Factors Associated With Attainment of Glycemic Targets Among Adults With Type 1 and Type 2 Diabetes in Canada: A Cross-sectional Study Using Primary and Specialty Care Electronic Medical Record Data.

OBJECTIVE: Using a new database combining primary and specialty care electronic medical record (EMR) data in Canada, we determined attainment of glycemic targets and associated predictors among adults with diabetes. METHODS: We conducted a cross-sectional observational study combining primary and specialty care EMR data in Canada. Adults with diabetes whose primary care provider contributed to the National Diabetes Repository or who were assessed at a diabetes specialty clinic (LMC Diabetes and Endocrinology) between July 3, 2015, and June 30, 2019, were included. Diabetes type was categorized as type 2 diabetes (T2D) not prescribed insulin, T2D prescribed insulin, and type 1 diabetes (T1D). Covariates were age, sex, income quintile, province, rural/urban location, estimated glomerular filtration rate, medications, and insulin pump use. Associations between predictors and the outcome (glycated hemoglobin [A1C] of ≤7.0%) were assessed by multivariable logistic regressions. RESULTS: Among 122,106 adults, consisting of 91,366 with T2D not prescribed insulin, 25,131 with T2D prescribed insulin, and 5,609 with T1D, attainment of an A1C of ≤7.0% was 60%, 25%, and 23%, respectively. Proportions with an A1C of ≤7.5% and ≤8.0% were 75% and 84% for those with T2D not prescribed insulin, 41% and 57% for those with T2D prescribed insulin, and 37% and 53% for those with T1D. Highest vs lowest income quintile was associated with greater odds of meeting the A1C target (adjusted odds ratio [95% confidence interval] for each diabetes category: 1.15 [1.10 to 1.21], 1.21 [1.10 to 1.33], and 1.29 [1.04 to 1.60], respectively). Individuals in Alberta and Manitoba had less antihyperglycemic medication use and attainment of A1C target than other provinces. CONCLUSIONS: Attainment of glycemic targets among adults with diabetes was poor and differed by income and geographic location, which must be addressed in national diabetes strategies.

Ultra rapid lispro showed greater reduction in postprandial glucose versus Humalog in children, adolescents and adults with type 1 diabetes mellitus.

AIM: This study compared the pharmacokinetics, glucodynamics and tolerability following single subcutaneous doses of ultra rapid lispro (URLi) versus Humalog in children (6-11 years), adolescents (12-17 years) and adults (18-64 years) with type 1 diabetes mellitus (T1D). MATERIALS AND METHODS: The study was a randomized, two-period, subject- and investigator-blind, crossover design in participants with T1D. Participants received a 0.2 U/kg bolus dose immediately before a liquid mixed meal tolerance test. Insulin lispro and glucose concentrations were measured. RESULTS: The study included 13 children, 14 adolescents and 15 adults. Consistently across the age groups, onset of appearance was 4-5 min faster, the early 50% tmax was reduced by 7-13 min, and exposure in the first 15 min was increased by 3.5-6.5-fold following URLi compared with Humalog (all p < .01). Exposure after 3 h was decreased by 37-58% (p = .02) and the duration was reduced by 56 min (p = .006) in children and 36 min (p = .022) in adolescents with URLi compared with Humalog. The maximum and overall exposure were similar between treatments. Postprandial glucose at 1 h was reduced by 42 mg/dl in children (p = .008), 19 mg/dl (p = .195) in adolescents and 34 mg/dl (p = .018) in adults following URLi versus Humalog. The glucose excursion during a 5-h test meal period was reduced by 16% in children and 9% in adolescents compared with Humalog. URLi was well tolerated in all age groups. CONCLUSIONS: URLi showed an accelerated insulin lispro absorption and greater postprandial glucose reduction compared with Humalog in children, adolescents and adults with T1D.

Effect of Mini-Dose Ready-to-Use Liquid Glucagon on Preventing Exercise-Associated Hypoglycemia in Adults With Type 1 Diabetes.

OBJECTIVE: To determine effect of mini-dose, ready-to-use glucagon on incidence of exercise-associated hypoglycemia (EAH) in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: Individuals initially participated in the in-clinic training phase for which they were randomly assigned to a crossover design: 150 µg glucagon (treatment arm A) or placebo (arm B) subcutaneously, immediately before exercise, plus 50% reduction in continuous subcutaneous insulin infusion (CSII) basal delivery rate. Completers were then rerandomly assigned in the 12-week outpatient investigational phase: arm A, B, or open-label C, 150 µg glucagon alone. Participants were to undertake their usual aerobic exercise at moderate to high intensity for 30 to 75 min in real-world settings. Data were analyzed for incidence of level 1 hypoglycemia based on self-monitoring blood glucose and for various secondary and exploratory end points. RESULTS: Of 48 participants who completed the training phase, 45 continued to the outpatient phase. For all exercise sessions in the outpatient phase (n = 795), incidence of level 1 hypoglycemia was lower in both glucagon arms (A, 12% [P < 0.0001]; C, 16% [P = 0.0032]) than in the placebo arm (B, 39%). Times below range, in range, and above range from 0 to 300 min did not significantly differ among treatment arms. Consumed grams of exercise carbohydrates were lower with glucagon use than with placebo use but did not reach statistical significance (P = 0.12). Adverse events were similar among treatment arms. CONCLUSIONS: Mini-dose glucagon with or without 50% reduction in CSII basal delivery rate may help to decrease EAH incidence in adults with type 1 diabetes.

Integrated safety and efficacy analysis of dasiglucagon for the treatment of severe hypoglycaemia in individuals with type 1 diabetes.

AIMS: To perform an integrated analysis of the safety and efficacy of dasiglucagon, a glucagon analogue available in a ready-to-use aqueous formulation, to treat severe hypoglycaemia (SH) in type 1 diabetes (T1D). MATERIALS AND METHODS: An integrated analysis of dasiglucagon safety was conducted on data from two placebo-controlled trials (placebo-controlled pool) and two placebo-controlled and four non-placebo-controlled trials (broad pool) in adults with T1D. An integrated analysis of dasiglucagon efficacy was conducted of pooled data and within demographic subgroups from the two placebo-controlled and two non-placebo-controlled trials in adults with T1D. RESULTS: Dasiglucagon had a similar safety and tolerability profile to that of reconstituted glucagon. In the placebo-controlled datasets, no serious adverse events (AEs), AEs leading to withdrawal from the trial, or deaths were reported. The most common causally related AEs were nausea (56.5%) and vomiting (24.6%). The broad pool safety analysis showed similar results. Dasiglucagon efficacy in time to plasma glucose recovery from insulin-induced SH was similar to that of reconstituted glucagon (median 10.0 and 12.0 minutes, respectively) and superior to placebo (median 40.0 minutes; P < 0.0001). The median recovery time was consistent across all placebo-controlled trial subgroups. CONCLUSIONS: Dasiglucagon was well tolerated and effective as a rapid rescue agent for insulin-induced SH in people with T1D.

IMpact of flash glucose Monitoring in pEople with type 2 Diabetes Inadequately controlled with non-insulin Antihyperglycaemic ThErapy (IMMEDIATE): A randomized controlled trial.

AIM: To examine the efficacy and patient satisfaction of intermittently scanned continuous glucose monitoring (isCGM) in adults using non-insulin therapies for the management of type 2 diabetes. MATERIALS AND METHODS: The IMMEDIATE study was a multisite, open label, randomized controlled trial with follow-up at 16 weeks. Adults with type 2 diabetes using at least one non-insulin therapy, with an HbA1c of 7.5% or higher (≥ 58 mmol/mol), were randomized 1:1 to receive an isCGM device plus diabetes self-management education (isCGM + DSME) or DSME alone. Enrolment occurred from 8 September 2020 to 24 December 2021. The primary outcome was percentage mean time in range (TIR), in the final 2-week period, measured via blinded CGM. RESULTS: One hundred and sixteen participants were randomized (mean age, 58 years; diabetes duration, 10 years; mean HbA1c, 8.6% [70 mmol/mol]). At 16 weeks of follow-up, the isCGM and DSME arm had a significantly greater mean TIR by 9.9% (2.4 hours) (95% CI, -17.3% to -2.5%; P < .01), significantly less time above range by 8.1% (1.9 hours) (95% CI, 0.5% to 15.7%; P = .037), and a greater reduction in mean HbA1c by 0.3% (3 mmol/mol) (95% CI, 0% to 0.7%; P = .048) versus the DSME arm. Time below range was low and not significantly different between groups and hypoglycaemic events were few in both groups. Glucose monitoring satisfaction was higher among isCGM users (adjusted difference -0.5 [95% CI, -0.7 to -0.3], P < .01). CONCLUSIONS: The IMMEDIATE study has shown that among non-insulin-treated individuals with type 2 diabetes, use of isCGM is associated with an improvement in glycaemic outcomes.

Randomized Comparison of Initiating the Fixed-Ratio Combination of iGlarLixi or Biosimilar Insulin Glargine Together With Gliclazide in Participants of South Asian Origin With Type 2 Diabetes: VARIATION 2 SA Trial.

OBJECTIVES: The objective of this study was to compare initiation of a fixed-ratio combination of insulin glargine and lixisenatide (iGlarLixi) vs insulin glargine U100 (iGlar) along with gliclazide, exclusively in people of South Asian origin with type 2 diabetes (T2D). METHODS: The Variability of glucose Assessed in a Randomized trial comparing the Initiation of A Treatment approach with biosimilar basal Insulin analog Or a titratable iGlarLixi combinatioN in type 2 diabetes among South Asian participants (VARIATION 2 SA) trial (ClinicalTrials.gov identifier: NCT03819790) randomized insulin-naïve adults with T2D having glycated hemoglobin (A1C) 7.1% to 11% to initiate either iGlarLixi or iGlar + gliclazide. Insulin doses were titrated similarly to a prebreakfast glucose target of 4.0 to 5.5 mmol/L. Average time in range (TIR) on a masked continuous glucose monitor (CGM), A1C, fasting plasma glucose (FPG) and weight were assessed at the end of the 12-week treatment period. RESULTS: Mean baseline characteristics for the 104 randomized participants were similar between treatment groups, including the following: age, 59±11 years; diabetes duration, 13.7±7.3 years; and A1C, 8.5%±1.2%. Coprimary outcomes of average TIRs within 24- and 12-h (6 am to 6 pm) periods at the end of trial were 70.5%±16.8% and 72.9%±17.6% for iGlarLixi, whereas these TIRs were 65.6%±21.6% and 67.3%±20.7% for the iGlar + gliclazide regimen, respectively, with no significant differences between groups (p=0.35 for 24-h TIR and p=0.14 for 12-h TIR). No significant difference in secondary outcomes was observed between treatment groups. Self-reported hypoglycemic events throughout the trial period and CGM-reported hypoglycemia (<4 and <3 mmol/L) were similar between randomized treatments. CONCLUSIONS: Initiation of iGlarLixi resulted in similar TIR, A1C, FPG, weight and hypoglycemia compared with the more affordable option of starting iGlar + gliclazide in adults of South Asian origin with T2D.

International comparison of glycaemic control in people with type 1 diabetes: an update and extension.

AIMS: To update and extend a previous cross-sectional international comparison of glycaemic control in people with type 1 diabetes. METHODS: Data were obtained for 520,392 children and adults with type 1 diabetes from 17 population and five clinic-based data sources in countries or regions between 2016 and 2020. Median HbA1c (IQR) and proportions of individuals with HbA1c < 58 mmol/mol (<7.5%), 58-74 mmol/mol (7.5-8.9%) and ≥75 mmol/mol (≥9.0%) were compared between populations for individuals aged <15, 15-24 and ≥25 years. Logistic regression was used to estimate the odds ratio (OR) of HbA1c < 58 mmol/mol (<7.5%) relative to ≥58 mmol/mol (≥7.5%), stratified and adjusted for sex, age and data source. Where possible, changes in the proportion of individuals in each HbA1c category compared to previous estimates were calculated. RESULTS: Median HbA1c varied from 55 to 79 mmol/mol (7.2 to 9.4%) across data sources and age groups so a pooled estimate was deemed inappropriate. OR (95% CI) for HbA1c < 58 mmol/mol (<7.5%) were 0.91 (0.90-0.92) for women compared to men, 1.68 (1.65-1.71) for people aged <15 years and 0.81 (0.79-0.82) aged15-24 years compared to those aged ≥25 years. Differences between populations persisted after adjusting for sex, age and data source. In general, compared to our previous analysis, the proportion of people with an HbA1c  < 58 mmol/l (<7.5%) increased and proportions of people with HbA1c ≥ 75 mmol/mol (≥9.0%) decreased. CONCLUSIONS: Glycaemic control of type 1 diabetes continues to vary substantially between age groups and data sources. While some improvement over time has been observed, glycaemic control remains sub-optimal for most people with Type 1 diabetes.

Immunogenicity and Safety of a 3-Antigen Hepatitis B Vaccine vs a Single-Antigen Hepatitis B Vaccine: A Phase 3 Randomized Clinical Trial.

Importance: There is a need for improved immunogenicity of hepatitis B virus (HBV) vaccines among young adults with risk of infection. Objectives: To demonstrate manufacturing equivalence of a 3-antigen (3A) HBV vaccine, evaluate noninferiority of seroprotection rate (SPR) of 3A-HBV vs single-antigen (1A) HBV after 2 and 3 vaccine doses, and compare safety and reactogenicity between 3A-HBV and 1A-HBV vaccines. Design, Setting, and Participants: This phase 3, double-blinded, randomized clinical trial included healthy adults aged 18 to 45 years randomized to 1 of three 3A-HBV groups or 1 control group receiving 1A-HBV. The trial was conducted at 37 community clinics and academic hospitals in Canada, Europe, the United Kingdom, and the United States between December 2017 and October 2019. Participants were followed up for 48 weeks after the first vaccination. Interventions: Intramuscular administration of 3A-HBV (10 µg) or 1A-HBV (20 µg) on days 0, 28, and 168. Main Outcomes and Measures: Geometric mean concentration (GMC) of serum hepatitis B surface antibodies (anti-HBs) and proportion of participants achieving seroprotection. Results: Of 2838 participants, 1638 (57.8%) were women, 2595 (91.5%) were White, and 161 (5.7%) were Black or African American. A total of 712 participants (25.1%) were randomized to the 1A-HBV group and 2126 (74.9%) to 3A-HBV. The mean (SD) age at informed consent was 33.5 (8.0) years. The study demonstrated 3A-HBV lot-to-lot consistency, as the 2-sided 95% CIs for each pairwise comparison for the anti-HBs GMC ratios were within 0.67 and 1.50 (eg, adjusted GMC ratio, lot A vs lot B: 0.82; 95% CI, 0.67-1.00; lot A vs lot C: 0.95; 95% CI, 0.78-1.15; lot B vs lot C: 1.16; 95% CI, 0.95-1.41). The SPR of the pooled 3A-HBV was noninferior to 1A-HBV and higher than 1A-HBV after 2 vaccinations at day 168 (90.4% [95% CI, 89.0%-91.8%] vs 51.6% [95% CI, 47.5%-55.6%]) and 3 vaccinations at day 196 (99.3% [95% CI, 98.7%-99.6%] vs 94.8% [95% CI, 92.7%-96.4%]). The mean GMC of anti-HBs with 3A-HBV was 7.9 times higher after 2 vaccinations at day 168 and 3.5 times higher after 3 vaccinations at day 196 compared with 1A-HBV (after 2 vaccinations, 3A-HBV: GMC, 118.7 mIU/mL; 95% CI, 108.0-129.0 mIU/mL; SE, 1.0 mIU/mL; 1A-HBV: GMC, 15.0 mIU/mL; 95% CI, 12.9-17.5 mIU/mL; SE, 1.0 mIU/mL; after 3 vaccinations, 3A-HBV: GMC, 5442.4 mIU/mL; 95% CI, 4967.0-5963.0 mIU/mL; SE, 1.0 mIU/mL; 1A-HBV: 1567.2 mIU/mL; 95% CI, 1338.0-1834.0 mIU/mL; SE, 1.0 mIU/mL). Rates of local and systemic reactogenicities were higher with 3A-HBV compared with 1A-HBV (local: 1805 of 2124 [85.0%] vs 469 of 712 [65.9%]; systemic: 1445 [68.0%] vs 428 [60.1%]). Vaccine discontinuation due to adverse events (AE) was uncommon, and serious AEs were infrequent, reported in 42 participants (2.0%) and 3 participants (0.4%) in the 3A-HBV and 1A-HBV groups, respectively. Conclusions and Relevance: In this study, consistently higher antibody concentrations and SPRs were found with 3A-HBV after 2 and 3 doses vs 1A-HBV in adults aged 18 to 45 years old. The safety and efficacy of 3A-HBV shows its usefulness for the prevention of hepatitis B in young healthy adults. Trial Registration: Clinicaltrials.gov Identifier: NCT03408730; EU Clinical Trials Number: 2017-001820-22.

Prevalence and Risk Evaluation of Diabetic Complications of the Foot Among Adults With Type 1 and Type 2 Diabetes in a Large Canadian Population (PEDAL Study).

OBJECTIVES: The lower limb complications of diabetes contribute significantly to patient morbidity and health-care costs in Canada. Despite practice guidelines, awareness of and screening for modifiable early pathologies has been inconsistent. Our study objective was to determine the prevalence and types of early foot pathology in a large, Canadian, community care-based diabetes population. METHODS: This study was a retrospective, observational analysis of the LMC Diabetes & Endocrinology foot care program launched in 2017. We examined foot pathologies associated with vascular, nerve, nail and dermatologic complications, as well as foot deformities. Individuals ≥18 years of age with diabetes, assessed by an LMC chiropodist in Ontario between February 2018 and April 2019, were included in the analysis. RESULTS: Of the 5,084 individuals assessed, 470 with type 1 diabetes and 3,903 with type 2 diabetes met the study criteria. Mean age, body mass index and diabetes duration were 61.5 years, 31.3 kg/m2 and 13.9 years, respectively. Reduced pedal pulses, sensory neuropathy and onychomycosis were reported in 8.9%, 16.7% and 14.5% of those in the type 1 diabetes group, and in 19.4%, 26.6% and 28.7% of those in the type 2 group, respectively. Hyperkeratosis was present in 51% and foot deformities were present in 44.5% among both groups. Foot ulcer prevalence was 1.7%, and pedal pulses, sensory neuropathy, hyperkeratosis and onychauxis, adjusted for age, sex, body mass index and diabetes duration, were each significantly associated with ulceration. CONCLUSIONS: In a large foot screening program of community-based adults with diabetes, modifiable early foot pathologies were prevalent and provided further evidence of the value of consistent screening to alleviate the morbidity and economic burden of lower limb complications.

Reliability and validity of the Chinese version of the LMC Skills, Confidence & Preparedness Index (SCPI) in patients with type 2 diabetes.

BACKGROUND: A variety of diabetes self-management instruments have been developed but few of them consist of the preparedness for diabetes self-management behavior. The novel psychometric evaluation tool "the LMC Skills, Confidence & Preparedness Index (SCPI)" measures three key aspects of a patient's diabetes self-management: knowledge of the skill, confidence in being able to perform skill and preparedness to implement the skill. The objective of this study was to translate, adapt and validate the SCPI for use in Chinese adult patients with type 2 diabetes. METHODS: This study followed the guideline recommended by the American Academy of Orthopaedic Surgeons Evidence Based Medicine Committee (AAOS) to indigenize the scale. Forward and back translation, and cross-cultural language debugging were completed according to the recommended steps. A convenience sample of Chinese patients with type 2 diabetes (n = 375) were recruited from a university-affiliated hospital in Shanghai. The validity (criterion, discriminant validity, and construct validity), reliability (internal consistency and test-retest reliability) and the interpretability of the instrument were examined. The content validity was calculated by experts' evaluation. RESULTS: The Chinese version of SCPI (C-SCPI) has good internal consistency with a Cronbach's alpha of 0.92. The ceiling effects of the preparedness subscales is 21%. The criterion validity of three dimensions of C-SCPI was established with significantly moderate correlations between the DKT, DES-SF and SDSCA (p < 0.05). The S-CVI of the whole scale was 0.83. Except for entry 21, the I-CVI values of all entries were greater than 0.78. The C-SCPI has also shown good discriminative validity with statistically significant differences between the patients with good and poor glycemic control. Confirmatory factor analysis showed that modified results indicate that the fitting degree of the model is good, χ2/df = 2.775, RMSEA = 0.069, CFI = 0.903, GFI = 0.873, TLI = 0.889, IFI = 0.904. The test-retest reliability coefficient was 0.61 (p < 0.01). CONCLUSION: We established a Chinese version of SCPI through translation and cross-cultural adaptation. The C-SCPI is reliable and valid for assessment of the level of self-management in Chinese patients with type 2 diabetes.

Dasiglucagon-A Next-Generation Glucagon Analog for Rapid and Effective Treatment of Severe Hypoglycemia: Results of Phase 3 Randomized Double-Blind Clinical Trial.

OBJECTIVE: To evaluate the efficacy and safety of dasiglucagon, a ready-to-use, next-generation glucagon analog in aqueous formulation for subcutaneous dosing, for treatment of severe hypoglycemia in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: This randomized, double-blind trial included 170 adult participants with type 1 diabetes, each randomly assigned to receive a single subcutaneous dose of 0.6 mg dasiglucagon, placebo, or 1 mg reconstituted glucagon (2:1:1 randomization) during controlled insulin-induced hypoglycemia. The primary end point was time to plasma glucose recovery, defined as an increase of ≥20 mg/dL from baseline without rescue intravenous glucose. The primary comparison was dasiglucagon versus placebo; reconstituted lyophilized glucagon was included as reference. RESULTS: Median (95% CI) time to recovery was 10 (10, 10) minutes for dasiglucagon compared with 40 (30, 40) minutes for placebo (P < 0.001); the corresponding result for reconstituted glucagon was 12 (10, 12) minutes. In the dasiglucagon group, plasma glucose recovery was achieved within 15 min in all but one participant (99%), superior to placebo (2%; P < 0.001) and similar to glucagon (95%). Similar outcomes were observed for the other investigated time points at 10, 20, and 30 min after dosing. The most frequent adverse effects were nausea and vomiting, as expected with glucagon treatment. CONCLUSIONS: Dasiglucagon provided rapid and effective reversal of hypoglycemia in adults with type 1 diabetes, with safety and tolerability similar to those reported for reconstituted glucagon injection. The ready-to-use, aqueous formulation of dasiglucagon offers the potential to provide rapid and reliable treatment of severe hypoglycemia.

The Canadian LMC Diabetes Registry: A Profile of the Demographics, Management, and Outcomes of Individuals with Type 1 Diabetes.

Objective: Clinical guidelines now define the standard of diabetes care, but few health care jurisdictions systematically assess their practicality and impact. The Canadian LMC Diabetes Registry includes the electronic health records of >50 endocrinologists in three provinces and provides quarterly real-time outcome reports to each endocrinologist. This retrospective cohort study aimed to characterize the demographics, treatment regimens, and outcomes of the type 1 diabetes (T1D) patient population in the registry. Research Design and Methods: Adults were included if they had a clinical diagnosis of T1D, had seen an LMC endocrinologist between July 1, 2015 and June 30, 2018, and had follow-up >6 months. This study is registered on clinicaltrials.gov (NCT04162067). Results: The resulting cohort included 3600 individuals with mean age of 43.9 ± 15.3 years and duration of diabetes of 21.5 ± 13.9 years. Mean hemoglobin A1C (HbA1c) was 8.1% ± 1.5% and only 22.5% had achieved HbA1c ≤7.0%. In each measure, individuals in younger cohorts showed poorer glycemic control than older cohorts. Within each age cohort, insulin pump users showed a lower mean HbA1c than those using multiple daily injections, especially in cohorts who were also not using a continuous glucose monitor. Overall, 63.1% reported at least weekly hypoglycemia, whereas 3.6% reported severe hypoglycemia ≥1 per year. Conclusions: Despite receiving care in an advanced well-resourced environment, within a public health care system, from specialists armed with regular patient outcomes feedback, most individuals with T1D are unable to achieve the goals recommended by clinical practice guidelines.

Semaglutide once weekly in people with type 2 diabetes: Real-world analysis of the Canadian LMC diabetes registry (SPARE study).

AIMS: To investigate real-world short-term clinical outcomes in adults with type 2 diabetes (T2D) who initiated semaglutide in a specialist endocrinology practice in Canada. MATERIALS AND METHODS: This study was a retrospective observational study using data from the Canadian LMC Diabetes Registry. Adults with T2D who were naïve to glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy, initiated semaglutide therapy as usual standard of care between February 2018 and February 2019, and maintained semaglutide therapy during follow-up, were eligible for analysis. The primary outcome was mean change in glycated haemoglobin (HbA1c) at 3- to 6-month follow-up. RESULTS: In the final analytical cohort (n = 937), there was a statistically significant mean ± SD reduction in HbA1c of -1.03 ± 1.24% (11.3 ± 13.6 mmol/mol, P < 0.001) and weight of -3.9 ± 4.0 kg (P < 0.001), with no significant change in self-reported incidence of hypoglycaemia. There was a significant reduction in HbA1c and weight regardless of number of co-therapies or semaglutide dose. However, adults using the 1.0-mg dose had a significantly greater reduction in HbA1c compared to adults using the 0.25- to 0.5-mg dose (between-group difference - 0.24 ± 0.06%, 2.6 ± 0.7 mmol/mol; P < 0.001). Adults using basal-bolus therapy required a significantly lower median total daily dose of insulin after adding semaglutide (0.82 vs. 0.93 U/kg; P < 0.001). CONCLUSIONS: This retrospective observational study demonstrated that GLP-1RA-naïve adults with T2D initiating semaglutide in a real-world clinical practice had a statistically and clinically significant reduction in HbA1c and body weight after 3 to 6 months, regardless of semaglutide dose or order of semaglutide therapy, with no significant change in reported incidence of hypoglycaemia.

Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes.

BACKGROUND: Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease. METHODS: In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m2 of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed. RESULTS: A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m2 in the allopurinol group and 67.3 ml per minute per 1.73 m2 in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m2 (95% confidence interval [CI], -1.9 to 1.9; P = 0.99). The mean decrease in the iohexol-based GFR was -3.0 ml per minute per 1.73 m2 per year with allopurinol and -2.5 ml per minute per 1.73 m2 per year with placebo (between-group difference, -0.6 ml per minute per 1.73 m2 per year; 95% CI, -1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups. CONCLUSIONS: We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.).

Validation of a type 1 diabetes algorithm using electronic medical records and administrative healthcare data to study the population incidence and prevalence of type 1 diabetes in Ontario, Canada.

INTRODUCTION: We aimed to develop algorithms distinguishing type 1 diabetes (T1D) from type 2 diabetes in adults ≥18 years old using primary care electronic medical record (EMRPC) and administrative healthcare data from Ontario, Canada, and to estimate T1D prevalence and incidence. RESEARCH DESIGN AND METHODS: The reference population was a random sample of patients with diabetes in EMRPC whose charts were manually abstracted (n=5402). Algorithms were developed using classification trees, random forests, and rule-based methods, using electronic medical record (EMR) data, administrative data, or both. Algorithm performance was assessed in EMRPC. Administrative data algorithms were additionally evaluated using a diabetes clinic registry with endocrinologist-assigned diabetes type (n=29 371). Three algorithms were applied to the Ontario population to evaluate the minimum, moderate and maximum estimates of T1D prevalence and incidence rates between 2010 and 2017, and trends were analyzed using negative binomial regressions. RESULTS: Of 5402 individuals with diabetes in EMRPC, 195 had T1D. Sensitivity, specificity, positive predictive value and negative predictive value for the best performing algorithms were 80.6% (75.9-87.2), 99.8% (99.7-100), 94.9% (92.3-98.7), and 99.3% (99.1-99.5) for EMR, 51.3% (44.0-58.5), 99.5% (99.3-99.7), 79.4% (71.2-86.1), and 98.2% (97.8-98.5) for administrative data, and 87.2% (81.7-91.5), 99.9% (99.7-100), 96.6% (92.7-98.7) and 99.5% (99.3-99.7) for combined EMR and administrative data. Administrative data algorithms had similar sensitivity and specificity in the diabetes clinic registry. Of 11 499 711 adults in Ontario in 2017, there were 24 789 (0.22%, minimum estimate) to 102 140 (0.89%, maximum estimate) with T1D. Between 2010 and 2017, the age-standardized and sex-standardized prevalence rates per 1000 person-years increased (minimum estimate 1.7 to 2.56, maximum estimate 7.48 to 9.86, p<0.0001). In contrast, incidence rates decreased (minimum estimate 0.1 to 0.04, maximum estimate 0.47 to 0.09, p<0.0001). CONCLUSIONS: Primary care EMR and administrative data algorithms performed well in identifying T1D and demonstrated increasing T1D prevalence in Ontario. These algorithms may permit the development of large, population-based cohort studies of T1D.

Goal achievement of HbA1c and LDL-cholesterol in a randomized trial comparing colesevelam with ezetimibe: GOAL-RCT.

AIM: To compare the efficacy and safety of colesevelam and ezetimibe as second-line low density lipoprotein-cholesterol (LDL-c)-lowering options in type 2 diabetes (T2D). MATERIALS AND METHODS: GOAL-RCT is a 24-week, open-label, randomized, pragmatic clinical trial. Subjects with T2D with uncontrolled HbA1c (7.1%-10%) and LDL-c (>2.0 mmol/L) were randomized 1:1 to colesevelam 3.75 g or ezetimibe 10 mg daily. The primary composite outcome was the proportion of participants achieving an LDL-c target of ≤2.0 mmol/L and HbA1c target of ≤7.0%. Intention to treat analysis was performed. RESULTS: Two hundred subjects were enrolled: mean age 59 ± 10 years; mean HbA1c 8.0%; mean LDL-c 2.5 mmol/L; 97% on statin therapy. The primary composite outcome was achieved by similar proportions of participants with colesevelam (14.6%) and ezetimibe (10.5%) (Pnon-inferiority < .001, Psuperiority = .41). LDL-c reduction from baseline was less with colesevelam compared with ezetimibe (14.0% vs. 23.2%, P < .01), as was the proportion of subjects achieving an LDL-c target of ≤2.0 mmol/L (47.6% and 67.0%, respectively; P = .007). Mean HbA1c was reduced with colesevelam (-0.26 ± 0.10%), while no change was observed with ezetimibe (difference P = .06). Adverse events and discontinuation rates were higher for colesevelam (20.2% and 31.1%) compared with ezetimibe (7.2% and 6.2%), respectively. CONCLUSIONS: Among subjects with T2D, the initiation of colesevelam or ezetimibe led to similar achievement of primary composite outcome (LDL-c and HbA1c within target), with ezetimibe recording a greater LDL-c reduction and better tolerability than colesevelam.

Remission of Type 2 Diabetes Following a Short-term Intervention With Insulin Glargine, Metformin, and Dapagliflozin.

OBJECTIVE: To examine diabetes remission following a short-term intensive metabolic intervention combining lifestyle and glucose-lowering approaches. METHODS: We conducted an open-label, randomized controlled trial in 154 patients with type 2 diabetes up to 8 years in duration on 0 to 2 glucose-lowering medications. Participants were randomized to (a) a 12-week intensive intervention comprising lifestyle approaches and treatment with insulin glargine, metformin, and dapagliflozin or (b) standard diabetes care. At 12 weeks, diabetes medications were discontinued in participants with hemoglobin A1c (HbA1C) < 7.3% (56 mmol/mol). Participants were then followed for diabetes relapse until 64 weeks. The primary outcome was complete or partial diabetes remission (HbA1C < 6.5% [48 mmol/mol] off chronic diabetes drugs) at 24 weeks. Main secondary outcomes were complete or partial diabetes remission at 36, 48, and 64 weeks. RESULTS: The primary outcome was achieved in 19 (24.7%) intervention group participants and 13 (16.9%) control group participants at 24 weeks (relative risk [RR] 1.5; 95% confidence interval [CI], 0.8-2.7). The relative risks of remission at 36, 48, and 64 weeks were 2.4 (95% CI, 1.2-5.0), 2.1 (95% CI, 1.0-4.4), and 1.8 (95% CI, 0.7-4.7), respectively. In an exploratory analysis, the intervention reduced the hazard of diabetes relapse with overt hyperglycemia by 43% (hazard ratio 0.57; 95% CI, 0.39-0.81). CONCLUSIONS: Our primary outcome of diabetes remission at 24 weeks was not statistically significantly different. However, our overall results suggest that some patients with early type 2 diabetes are able to achieve sustained diabetes remission following a short-term intensive intervention. Further studies are needed to optimize the combined therapeutic approach used.

Flexible insulin therapy with a hybrid regimen of insulin degludec and continuous subcutaneous insulin infusion with pump suspension before exercise in physically active adults with type 1 diabetes (FIT Untethered): a single-centre, open-label, proof-of-concept, randomised crossover trial.

BACKGROUND: People with type 1 diabetes who use continuous subcutaneous insulin infusion (CSII, or insulin pump therapy) often remove their pump before extended periods of exercise, but this approach might result in reduced glycaemic control and increased risk of hyperglycaemia and ketogenesis. We aimed to assess the efficacy and safety of a hybrid approach, in which basal insulin delivery was divided between CSII and a daily injection of insulin degludec. METHODS: In this single-centre, open-label, proof-of-concept, randomised crossover trial done at the LMC Diabetes & Endocrinology research centre, we recruited physically active and aerobically fit participants aged 18 years or older with type 1 diabetes who were using CSII. Participants were randomly assigned (1:1) by use of a computer-generated sequence to one of two sequences of either usual CSII, involving the continuation of the participant's usual CSII regimen, followed by crossover to hybrid CSII, in which the delivery of the participant's usual daily basal insulin dose was split (50% delivered by CSII and 50% delivered by a once-daily morning injection of 100 U/mL insulin degludec), or the opposite sequence (ie, hybrid CSII followed by crossover to usual CSII). Treatment was not masked to the investigators or participants. For each intervention, participants completed a moderate-intensity and a high-intensity in-clinic exercise session in the first week, followed by four high-intensity and two moderate-intensity home-based exercise sessions in the subsequent 3 weeks. Insulin pumps were suspended or disconnected 60 min before exercise and reconnected immediately after exercise during both treatment regimens. The coprimary outcomes were: (1) time spent in the target control range of 4·0-10·0 mmol/L blood glucose after high-intensity exercise, and (2) time spent in target control range of 4·0-10·0 mmol/L blood glucose after moderate-intensity exercise, measured by continuous glucose monitoring in the 6-h period from the start of the high-intensity and moderate-intensity in-clinic exercise sessions. Outcomes were assessed in a modified intention-to-treat population that included all participants who started both intervention phases and completed all of the in-clinic exercise visits. This trial is registered with ClinicalTrials.gov, NCT03838783, and is complete. FINDINGS: Between May 15, 2018, and March 5, 2019, we assessed 43 patients for eligibility, of whom 31 were randomly assigned to receive the usual CSII regimen (n=14) or hybrid CSII regimen (n=17) in the first phase (before crossover). The analysis population consisted of 24 participants who completed both study phases. Compared with the usual CSII regimen, participants on the hybrid CSII regimen had a significantly longer time in blood glucose range of 4-10 mmol/L during the 6-h period from the start of both moderate-intensity (mean difference 86 min [95% CI 61-147], p=0·005; percentage time in range 64% [SD 35] vs 40% [35]) and high-intensity in-clinic exercise session (60 min [11-109], p=0·01; 66% [32] vs 50% [27]). Participants on the hybrid CSII regimen also showed a higher time in blood glucose range of 4-10 mmol/L during home-based exercise sessions (mean difference 23 min [95% CI -1 to 46], p=0·055), with significantly lower time spent in hyperglycaemia than participants on the usual CSII regimen (mean difference 25 min [2-48], p=0·04). These exploratory outcomes also showed no significant difference in the amount of time spent in hypoglycaemia, nor the number of hypoglycaemic events, between the two interventions. There were three study-related adverse events reported with the usual CSII regimen (two hypotension events and one nausea event) and four with the hybrid CSII regimen (two hypotension events and two nausea events). INTERPRETATION: A hybrid regimen of injected insulin degludec and CSII (with pump removal during exercise) appears to be safe and effective in adults with type 1 diabetes who exercise regularly. This approach could offer improved glycaemic control immediately after exercise and should be further assessed in a larger-scale randomised trial. FUNDING: Novo Nordisk.

Screening and Treatment Outcomes in Adults and Children With Type 1 Diabetes and Asymptomatic Celiac Disease: The CD-DIET Study.

OBJECTIVE: To describe celiac disease (CD) screening rates and glycemic outcomes of a gluten-free diet (GFD) in patients with type 1 diabetes who are asymptomatic for CD. RESEARCH DESIGN AND METHODS: Asymptomatic patients (8-45 years) were screened for CD. Biopsy-confirmed CD participants were randomized to GFD or gluten-containing diet (GCD) to assess changes in HbA1c and continuous glucose monitoring over 12 months. RESULTS: Adults had higher CD-seropositivity rates than children (6.8% [95% CI 4.9-8.2%, N = 1,298] vs. 4.7% [95% CI 3.4-5.9%, N = 1,089], P = 0.035) with lower rates of prior CD screening (6.9% vs. 44.2%, P < 0.0001). Fifty-one participants were randomized to a GFD (N = 27) or GCD (N = 24). No HbA1c differences were seen between the groups (+0.14%, 1.5 mmol/mol; 95% CI -0.79 to 1.08; P = 0.76), although greater postprandial glucose increases (4-h +1.5 mmol/L; 95% CI 0.4-2.7; P = 0.014) emerged with a GFD. CONCLUSIONS: CD is frequently observed in asymptomatic patients with type 1 diabetes, and clinical vigilance is warranted with initiation of a GFD.