Trends in Incidence of Hospitalization for Hypoglycemia and Diabetic Ketoacidosis in Individuals With Type 1 or Type 2 Diabetes With and Without Severe Mental Illness in Denmark From 1996 to 2020: A Nationwide Study.

OBJECTIVE: To examine trends in incidence of acute diabetes complications in individuals with type 1 or type 2 diabetes with and without severe mental illness (SMI) in Denmark by age and calendar year. RESEARCH DESIGN AND METHODS: We conducted a cohort study using nationwide registers from 1996 to 2020 to identify individuals with diabetes, ascertain SMI status (namely, schizophrenia, bipolar disorder, or major depression) and identify the outcomes: hospitalization for hypoglycemia and diabetic ketoacidosis (DKA). We used Poisson regression to estimate incidence rates (IRs) and incidence rate ratios (IRRs) of recurrent hypoglycemia and DKA events by SMI, age, and calendar year, accounting for sex, diabetes duration, education, and country of origin. RESULTS: Among 433,609 individuals with diabetes, 8% had SMI. Risk of (first and subsequent) hypoglycemia events was higher for individuals with SMI than for those without SMI (for first hypoglycemia event, IRR: type 1 diabetes, 1.77 [95% CI 1.56-2.00]; type 2 diabetes, 1.64 [95% CI 1.55-1.74]). Individuals with schizophrenia were particularly at risk for recurrent hypoglycemia events. The risk of first DKA event was higher in individuals with SMI (for first DKA event, IRR: type 1 diabetes, 1.78 [95% CI 1.50-2.11]; type 2 diabetes, 1.85 [95% CI 1.64-2.09]). Except for DKA in the type 2 diabetes group, IR differences between individuals with and without SMI were highest in younger individuals (<50 years old) but stable across the calendar year. CONCLUSIONS: SMI is an important risk factor for acute diabetes complication and effective prevention is needed in this population, especially among the younger population and those with schizophrenia.

Heterogeneity in glycaemic control in children and adolescents with type 1 diabetes: A latent class trajectory analysis of Danish nationwide data.

AIMS: Suboptimal glycaemic control in children and adolescents with type 1 diabetes is prevalent and associated with increased risk of diabetes-related complications and mortality later in life. First, we aimed to identify distinct glycated haemoglobin (HbA1c) trajectories in children and adolescents (2-19 years) with type 1 diabetes. Second, we examined their associations with clinical and socio-demographic factors. METHODS: Data were obtained from the Danish Registry of Childhood and Adolescent Diabetes (DanDiabKids) comprising all Danish children and adolescents diagnosed with type 1 diabetes from 1996 to 2019. Subgroups of distinct mean trajectories of HbA1c were identified using data-driven latent class trajectory modelling. RESULTS: A total of 5889 children (47% female) had HbA1c measured a median of 6 times (interquartile range 3-8) and contributing to 36,504 measurements. We identified four mean HbA1c trajectories, referred to as 'Stable but elevated HbA1c' (83%), 'Increasing HbA1c' (5%), 'Late HbA1c peak' (7%), and 'Early HbA1c peak' (5%). Compared to the 'Stable but elevated HbA1c' group, the three other groups presented rapidly deteriorating glycaemic control during late childhood or adolescence, had higher HbA1c at study entry, and included fewer pump users, higher frequency of inadequate blood glucose monitoring, more severe hypoglycaemic events, lower proportions with Danish origin, and worse educational status of parents. The groups also represented significant differences by healthcare region. CONCLUSIONS: Children and adolescents with type 1 diabetes experience heterogenous trajectories with different timings and magnitudes of the deterioration of HbA1c levels, although the majority follow on average a stable, yet elevated HbA1c trajectory. The causes and long-term health implications of these heterogenous trajectories need to be addressed.

Patient referrals from Greenland to Rigshospitalet in Denmark.

INTRODUCTION: Patients from Greenland are transferred overseas for highly specialised treatment, mainly to the National University Hospital, Rigshospitalet, Denmark. We aimed to investigate the pattern of transfers from Greenland to Denmark, focusing on cardiology. METHODS: This descriptive quality assurance study included all Greenlandic citizens receiving healthcare services at Rigshospitalet from 2017-2021. Unique patients and disease courses were accounted for and patients were stratified across specialties. RESULTS: A total of 3,201 unique patients (56% males, mean age 51.0 years, 325 were 18 years or younger) from Greenland received healthcare services at Rigshospitalet. As some patients were seen two or more times, this corresponds to almost 900 patients (approximately 1,500 disease courses) or 1.2% of the entire Greenlandic population being referred annually. The referrals increased by 52% during the period. The Centre of Head and Orthopaedics received most referrals, followed by the Heart Centre. A modest increase in referrals due to heart diseases was observed with ischaemic heart disease being the more prevalent diagnosis. Coronary artery revascularisation rates in Greenlandic citizens aged 55-74 years were at least as high as in the same age-group for all Danes. CONCLUSION: During the past five years, a 52% increase has been observed in the referral rate from Greenland to Rigshospitalet for diagnostics and treatment. In cardiology, ischaemic heart disease represented the largest share with a high revascularisation rate being observed in older Greenlandic citizens. FUNDING: None. TRIAL REGISTRATION: Not relevant.

Time Trends in the Incidence of Diabetic Ketoacidosis Leading to Hospital Admission Among Adults With Type 1 Diabetes: A Nationwide Danish Register Study.

OBJECTIVE: Diabetic ketoacidosis (DKA) is a life-threatening but preventable complication in people with type 1 diabetes. We aimed to quantify the incidence of DKA according to age and describe the time trend of DKA among adults with type 1 diabetes in Denmark. RESEARCH DESIGN AND METHODS: Individuals aged ≥18 years with type 1 diabetes were identified from a nationwide Danish diabetes register. Hospital admissions due to DKA were ascertained from the National Patient Register. The follow-up period was from 1996 to 2020. RESULTS: The cohort consisted of 24,718 adults with type 1 diabetes. The incidence rate of DKA per 100 person-years (PY) decreased with increasing age for both men and women. From 20 to 80 years of age, the DKA incidence rate decreased from 3.27 to 0.38 per 100 PY. From 1996 to 2008, the incidence rate of DKA increased for all age-groups, with a subsequent minor decrease in incidence rate until 2020. From 1996 to 2008, the incidence rates increased from 1.91 to 3.77 per 100 PY for a 20-year-old individual and from 0.22 to 0.44 per 100 PY for an 80-year-old individual living with type 1 diabetes. From 2008 to 2020 the incidence rates decreased from 3.77 to 3.27 and from 0.44 to 0.38 per 100 PY, respectively. CONCLUSIONS: The incidence rates of DKA are declining for all ages, with an overall decline from 2008 for both men and women. This likely reflects improved diabetes management for individuals with type 1 diabetes in Denmark.

Predicting the HbA1c level following glucose-lowering interventions in individuals with HbA1c-defined prediabetes: a post-hoc analysis from the randomized controlled PRE-D trial.

PURPOSE: To investigate whether the prediction of post-treatment HbA1c levels can be improved by adding an additional biomarker of the glucose metabolism in addition to baseline HbA1c. METHODS: We performed an exploratory analysis based on data from 112 individuals with prediabetes (HbA1c 39-47 mmol) and overweight/obesity (BMI ≥ 25 kg/m2), who completed 13 weeks of glucose-lowering interventions (exercise, dapagliflozin, or metformin) or control (habitual living) in the PRE-D trial. Seven prediction models were tested; one basic model with baseline HbA1c as the sole glucometabolic marker and six models each containing one additional glucometabolic biomarker in addition to baseline HbA1c. The additional glucometabolic biomarkers included: 1) plasma fructosamine, 2) fasting plasma glucose, 3) fasting plasma glucose × fasting serum insulin, 4) mean glucose during a 6-day free-living period measured by a continuous glucose monitor 5) mean glucose during an oral glucose tolerance test, and 6) mean plasma glucose × mean serum insulin during the oral glucose tolerance test. The primary outcome was overall goodness of fit (R2) from the internal validation step in bootstrap-based analysis using general linear models. RESULTS: The prediction models explained 46-50% of the variation (R2) in post-treatment HbA1c with standard deviations of the estimates of ~2 mmol/mol. R2 was not statistically significantly different in the models containing an additional glucometabolic biomarker when compared to the basic model. CONCLUSION: Adding an additional biomarker of the glucose metabolism did not improve the prediction of post-treatment HbA1c in individuals with HbA1c-defined prediabetes.

The effect of traditional diet on glucose homoeostasis in carriers and non-carriers of a common TBC1D4 variant in Greenlandic Inuit: a randomised crossover study.

Consumption of traditional foods is decreasing amid a lifestyle transition in Greenland as incidence of type 2 diabetes (T2D) increases. In homozygous carriers of a TBC1D4 variant, conferring postprandial insulin resistance, the risk of T2D is markedly higher. We investigated the effects of traditional marine diets on glucose homoeostasis and cardio-metabolic health in Greenlandic Inuit carriers and non-carriers of the variant in a randomised crossover study consisting of two 4-week dietary interventions: Traditional (marine-based, low-carbohydrate) and Western (high in imported meats and carbohydrates). Oral glucose tolerance test (OGTT, 2-h), 14-d continuous glucose and cardio-metabolic markers were assessed to investigate the effect of diet and genotype. Compared with the Western diet, the Traditional diet reduced mean and maximum daily blood glucose by 0·17 mmol/l (95 % CI 0·05, 0·29; P = 0·006) and 0·26 mmol/l (95 % CI 0·06, 0·46; P = 0·010), respectively, with dose-dependency. Furthermore, it gave rise to a weight loss of 0·5 kg (95 % CI; 0·09, 0·90; P = 0·016) relative to the Western diet and 4 % (95 % CI 1, 9; P = 0·018) lower LDL:HDL-cholesterol, which after adjustment for weight loss appeared to be driven by HDL elevation (0·09 mmol/l (0·03, 0·15), P = 0·006). A diet-gene interaction was indicated on insulin sensitivity in the OGTT (p = 0·093), which reflected a non-significant increase of 1·4 (-0·6, 3·5) mmol/l in carrier 2-h glucose. A Traditional diet marginally improved daily glycaemic control and plasma lipid profile compared with a Westernised diet in Greenlandic Inuit. Possible adverse effects on glucose tolerance in carriers of the TBC1D4 variant warrant further studies.

Indicators of quality of diabetes care in persons with type 2 diabetes with and without severe mental illness: a Danish nationwide register-based cohort study.

Background: This study aims to examine quality of diabetes care in persons with type 2 diabetes with and without severe mental illness (SMI). Methods: In a nationwide prospective register-based study, we followed persons with type 2 diabetes in Denmark with and without SMI including schizophrenia, bipolar disorder, or major depression. Quality of care was measured as receipt of care (hemoglobin A1c, low-density lipoprotein-cholesterol and urine albumin creatinine ratio assessment and eye and foot screening) and achievement of treatment targets between 2015 and 2019. Quality of care was compared in persons with and without SMI using generalized linear mixed models adjusted for key confounders. Findings: We included 216,537 persons with type 2 diabetes. At entry 16,874 (8%) had SMI. SMI was associated with lower odds of receiving care, with the most pronounced difference in urine albumin creatinine ratio assessment and eye screening (OR: 0.55, 95% CI: 0.53-0.58 and OR: 0.37 95% CI: 0.32-0.42, respectively). Among those with an assessment, we found that SMI was associated with higher achievement of recommended hemoglobin A1c levels and lower achievement of recommended low-density lipoprotein-cholesterol levels. Achievement of recommended low-density lipoprotein-cholesterol levels was similar in persons with versus without schizophrenia. Interpretation: Compared to persons without SMI, persons with SMI were less likely to receive process of care, with the most pronounced differences in urine albumin creatinine ratio assessment and eye screening. Funding: This study was funded by Steno Diabetes Center Copenhagen through an unrestricted grant from Novo Nordisk Foundation.

Dyslipidemia and the preventive potential in the Greenlandic population.

Background: Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for development of cardiovascular diseases. Based on available clinical data, we aimed to investigate the plasma lipid profile in the Greenlandic population, the proportion on cholesterol-lowering treatment and the adherence to local indications for cholesterol-lowering therapy. Methods: This is an observational cross-sectional study of the adult (≥21 years) Greenlandic population with focus on clinically determined lipid levels from 2017 to early 2022. We investigated levels of dyslipidemia and assessed cholesterol-lowering medication usage in individuals with an indication according to current Greenlandic guidelines, which include a) LDL-C >5 mmol/l, b) diabetes, c) diagnosed atherosclerotic disease and 4) a SCORE2 >7.5%. Results: In the adult Greenlandic population of 40,565 individuals a lipid profile was available in 13,895 with a mean LDL-C of 3.0 mmol/L and 976 (7%) had a LDL-C >5 mmol/l. One or more indications for cholesterol-lowering medication was present in 3988 individuals and a total of 5464 adult Greenlanders either fulfilled local criteria for statin therapy or received a statin (some without current indication) and among these, 2232 (41%) individuals received no statin. Conclusion: These findings indicate that clinically significant dyslipidemia is common in the adult Greenlandic population and that the cardiovascular preventive potential of cholesterol-lowering therapy is currently underutilized.

A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland.

Background: The genetic disease architecture of Inuit includes a large number of common high-impact variants. Identification of such variants contributes to our understanding of the genetic aetiology of diseases and improves global equity in genomic personalised medicine. We aimed to identify and characterise novel variants in genes associated with Maturity Onset Diabetes of the Young (MODY) in the Greenlandic population. Methods: Using combined data from Greenlandic population cohorts of 4497 individuals, including 448 whole genome sequenced individuals, we screened 14 known MODY genes for previously identified and novel variants. We functionally characterised an identified novel variant and assessed its association with diabetes prevalence and cardiometabolic traits and population impact. Findings: We identified a novel variant in the known MODY gene HNF1A with an allele frequency of 1.9% in the Greenlandic Inuit and absent elsewhere. Functional assays indicate that it prevents normal splicing of the gene. The variant caused lower 30-min insulin (ß = -232 pmol/L, ßSD = -0.695, P = 4.43 × 10-4) and higher 30-min glucose (ß = 1.20 mmol/L, ßSD = 0.441, P = 0.0271) during an oral glucose tolerance test. Furthermore, the variant was associated with type 2 diabetes (OR 4.35, P = 7.24 × 10-6) and HbA1c (ß = 0.113 HbA1c%, ßSD = 0.205, P = 7.84 × 10-3). The variant explained 2.5% of diabetes variance in Greenland. Interpretation: The reported variant has the largest population impact of any previously reported variant within a MODY gene. Together with the recessive TBC1D4 variant, we show that close to 1 in 5 cases of diabetes (18%) in Greenland are associated with high-impact genetic variants compared to 1-3% in large populations. Funding: Novo Nordisk Foundation, Independent Research Fund Denmark, and Karen Elise Jensen's Foundation.

Childhood body mass index trajectories, adult-onset type 2 diabetes, and obesity-related cancers.

BACKGROUND: Elevated childhood body mass index (BMI), commonly examined as a "once-only" value, increases the risk of cancer and type 2 diabetes (T2D) in adulthood. Continuous exposure to adiposity during childhood may further increase cancer risk. We examined whether longitudinal childhood BMI trajectories were associated with adult obesity-related cancer and the role of adult-onset T2D in these associations. METHODS: Five sex-specific latent class BMI trajectories were generated for 301 927 children (149 325 girls) aged 6-15 years from the Copenhagen School Health Records Register. Information on obesity-related cancers and T2D was obtained from national health registers. Incidence rate ratios (IRR), cumulative incidences, and confidence intervals (CI) were estimated using Poisson regressions. RESULTS: Compared with the average childhood BMI trajectory (containing approximately 40% of individuals), the rate of obesity-related cancer (excluding breast cancer) increased with higher childhood BMI trajectories among women. The highest rates occurred in the overweight (IRR = 1.27, 95% CI = 1.17 to 1.38) and obesity (IRR = 1.79, 95% CI = 1.53 to 2.08) BMI trajectories. Similar patterns were observed among men. In contrast, women with the obesity childhood BMI trajectory had the lowest rate of pre- and postmenopausal breast cancer (IRR = 0.59, 95% CI = 0.43 to 0.80, and IRR = 0.41, 95% CI = 0.30 to 0.57, respectively). For all trajectories, the cumulative risk of obesity-related cancer increased with adult-onset T2D. CONCLUSION: Consistent childhood overweight or obesity may increase the rates of adult obesity-related cancer and decrease the rates of breast cancer. Adult-onset T2D conferred additional risk for obesity-related cancer, but the effect did not differ across childhood BMI trajectories.

An LDLR missense variant poses high risk of familial hypercholesterolemia in 30% of Greenlanders and offers potential of early cardiovascular disease intervention.

The common Arctic-specific LDLR p.G137S variant was recently shown to be associated with elevated lipid levels. Motivated by this, we aimed to investigate the effect of p.G137S on metabolic health and cardiovascular disease risk among Greenlanders to quantify its impact on the population. In a population-based Greenlandic cohort (n = 5,063), we tested for associations between the p.G137S variant and metabolic health traits as well as cardiovascular disease risk based on registry data. In addition, we explored the variant's impact on plasma NMR measured lipoprotein concentration and composition in another Greenlandic cohort (n = 1,629); 29.5% of the individuals in the cohort carried at least one copy of the p.G137S risk allele. Furthermore, 25.4% of the heterozygous and 54.7% of the homozygous carriers had high levels (>4.9 mmol/L) of serum LDL cholesterol, which is above the diagnostic level for familial hypercholesterolemia (FH). Moreover, p.G137S was associated with an overall atherosclerotic lipid profile, and increased risk of ischemic heart disease (HR [95% CI], 1.51 [1.18-1.92], p = 0.00096), peripheral artery disease (1.69 [1.01-2.82], p = 0.046), and coronary operations (1.78 [1.21-2.62], p = 0.0035). Due to its high frequency and large effect sizes, p.G137S has a marked population-level impact, increasing the risk of FH and cardiovascular disease for up to 30% of the Greenlandic population. Thus, p.G137S is a potential marker for early intervention in Arctic populations.

Advanced glycation end-products are associated with diabetic neuropathy in young adults with type 1 diabetes.

Aims/hypothesis: Advanced glycation end-products (AGEs) may contribute to the development of diabetic neuropathy. In young adults with type 1 diabetes, we aimed to investigate the association between AGEs and cardiovascular autonomic neuropathy (CAN) and distal symmetric polyneuropathy (DSPN). Methods: This cross-sectional study comprised 151 young adults. CAN was assessed by cardiovascular autonomic reflex tests; lying-to-standing test, deep breathing test (E/I), Valsalva manoeuvre, and heart rate variability indices; and the mean square of the sum of the squares of differences between consecutive R-R intervals and standard deviation of normal-to-normal intervals (SDNN), high- (HF) and low-frequency (LF) power, total frequency power, and the LF/HF ratio. DSPN was assessed by light touch, pain and vibration perception threshold (VPT), neuropathy questionnaires, and objective measures. AGEs were analysed in four groups using z-scores adjusted for relevant confounders and multiple testing: i) "glycolytic dysfunction", ii) "lipid peroxidation", iii) "oxidative stress", and iv) "glucotoxicity". Results: A higher z-score of "glycolytic dysfunction" was associated with higher VPT (4.14% (95% CI 1.31; 7.04), p = 0.004) and E/I (0.03% (95% CI 0.01; 0.05), p = 0.005), "lipid peroxidation" was associated with higher LF/HF ratio (37.72% (95% CI 1.12; 87.57), p = 0.044), and "glucotoxicity" was associated with lower SDNN (-4.20% (95% CI -8.1416; -0.0896), p = 0.047). No significance remained after adjustment for multiple testing. Conclusions/interpretations: In young adults with type 1 diabetes, increased levels of AGEs involving different metabolic pathways were associated with several measures of CAN and DSPN, suggesting that AGEs may play a diverse role in the pathogeneses of diabetic neuropathy.

Childhood body mass index trajectories and associations with adult-onset chronic kidney disease in Denmark: A population-based cohort study.

BACKGROUND: Although excess adult adiposity is a strong risk factor for chronic kidney disease (CKD), evidence for associations with early life body size is limited. We investigated whether childhood body mass index (BMI) trajectories are associated with adult-onset CKD and end-stage kidney disease (ESKD) using a population-based cohort. Further, we examined the role of adult-onset type 2 diabetes (T2D) in these associations. METHODS AND FINDINGS: We included 151,506 boys and 148,590 girls from the Copenhagen School Health Records Register, born 1930 to 1987 with information on measured weights and heights at ages 6 to 15 years. Five sex-specific childhood BMI trajectories were analyzed. Information on the main outcomes CKD and ESKD, as well as T2D, came from national health registers. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated using Poisson regression adjusted for year of birth. During a median of 30.8 person-years of follow-up, 5,968 men and 3,903 women developed CKD and 977 men and 543 women developed ESKD. For both sexes, the rates of CKD and ESKD increased significantly with higher child BMI trajectories in comparison with the average BMI trajectory (40% to 43% of individuals) and the below-average BMI trajectory (21% to 23% of individuals) had the lowest rates. When including T2D, most associations were significant and men (IRR = 1.39, 95% CI: 1.13 to 1.72) and women (IRR = 1.54, 95% CI: 1.28 to 1.86) with the obese childhood BMI trajectory (2% of individuals) had significantly higher CKD rates than the average BMI trajectory, whereas for ESKD, the associations were positive, but nonsignificant, for men (IRR = 1.38, 95% CI: 0.83 to 2.31) but significant for women (IRR = 1.97, 95% CI: 1.25 to 3.11) with the obese BMI trajectory. A main study limitation is the use of only hospital-based CKD diagnoses. CONCLUSIONS: Individuals with childhood BMI trajectories above average had higher rates of CKD and ESKD than those with an average childhood BMI trajectory. When including T2D, most associations were significant, particularly with CKD, emphasizing the potential information that the early appearance of above-average BMI growth patterns provide in relation to adult-onset CKD beyond the information provided by T2D development.

Body mass index trajectories in childhood and incidence rates of type 2 diabetes and coronary heart disease in adulthood: A cohort study.

AIMS: We examined associations between five body mass index (BMI) trajectories from ages 6-15 years and register-based adult-onset type 2 diabetes mellitus (T2D) and coronary heart disease (CHD) with and without adjustment for adult BMI. METHODS: Child and adult BMI came from two Danish cohorts and 13,205 and 13,438 individuals were included in T2D and CHD analyses, respectively. Trajectories were estimated by latent class modelling. Incidence rate ratios (IRRs) were estimated with Poisson regression. RESULTS: In models without adult BMI, compared to the lowest trajectory, among men the T2D IRRs were 0.92 (95 %CI:0.77-1.09) for the second lowest trajectory and 1.51 (95 %CI:0.71-3.20) for the highest trajectory. The corresponding IRRs in women were 0.92 (95 %CI:0.74-1.16) and 3.58 (95 %CI:2.30-5.57). In models including adult BMI, compared to the lowest trajectory, T2D IRRs in men were 0.57 (95 %CI:0.47-0.68) for the second lowest trajectory and 0.26 (95 %CI:0.12-0.56) for the highest trajectory. The corresponding IRRs in women were 0.60 (95 %CI:0.48-0.75) and 0.59 (95 %CI:0.36-0.96). The associations were similar in direction, but not statistically significant, for CHD. CONCLUSIONS: Incidence rates of adult-onset T2D were greater for a high child BMI trajectory than a low child BMI trajectory, but not in models that included adult BMI.

Trajectory and predictors of HbA1c in children and adolescents with type 1 diabetes-A Danish nationwide cohort study.

OBJECTIVES: Poor glycemic control in type 1 diabetes increases the risk of chronic complications and it is essential to identify life periods and predictors associated with deteriorating HbA1c . The aim was to describe specific HbA1c trajectories in Danish children and adolescents with type 1 diabetes and study associations with clinical and sociodemographic factors. RESEARCH DESIGN AND METHODS: 5889 children with type 1 diabetes were included from the nationwide Danish Registry of Childhood and Adolescent Diabetes with annual visits during 1996-2019. Trajectories of HbA1c were modeled with linear mixed-effects models (using age as time scale, included as cubic spline) and with an individual-specific random intercept and slope. The following cofactors were included stepwise into the model: sex, age at diagnosis, calendar year, parental education, immigrant status, health care region, blood glucose monitoring (BGM) frequency, treatment modalities: continuous subcutaneous insulin infusion (pump) versus multiple daily insulin injection therapy (pen) and continuous glucose monitoring. RESULTS: HbA1c overall increased during age while there was a significant decreasing secular trend. Older age at diagnosis was associated with a steeper trajectory, and non-Danish origin and shorter parental education were each associated with higher levels of HbA1c across age. A lower BGM frequency was associated with a markedly poorer HbA1c trajectory, while no significant differences were shown for different treatment modalities. CONCLUSIONS: Glycemic outcome worsened with age during childhood and adolescence, which is of clinical concern. Important predictors for a poorer glycemic trajectory were later age at diabetes diagnosis, shorter parental education, non-Danish origin and, in particular low BGM frequency.

Severe Mental Illness and the Risk of Diabetes Complications: A Nationwide, Register-based Cohort Study.

CONTEXT: Individuals with severe mental illness (SMI) are at increased risk of developing type 2 diabetes. OBJECTIVE: This work explores whether individuals with diabetes and SMI are also at increased risk of diabetes complications and the potential age-specific differences in development of these. METHODS: Using nationwide registry data, we followed the entire Danish population with type 2 diabetes from January 1, 1996 to December 31, 2018. Exposure was SMI (schizophrenia, bipolar, or depression disorders). Outcome was diabetes complications (nephropathy, retinopathy, lower limp amputations, and cardiovascular disease). We applied Poisson regression models to estimate overall incidence rate ratios (IRRs) and age-specific incidence rates (IRs) and IRRs of the first event of each complication in individuals with SMI compared to individuals without SMI. The models were adjusted for sex, age, diabetes duration, calendar year, education, and migration status. RESULTS: We followed 371 625 individuals with type 2 diabetes, of whom 30 102 had coexisting diagnosed SMI. Individuals with SMI had a higher IR of nephropathy (IRR: 1.15; 95% CI, 1.12-1.18), amputations (IRR: 1.15; 95% CI, 1.04-1.28), and cardiovascular disease (men: IRR: 1.10; 95% CI, 1.05-1.15, women: IRR: 1.18; 95% CI, 1.13-1.22) but a lower IR of retinopathy (IRR: 0.75; 95% CI, 0.70-0.81) when compared to individuals without SMI, after adjustment for confounders. For all complications except amputations, the difference in IR was highest in the younger age groups. CONCLUSION: Individuals with type 2 diabetes and SMI had a higher risk and an earlier onset of several diabetes complications diagnoses, emphasizing focusing on improving diabetes management in younger age groups with SMI.

Loss of Sucrase-Isomaltase Function Increases Acetate Levels and Improves Metabolic Health in Greenlandic Cohorts.

BACKGROUND & AIMS: The sucrase-isomaltase (SI) c.273_274delAG loss-of-function variant is common in Arctic populations and causes congenital sucrase-isomaltase deficiency, which is an inability to break down and absorb sucrose and isomaltose. Children with this condition experience gastrointestinal symptoms when dietary sucrose is introduced. We aimed to describe the health of adults with sucrase-isomaltase deficiency. METHODS: The association between c.273_274delAG and phenotypes related to metabolic health was assessed in 2 cohorts of Greenlandic adults (n = 4922 and n = 1629). A sucrase-isomaltase knockout (Sis-KO) mouse model was used to further elucidate the findings. RESULTS: Homozygous carriers of the variant had a markedly healthier metabolic profile than the remaining population, including lower body mass index (ß [standard error], -2.0 [0.5] kg/m2; P = 3.1 × 10-5), body weight (-4.8 [1.4] kg; P = 5.1 × 10-4), fat percentage (-3.3% [1.0%]; P = 3.7 × 10-4), fasting triglyceride (-0.27 [0.07] mmol/L; P = 2.3 × 10-6), and remnant cholesterol (-0.11 [0.03] mmol/L; P = 4.2 × 10-5). Further analyses suggested that this was likely mediated partly by higher circulating levels of acetate observed in homozygous carriers (ß [standard error], 0.056 [0.002] mmol/L; P = 2.1 × 10-26), and partly by reduced sucrose uptake, but not lower caloric intake. These findings were verified in Sis-KO mice, which, compared with wild-type mice, were leaner on a sucrose-containing diet, despite similar caloric intake, had significantly higher plasma acetate levels in response to a sucrose gavage, and had lower plasma glucose level in response to a sucrose-tolerance test. CONCLUSIONS: These results suggest that sucrase-isomaltase constitutes a promising drug target for improvement of metabolic health, and that the health benefits are mediated by reduced dietary sucrose uptake and possibly also by higher levels of circulating acetate.

Cardiovascular outcomes with sodium-glucose cotransporter-2 inhibitors vs other glucose-lowering drugs in 13 countries across three continents: analysis of CVD-REAL data.

BACKGROUND: Randomized, controlled cardiovascular outcome trials may not be fully representative of the management of patients with type 2 diabetes across different geographic regions. We conducted analyses of data from the multinational CVD-REAL consortium to determine the association between initiation of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and cardiovascular outcomes, including subgroup analyses based on patient characteristics. METHODS: De-identified health records from 13 countries across three continents were used to identify patients newly-initiated on SGLT-2i or other glucose-lowering drugs (oGLDs). Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching for oGLD initiation. In the matched groups hazard ratios (HRs) for hospitalization for heart failure (HHF), all-cause death (ACD), the composite of HHF or ACD, myocardial infarction (MI) and stroke were estimated by country, and pooled using a weighted meta-analysis. Multiple subgroup analyses were conducted across patient demographic and clinical characteristics to examine any heterogeneity in treatment effects. RESULTS: Following matching, 440,599 new users of SGLT-2i and oGLDs were included in each group. Mean follow-up time was 396 days for SGLT-2i initiation and 406 days for oGLDs initiation. SGLT-2i initiation was associated with a lower risk of HHF (HR: 0.66, 95%CI 0.58-0.75; p < 0.001), ACD (HR: 0.52, 95%CI 0.45-0.60; p < 0.001), the composite of HHF or ACD (HR: 0.60, 95%CI 0.53-0.68; p < 0.001), MI (HR: 0.85, 95%CI 0.78-0.92; p < 0.001), and stroke (HR: 0.78, 95%CI 0.72-0.85; p < 0.001); regardless of patient characteristics, including established cardiovascular disease, or geographic region. CONCLUSIONS: This CVD-REAL study extends the findings from the SGLT-2i clinical trials to the broader setting of an ethnically and geographically diverse population, and across multiple subgroups. Trial registration NCT02993614.

A large remaining potential in lipid-lowering drug treatment in the type 2 diabetes population: A Danish nationwide cohort study.

AIM: To assess lipid-lowering drug (LLD) use patterns during 1996-2017 and examine lipid levels in relation to the use of LLDs and prevalent atherosclerotic cardiovascular disease (ASCVD). METHODS: Using a nationwide diabetes register, 404 389 individuals with type 2 diabetes living in Denmark during 1996-2017 were identified. Individuals were followed from 1 January 1996 or date of type 2 diabetes diagnosis until date of emigration, death or 1 January 2017. Redemptions of prescribed LLDs were ascertained from the nationwide Register of Medicinal Products Statistics. Data on lipid levels were sourced from the National Laboratory Database since 2010. LLD coverage was calculated at any given time based on the redeemed amount and dose. Trends in lipid levels were estimated using an additive mixed-effect model. Low-density lipoprotein cholesterol (LDL-C) goal attainment was assessed based on recommended targets by the 2011, 2016 and 2019 guidelines for management of dyslipidaemias. RESULTS: LLD use has decreased since 2012 and only 55% of those with type 2 diabetes were LLD users in 2017. A decline in levels of total cholesterol and LDL-C, and an increase in triglycerides, was observed during 2010-2017. Annual mean levels of LDL-C were lower among LLD users compared with non-users (in 2017: 1.84 vs. 2.57 mmol/L). A greater fraction of LLD users achieved the LDL-C goal of less than 1.8 mmol/L compared with non-users (in 2017: 51.7% and 19%, respectively). Among LLD users with prevalent ASCVD, 26.9% and 55% had, as recommended by current 2019 European guidelines, an LDL-C level of less than 1.4 mmol/L and less than 1.8 mmol/L, respectively, in 2017. CONCLUSIONS: LLD use and LDL-C levels are far from optimal in the Danish type 2 diabetes population and improvement in LLD use could reduce ASCVD events.