ArticlesInsulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial
Introduction
The physiological replacement of insulin in patients with type 1 diabetes mellitus is challenging because exogenous insulin needs to cover both basal and meal-related (bolus) insulin requirements. In landmark trials, intensive basal-bolus therapy was successful in improving glycaemic control and reducing the risk of long-term complications that are associated with type 1 diabetes mellitus.1, 2
The American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) recommend a glycated haemoglobin (HbA1c) target of less than 7% (<53 mmol/mol), without substantial hypoglycaemia.3, 4 A history of hypoglycaemia and the fear of further episodes, particularly at night, can lead to poor adherence to treatment and compromise glycaemic control.5, 6, 7, 8 Nocturnal hypoglycaemia is associated with poor quality of sleep, decreased sense of wellbeing, fatigue, and reduced productivity.5, 7, 9, 10
The risk of hypoglycaemia is partly due to impaired protective endocrine and physiological responses but limitations in subcutaneous insulin delivery contribute substantially to hypoglycaemic risk. Subcutaneous absorption is not reproducible and insulin entry directly into the peripheral circulation (bypassing portal circulation) is not linked to glucose sensing. Insulin analogues have been developed to improve the physiological coverage of the need for insulin. Basal insulin analogues such as insulin glargine and insulin detemir have longer duration of action and lower risks of hypoglycaemia than neutral protamine Hagedorn insulin, especially at night.11 However, neither insulin reliably provides 24 h basal insulin replacement on all days in all patients with type 1 diabetes mellitus, and once-daily dosing with these analogues can be inadequate; thus, an insulin with a more predictable and longer duration of action is needed.12
Insulin degludec is an ultra-longacting insulin that is in clinical development. On subcutaneous injection, it forms a depot of soluble multihexamers from which insulin is slowly and continuously absorbed into the circulation.13 Pharmacokinetic data show that insulin degludec has a flat, stable profile at steady state and a terminal half-life of more than 25 h, which is twice that of insulin glargine, and a duration of action greater than 40 h.13, 14 In a phase 2 trial, glycaemic control with insulin degludec in patients with type 1 diabetes mellitus was similar to that with insulin glargine but the rate of hypoglycaemia was lower,15 perhaps because in pharmacodynamic studies the day-to-day variability with insulin degludec was four times lower.16
We compared the efficacy and safety of insulin degludec with that of insulin glargine, both administered once daily in a basal-bolus regimen with rapid-acting insulin aspart as meal-time insulin in participants with type 1 diabetes mellitus in this BEGIN Basal-Bolus Type 1 trial.
Section snippets
Study design and participants
In a 52 week, randomised, controlled, open-label, multinational, parallel design, treat-to-target, non-inferiority trial, participants with type 1 diabetes mellitus were given insulin degludec or insulin glargine, with insulin aspart as the meal-time insulin. The trial was undertaken at 79 sites that were university-affiliated, public and private hospitals and clinical research centres in six countries (France, Germany, Russia, South Africa, the UK, and the USA).
Adults (aged ≥18 years) who had
Results
626 of 629 participants who were randomly assigned to treatment between Sept 1, 2009, and Nov 8, 2010, were given one of the trial drugs, and most (404 [86%] of 472 in insulin degludec group and 137 [87%] of 157 in insulin glargine group) completed the trial (figure 1). The overall withdrawal pattern was similar in the two groups.
Baseline characteristics were representative of a population with type 1 diabetes mellitus with reasonably good glycaemic control (mean HbA1c 7·7%, 60·7 mmol/mol,
Discussion
Reduction in HbA1c concentration from baseline with insulin degludec and insulin glargine was similar, thus establishing non-inferiority of insulin degludec to insulin glargine in improving long-term glycaemic control in type 1 diabetes. Further evidence of improved glycaemic control with both insulins was the reduction in FPG and SMPG. Mean SMPG before breakfast was significantly lower with insulin degludec than with insulin glargine; reduction in laboratory-reported FPG tended to be greater
References (24)
- et al.
The impact of non-severe hypoglycemic events on work productivity and diabetes management
Value Health
(2011) - et al.
Recommendations for the design and optimization of immunoassays used in the detection of host antibodies against biotechnology products
J Immunol Methods
(2004) - et al.
Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes
N Engl J Med
(2005) 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
(1993)Standards of medical care in diabetes–2011
Diabetes Care
(2011)- et al.
Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes
Diabetes Care
(2009) - et al.
Impact of hypoglycaemia on quality of life and productivity in type 1 and type 2 diabetes
Curr Med Res Opin
(2005) How hypoglycaemia can affect the life of a person with diabetes
Diabetes Metab Res Rev
(2008)- et al.
Hypoglycemia unawareness is associated with reduced adherence to therapeutic decisions in patients with type 1diabetes: evidence from a clinical audit
Diabetes Care
(2009) - et al.
The continuous glucose monitoring system is useful for detecting unrecognized hypoglycemias in patients with type 1 and type 2 diabetes but is not better than frequent capillary glucose measurements for improving metabolic control
Diabetes Care
(2003)
Well-being, cerebral function, and physical fatigue after nocturnal hypoglycemia in IDDM
Diabetes Care
Hypoglycemia rates with basal insulin analogs
Diabetes Technol Ther
Cited by (314)
100 years of the commercialization of insulin: A race yet to end
2023, Medicina ClinicaScreening of glucose tolerance abnormalities and diabetes in people with cystic fibrosis: A French position
2023, Medecine des Maladies MetaboliquesEfficacy and safety of basal insulin degludec 100 IU/mL versus glargine 300 IU/mL for type 1 diabetes: The single-center INEOX randomized controlled trial
2023, Diabetes Research and Clinical PracticeInsulin therapy in type 1 diabetes: A continuing evolution
2023, Medecine des Maladies Metaboliques
- ‡
Members listed in appendix p 29