetes mellitus. No study on Glypican-4 in pregnancy and pregnancy-related insulin resistance has been published yet. GPC-4 levels were investigated in 59 overweight women throughout their pregnancy at the Medical University of Vienna. GPC-4 levels, fasting insulin, fasting glucose, estradiol, liver and renal parameters, and markers of bone development were assessed before the < 21st week of gestation (GW), and at GW 35-37. GPC-4 levels increased from < 21 GW (mean = 2.38 pg/ml, SD = 0.68 pg/ml) to GW 35-37 (mean = 2.96 pg/ml, SD = 0.77 pg/ml, p < 0.001). At the same time, GPC-4 levels correlated negatively with estimated glomerular filtration rate (eGFR), serum protein and serum albumin levels and were positively related to creatinine and uric acid levels at GW 35-37. Concerning glucose metabolism, GPC-4 levels were inversely related to ISSI-2, fasting insulin and HOMA-IR, however, not significantly different between women with normal glucose tolerance (NGT) and GDM (p = 0.239). In conclusion, GPC-4 levels rose significantly during pregnancy, correlated negatively with fasting insulin and HOMA-IR but might not be related to gestational diabetes mellitus status.

The Effect of Cardiovascular Comorbidities on Women Compared to Men: Longitudinal Retrospective Analysis.

BACKGROUND: Although men are more prone to developing cardiovascular disease (CVD) than women, risk factors for CVD, such as nicotine abuse and diabetes mellitus, have been shown to be more detrimental in women than in men. OBJECTIVE: We developed a method to systematically investigate population-wide electronic health records for all possible associations between risk factors for CVD and other diagnoses. The developed structured approach allows an exploratory and comprehensive screening of all possible comorbidities of CVD, which are more connected to CVD in either men or women. METHODS: Based on a population-wide medical claims dataset comprising 44 million records of inpatient stays in Austria from 2003 to 2014, we determined comorbidities of acute myocardial infarction (AMI; International Classification of Diseases, Tenth Revision [ICD-10] code I21) and chronic ischemic heart disease (CHD; ICD-10 code I25) with a significantly different prevalence in men and women. We introduced a measure of sex difference as a measure of differences in logarithmic odds ratios (ORs) between male and female patients in units of pooled standard errors. RESULTS: Except for lipid metabolism disorders (OR for females [ORf]=6.68, 95% confidence interval [CI]=6.57-6.79, OR for males [ORm]=8.31, 95% CI=8.21-8.41), all identified comorbidities were more likely to be associated with AMI and CHD in females than in males: nicotine dependence (ORf=6.16, 95% CI=5.96-6.36, ORm=4.43, 95% CI=4.35-4.5), diabetes mellitus (ORf=3.52, 95% CI=3.45-3.59, ORm=3.13, 95% CI=3.07-3.19), obesity (ORf=3.64, 95% CI=3.56-3.72, ORm=3.33, 95% CI=3.27-3.39), renal disorders (ORf=4.27, 95% CI=4.11-4.44, ORm=3.74, 95% CI=3.67-3.81), asthma (ORf=2.09, 95% CI=1.96-2.23, ORm=1.59, 95% CI=1.5-1.68), and COPD (ORf=2.09, 95% CI 1.96-2.23, ORm=1.59, 95% CI 1.5-1.68). Similar results could be observed for AMI. CONCLUSIONS: Although AMI and CHD are more prevalent in men, women appear to be more affected by certain comorbidities of AMI and CHD in their risk for developing CVD.

Oral Contraceptive Intake and Iodine Status in Young Women.

OBJECTIVE: Similar to pregnant women, women taking an oral contraceptive (OC) might have elevated iodine requirements due to the altered hormonal state. This is the first study aimed at investigating the prevalence of iodine deficiency and possible influences of OC intake on urine creatinine and iodine levels in young women. METHODS: One hundred fifty-five women between the age of 18 and 35 years (62 taking an OC and 93 controls) participated in a cross-sectional pilot study at the Medical University of Vienna, which included a 1-spot urine sample and a questionnaire on OC intake as well as a food questionnaire. RESULTS: The median urinary iodine concentration (UIC) in this study was 68 µg/L (41, 111 µg/L) suggesting an inadequate iodine status in the women according to the WHO guidelines. Median UIC (OC: 89 µg/L, IQR 55-120; control: 59 µg/L, IQR 39-91, p = 0.010) and urine creatinine (OC: median = 99.0 µg/L, IQR 74.9-175.5; control: 77.0 µg/L, IQR 49.6-147.2, p = 0.030) levels were significantly higher in OC women than in the control group. UIC corrected for urine creatinine was comparable between both groups. CONCLUSION: With similar creatinine-corrected UICs in both groups, OC intake might not have a significant impact on iodine status. However, the low median UIC in a vulnerable group of young women potentially conceiving in the following years points at the necessity of optimizing the iodine intake in the Austrian population and reiterates the insufficiency of the current iodine supplementation measures.

Sex, Gender, and Cardiovascular Health in Canadian and Austrian Populations.

BACKGROUND: Evidence differentiating the effect of biological sex from psychosociocultural factors (gender) in different societies and its relation to cardiovascular diseases is scarce. We explored the association between sex, gender, and cardiovascular health (CVH) among Canadian (CAN) and Austrian (AT) populations. METHODS: The Canadian Community Health Survey (CCHS) (n = 63,522; 55% female) and Austrian Health Interview Survey (AT-HIS) (n = 15,771; 56% female) were analyzed in a cross-sectional survey design. The CANHEART/ATHEART index, a measure of ideal CVH composed of 6 cardiometabolic risk factors (smoking, physical activity, fruit and vegetable consumption, overweight/obesity, diabetes, and hypertension; range 0-6; higher scores reflecting better CVH) was calculated for both databases. A composite measure of psychosociocultural gender was computed for each country (range 0-1, higher score identifying characteristics traditionally ascribed to women). RESULTS: Median CANHEART 4 (interquartile range 3-5) and CAN gender scores 0.55 (0.49-0.60) were similar to median ATHEART 4 (3-5) and AT gender scores 0.55 (0.46-0.64). Although higher gender scores (CCHS: ß = -1.33, 95% confidence interval [CI] -1.44 to -1.22; AT-HIS: ß = -1.08, 95% CI -1.26 to -0.89)) were associated with worse CVH, female sex (CCHS: ß = 0.35, 95% CI (0.33-0.37); AT-HIS: ß = 0.60, 95% CI (0.55-0.64)) was associated with better CVH in both populations. In addition, higher gender scores were associated with increased prevalence of heart disease compared with female sex. The magnitude of this risk was higher in Austrians. CONCLUSIONS: These results demonstrate that individuals with characteristics typically ascribed to women reported poorer cardiovascular health and higher risk of heart disease, independently from biological sex and baseline CV risk factors, in both countries. Female sex exhibited better CV health and a lower prevalence of heart disease than male in both populations. However, gender factors and magnitude of gender impact varied by country.

Systemic inflammation scores correlate with survival prognosis in patients with newly diagnosed brain metastases.

BACKGROUND: Systemic inflammation measured by the neutrophil-to-lymphocyte ratio (NLR), leucocyte-to-lymphocyte ratio (LLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and CRP/albumin ratio (CRP/Alb) was shown to impact the survival prognosis in patients with extracranial solid cancer. METHODS: One thousand two hundred and fifty patients with newly diagnosed brain metastases (BM) were identified from the Vienna Brain Metastasis Registry. RESULTS: PLR and CRP/Alb were higher in patients with progressive extracranial disease and lower in patients with no evidence of extracranial disease. Lower NLR (cut-off = 5.07; 9.3 vs. 5.0 months), LLR (cut-off = 5.76; 10.0 vs. 5.3 months), PLR (cut-off = 335; 8.0 vs. 3.8 months), MLR (cut-off = 0.53; 6.0 vs. 3.5 months) and CRP/Alb (cut-off = 2.93; 8.5 vs. 3.7 months; padj < 0.05) were associated with longer overall survival (OS). In multivariate analysis with graded prognostic assessment (hazard ratio (HR) 1.45; 95% confidence interval (CI): 1.32-1.59; padj = 1.62e - 13), NLR (HR 1.55; 95% CI: 1.38-1.75; padj = 1.92e - 11), LLR (HR 1.57; 95% CI: 1.39-1.77; padj = 1.96e - 11), PLR (HR 1.60; 95% CI: 1.39-1.85; padj = 2.87955e - 9), MLR (HR 1.41; 95% CI: 1.14-1.75; padj = 0.027) and CRP/Alb (HR 1.83; 95% CI: 1.54-2.18; padj = 2.73e - 10) remained independent factors associated with OS at BM diagnosis. CONCLUSIONS: Systemic inflammation, measured by NLR, LLR, PLR, MLR and CRP/Alb, was associated with OS in patients with BM. Further exploration of immune modulating therapies is warranted in the setting of BM.

Diabetes Mellitus is Associated with a Higher Relative Risk for Parkinson's Disease in Women than in Men.

BACKGROUND: In general, the risk to develop Parkinson's disease (PD) is higher in men compared to women. Besides male sex and genetics, research suggests diabetes mellitus (DM) is a risk factor for PD as well. OBJECTIVE: In this population-level study, we aimed at investigating the sex-specific impact of DM on the risk of developing PD. METHODS: Medical claims data were analyzed in a cross-sectional study in the Austrian population between 1997 and 2014. In the age group of 40-79 and 80+, 235,268 patients (46.6%females, 53.4%males) with DM were extracted and compared to 1,938,173 non-diabetic controls (51.9%females, 48.1%males) in terms of risk of developing PD. RESULTS: Men with DM had a 1.46 times increased odds ratio (OR) to be diagnosed with PD compared to non-diabetic men (95%CI 1.38-1.54, p < 0.001). The association of DM with newly diagnosed PD was significantly greater in women (OR = 1.71, 95%CI 1.60-1.82, p < 0.001) resulting in a relative risk increase of 1.17 (95%CI 1.11-1.30) in the age group 40 to 79 years. In 80+-year-olds the relative risk increase is 1.09 (95%CI 1.01-1.18). CONCLUSION: Although men are more prone to develop PD, women see a higher risk increase in PD than men amongst DM patients.

CTRP-1 levels are related to insulin resistance in pregnancy and gestational diabetes mellitus.

Recent studies have shown higher levels of CTRP-1 (C1QTNF-related protein) in patients with type 2 diabetes compared to controls. We aimed at investigating CTRP-1 in gestational diabetes mellitus (GDM). CTRP-1 levels were investigated in 167 women (93 with normal glucose tolerance (NGT), 74 GDM) of a high-risk population for GDM. GDM was further divided into GDM subtypes depending on a predominant insulin sensitivity issue (GDM-IR) or secretion deficit (GDM-IS). Glucose tolerance was assessed with indices [Matsuda index, Stumvoll first phase index, insulin-secretion-sensitivity-index 2 (ISSI-2), area-under-the-curve (AUC) insulin, AUC glucose] derived from an oral glucose tolerance test (oGTT) performed at < 21 and 24-28 weeks of gestation. In pregnancy, CTRP-1 levels of GDM (76.86 ± 37.81 ng/ml) and NGT (82.2 ± 35.34 ng/ml; p = 0.104) were similar. However, GDM-IR women (65.18 ± 42.18 ng/ml) had significantly lower CTRP-1 levels compared to GDM-IS (85.10 ± 28.14 ng/ml; p = 0.009) and NGT (p = 0.006). CTRP-1 levels correlated negatively with weight, AUC insulin, Stumvoll first phase index, bioavailable estradiol and positively with HbA1c, Matsuda Index and ISSI-2. A multiple regression analysis revealed bioavailable estradiol (ß = - 0.280, p = 0.008) and HbA1c (ß = 0.238; p = 0.018) as the main variables associated with CTRP-1 in GDM. Postpartum, waist and hip measurements were predictive of CRTP-1 levels instead. CTRP-1 levels were higher postpartum than during pregnancy (91.92 ± 47.27 vs.82.44 ± 38.99 ng/ml; p = 0.013). CTRP-1 is related to insulin resistance in pregnancy and might be a metabolic biomarker for insulin resistance in GDM. CTRP-1 levels were significantly lower during pregnancy than postpartum, probably due to rising insulin resistance during pregnancy.

Diabetes mellitus is associated with a higher risk for major depressive disorder in women than in men.

INTRODUCTION: Both diabetes mellitus and being female significantly increase the risk of being diagnosed with major depressive disorder (MDD). The diagnosis of MDD, combined with diabetes mellitus, can be detrimental in terms of mortality and morbidity. We aimed at investigating the impact of diabetes mellitus on the gender gap in MDD over the course of a human lifetime. RESEARCH DESIGN AND METHODS: In a cross-sectional study over the course of 17 years, medical claims data of the general Austrian population (n=8 996 916) between 1997 and 2014 was analyzed. Of these, 123 232 patients with diabetes mellitus were extracted and compared with non-diabetic controls. RESULTS: In a cohort of 123 232 patients with diabetes mellitus and 1 933 218 controls (52% females, 48% males), women with diabetes had 2.55 times increased ORs to be diagnosed with MDD compared with women without diabetes (95% CI 2.48 to 2.62, p<0.001) between the age of 30 and 69 years. The effect of diabetes mellitus on the prevalence of MDD was significantly smaller in men (OR=1.85, 95% CI 1.80 to 1.91, p<0.001). Between 0 and 30 years and after age 70 years, the gender gap of MDD was not different between patients with and without diabetes mellitus. The peak of the gender gap in MDD in patients with diabetes mellitus was around the age of 40-49 years. A sensitivity analysis identified overweight, obesity and alcohol dependence as the most potent influencing factors of the widening of the gender gap among patients with diabetes mellitus. CONCLUSIONS: Diabetes mellitus is a stronger risk factor for MDD in women than in men, with the greatest width of the gender gap between 40 and 49 years. High-risk patients for MDD, such as overweight female patients with diabetes, should be more carefully assessed and monitored.

Betatrophin is downregulated in pregnant women with a history of RYGB operation and a high risk of postprandial hypoglycaemia.

Betatrophin is a liver and adipose tissue-derived protein which has recently been linked to glucose metabolism. So far, no data exist about the role of betatrophin in pregnant women with a history of Roux-En-Y gastric bypass (RYGB) operation with a high risk of postprandial hypoglycaemia. In this prospective clinical study, an oral glucose tolerance test (OGTT) and an intravenous glucose tolerance test (IVGTT) were performed between the 24th and 28th week of pregnancy and 3-6 months post-partum in a cohort of obese and normal-weight pregnant women, as well as in women with a history of RYGB operation. In the cohort of pregnant women with RYGB and exaggerated risk of postprandial hypoglycaemic events, basal and dynamic betatrophin levels during the OGTT were lower than in the obese or normal-weight pregnant women (basal levels: 13.66 ± 5.88 vs. 19.03 ± 4.15 vs. 15.68 ± 6.48, p = 0.016; OGTT 60': 13.33 ± 5.40 vs. 17.37 ± 3.16 vs. 15.84 ± 4.99, p = 0.030). During the OGTT, basal and dynamic betatrophin levels at 60' were positively associated with glucose levels at 60 min (r = 0.55, p = 0.01 and r = 0.45, p = 0.039). This positive association was followed by significant hypoglycaemic events in the RYGB group. It was only in the RYGB group that betatrophin was negatively related to the disposition index (rho = -0.53, p = 0.014). After pregnancy there was a decrease in basal and stimulated betatrophin levels during the OGTT in all three patient groups. In comparison to normal-weight and obese pregnant women, women with a history of RYGB operation and a high risk of postprandial hypoglycaemic events have lower levels of betatrophin. This indicate a mechanistic role in order to decrease the risk of postprandial hypoglycaemia in this specific cohort.

Secretagogin is Related to Insulin Secretion but Unrelated to Gestational Diabetes Mellitus Status in Pregnancy.

Secretagogin (SCGN) is a calcium binding protein related to insulin release in the pancreas. Although SCGN is not co-released with insulin, plasma concentrations have been found to be increased in type 2 diabetes mellitus patients. Until now, no study on SCGN levels in pregnancy or patients with gestational diabetes mellitus (GDM) has been published. In 93 women of a high-risk population for GDM at the Medical University of Vienna, secretagogin levels of 45 GDM patients were compared to 48 women with a normal glucose tolerance (NGT). Glucose tolerance, insulin resistance and secretion were assessed with oral glucose tolerance tests (OGTT) between the 10th and 28th week of gestation (GW) and postpartum. In all women, however, predominantly in women with NGT, there was a significant positive correlation between SCGN levels and Stumvoll first (rp = 0.220, p = 0.032) and second phase index (rp = 0.224, p = 0.028). SCGN levels were not significantly different in women with NGT and GDM. However, SCGN was higher postpartum than during pregnancy (postpartum: 88.07 ± 35.63 pg/mL; pregnancy: 75.24 ± 37.90 pg/mL, p = 0.004). SCGN was directly correlated with week of gestation (rp = 0.308; p = 0.021) and triglycerides (rp = 0.276; p = 0.038) in women with GDM. Therefore, SCGN is related to insulin secretion and hyperinsulinemia during pregnancy; however, it does not display differences between women with NGT and GDM.

High-risk multimorbidity patterns on the road to cardiovascular mortality.

BACKGROUND: Multimorbidity, the co-occurrence of two or more diseases in one patient, is a frequent phenomenon. Understanding how different diseases condition each other over the lifetime of a patient could significantly contribute to personalised prevention efforts. However, most of our current knowledge on the long-term development of the health of patients (their disease trajectories) is either confined to narrow time spans or specific (sets of) diseases. Here, we aim to identify decisive events that potentially determine the future disease progression of patients. METHODS: Health states of patients are described by algorithmically identified multimorbidity patterns (groups of included or excluded diseases) in a population-wide analysis of 9,000,000 patient histories of hospital diagnoses observed over 17 years. Over time, patients might acquire new diagnoses that change their health state; they describe a disease trajectory. We measure the age- and sex-specific risks for patients that they will acquire certain sets of diseases in the future depending on their current health state. RESULTS: In the present analysis, the population is described by a set of 132 different multimorbidity patterns. For elderly patients, we find 3 groups of multimorbidity patterns associated with low (yearly in-hospital mortality of 0.2-0.3%), medium (0.3-1%) and high in-hospital mortality (2-11%). We identify combinations of diseases that significantly increase the risk to reach the high-mortality health states in later life. For instance, in men (women) aged 50-59 diagnosed with diabetes and hypertension, the risk for moving into the high-mortality region within 1 year is increased by the factor of 1.96 ± 0.11 (2.60 ± 0.18) compared with all patients of the same age and sex, respectively, and by the factor of 2.09 ± 0.12 (3.04 ± 0.18) if additionally diagnosed with metabolic disorders. CONCLUSIONS: Our approach can be used both to forecast future disease burdens, as well as to identify the critical events in the careers of patients which strongly determine their disease progression, therefore constituting targets for efficient prevention measures. We show that the risk for cardiovascular diseases increases significantly more in females than in males when diagnosed with diabetes, hypertension and metabolic disorders.