Basal Insulin Degludec and Glycemic Control Compared to Aspart Via Insulin Pump in Type 1 Diabetes (BIGLEAP): A Single-Center, Open-Label, Randomized, Crossover Trial

doi:10.1016/j.eprac.2021.11.001

Endocrine Practice

Volume 28, Issue 2, February 2022, Pages 165-172

https://doi.org/10.1016/j.eprac.2021.11.001 Get rights and content

Abstract

Objective

We compared the efficacy of the second-generation basal insulin degludec (IDeg) to that of insulin aspart via pump using continuous glucose monitoring in patients with well-controlled type 1 diabetes.

Methods

In this 40-week, single-center, randomized, crossover-controlled trial, adults with well-controlled type 1 diabetes (hemoglobin A1C of <7.5% [<58 mmol/mol]) (N = 52) who were using an insulin pump and continuous glucose monitoring were randomized to 1 of 2 treatments for a 20-week period: a single daily injection of IDeg with bolus aspart via pump or a continuous subcutaneous insulin infusion (CSII) with aspart, followed by crossover to the other treatment. The primary endpoint was time in range (70-180 mg/dL) during the final 2 weeks of each treatment period.

Results

Fifty-two patients were randomized and completed both treatment periods. The time in range for IDeg and CSII was 71.5% and 70.9%, respectively (P = .553). The time in level 1 hypoglycemia for the 24-hour period with IDeg and CSII was 2.19% and 1.75%, respectively (P = .065). The time in level 2 hypoglycemia for the 24-hour period with IDeg and CSII was 0.355% and 0.271%, respectively (P = .212), and the nocturnal period was 0.330% and 0.381%, respectively (P = .639). The mean standard deviation of blood glucose levels for the 24-hour period for IDeg and CSII was 52.4 mg/dL and 51.0 mg/dL, respectively (P = .294). The final hemoglobin A1C level for each treatment was 7.04% (53 mmol/mol) with IDeg, and 6.95% (52 mmol/mol) with CSII (P = .288). Adverse events were similar between treatments.

Conclusion

We observed similar glycemic control between IDeg and insulin aspart via CSII for basal insulin coverage in patients with well-controlled type 1 diabetes.

Introduction

Continuous subcutaneous insulin infusion (CSII) has become the “gold standard” for the management of type 1 diabetes. Clinical trials have demonstrated that CSII, compared with multiple daily insulin injections (MDI), improves glycemic control; may reduce the incidence of hypoglycemia; and improves patient satisfaction and quality of life.1, 2, 3 These trials compared MDI regimens using neutral protamine Hagedorn or first-generation basal insulin analogs with CSII. Insulin degludec (IDeg) is a second-generation ultralong-acting insulin analog with a flat, stable glucodynamic profile and a duration of action of >42 hours.⁴ In glucose clamp studies and across multiple clinical trials, IDeg has demonstrated lower intraindividual between-day variability and less hypoglycemia than insulin glargine U100 in type 1 and type 2 diabetes.⁵ To date, no study has compared CSII with MDI with IDeg. The purpose of this prospective, randomized crossover trial was to compare glycemic control assessed by continuous glucose monitoring (CGM) between 2 methods of basal insulin delivery: either a single daily injection of IDeg, or CSII with insulin aspart in people with type 1 diabetes with optimized glycemic control using open-loop CSII and CGM. Bolus insulin was delivered via pump in both treatment groups to isolate and compare basal insulin effects independent of bolus insulin delivery method.

Section snippets

Study Design and Patients

The BIGLEAP trial was a phase 4, single-center, open-label, randomized crossover-controlled, proof-of-concept trial of patients with well-controlled type 1 diabetes conducted at Mountain Diabetes and Endocrine Center, an outpatient private endocrinology practice and research center. A 2-period crossover trial design was chosen to best allow treatment comparisons in a specific study population (ie, device-experienced individuals with good baseline glycemic control). In a crossover trial,

Results

Fifty-nine patients were screened for eligibility, of whom 53 were randomized. Participants were randomly assigned to 1 of 2 treatment sequences: 25 patients were assigned to a single daily injection of IDeg with bolus insulin aspart administered via pump, and 28 patients were assigned to their usual CSII regimen, each for a 20-week treatment period. Each group then crossed over to the other treatment for a second 20-week period. Five patients withdrew prior to randomization, and 1 patient

Discussion

To the authors knowledge, the BIGLEAP trial is the first trial comparing IDeg as basal insulin in combination with bolus insulin aspart to open-loop CSII aspart via pump in patients with well-controlled type 1 diabetes in combination with CGM. This trial found that IDeg provided similar 24-hour glycemic control compared with CSII aspart in terms of TIR and overall and nocturnal hypoglycemia.

This study was designed and powered to evaluate the superiority, rather than the noninferiority, of IDeg

Conclusion

In this crossover trial of patients with well-controlled type 1 diabetes using CSII and CGM, the substitution of IDeg for continuously infused insulin aspart for basal insulin delivery resulted in comparable glycemic control with equally low overall and nocturnal hypoglycemia. This study should improve the confidence of health care providers and patients that IDeg is an acceptable basal insulin alternative to basal insulin delivered via insulin pump should patients need to discontinue using

Acknowledgment

We thank the study patients and clinical research coordinators who carried out this trial. We dedicate this study with love and gratitude to the memories of Dr Vernon Hendrix, who contributed to the study design and to Benjamin Lane who performed the statistical analysis of the study data. This work was supported by Novo Nordisk, Baegsvard, Denmark. Novo Nordisk had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

Author Contributions

W.L. designed the trial

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Cited by (3)

Continuous glucose monitoring and metrics for clinical trials: an international consensus statement
2023, The Lancet Diabetes and Endocrinology
Randomised controlled trials and other prospective clinical studies for novel medical interventions in people with diabetes have traditionally reported HbA_1c as the measure of average blood glucose levels for the 3 months preceding the HbA_1c test date. The use of this measure highlights the long-established correlation between HbA_1c and relative risk of diabetes complications; the change in the measure, before and after the therapeutic intervention, is used by regulators for the approval of medications for diabetes. However, with the increasing use of continuous glucose monitoring (CGM) in clinical practice, prospective clinical studies are also increasingly using CGM devices to collect data and evaluate glucose profiles among study participants, complementing HbA_1c findings, and further assess the effects of therapeutic interventions on HbA_1c. Data is collected by CGM devices at 1–5 min intervals, which obtains data on glycaemic excursions and periods of asymptomatic hypoglycaemia or hyperglycaemia (ie, details of glycaemic control that are not provided by HbA_1c concentrations alone that are measured continuously and can be analysed in daily, weekly, or monthly timeframes). These CGM-derived metrics are the subject of standardised, internationally agreed reporting formats and should, therefore, be considered for use in all clinical studies in diabetes. The purpose of this consensus statement is to recommend the ways CGM data might be used in prospective clinical studies, either as a specified study endpoint or as supportive complementary glucose metrics, to provide clinical information that can be considered by investigators, regulators, companies, clinicians, and individuals with diabetes who are stakeholders in trial outcomes. In this consensus statement, we provide recommendations on how to optimise CGM-derived glucose data collection in clinical studies, including the specific glucose metrics and specific glucose metrics that should be evaluated. These recommendations have been endorsed by the American Association of Clinical Endocrinologists, the American Diabetes Association, the Association of Diabetes Care and Education Specialists, DiabetesIndia, the European Association for the Study of Diabetes, the International Society for Pediatric and Adolescent Diabetes, the Japanese Diabetes Society, and the Juvenile Diabetes Research Foundation. A standardised approach to CGM data collection and reporting in clinical trials will encourage the use of these metrics and enhance the interpretability of CGM data, which could provide useful information other than HbA_1c for informing therapeutic and treatment decisions, particularly related to hypoglycaemia, postprandial hyperglycaemia, and glucose variability.
Are nocturnal hypoglycemia prevention strategies influenced by diabetes technology usage? A BETTER registry analysis
2022, Diabetes Research and Clinical Practice
Citation Excerpt :
CSII users relying on insulin adjustment was expected as CSII offers more flexibility for insulin delivery [26]. Although there is contradicting evidence supporting the superiority of CSII alone compared to MDI [26,27], coupling a CSII with an rtCGM device showed more promising results as AID has been reported to nearly eliminate NH occurrence amongst PWT1D [10,28]. Snacks containing a source of carbohydrates and protein are a widely used strategy for the prevention of NH; nevertheless, the optimal composition of this snack remains unknown [2,16,29,30], with little evidence to support the systematic use of this strategy to prevent NH amongst PWT1D using insulin analogs or CSII [10,16].
To assess the association of nocturnal hypoglycemia prevention strategies (NH-PS) and diabetes technology usage (insulin pump and/or continuous glucose monitors [CGM]) in people with type 1 diabetes (PWT1D).
Logistic regression models were used to describe associations between self-reported NH-PS and diabetes technology (pump with intermittently-scanned or real-time CGM (isCGM or rtCGM), or automated insulin delivery (AID)), hypoglycemia history, and fear of hypoglycemia (FOH).
Among 831 adults (65 % female, aged 44 ± 15 years, T1D duration 26 ± 15 years), 32 % reported HbA1c ≤ 7.0 %, 88 % used ≥ 1 diabetes technology, 66 % reported ≥ 1 symptomatic NH in the past month, and 64 % used ≥ 2 NH-PS. Compared to multiple daily injections (MDI) + capillary blood glucose (CBG), bedtime snack consumption was less likely among pump + isCGM (OR [95 %CI]: 0.55 [0.31, 0.98]), pump + rtCGM (0.40 [0.20, 0.81]), and AID (0.34 [0.17, 0.66]) users, while evening insulin basal reduction was associated with CSII + CBG (3.15 [1.25, 7.99]), pump + isCGM 4.00 [1.99, 8.01]), and pump + rtCGM 2.89 [1.28, 6.50] use. Elevated FOH was associated with snack consumption (1.37 [1.00, 1.89]), evening bolus insulin avoidance (1.77 [1.11, 2.83]), limiting exercise (2.50 [1.30, 4.82]), and limiting alcohol consumption (2.33 [1.15, 4.70]) as NH-PS.
Technology use and elevated FOH might influence PWT1D’ choice of NH-PS.
Glycemic variability: Measurement, target, impact on complications of diabetes and does it really matter?
2024, Journal of Diabetes Investigation

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Original ArticleBasal Insulin Degludec and Glycemic Control Compared to Aspart Via Insulin Pump in Type 1 Diabetes (BIGLEAP): A Single-Center, Open-Label, Randomized, Crossover Trial

Abstract

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Study Design and Patients

Results

Discussion

Conclusion

Acknowledgment

Author Contributions

Am J Med Sci

Endocr Pract

Lancet Diabetes Endocrinol

Lancet

Methods for Insulin Delivery and Glucose Monitoring: Comparative Effectiveness

Agency for Healthcare Research and Quality

A review of the pharmacological properties of insulin degludec and their clinical relevance

Clin Pharmacokinet

Comparative safety and efficacy of insulin degludec with insulin glargine in type 2 and type 1 diabetes: a meta-analysis of randomized controlled trials

Acta Diabetol

The two-period cross-over clinical trial

Br J Clin Pharmacol

Understanding and assessing the impact of treatment in diabetes: the treatment-related impact measures for diabetes and devices (TRIM-Diabetes and TRIM-Diabetes Device)

Health Qual Life Outcomes

Outcomes of using flash glucose monitoring technology by children and young people with type 1 diabetes in a single arm study

Pediatr Diabetes

REPLACE-BG: a randomized trial comparing continuous glucose monitoring with and without routine blood glucose monitoring in adults with well-controlled type 1 diabetes

Diabetes Care

The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus

N Engl J Med

In type 1 diabetic patients with good glycaemic control, blood glucose variability is lower during continuous subcutaneous insulin infusion than during multiple daily injections with insulin glargine

Diabet Med

Clinical review: Hypoglycemia with intensive insulin therapy: a systematic review and meta-analyses of randomized trials of continuous subcutaneous insulin infusion versus multiple daily injections

J Clin Endocrinol Metab

State of type 1 diabetes management and outcomes from the T1D Exchange in 2016-2018

Diabetes Technol Ther

Original Article
Basal Insulin Degludec and Glycemic Control Compared to Aspart Via Insulin Pump in Type 1 Diabetes (BIGLEAP): A Single-Center, Open-Label, Randomized, Crossover Trial