Cross-sectional versus sequential quality indicators of risk factor management in patients with Type 2 diabetes

BACKGROUND:: The fairness of quality assessment methods is under debate. Quality indicators incorporating the longitudinal nature of care have been advocated but their usefulness in comparison to more commonly used cross-sectional measures is not clear. AIMS:: To compare cross-sectional and sequential quality indicators for risk factor management in patients with type 2 diabetes. METHODS:: The study population consisted of 1912 patients who received diabetes care from one of 40 general practitioners in The Netherlands. Clinical outcomes, prescriptions, and demographic data were collected from electronic medical records. Quality was assessed for glycemic, blood pressure, and lipid control using indicators focusing on clinical outcomes, and treatment in relation to outcomes. Indicator results were compared with a reference method based on national guidelines for general practice. RESULTS:: According to the reference method, 76% of the patients received management as recommended for glycemic control, 58% for blood pressure control, and 67% for lipid control. Cross-sectional indicators looking at patients adequately controlled gave estimates that were 10-25% lower than the reference method. Estimates from indicators focusing on uncontrolled patients receiving treatment were 10-40% higher than the reference method for blood pressure and glycemic control. Sequential indicators focusing on improvement in clinical outcomes or assessing treatment modifications in response to poor control gave results closer to the reference method. CONCLUSIONS:: Sequential indicators are valuable for estimating quality of risk factor management in patients with diabetes. Such indicators may provide a more accurate and fair judgment than currently used cross-sectional indicators

Cardiometabolic treatment decisions in patients with type 2 diabetes: the role of repeated measurements and medication burden

Purpose Clinical guidelines for cardiometabolic risk management indicate a simple threshold-based strategy for treatment, but physicians and their patients may be reluctant to modify drug treatment after a single elevated measurement. We determined how repeated measurements of blood pressure, cholesterol and haemoglobin A1c affect general practitioners' decisions to start or intensify medication in patients with type 2 diabetes. We also evaluated whether medication burden altered these decisions. Methods We conducted a cohort study in 3029 patients managed by 62 general practitioners (GPs). We assessed the predictive value of the last risk factor measurement, the number of successive measurements above target level and the percentage change between the last two measurements. Medication burden was assessed as the number of drugs concurrently used. Effects on treatment decisions were estimated by multilevel logistic regression analysis, correcting for clustering at GP level. Results Repeated high levels of diastolic blood pressure increased the likelihood to start antihypertensive medication (OR=2.08, CI 1.37 to 3.17). Repeated high haemoglobin A1c levels affected intensification of oral glucose-lowering medication (OR=1.71, CI 1.44 to 2.03). Modification of lipid-lowering medication was limited, and only affected by the last total cholesterol level. Starting treatment for all three risk factors, as well as intensifying antihypertensive treatment, was more likely in patients already using more drugs for other chronic diseases. Conclusions Waiting for the next measurement before deciding to change medication can explain in part the apparent undertreatment for hypertension and hyperglycaemia, but not for hypercholesterolaemia. Medication burden was not a barrier for treatment modification

Vitamin D deficiency: universal risk factor for multifactorial diseases?

In the Western world, the majority of morbidity and mortality are caused by multifactorial diseases. Some risk factors are related to more than one type of disease. These so-called universal risk factors are highly relevant to the population, as reduction of universal risk factors may reduce the prevalence of several types of multifactorial disease simultaneously. Vitamin D deficiency is traditionally seen as an etiological factor in bone disorders such as rickets and osteomalacia. Recent studies also suggest a role for vitamin D deficiency in multifactorial disorders, including progressive renal function loss and cardiovascular disease; it is also a risk factor for frailty. The potentially pleiotropic effects of vitamin D analogues support the hypothesis that vitamin D deficiency is a universal risk factor. Here we review molecular actions of the vitamin D receptor (VDR), to identify mechanisms and pathways for vitamin D deficiency as a universal risk factor. To identify genes directly regulated by the VDR, we searched for genes containing vitamin D response elements (VDREs). A further refinement was made by selecting only VDRE-containing genes with documented modulation by VDR analogues in vivo. Our search yielded a limited number of factors possibly related to pleiotropic effects of vitamin D, including growth factors, hormones, inflammatory factors and factors related to calcium homeostasis. Results from observational, intervention and mechanistic studies indicate that vitamin D is a universal risk factor involved in diverse multifactorial conditions. Further exploration of the multifaceted actions of vitamin D may pave the way for disease-overriding intervention strategies

Thyroid peroxidase antibodies, levels of thyroid stimulating hormone and development of hypothyroidism in euthyroid subjects

OBJECTIVE: Thyroid peroxidase antibodies (TPOAbs) have been found to be related to the levels of thyroid stimulating hormone (TSH) and to predict future development of thyroid failure in selected populations. We investigated these relations in a euthyroid general population. DESIGN: Cross-sectional investigation of the relationship of TPOAbs and levels of TSH in euthyroid subjects. Prospective investigation of the association of TPOAbs and TSH with development of hypothyroidism. Incident hypothyroidism was defined as initiation of l-thyroxine in the absence of thyreostatic medication. SUBJECTS: The study was performed in a random sample of 2703 participants of the PREVEND study. A total of 309 subjects were excluded from analyses, mainly because of TSH outside the reference range (0.35-4.94mIU/l; n=115). RESULTS: Mean (SD) baseline age was 47.7 (12.5) years, with 50.8% females. Prevalence of positive TPOAbs (>/=12kU/l) was 8.4%. TSH concentrations were increased in subjects with TPOAbs (P<0.001). During a median follow-up of 9.1years, 15 (0.6%) subjects developed hypothyroidism (3.5% in TPOAbs positive vs. 0.4% in TPOAbs negative subjects; P<0.001). Female sex (P=0.02), and TSH (P<0.001) were also significantly associated with incident hypothyroidism. In multivariate analysis, TSH and TPOAbs remained independent predictors (both P<0.001). CONCLUSIONS: We confirmed the positive relationship of the presence of TPOAbs with levels of TSH and showed that TPOAbs and TSH predict future development of hypothyroidism. These results are consistent with the presence of TPOAbs necessitating a compensatory increase in levels of TSH for maintenance of euthyroidism, even in the euthyroid range

Plasma agouti-related protein concentrations are decreased in individuals with impaired awareness of hypoglycaemia

Background and aims: Individuals with type 1 diabetes may develop impaired awareness of hypoglycaemia (IAH). This is a complication characterized by a reduction or loss of hypoglycaemic symptoms. Adaptations in the central and/or damage in the peripheral nervous system likely contribute to the pathophysiology of IAH. In this study, a non-hypothesis driven proteomics analysis approach was used to investigate any potential pathophysiological pathways in IAH.Materials and methods: A nested-case control study was conducted using individuals participating in the Dutch Type 1 Diabetes Biomarker study. Individuals of Western European descent were included if they had completed the Dutch Clarke questionnaire and had a diabetes duration of greater than 10 years. Exclusion criteria was the presence of clinical cardiovascular disease. Targeted proteomics analysis was conducted using the Olink® target 96 Cardiovascular II panel (Uppsala, Sweden). Individuals with IAH were compared to age- and sex-matched controls. Statistical analyses were conducted using the OlinkAnalyze package in R. Differential expression of normalised protein expression (NPX) were statistically assessed with t-tests for univariate analyses and using linear regression in multivariate analyses.Results: The plasma protein from 67 individuals with IAH were compared to 108 individuals without IAH. Median age and diabetes duration were 44 years and 23 years, respectively. Mean HbA1c was 60mmol/mol (7.6%). In total, 162 samples and 92 proteins passed quality control and were analysed. In the univariate analysis, agouti-related peptide (AGRP) concentration was significantly lower in the IAH vs controls (6.12 NPX vs 6.44 NPX, FDR adjusted P = 0.013). In multivariate models adjusted for sex and diabetes duration, AGRP remained significant before p-value adjustment (p=0.000697), however, was not significant when adjusted for FDR.Conclusion: AGRP is secreted in the arcuate nucleus and the adrenal gland. In addition to the orexigenic effects, AGRP plays a role in hypothalamic pituitary adrenal (HPA) axis stimulation. AGRP secreting neurons in the arcuate nucleus can stimulate the HPA-axis through the paraventricular hypothalamus (PVH). Previous studies have hypothesized that glucose-sensing neurons are present in the PVH and ARC, which may further establish the importance of this pathway in the pathophysiology of IAH.Supported by: JDRF, DFN, FoDFDisclosure: R. Varkevisser: Grants; Juvenile DIabetes Research Foundation, DiabetesFonds NL, Friends of Diabeter Foundation

Plasma agouti-related protein concentrations are decreased in individuals with impaired awareness of hypoglycaemia

Background and aims: Individuals with type 1 diabetes may develop impaired awareness of hypoglycaemia (IAH). This is a complication characterized by a reduction or loss of hypoglycaemic symptoms. Adaptations in the central and/or damage in the peripheral nervous system likely contribute to the pathophysiology of IAH. In this study, a non-hypothesis driven proteomics analysis approach was used to investigate any potential pathophysiological pathways in IAH.Materials and methods: A nested-case control study was conducted using individuals participating in the Dutch Type 1 Diabetes Biomarker study. Individuals of Western European descent were included if they had completed the Dutch Clarke questionnaire and had a diabetes duration of greater than 10 years. Exclusion criteria was the presence of clinical cardiovascular disease. Targeted proteomics analysis was conducted using the Olink® target 96 Cardiovascular II panel (Uppsala, Sweden). Individuals with IAH were compared to age- and sex-matched controls. Statistical analyses were conducted using the OlinkAnalyze package in R. Differential expression of normalised protein expression (NPX) were statistically assessed with t-tests for univariate analyses and using linear regression in multivariate analyses.Results: The plasma protein from 67 individuals with IAH were compared to 108 individuals without IAH. Median age and diabetes duration were 44 years and 23 years, respectively. Mean HbA1c was 60mmol/mol (7.6%). In total, 162 samples and 92 proteins passed quality control and were analysed. In the univariate analysis, agouti-related peptide (AGRP) concentration was significantly lower in the IAH vs controls (6.12 NPX vs 6.44 NPX, FDR adjusted P = 0.013). In multivariate models adjusted for sex and diabetes duration, AGRP remained significant before p-value adjustment (p=0.000697), however, was not significant when adjusted for FDR.Conclusion: AGRP is secreted in the arcuate nucleus and the adrenal gland. In addition to the orexigenic effects, AGRP plays a role in hypothalamic pituitary adrenal (HPA) axis stimulation. AGRP secreting neurons in the arcuate nucleus can stimulate the HPA-axis through the paraventricular hypothalamus (PVH). Previous studies have hypothesized that glucose-sensing neurons are present in the PVH and ARC, which may further establish the importance of this pathway in the pathophysiology of IAH.Supported by: JDRF, DFN, FoDFDisclosure: R. Varkevisser: Grants; Juvenile DIabetes Research Foundation, DiabetesFonds NL, Friends of Diabeter Foundation

Plasma agouti-related protein concentrations are decreased in individuals with impaired awareness of hypoglycaemia

Background and aims: Individuals with type 1 diabetes may develop impaired awareness of hypoglycaemia (IAH). This is a complication characterized by a reduction or loss of hypoglycaemic symptoms. Adaptations in the central and/or damage in the peripheral nervous system likely contribute to the pathophysiology of IAH. In this study, a non-hypothesis driven proteomics analysis approach was used to investigate any potential pathophysiological pathways in IAH.Materials and methods: A nested-case control study was conducted using individuals participating in the Dutch Type 1 Diabetes Biomarker study. Individuals of Western European descent were included if they had completed the Dutch Clarke questionnaire and had a diabetes duration of greater than 10 years. Exclusion criteria was the presence of clinical cardiovascular disease. Targeted proteomics analysis was conducted using the Olink® target 96 Cardiovascular II panel (Uppsala, Sweden). Individuals with IAH were compared to age- and sex-matched controls. Statistical analyses were conducted using the OlinkAnalyze package in R. Differential expression of normalised protein expression (NPX) were statistically assessed with t-tests for univariate analyses and using linear regression in multivariate analyses.Results: The plasma protein from 67 individuals with IAH were compared to 108 individuals without IAH. Median age and diabetes duration were 44 years and 23 years, respectively. Mean HbA1c was 60mmol/mol (7.6%). In total, 162 samples and 92 proteins passed quality control and were analysed. In the univariate analysis, agouti-related peptide (AGRP) concentration was significantly lower in the IAH vs controls (6.12 NPX vs 6.44 NPX, FDR adjusted P = 0.013). In multivariate models adjusted for sex and diabetes duration, AGRP remained significant before p-value adjustment (p=0.000697), however, was not significant when adjusted for FDR.Conclusion: AGRP is secreted in the arcuate nucleus and the adrenal gland. In addition to the orexigenic effects, AGRP plays a role in hypothalamic pituitary adrenal (HPA) axis stimulation. AGRP secreting neurons in the arcuate nucleus can stimulate the HPA-axis through the paraventricular hypothalamus (PVH). Previous studies have hypothesized that glucose-sensing neurons are present in the PVH and ARC, which may further establish the importance of this pathway in the pathophysiology of IAH.Supported by: JDRF, DFN, FoDFDisclosure: R. Varkevisser: Grants; Juvenile DIabetes Research Foundation, DiabetesFonds NL, Friends of Diabeter Foundation

Targeted metabolomics of impaired awareness of hypoglycaemia in individuals with type 1 diabetes

Background and aims: Impaired awareness of hypoglycaemia (IAH) is a complication of insulin therapy that affects 20-40% of individuals with type 1 diabetes. IAH is partly explained by the absence of the sympathoadrenal response and adaptations of the brain; however, the exact pathophysiology behind this attenuation is not yet fully understood. Metabolomics is a rapidly evolving field that uses high-throughput data to help identify patterns in disease states in a non-hypothesis-driven approach. In this study, we aimed to identify metabolic signatures in IAH to elucidate potential pathophysiological pathways.Materials and methods: Individuals in the Dutch type 1 diabetes biomarker study who completed the Clarke questionnaire were included in this study. Individuals were excluded if they had cardiovascular disease or were non-western European. Plasma samples from individuals with IAH and age-sex-matched individuals without IAH (NAH) were analysed using the targeted Biocrates AbsoluteIDQ® p180 assay. Metabolite data were analysed using MetaboAnalyst 5.0. After quality control, metabolite data were normalised, and general linear models adjusted for sex and diabetes duration were fitted using the limma package in R. Genome-wide association studies (GWAS) were then conducted with metabolites with p &lt;0.05 and SNPs reaching genome-wide significance were re-introduced in the linear models as confounders.Results: In total, 578 individuals completed the Clarke questionnaire. After exclusion, 67 individuals with IAH and 108 with NAH were selected for analysis. The median age was 44 years, with a diabetes duration of 23 years. Insulin dosage was 50 units per day, and the mean HbA1c was 60mmol/mol (7.6%). When adjusted for sex and diabetes duration, 10 metabolites were found to have p-values &lt; 0.05. GWAS of these 10 metabolites led to genome-wide significant findings in two metabolites, sphingomyelin C24:1-OH and phosphatidylcholine diacyl C36:6, rs2071499 (G&gt;A) on chromosome 1 and rs2876585 (C&gt;T) on chromosome 6, respectively. When adjusted for the significant SNPs, 11 metabolites reached p&lt;0.05. No metabolites reached significance when p-values were adjusted for false discovery rate. These 11 metabolites were sphingomyelins and phosphatidylcholines.Conclusion: Phosphatidylcholines are metabolites important in the biosynthesis of sphingomyelin, which is an important component of the myelin sheath in nerve cells. However, potentially more importantly, these two metabolites are involved in the sphingomyelin cycle; this is in metabolic flux with the ceramide/diacylglycerol pool, which has previously been implicated in diabetes-related complications.Supported by: JDRF, DFN, FoDFDisclosure: B.H.R. Wolffenbuttel: Grants; Juvenile Diabetes Research Foundation, DiabetesFonds NL, Friends of Diabeter Foundation

Plasma agouti-related protein concentrations are decreased in individuals with impaired awareness of hypoglycaemia

Background and aims: Individuals with type 1 diabetes may develop impaired awareness of hypoglycaemia (IAH). This is a complication characterized by a reduction or loss of hypoglycaemic symptoms. Adaptations in the central and/or damage in the peripheral nervous system likely contribute to the pathophysiology of IAH. In this study, a non-hypothesis driven proteomics analysis approach was used to investigate any potential pathophysiological pathways in IAH.Materials and methods: A nested-case control study was conducted using individuals participating in the Dutch Type 1 Diabetes Biomarker study. Individuals of Western European descent were included if they had completed the Dutch Clarke questionnaire and had a diabetes duration of greater than 10 years. Exclusion criteria was the presence of clinical cardiovascular disease. Targeted proteomics analysis was conducted using the Olink® target 96 Cardiovascular II panel (Uppsala, Sweden). Individuals with IAH were compared to age- and sex-matched controls. Statistical analyses were conducted using the OlinkAnalyze package in R. Differential expression of normalised protein expression (NPX) were statistically assessed with t-tests for univariate analyses and using linear regression in multivariate analyses.Results: The plasma protein from 67 individuals with IAH were compared to 108 individuals without IAH. Median age and diabetes duration were 44 years and 23 years, respectively. Mean HbA1c was 60mmol/mol (7.6%). In total, 162 samples and 92 proteins passed quality control and were analysed. In the univariate analysis, agouti-related peptide (AGRP) concentration was significantly lower in the IAH vs controls (6.12 NPX vs 6.44 NPX, FDR adjusted P = 0.013). In multivariate models adjusted for sex and diabetes duration, AGRP remained significant before p-value adjustment (p=0.000697), however, was not significant when adjusted for FDR.Conclusion: AGRP is secreted in the arcuate nucleus and the adrenal gland. In addition to the orexigenic effects, AGRP plays a role in hypothalamic pituitary adrenal (HPA) axis stimulation. AGRP secreting neurons in the arcuate nucleus can stimulate the HPA-axis through the paraventricular hypothalamus (PVH). Previous studies have hypothesized that glucose-sensing neurons are present in the PVH and ARC, which may further establish the importance of this pathway in the pathophysiology of IAH.Supported by: JDRF, DFN, FoDFDisclosure: R. Varkevisser: Grants; Juvenile DIabetes Research Foundation, DiabetesFonds NL, Friends of Diabeter Foundation

Targeted metabolomics of impaired awareness of hypoglycaemia in individuals with type 1 diabetes

Background and aims: Impaired awareness of hypoglycaemia (IAH) is a complication of insulin therapy that affects 20-40% of individuals with type 1 diabetes. IAH is partly explained by the absence of the sympathoadrenal response and adaptations of the brain; however, the exact pathophysiology behind this attenuation is not yet fully understood. Metabolomics is a rapidly evolving field that uses high-throughput data to help identify patterns in disease states in a non-hypothesis-driven approach. In this study, we aimed to identify metabolic signatures in IAH to elucidate potential pathophysiological pathways.Materials and methods: Individuals in the Dutch type 1 diabetes biomarker study who completed the Clarke questionnaire were included in this study. Individuals were excluded if they had cardiovascular disease or were non-western European. Plasma samples from individuals with IAH and age-sex-matched individuals without IAH (NAH) were analysed using the targeted Biocrates AbsoluteIDQ® p180 assay. Metabolite data were analysed using MetaboAnalyst 5.0. After quality control, metabolite data were normalised, and general linear models adjusted for sex and diabetes duration were fitted using the limma package in R. Genome-wide association studies (GWAS) were then conducted with metabolites with p &lt;0.05 and SNPs reaching genome-wide significance were re-introduced in the linear models as confounders.Results: In total, 578 individuals completed the Clarke questionnaire. After exclusion, 67 individuals with IAH and 108 with NAH were selected for analysis. The median age was 44 years, with a diabetes duration of 23 years. Insulin dosage was 50 units per day, and the mean HbA1c was 60mmol/mol (7.6%). When adjusted for sex and diabetes duration, 10 metabolites were found to have p-values &lt; 0.05. GWAS of these 10 metabolites led to genome-wide significant findings in two metabolites, sphingomyelin C24:1-OH and phosphatidylcholine diacyl C36:6, rs2071499 (G&gt;A) on chromosome 1 and rs2876585 (C&gt;T) on chromosome 6, respectively. When adjusted for the significant SNPs, 11 metabolites reached p&lt;0.05. No metabolites reached significance when p-values were adjusted for false discovery rate. These 11 metabolites were sphingomyelins and phosphatidylcholines.Conclusion: Phosphatidylcholines are metabolites important in the biosynthesis of sphingomyelin, which is an important component of the myelin sheath in nerve cells. However, potentially more importantly, these two metabolites are involved in the sphingomyelin cycle; this is in metabolic flux with the ceramide/diacylglycerol pool, which has previously been implicated in diabetes-related complications.Supported by: JDRF, DFN, FoDFDisclosure: B.H.R. Wolffenbuttel: Grants; Juvenile Diabetes Research Foundation, DiabetesFonds NL, Friends of Diabeter Foundation