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Aim: To analyse patterns of glucose-lowering therapies among people with type 2 diabetes (T2D) in Denmark from 2016 to 2023., Materials and Methods: We examined time trends in the clinical profiles of people with T2D who initiated different glucose-lowering therapy classes for the first time. We furthermore investigated individual-level treatment trajectories following first-ever glucose-lowering therapy in people with or without cardiorenal disease. The study utilized data from the nationwide Danish health registries and included all individuals who filled a first-ever prescription for metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), sodium-glucose co-transporter-2 inhibitors (SGLT-2is) or insulin, excluding those without HbA1c-confirmed T2D or probable type 1 diabetes., Results: We included 260 393 individuals initiating a new glucose-lowering therapy class from 2016 to 2023, during which there were 6- and 3-fold increases in initiators of GLP-1RAs and SGLT-2is, respectively. The median HbA1c level at treatment initiation with GLP-1RAs or SGLT-2is decreased, from 67-68 mmol/mol in 2016-2017 to 57-58 mmol/mol in 2022-2023. Among individuals who initiated metformin as first-line therapy, the proportion who started additional glucose-lowering therapy within 2 years increased from 25% in 2016 to 40% in 2021. Among the 38% of individuals who had established cardiorenal disease when they initiated first-ever glucose-lowering therapy in 2020, 22% used SGLT-2is and 18% GLP-1RAs after 2.5 years, compared with 17% and 21% among initiators without cardiorenal disease, respectively., Conclusions: Our study documents a trend towards earlier T2D treatment intensification and an increase in the use of GLP-1RAs and SGLT-2is in Denmark. However, optimal T2D treatment is still not received by most individuals with early T2D and established cardiorenal disease., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To assess the level of adherence to glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment using real-world data and to investigate the sociodemographic and clinical factors associated with discontinuation of GLP-1RAs., Methods: First-time users of GLP-1RAs with type 2 diabetes mellitus (T2DM), aged ≥18 years, in the period 2007 to 2020, were identified using Danish registries, allowing all participants a minimum of 18 months' follow-up. Adherence to GLP-1RA therapy (medication possession ratio >0.80) and discontinuation of GLP-1RA therapy was estimated at 6- and 12-month follow-ups. Multivariable cause-specific Cox regression was used to identify sociodemographic and clinical factors associated with risk of discontinuation., Results: In total, 44 343 first-time users of GLP-1RAs with T2DM were identified (mean age 58.6 years, 42.7% female, median duration of T2DM 6.8 years, median glycated haemoglobin level 65 mmol/mol). The absolute risk of discontinuing GLP-1RA treatment within 6 months was 14.2% (95% confidence interval [CI] 13.9-14.6) and 21.2% (95% CI 20.8-21.5) within 12 months. At 6 months, 50.4% were adherent to GLP-1RA therapy and at 12 months, 48.6% remained adherent. In the multivariable model, younger (<40 years) and older age (>75 years), higher Charlson Comorbidity Index score, lower household income, high school and longer university degree as educational attainment level, and longer diabetes duration were associated with a higher risk of discontinuing GLP-1RA treatment., Conclusion: Approximately one in five patients discontinued GLP-1RA therapy within the first 12 months and only half were adherent. Overall, lower socioeconomic status and higher comorbidity burden were associated with higher risk of discontinuing GLP-1RA treatment., (© 2024 John Wiley & Sons Ltd.)

Importance: Female community health volunteers (FCHVs) are frontline community health workers who have been a valuable resource in improving public health outcomes in Nepal, but their value is understudied in diabetes care., Objective: To assess whether an FCHV-delivered intervention is associated with reduced blood glucose levels among adults with type 2 diabetes., Design, Setting, and Participants: This community-based, open-label, 2-group, cluster randomized clinical trial with a 12-month delayed control group design was conducted in 14 clusters of a semiurban setting in Western Nepal. A total of 244 adults with type 2 diabetes were recruited between November 2016 and April 2017. The follow-up assessment was conducted at 12 months after enrollment. Data analysis was performed from January to February 2019., Interventions: Seven clusters were randomized to the FCHV-delivered intervention in which 20 FCHVs provided home visits 3 times a year (once every 4 months) for health promotion counseling and blood glucose monitoring. If participants had blood glucose levels of 126 mg/dL or higher, the FCHVs referred them to the nearest health facility, and if participants were taking antihyperglycemic medication, they were followed up by the FCHVs for adherence to their medication. Seven clusters were randomized to usual care (control group)., Main Outcomes and Measures: The primary outcome was the change in mean fasting blood glucose from baseline to 12-month follow-up. Secondary outcomes included changes in mean systolic blood pressure, mean diastolic blood pressure, mean body mass index, percentage change in the proportion of low physical activity, harmful alcohol consumption, current smoking, low fruit and vegetable intake, and antihyperglycemic medication status., Results: Of 244 participants, 120 women (56.6%) and 92 men (43.4%) completed the trial. At baseline, the mean (SD) age was 51.71 (8.77) years; 127 participants were in the intervention group, and 117 participants were in the control group (usual care). At baseline, the mean (SD) fasting blood glucose level was 156.06 (44.48) mg/dL (158.48 [45.50] mg/dL in the intervention group and 153.43 [43.39] mg/dL in the control group). At 12-month follow-up, the mean fasting blood glucose decreased by 22.86 mg/dL in the intervention group, whereas it increased by 7.38 mg/dL in the control group. The mean reduction was 27.90 mg/dL greater with the intervention (95% CI, -37.62 to -18.18 mg/dL; P < .001). In secondary outcome analyses, there was a greater decline in mean systolic blood pressure in the intervention group than in the control group (-5.40 mm Hg; 95% CI, -8.88 to -1.92 mm Hg; P = .002). There was detectable difference in the intake of antihyperglycemic medication between the groups (relative risk, 1.35; 95% CI, 1.1 to 1.74; P = .02)., Conclusions and Relevance: These findings suggest that an FCHV-delivered intervention is associated with reduced blood glucose levels among adults with type 2 diabetes in a low-resource setting in Nepal., Trial Registration: ClinicalTrials.gov Identifier: NCT03304158.

Aims: To present the longer-term impact of multifactorial treatment of type 2 diabetes on self-reported health status, diabetes-specific quality of life, and diabetes treatment satisfaction at 10-year follow up of the ADDITION-Europe trial., Methods: The ADDITION-Europe trial enrolled 3057 individuals with screen-detected type 2 diabetes from four centres [Denmark, the UK (Cambridge and Leicester) and the Netherlands], between 2001 and 2006. Participants were randomized at general practice level to intensive treatment or to routine care . The trial ended in 2009 and a 10-year follow-up was performed at the end of 2014. We measured self-reported health status (36-item Short-Form Health Survey and EQ-5D), diabetes-specific quality of life (Audit of Diabetes-Dependent Quality of Life questionnaire), and diabetes treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire) at different time points during the study period. A mixed-effects model was applied to estimate the effect of intensive treatment (intention-to-treat analyses) on patient-reported outcome measures for each centre. Centre-specific estimates were pooled using a fixed effects meta-analysis., Results: There was no difference in patient-reported outcome measures between the routine care and intensive treatment arms in this 10-year follow-up study [EQ-5D: -0.01 (95% CI -0.03, 0.01); Physical Composite Score (36-item Short-Form Health Survey): -0.27 (95% CI -1.11, 0.57), Audit of Diabetes-Dependent Quality of Life questionnaire: -0.01 (95% CI -0.11, 0.10); and Diabetes Treatment Satisfaction Questionnaire: -0.20 (95% CI -0.70, 0.29)]., Conclusions: Intensive, multifactorial treatment of individuals with screen-detected type 2 diabetes did not affect self-reported health status, diabetes-specific quality of life, or diabetes treatment satisfaction at 10-year follow-up compared to routine care., (© 2020 Diabetes UK.)

Aims: To identify currently available studies on the association between psychosocial factors and HbA 1c in adults with insulin pump-treated type 1 diabetes, by performing a systematic review of the literature., Methods: MEDLINE, Embase, CINAHL and PsycINFO were searched for original studies on the association between psychosocial factors and HbA 1c in ≥ 50 adult, non-pregnant, insulin pump users with type 1 diabetes., Results: The search resulted in 1777 unique records, of which eight were eligible for inclusion. All identified studies were observational, with sample sizes ranging from 51 to 214. Seven different psychosocial factors were investigated in the eight studies. Study analysis suggested that HbA 1c may be associated with diabetes numeracy and quality of life. There were no indications of associations between HbA 1c and fear of hypoglycaemia or self-efficacy. Results regarding associations between HbA 1c and coping style, diabetes distress and locus of control were inconsistent., Conclusions: This systematic review summarizes the currently limited information on the association between psychosocial factors and HbA 1c during insulin pump therapy. The evidence base of the included studies was weak, and this review highlights the need for more research in these areas, with improved methodological and theoretical frameworks, including exploration of a broader spectrum of psychosocial variables and their potential association with HbA 1c and other metabolic outcomes. (PROSPERO International prospective register of systematic reviews registration no: CRD42020145705)., (© 2020 Diabetes UK.)

Aims: To examine the nationwide trends in antidiabetic drug utilization and expenditure in Denmark over the past 22 years., Methods: Data on antidiabetic use and expenditure from 1996 to 2017 were retrieved from the Register of Medicinal Product Statistics. Antidiabetic drug use is reported as defined daily dose (DDD) in total counts and per 1000 inhabitants/d. Expenditure is reported as volume sold in total counts per 1000 inhabitants and as annual mean expenditure., Results: Throughout the study period, the total use of antidiabetic drugs increased from 16.4 to 55.8 DDDs per 1000 inhabitants/d, while total expenditure increased from €59 to €286 m. The introduction of glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors has, since 2005, led to considerable variation in the proportional use of the different drug classes. Use of insulin and insulin analogues accounted for the majority of the cost of antidiabetic drugs, peaking at 75% in 2008; however, its proportional impact on overall antidiabetic drug expenditure decreased to ~44% in 2017. In contrast, a steep increase in GLP-1RA expenditure was observed from 2010 to 2017, reaching an annual cost of €85 m (~29% of all antidiabetic expenditure)., Conclusion: Antidiabetic drug utilization and cost in Denmark has increased considerably over the last 22 years, in accordance with the increased incidence of type 2 diabetes and changes in treatment guidelines. The release of several novel antidiabetic drugs seems to be responsible for the increase in antidiabetic drug expenditure., (© 2019 John Wiley & Sons Ltd.)

Aim: The aim of the study was to evaluate the association between C-peptide levels, glycaemic variability and hypoglycaemia in patients with insulin-treated type 2 diabetes (T2D)., Methods: A total of 98 patients with T2D treated with basal-bolus insulin were enrolled in a cross-sectional study. Glycaemic variability and hypoglycaemia were assessed from continuous glucose monitoring (CGM) data recorded over 6 days: Glycemic variability was assessed by calculating the mean coefficient of variation (CV), while hypoglycemia was defined as sensor glucose levels ≤ 3.9 mmol/L or < 3.0 mmol/L. Fasting C-peptide and fasting glucose were measured on day 1., Results: Low levels of fasting C-peptide correlated with higher CV (r = -0.53, P < 0.0001). In a multivariate regression model with HbA 1c , body mass index, diabetes duration and total daily insulin dose, only C-peptide was significantly associated with CV. Patients with ≥ 1 episode of hypoglycaemia had significantly lower median C-peptide levels than patients without hypoglycaemia (274 (136-620) pmol/L vs. 675 (445-1013) pmol/L, respectively; P = 0.0004). Also, 17 patients clinically diagnosed with T2D had detectable glutamic acid decarboxylase (GAD) antibodies (≥ 5 U/mL). These GAD-positive patients had significantly lower fasting C-peptide, higher CV and greater frequency of hypoglycaemia than GAD-negative patients., Conclusion: In patients with insulin-treated T2D, low levels of C-peptide are associated with greater glycaemic variability and higher risk of hypoglycaemia, suggesting that C-peptide levels should be taken into consideration when optimizing insulin treatment and assessing hypoglycaemia risk., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Aims: To investigate whether the benefits of switching to insulin degludec observed in the European retrospective chart review study EU-TREAT were dependent on the previous basal insulin used., Methods: People with Type 1 or Type 2 diabetes were switched to insulin degludec from other basal insulins ≥6 months before data collection. Participants were stratified into three groups based on their previous basal insulin: insulin glargine 100 units/ml (Type 1: n=888; Type 2: n=259); insulin detemir (Type 1: n=726; Type 2: n=415); and neutral protamine Hagedorn (Type 1: n=53; Type 2: n=95). Their glycaemic control and hypoglycaemia incidence at 6 and 12 months post-switch vs pre-switch was then evaluated., Results: Significant HbA 1c reductions were achieved in all previous basal insulin groups for participants with Type 1 diabetes [insulin glargine 100 units/ml: -2.08 mmol/mol (-0.19%); insulin detemir: -2.40 mmol/mol (-0.22%)] and those with Type 2 diabetes [insulin glargine 100 units/ml: -5.90 mmol/mol (-0.54%); insulin detemir: -6.01 mmol/mol (-0.55%); neutral protamine Hagedorn: -2.73 mmol/mol (-0.25%)] at 6 months, except for the relatively small neutral protamine Hagedorn group in those with Type 1 diabetes [-1.75 mmol/mol (-0.16%)], where statistical significance was not reached. At 6 months in the Type 1 diabetes group, switching to insulin degludec from insulin glargine 100 units/ml resulted in significantly lower hypoglycaemia rates across all hypoglycaemia categories; for the insulin detemir group, this significance was also observed for severe and nocturnal non-severe hypoglycaemia, while the low number of people in the neutral protamine Hagedorn group resulted in nonsignificant reductions in hypoglycaemia rates. At 6 months in the people with Type 2 diabetes, switching to insulin degludec resulted in significantly lower rates of hypoglycaemia across all categories for all groups. Similar outcomes were observed at 12 months., Conclusions: Switching to insulin degludec from other basal insulins can improve glycaemic control and/or reduce hypoglycaemia risk in people with diabetes (although there was a nonsignificant reduction in HbA 1c and hypoglycaemia rates for the neutral protamine Hagedorn group in Type 1 diabetes) under routine care., (© 2019 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

In this post hoc analysis we investigated the effects of insulin degludec/liraglutide fixed-ratio combination (IDegLira) versus comparators on cardiovascular (CV) risk markers in participants in the DUAL II (vs. insulin degludec), DUAL V (vs. insulin glargine 100 units/mL) and DUAL VII (vs. basal-bolus therapy) trials, grouped by sex, age (<65 years, ≥65 years) and diabetes duration (<10 years, ≥10 years). Treatment contrasts were in favour of IDegLira in many subgroups for changes from baseline in glycated haemoblogin (DUAL II, DUAL V), body weight (all three trials), systolic blood pressure (BP; all three trials), HDL cholesterol (DUAL VII) and LDL cholesterol (DUAL II, DUAL V). Higher heart rates were seen with IDegLira versus comparators (all three trials) plus significantly higher diastolic BP in men (DUAL V). Differences in treatment effect were seen between sexes in waist circumference (DUAL II), systolic BP (DUAL II, DUAL V) and triglycerides (DUAL VII), and between diabetes durations in LDL cholesterol (DUAL V). In conclusion, IDegLira is associated with a general improvement in CV risk markers compared with basal insulin or basal-bolus therapy after 26 weeks of treatment., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To report results at week 208, including a 104-week masked extension, of the EMPA-REG H2H-SU trial in patients with type 2 diabetes with inadequate glycaemic control on metformin, in which empagliflozin 25 mg given for 104 weeks provided a sustained reduction in glycated haemoglobin (HbA1c) with a small but statistically significant benefit vs glimepiride, sustained reductions in weight and blood pressure, and low risk of hypoglycaemia., Research Design and Methods: Patients with type 2 diabetes and HbA1c 53-86 mmol/mol (7% to 10%) were randomized to empagliflozin 25 mg or glimepiride 1 to 4 mg for 104 weeks as add-on to metformin. Patients who completed the randomized treatment period could participate in a 104-week extension in which they continued the double-blind treatment allocated at randomization., Results: Of 765 and 780 patients treated with empagliflozin and glimepiride, 576 and 549 patients, respectively, entered the extension period of the study. At week 208, the adjusted mean difference in change from baseline in HbA1c with empagliflozin vs glimepiride was -1.96 mmol/mol, 95% CI -3.57, -0.35 (-0.18%, 95% CI -0.33, -0.03); P = 0.0172. Rescue therapy was given to 23% of patients on empagliflozin and 34% on glimepiride (odds ratio 0.56 [95% CI 0.45, 0.71]; P < 0.0001). Confirmed hypoglycaemic adverse events (plasma glucose ≤3.9 mmol/L and/or requiring assistance) occurred in 3% of patients on empagliflozin and 28% on glimepiride (odds ratio 0.08 [95% CI 0.05, 0.13]; P < 0.0001)., Conclusions: In patients with type 2 diabetes, empagliflozin 25 mg as add-on to metformin for 208 weeks reduced HbA1c with a significantly lower risk of hypoglycaemia and a significantly smaller proportion of patients receiving rescue therapy compared with glimepiride., (© 2018 John Wiley & Sons Ltd.)

Aim: To compare clinical baseline data in individuals with Type 2 diabetes and normoalbuminuria, who are at high or low risk of diabetic kidney disease based on the urinary proteomics classifier CKD273., Methods: We conducted a prospective, randomized, double-blind, placebo-controlled international multicentre clinical trial and observational study in participants with Type 2 diabetes and normoalbuminuria, stratified into high- or low-risk groups based on CKD273 score. Clinical baseline data for the whole cohort and stratified by risk groups are reported. The associations between CKD273 and traditional risk factors for diabetic kidney disease were evaluated using univariate and logistic regression analysis., Results: A total of 1777 participants from 15 centres were included, with 12.3% of these having a high-risk proteomic pattern. Participants in the high-risk group (n=218), were more likely to be men, were older, had longer diabetes duration, a lower estimated GFR and a higher urinary albumin:creatinine ratio than those in the low-risk group (n=1559, P<0.02). Numerical differences were small and univariate regression analyses showed weak associations (R 2 < 0.04) of CKD273 with each baseline variable. In a logistic regression model including clinical variables known to be associated with diabetic kidney disease, estimated GFR, gender, log urinary albumin:creatinine ratio and use of renin-angiotensin system-blocking agents remained significant determinants of the CKD273 high-risk group: area under the curve 0.72 (95% CI 0.68-0.75; P<0.01)., Conclusions: In this population of individuals with Type 2 diabetes and normoalbuminuria, traditional diabetic kidney disease risk factors differed slightly between participants at high risk and those at low risk of diabetic kidney disease, based on CKD273. These data suggest that CKD273 may provide additional prognostic information over and above the variables routinely available in the clinic. Testing the added value will be subject to our ongoing study. (European Union Clinical Trials Register: EudraCT 2012-000452-34 and Clinicaltrials.gov: NCT02040441)., (© 2018 Diabetes UK.)

Aims: Allergy to recombinant human (rDNA) insulin preparations is a rare complication of insulin therapy. However, insulin preparations contain several allergens, and several disorders can resemble insulin allergy. Studies evaluating the diagnostic procedures on suspected insulin allergy are extremely few., Methods: Since January 1998, we have used a standardized investigative procedure during admittance to the medical ward allowing observation and repeated recording of reactions to intradermal skin test (performed with a commercially available kit containing isolated insulin allergens). Data on all investigated cases until April 2003 were collected retrospectively, and self-reported efficacy of intervention was compared to clinical data., Results: Twenty-two patients were included. In nine (41%) cases, non-insulin allergic causes were discovered and successfully treated: poor injection technique (n = 5), skin disease (n = 3) and other systemic allergy (n = 1). Nine other patients were found to be allergic to protamine (n = 3) or rDNA insulin (n = 6), and specific treatment was associated with relief in 8 patients (89%). Four patients had local reactions of unknown causes but symptom relief was obtained in three cases by unspecific therapy. Overall, 20 (91%) reported relief of symptoms., Conclusion: Our standardized investigative procedure of suspected insulin preparation (IP) allergy was associated with relief of symptoms in > 90% of patients. IP allergy was diagnosed in 41%, and intradermal testing with isolated insulin allergens was a prerequisite in identification of culprit allergen and targeting of treatment.