Reinhard W. Holl

Oscillometric twenty-four-hour ambulatory blood pressure values in healthy children and adolescents: A multicenter trial including 1141 subjects

Ambulatory blood pressure (ABP) monitoring is increasingly used to evaluate the blood pressure of children and adolescents. The upper normal ABP values in the pediatric age group are still unknown, because reference values based on a sufficiently high number of healthy children have not yet been published. In this multicenter trial, we pooled ABP records of 1141 healthy children and adolescents with a body height between 115 and 185 cm. The study was carried out by seven centers according to a common protocol. The 50th percentile for 24-hour systolic ABP increased moderately with height, from 103 to 113 mm Hg in girls and from 105 to 120 mm Hg in boys. The 50th percentile for diastolic 24-hour means was 66 +/- 1 mm Hg, irrespective of height or gender. Diastolic daytime means were 73 +/- 1 mm Hg, which is remarkably high compared with reference values for casual blood pressure. The mean nocturnal systolic and diastolic ABP (midnight to 6 AM) was 13% +/- 6% and 23% +/- 9% lower compared with the daytime means (8 AM to 8 PM), respectively. This multicenter study provides well-based limits of normal ABP in mid-European children.

Thyroid Autoimmunity in Children and Adolescents With Type 1 Diabetes: A multicenter survey

OBJECTIVE To investigate thyroid autoimmunity in a very large nationwide cohort of children and adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS Data were analyzed from 17,749 patients with type 1 diabetes aged 0.1-20 years who were treated in 118 pediatric diabetes centers in Germany and Austria. Antibodies to thyroglobulin (anti-TG) and thyroperoxidase (anti-TPO) were measured and documented at least once in 7,097 patients. A total of 49.5% of these patients were boys, the mean age was 12.4 years (range 0.3-20.0 years), and the mean duration of diabetes was 4.5 years (range 0.0-19.5 years). A titer exceeding 100 units/ml or 1:100 was considered significantly elevated. RESULTS In 1,530 patients, thyroid antibody levels were elevated on at least one occasion, whereas 5,567 were antibody-negative during the observation period. Patients with thyroid antibodies were significantly older (P < 0.001), had a longer duration of diabetes (P < 0.001), and developed diabetes later in life (P < 0.001) than those without antibodies. A total of 63% of patients with positive antibodies were girls, compared with 45% of patients without antibodies (P < 0.001). The prevalence of significant thyroid antibody titers increased with increasing age; the highest prevalence was in the 15- to 20-year age group (anti-TPO: 16.9%, P < 0.001; anti-TG: 12.8%, P < 0.001). Thyroid-stimulating hormone (TSH) levels were higher in patients with thyroid autoimmunity (3.34 microU/ml, range 0.0-615.0 microU/ml) than in control subjects (1.84 microU/ml, range 0.0-149.0 microU/ml) (P < 0.001). Even higher TSH levels were observed in patients with both anti-TPO and anti-TG (4.55 microU/ml, range 0.0-197.0 microU/ml). CONCLUSIONS Thyroid autoimmunity seems to be particularly common in girls with diabetes during the second decade of life and may be associated with elevated TSH levels, indicating subclinical hypothyroidism.

Insulin management and metabolic control of Type 1 diabetes mellitus in childhood and adolescence in 18 countries

Insulin regimens and metabolic control in children and adolescents with Type 1 diabetes mellitus were evaluated in a cross‐sectional, non‐population‐based investigation, involving 22 paediatric departments, from 18 countries in Europe, Japan, and North America. Blood samples and information were collected from 2873 children from March to August 1995. HbA1c was determined once and analysed centrally (normal range 4.4–6.3 %, mean 5.4 %). Year of birth, sex, duration of diabetes, height, body weight, number of daily insulin injections, types and doses of insulin were recorded. Average HbA1c in children under 11 years was 8.3 ± 1.3 % (mean ± SD) compared with 8.9 ± 1.8 % in those aged 12–18 years. The average insulin dose per kg body weight was almost constant (0.65 U kg−124 h−1) in children aged 2–9 years for both sexes, but there was a sharp increase during the pubertal years, particularly in girls. The increase in BMI of children with diabetes was much faster during adolescence compared to healthy children, especially in females. Sixty per cent of the children (n = 1707) used two daily insulin injections while 37 % (n = 1071) used three or more. Of those on two or three injections daily, 37 % used pre‐mixed insulins, either alone or in combination with short‐ and intermediate‐acting insulin. Pre‐adolescent children on pre‐mixed insulin showed similar HbA1c levels to those on a combination of short‐ and long‐acting insulins, whereas in adolescents significantly better HbA1c values were achieved with individual combinations. Very young children were treated with a higher proportion of long‐acting insulin. Among adolescent boys, lower HbA1c was related to use of more short‐acting insulin. This association was not found in girls. We conclude that numerous insulin injection regimens are currently used in paediatric diabetes centres around the world, with an increasing tendency towards intensive diabetes management, particularly in older adolescents. Nevertheless, the goal of near normoglycaemia is achieved in only a few.

Diabetic Nephropathy in 27,805 Children, Adolescents, and Adults With Type 1 Diabetes: Effect of diabetes duration, A1C, hypertension, dyslipidemia, diabetes onset, and sex

OBJECTIVE—To give an up-to-date profile of nephropathy and the involvement of risk factors in a large, prospective cohort of patients with type 1 diabetes and largely pediatric and adolescent onset of disease. RESEARCH DESIGN AND METHODS—A total of 27,805 patients from the nationwide, prospective German Diabetes Documentation System survey were included in the present analysis. Inclusion criteria were at least two documented urine analyses with identical classification. Urine analyses, treatment regimens, diabetes complications, and risk factors were recorded prospectively. Baseline characteristics were age at diagnosis 9.94 years (median [interquartile range 5.8–14.3]), age at last visit 16.34 years (12.5–22.2), and follow-up time 2.5 years (0.43–5.3). Cumulative incidence of nephropathy was tested by Kaplan-Meier analysis and association with risk factors by logistic regression. RESULTS—Nephropathy was classified as normal in 26,605, microalbuminuric in 919, macroalbuminuric in 78, and end-stage renal disease (ESRD) in 203 patients. After calculated diabetes duration of 40 years, 25.4% (95% CI 22.3–28.3) had microalbuminuria and 9.4% (8.3–11.4) had macroalbuminuria or ESRD. Risk factors for microalbuminuria were diabetes duration (odds ratio 1.033, P < 0.0001), A1C (1.13, P < 0.0001), LDL cholesterol (1.003, P < 0.0074), and blood pressure (1.008, P < 0.0074), while childhood diabetes onset (1.011, P < 0.0001) was protective. Male sex was associated with the development of macroalbuminuria. CONCLUSIONS—Diabetes duration, A1C, dyslipidemia, blood pressure, and male sex were identified as risk factors for nephropathy. Therefore, besides the best possible metabolic control, early diagnosis and prompt treatment of dyslipidemia and hypertension is mandatory in patients with type 1 diabetes.

Frequency of SMBG correlates with HbA1c and acute complications in children and adolescents with type 1 diabetes

Ziegler R, Heidtmann B, Hilgard D, Hofer S, Rosenbauer J, Holl R; for the DPV‐Wiss‐Initiative. Frequency of SMBG correlates with HbA1c and acute complications in children and adolescents with type 1 diabetes.

Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors)

Background -Reduction in cardiovascular death and hospitalization for heart failure (HHF) was recently reported with the sodium-glucose co-transporter-2 inhibitor (SGLT-2i) empagliflozin in type 2 diabetes patients with atherosclerotic cardiovascular disease. We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose lowering drugs (oGLDs) in six countries to determine if these benefits are seen in real-world practice, and across SGLT-2i class. Methods -Data were collected via medical claims, primary care/hospital records and national registries from the US, Norway, Denmark, Sweden, Germany and the UK. Propensity score for SGLT-2i initiation was used to match treatment groups. Hazard ratios (HRs) for HHF, death and their combination were estimated by country and pooled to determine weighted effect size. Death data were not available for Germany. Results -After propensity matching, there were 309,056 patients newly initiated on either SGLT-2i or oGLD (154,528 patients in each treatment group). Canagliflozin, dapagliflozin, and empagliflozin accounted for 53%, 42% and 5% of the total exposure time in the SGLT-2i class, respectively. Baseline characteristics were balanced between the two groups. There were 961 HHF cases during 190,164 person-years follow up (incidence rate [IR] 0.51/100 person-years). Of 215,622 patients in the US, Norway, Denmark, Sweden, and UK, death occurred in 1334 (IR 0.87/100 person-years), and HHF or death in 1983 (IR 1.38/100 person-years). Use of SGLT-2i, versus oGLDs, was associated with lower rates of HHF (HR 0.61; 95% CI 0.51-0.73; p<0.001); death (HR 0.49; 95% CI 0.41-0.57; p<0.001); and HHF or death (HR 0.54; 95% CI 0.48-0.60, p<0.001) with no significant heterogeneity by country. Conclusions -In this large multinational study, treatment with SGLT-2i versus oGLDs was associated with a lower risk of HHF and death, suggesting that the benefits seen with empagliflozin in a randomized trial may be a class effect applicable to a broad population of T2D patients in real-world practice (NCT02993614). Clinical Trial Registration -URL: ClinicalTrials.gov; Unique Identifier: NCT02993614.Background: Reduction in cardiovascular death and hospitalization for heart failure (HHF) was recently reported with the sodium-glucose cotransporter-2 inhibitor (SGLT-2i) empagliflozin in patients with type 2 diabetes mellitus who have atherosclerotic cardiovascular disease. We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose-lowering drugs in 6 countries to determine if these benefits are seen in real-world practice and across SGLT-2i class. Methods: Data were collected via medical claims, primary care/hospital records, and national registries from the United States, Norway, Denmark, Sweden, Germany, and the United Kingdom. Propensity score for SGLT-2i initiation was used to match treatment groups. Hazard ratios for HHF, death, and their combination were estimated by country and pooled to determine weighted effect size. Death data were not available for Germany. Results: After propensity matching, there were 309 056 patients newly initiated on either SGLT-2i or other glucose-lowering drugs (154 528 patients in each treatment group). Canagliflozin, dapagliflozin, and empagliflozin accounted for 53%, 42%, and 5% of the total exposure time in the SGLT-2i class, respectively. Baseline characteristics were balanced between the 2 groups. There were 961 HHF cases during 190 164 person-years follow-up (incidence rate, 0.51/100 person-years). Of 215 622 patients in the United States, Norway, Denmark, Sweden, and the United Kingdom, death occurred in 1334 (incidence rate, 0.87/100 person-years), and HHF or death in 1983 (incidence rate, 1.38/100 person-years). Use of SGLT-2i, versus other glucose-lowering drugs, was associated with lower rates of HHF (hazard ratio, 0.61; 95% confidence interval, 0.51–0.73; P<0.001); death (hazard ratio, 0.49; 95% confidence interval, 0.41–0.57; P<0.001); and HHF or death (hazard ratio, 0.54; 95% confidence interval, 0.48–0.60; P<0.001) with no significant heterogeneity by country. Conclusions: In this large multinational study, treatment with SGLT-2i versus other glucose-lowering drugs was associated with a lower risk of HHF and death, suggesting that the benefits seen with empagliflozin in a randomized trial may be a class effect applicable to a broad population of patients with type 2 diabetes mellitus in real-world practice. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02993614.

Insulin injection regimens and metabolic control in an international survey of adolescents with type 1 diabetes over 3 years: Results from the Hvidore study group

Abstract. The optimal insulin regimen for paediatric patients with type 1 diabetes remains controversial. Therefore this multicentre study was performed in adolescents over a 3-year period to assess metabolic control, severe hypoglycaemia, and weight gain in relation to insulin injection regimens. Out of 2873 children and adolescents in an international survey in 1995, 872 adolescents (433 boys, 439 girls, mean age in 1995 11.3±2.2 years) were restudied in 1998, relating insulin regimens to HbA1c measured in a central laboratory. In addition, the daily dose of insulin, changes in body mass index (BMI), and events of severe hypoglycaemia were evaluated. Over 3 years, the use of multiple injection regimens increased from 42% to 71%: 251 patients remained on twice daily insulin, 365 remained on multiple injections and 256 shifted from twice daily insulin to multiple injections. In all three subgroups an increase in insulin dose, a deterioration of metabolic control, and an increase in BMI were observed. Metabolic control deteriorated less than expected over 3 years during adolescence (HbA1c 1995: 8.7±1.6%; 1998 observed: 8.9±1.6%, HbA1c expected for 1998: 9.0%). BMI increased more than expected, the increase was greatest in patients switching from twice daily to multiple injections, and higher in females compared to males. Conclusion: in this international study, metabolic control was unsatisfactory in many adolescents with type 1 diabetes irrespective of the insulin regimen. No improvement in metabolic control was observed in this cross-sectional survey, over 3 years in any of the subgroups. Even the group switching from twice to multiple injections did not improve blood glucose control and the increase in body mass index was most pronounced in this group. Conclusive evidence, however, should be based on prospectively planned, randomised therapeutic trials in paediatric patients.

Cardiovascular risk in 26,008 European overweight children as established by a multicenter database.

Objective: Although the obesity epidemic is progressing in European children too, there is no consensus on the population‐specific prevalence of comorbidities or efficient diagnostic strategies. Therefore, weight‐related risk factors, their interrelationship, and association with biological parameters were assessed in a large group of overweight (OW) children, documented by an electronic database.

The ‘accelerator hypothesis’: relationship between weight, height, body mass index and age at diagnosis in a large cohort of 9,248 German and Austrian children with type 1 diabetes mellitus

Aims/hypothesisThe aim of this study was to investigate whether either increased weight or BMI are associated with the earlier manifestation of type 1 diabetes mellitus in children.MethodsWe evaluated anthropometric measurements in a large cohort of 9,248 patients of European extraction who were diagnosed in the years 1990–2003 in 116 pediatric clinics throughout Germany and Austria.ResultsPatients were divided into four groups according to age (0–4.9 years, 5–9.9 years, 10–14.9 years and 15–20 years). Significantly higher standard deviation scores (SDSs) for weight and BMI at diabetes onset were found for both boys and girls in the three younger age groups (up to 14.9 years of age) compared with the reference population (p<0.00001). In addition, the BMI SDS and the weight SDS were significantly higher in the 0–4.9-years age group than in all other groups (p<0.00001), and BMI SDS at onset gradually decreased with increasing age at manifestation (p<0.0001). Over the >10-year study period, there was a continuous rise in the weight-SDS and the BMI-SDS in the cohort (p<0.0001), especially in the 5–9.9-years and the 10–14.9-years age groups. Multivariate analysis revealed a significant influence of male sex and of year of manifestation on BMI SDS (p<0.0001) and demonstrated a negative association between the patients’ BMI SDS and age at diagnosis, with a mean annual decrease in BMI SDS of −0.0248 (95% CI −0.0294 to −0.0202, p<0.0001).Conclusions/interpretationA higher BMI was associated with a younger age at diabetes onset. Increased weight gain could therefore be a risk factor for the early manifestation of type 1 diabetes.

Improved Metabolic Control in Children and Adolescents With Type 1 Diabetes A trend analysis using prospective multicenter data from Germany and Austria

OBJECTIVE To investigate the temporal trend of metabolic control and potential predictors in German and Austrian children and adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS This study is based on a large, multicenter database for prospective longitudinal documentation of diabetes care in Germany and Austria. Data from 30,708 patients documented in 305 diabetes centers between 1995 and 2009 were analyzed. Generalized linear mixed regression models were used to adjust trend analysis for relevant confounders. RESULTS Unadjusted mean HbA1c decreased from 8.7 ± 1.8% in 1995 to 8.1 ± 1.5% in 2009. In multiple regression analysis, treatment year, age, sex, diabetes duration, migration background, BMI-SDS, and daily insulin dose were significant predictors of metabolic control (P < 0.001). After multiple adjustment, mean HbA1c decreased significantly by 0.038% per year (95% CI 0.032–0.043%), average odds ratio (OR) per year for HbA1c >7.5% (>9.0%) was 0.969 (95% CI 0.961–0.977) (0.948, 95% CI 0.941–0.956). Intensified insulin regimen was associated with lower frequency of poor metabolic control (HbA1c >9%; P = 0.005) but not with average HbA1c (P = 0.797). Rate of severe hypoglycemia and hypoglycemic coma decreased significantly (relative risk [RR] per year 0.948, 95% CI 0.918–0.979; RR 0.917, 95% CI 0.885–0.950) over the study period. Diabetic ketoacidosis rate showed no significant variation over time. CONCLUSIONS This study showed a significant improvement in metabolic control in children and adolescents with type 1 diabetes during the past decade and a simultaneous decrease in hypoglycemic events. The improvement was not completely explained by changes in the mode of insulin treatment. Other factors such as improved patient education may have accounted for the observed trend.