Background and Aims

URLi is a novel insulin lispro formulation developed to more closely match physiological insulin secretion. This Phase 3, 16-week, treat-to-target study evaluated efficacy and safety of URLi vs. Lispro in adults with T1D on CSII. Primary endpoint was HbA1c change from baseline.

Methods

After a 2-week lead-in on Lispro, patients were randomised to double-blind URLi (N=215) or Lispro (N=217). Two-week blinded continuous glucose monitoring (CGM) sessions were conducted prior to randomisation, and at weeks 8 and 16. Additionally, a standardised meal test was performed at randomisation and at week 16 to evaluate PPG control.

Results

Change from baseline to week 16 in HbA1c for URLi was non-inferior to Lispro: least squares mean (LSM) difference 0.3 mmol/mol (0.02%) with 95% CI of -0.6 to +1.2 mmol/mol (-0.06 to +0.11%). URLi was superior to Lispro in controlling 1- and 2-h PPG levels during the meal test (Figure). Compared to lispro, URLi resulted in significantly less percent time in hypoglycaemia (<3.0 mmol/L [54 mg/dL]) over the nighttime and 24-hour period: LSM difference -0.97% and -0.52%, respectively, both p<0.05. Time spent between 3.9-10.0 mmol/L (70-180 mg/dL) and in hyperglycaemia was similar between groups.

Incidence of treatment-emergent adverse events was higher with URLi (60.5% vs. 44.7%), primarily driven by infusion site reaction and infusion site pain. The rate and incidence of severe hypoglycaemia and diabetic ketoacidosis were similar between groups.

Conclusions

URLi was efficacious, providing superior PPG control and an acceptable safety profile compared to Lispro in patients with T1D on CSII.

Background and Aims

The clinical benefits of Insulin glargine 300U/mL (Gla-300), a second-generation basal insulin analog, have been confirmed in real-world studies in the US and Western Europe. However real-world effectiveness and safety of Gla-300 in wider geographic regions is needed. ATOS is a prospective, 12-month, observational study assessing real-world effectiveness and safety of Gla-300 in countries outside US and Western Europe.

Methods

Adults (≥18 years) with T2DM, uncontrolled (HbA_1c >7–≤11%) on ≥1 oral antihyperglycaemic drug (OAD) in whom the treating physician had decided to add Gla-300 were recruited from Asia, Middle East and Africa, Eastern Europe and Latin America.

Results

Overall, 4422 participants (51.8% females) were eligible. Mean (SD) age was 57.2 (10.8) years, duration of diabetes was 10.2 (6.2) years and baseline HbA_1c was 9.28 (1.00)%. Physician-set individualized HbA_1c(%) goals at baseline were <7: 13.7%; 7–<7.5: 70.4%; 7.5–<8: 11.8%; ≥8: 4.1%. The proportion of patients achieving their HbA_1c goal at Month 6 (primary endpoint) and Month 12 was 25.2% (95%CI: 23.8-26.6) and 44.5% respectively; HbA_1c reductions from baseline to Month 6 and 12 were -1.50 and -1.87 respectively. The documented hypoglycaemia incidence (<2%) and change in body weight (LSM, -0.1 (95%CI: -0.3-0.0) at Month 12) was low. Treatment-emergent adverse events (TEAEs) were reported in 283 (6.4%) patients, with 57 (1.3%) serious TEAEs.

Conclusions

In a real-life setting in countries outside US and Western Europe, initiation of Gla-300 in people with T2DM uncontrolled on OADs resulted in improved glycaemic control and low rates of hypoglycaemia with minimal weight change.

Data first submitted to AACE-GulfChapter 2020.

Background and Aims

To evaluate whether switching from traditional mealtime insulin analogs to fast-acting insulin aspart (Fiasp) in routine clinical practice is efficacious and safe in adult people with type 1 diabetes (PWD1) using intermittent or real-time continuous glucose monitoring (iCGM or rtCGM).

Methods

Data from 438 adult PWD1 (60% men, age 44.6±16.1 years, duration of diabetes 21.5±14.0 years, iCGM/rtCGM: 391/47, injections/pump: 409/29), initiating Fiasp between January 2018 and May 2020 were retrospectively analyzed. Primary endpoint was the evolution of time in range (TIR:70-180 mg/dl) at 12 months. Secondary endpoints included change in Time<70, Time<54, Time>180 and Time>250 mg/dl, coefficient of variation (CV), standard deviation (SD), HbA1c, insulin doses, and composite endpoint of reaching TIR>70% and Time<70 mg/dl of <4%.

Results

Time in range improved from 50.3±15.6% to 55.5±15.2% (p<0.0001), corresponding to an increase of 75 minutes/day. Time<70 mg/dl decreased from 7.4±5.5% to 6.8±5.5% (p=0.037), Time<54 mg/dl evolved from 3.1±3.3% to 2.5±3.0% (p=0.003), Time>180 mg/dl decreased from 42.3±16.7% to 37.7±16.9% (p<0.0001) and Time>250 mg/dl decreased from 16.5±12.8% to 13.1±12.5% (p<0.0001). Glucose variability also improved (CV from 41.9±7.0% to 40.3±6.9%, p=0.002 and SD from 72.7±18.0 to 65.8±18.5 mg/dl, p<0.0001). The number of people reaching the composite endpoint TIR>70% and Time<70 mg/dl of <4% increased from 36.1% to 42.6% (p=0.047). HbA1c (from 7.8±1.1% to 7.7±1.0%) and insulin doses (0.66±0.24 to 0.62±0.21 units/kg body weight/day) remained stable.

Conclusions

Switching to Fiasp resulted in a 75 min/day increase in TIR, in combination with less time spent below range in a real-world study of adult PWD1.

Background and Aims

Nasal glucagon (NG), a ready-to-use drug-device combination for treatment of severe hypoglycaemia, contains 3 mg glucagon dry powder that is absorbed passively through nasal mucosa. We examined the efficacy and safety of NG compared to 1 mg injectable glucagon (IG) in reversing insulin-induced hypoglycaemia in a global population of adults with type 1 diabetes (T1D) and type 2 diabetes (T2D.). Notably, this is the first analysis including pooled T2D data.

Methods

Post-hoc analyses used data from 3 randomised, cross-over studies. Treatment success was defined as an increase in blood glucose to ≥3.9 mmol/L (70 mg/dL) or an increase of ≥1.1 mmol/L (20 mg/dL) from nadir blood glucose within 30 min of receiving glucagon. Tolerability was assessed using treatment-emergent adverse events and a symptom questionnaire.

Results

In the T1D+T2D pooled analysis, 99.5% (213/214) of NG and 100% (214/214) of IG administrations achieved treatment success in a mean (median) time of 13 (10) minutes and 11 (10) minutes, respectively. The times (mean [median]) for achieving treatment success for participants with T2D (N=41) were similar for NG (12 [10] minutes) and IG (11 [10] minutes). NG and IG induced similar blood glucose changes (figure). NG and IG had similar incidences of nausea and vomiting, with NG having a higher rate of side effects related to nasal administration [headache (13% NG, 7% IG), nasal discomfort (4% NG, 1% IG), etc.]. Separate T1D and T2D analyses showed similar results as T1D+T2D.

Conclusions

NG was efficacious and well-tolerated in reversing insulin-induced hypoglycaemia in adults with T1D and T2D.

Background and Aims

Insulin has been used to treat diabetes for 100 years but current insulin formulations are too slow to maintain tight glycemic control at mealtimes. We have developed a new class of amphiphilic copolymers as stabilizing agents for insulin formulations, enabling the development of an ultrafast acting monomeric insulin lispro (UFAL) formulation with the potential to improve glucose control and reduce burden for patients with diabetes.

Methods

We compared the pharmacokinetics of UFAL to Humalog using a pig model of insulin-deficient diabetes where plasma lispro concentrations were determined by ELISA on collected blood samples after subcutaneous administration. For analysis of pharmacokinetic parameters, pharmacokinetic curves were coded and were analyzed by a blinded researcher.

Results

We show that UFAL remains stable for 25±1 hours under stressed aging conditions that cause Humalog to aggregate in only 5±2 hours. In diabetic pigs, peak insulin exposure was determined to be 9±4 min for UFAL and 25±10 min for Humalog. Pharmacokinetic modeling based on the pig data predicts peak exposure in humans to be at 10 min for UFAL and 43 min for Humalog, in excellent agreement with human clinical data for Humalog, suggesting that UFAL may have unprecedented pharmacokinetics for an injectable formulation.

Conclusions

The ultrafast pharmacokinetics observed for UFAL coupled with the dramatically improved stability over current insulin formulations are highly distinguishing for compatibility with pump and closed-loop systems. Our stable ultrafast insulin formulation has the potential to improve diabetes management and reduce patient burden around mealtime glucose management.

Background and Aims

Dapagliflozin is approved in the EU for patients with type 1 diabetes (T1D) with BMI ≥ 27 kg/m². Our aim was to evaluate its safety and efficacy on standardized CGM metrics in T1D patients using CGM.

Methods

We conducted a prospective study including all T1D patients with BMI ≥ 27 kg/m² using CGM who were precribed dapagliflozin 5 mg daily and were followed for at least 6 months. Education concerning ketosis prevention was given to all patients before initiating dapagliflozin. Weight, standardized CGM metrics and ketosis episodes were registered before and after 3 and 6 months of treatment. Data were analyzed with univariate repeated-measures ANOVA using SPSS Statistics.

Results

13 patients were included from November 2019 to July 2020: 5 were male and 8 female, 9 on insulin pump and 4 on multiple dose injections, 8 on real-time CGM and 5 on intermittently-scanned CGM, with baseline characteristics as follows: age 45.9±7.2 years, BMI 31±3.7 kg/m², HbA1c 7.5±0.7% and TIR 56.2±9.2%.

Medication was discontinued in 3 patients due to ketosis (n=2) and ketoacidosis (n=1). Patients who completed the 6 months period showed significant increase in TIR and a significant decrease in weight, BMI, TBR, TAR and CV, and a non-significant decrease in GMI and mean glucose (Table 1).

There were 8 ketotic decompensations and 1 ketoacidosis that required ICU care. 2 patients had mild urinary tract infections.

Conclusions

Dapagliflozin led to further improvement in CGM metrics in patients with T1D. Nevertheless, despite a structured ketone-prevention program, ketosis risk was increased.

Background and Aims

Multiple daily insulin injection (MDI) regimens in type 2 diabetes (T2D) can provide optimal glycemic control but cause significant treatment burden, hence simpler therapies with similar efficacy are needed. Our preliminary 3-month follow-up data showed that switching from MDI to once daily IDegLira, a fixed-ratio combination of insulin degludec and liraglutide, in relatively well-controlled (HbA1c<7.5%) subjects with T2D using low total daily insulin dose is safe and provides similar or better glycemic control. Our aim was to confirm the sustained efficacy and safety of the simplified treatment during a 12-month follow-up.

Methods

72 adults with T2D (mean±SD: age 63.8±9.5 years, HbA1c 6.36±0.70%, BMI 33.01±6.47kg/m², body weight 92.95±18.83kg, total daily insulin dose: 43.2±10.8 units, duration of diabetes 9.7±7.5 years) treated with MDI±metformin participated in our study. Previous insulins were stopped and once daily IDegLira was started. IDegLira was titrated by the patients every 3 days with 2 dosage units to achieve a self-measured pre-breakfast plasma glucose concentration of <6mmol/L.

Results

After 12-month of follow-up good glycemic control was maintained, while body weight and BMI decreased significantly. Mean HbA1c changed by -0.15% to 6.21±0.82% (p= 0.109), body weight changed by -3.89kg to 89.06±18.61kg (p<0.0001) and BMI changed to 31.61±6.22kg/m². The simplified treatment was safe and well-tolerated. Percentage of patients experiencing hypoglycemia was 49% during the month before simplification and 17% during the last 3 months of the follow-up.

Conclusions

Our 12-month data confirm that insulin-therapy simplification with IDegLira in patients with well-controlled T2D is safe, may induce weight loss and results in similar glycemic control.

Background and Aims

Pramlintide improves PPG through delaying gastric emptying, reducing glucagon secretion, and promoting satiety. ADO09 is a stable co-formulation of pramlintide and insulin A21G under development. This double-blind, randomised, 2-period cross-over trial compared pre-meal ADO09 versus insulin aspart over 24 days in 28 T1D participants.

Methods

During a 28 days run-in period, basal insulin was switched to insulin degludec. The cross-over treatment periods consisted of 3 inpatient days (baseline assessments), followed by 3 outpatient weeks and a final inpatient mixed-meal-tolerance-test (MMTT) on day 24. Blood glucose, glucagonemia and kinetics of gastric emptying were analyzed, as were CGM-metrics. The two treatment periods were separated by a 5 to 7 day washout.

Results

Incremental plasma glucose AUCs during MMTT with ADO09 were reduced by >100% after 2h (p<0.001) and by 39% after 4h (not significant), gastric emptying was slower (Tmax +312%, p<0.0001) and glucagon suppressed by 78% over 0-2h (p<0.0001) versus insulin aspart. ADO09 showed improved CGM-metrics in the outpatient period with higher Time-In-Range (+51 min, p=0.01). Time <70 mg/dL was slightly higher (+9.6 min, p=0.046) as were hypoglycemic events (142 vs. 115). ADO09 reduced body weight (-0.7kg vs baseline, p=0.01). Mean daily ADO09 doses were lower than insulin aspart’s (17 vs 22 U, p<0.0001). Both treatments were well tolerated with more, but transient gastrointestinal adverse events (24 vs 6) with ADO09, consistent with the known side effect profile of pramlintide.

Conclusions

ADO09 was well tolerated and significantly improved post-prandial blood glucose control, CGM-metrics, weight control and bolus insulin needs versus insulin aspart over 24 days.

Background and Aims

We have previously shown an association between the HLA haplotype DR3-DQ2 and a positive treatment effect of GAD-alum in individuals recently diagnosed with type 1 diabetes. In this study we sought to further investigate the influence of HLA, number of injections and administration route on the clinical effect of GAD/alum treatment.

Methods

We combined individual-level data (n=627) from four placebo controlled randomized clinical trials of both subcutaneous and intralymphatic GAD-alum immunotherapy. We estimated the treatment effect at 15 months from baseline on C-peptide retention, HbA1c, insulin dose and insulin adjusted HbA1c (IDAA1c) using a mixed model repeated measures model including terms for HLA subgroup and number of doses. The effect of administration route was evaluated using a Bayesian model.

Results

A significant treatment effect was seen in individuals carrying HLA DR3-DQ2 (n=313), with the best effect seen in those receiving three-four doses showing an effect ratio of 1.48 (adjusted P<0.0001) on preserving C-peptide compared to 1.21 (p=0.092) for those receiving two doses. A lower HbA1c was also seen in the three-four dose group compared to placebo (-4.74mmol/mol, adjusted P<0.01). Despite using only 1/5 of the dose, there was a 98%, 99%, 71% and 97% probability that three intralymphatic injections were superior to three subcutaneous injections for C-peptide retention, HbA1c, insulin dose and IDAA1c, and safety profiles were comparable.

Conclusions

These analyses highlight the importance of genetics, dosing regimen, and administration route in immunotherapeutic treatment of type 1 diabetes and a clinically relevant potential for intralymphatic GAD-alum.