Insulin analogues and severe hypoglycaemia in type 1 diabetes☆
Introduction
People with type 1 diabetes are at daily risk of episodes of severe hypoglycaemia. The episodes are feared by the patients as much as becoming blind and losing kidney function due to diabetes [1], [2], they are associated with reduced quality of life [3], and may, although rarely, lead to permanent brain damage or death [4]. Moreover, mild episodes of hypoglycaemia and treatment of severe hypoglycaemic episodes contribute substantially to healthcare costs [5], [6]. The DCCT [7] showed a lower frequency of episodes of severe hypoglycaemia compared with earlier studies [1], [8], [9]. Participants in the DCCT study were, however, selected by excluding those who had a history of severe hypoglycaemia and a long duration of diabetes, which are known to increase the risk of severe hypoglycaemia [7], [9], [10]. Recent studies have shown that severe hypoglycaemia is still a major problem [11], [12].
Conventional insulins do not replicate the pattern of basal and postprandial endogenous secretion of insulin. Insulin analogues are modified human insulins developed to address this limitation. Their effect on haemoglobinA1c is comparable to those of human insulins [13], [14]. Theoretically, use of insulin analogues – as compared to conventional insulins – should provide a more predictable effect on blood glucose levels and therefore potentially decrease the risk of hypoglycaemia. Previous studies have reported lower risk of minor and nocturnal hypoglycaemia [15], however, the effect on severe hypoglycaemia remains tentative [13], [14], [16]. This is probably due to a consistent exclusion of high-risk subjects from clinical trials resulting in insufficient power to detect differences in frequencies of severe hypoglycaemia between treatments [15], [17], [18], [19].
The present study reports frequency of episodes of severe hypoglycaemia in clinical practice in a large unselected group of patients treated with insulin analogues, human insulin, or mixed regimens.
Section snippets
Patients
The study is a six-center cross-sectional questionnaire survey including patients with type 1 diabetes from five Danish general hospitals (Hillerød University Hospital, Odense University Hospital, Aarhus University Hospital, Hvidovre University Hospital, Bispebjerg University Hospital) and one diabetes center (Steno Diabetes Center). Data were collected between November 2006 and June 2007 with the purpose of recruiting subjects for a randomised trial investigating the effect of insulin
Patient population
Clinical characteristics of the patient population are presented in Table 1. The population consisted of 53% men, the mean age was 48 years and the mean duration of diabetes was 23 years. A majority of the patients reported normal (47%) or impaired (41%) awareness of hypoglycaemia, whereas 12% of patients were unaware.
Hypoglycaemic episodes
A total of 4579 episodes of severe hypoglycaemia were reported by 3813 patients during the preceding year, corresponding to an overall frequency of severe hypoglycaemia of 1.21 ±
Discussion
In our study we retrospectively recorded episodes of severe hypoglycaemia in a large unselected population of patients with type 1 diabetes. We found that frequencies of episodes of severe hypoglycaemia were significantly higher in patients treated with long-acting insulin analogues compared to those treated with long-acting human insulin, both in an adjusted and an unadjusted analysis. In an adjusted (but not an unadjusted) analysis use of short-acting insulin analogues was associated with
Conflict of interest
The authors have a competing interest to declare. H.B.-N. has received lecture fee from Novo Nordisk A/S. H.-H.P. owns stock options in Novo Nordisk A/S. B.T. served on advisory boards for Novo Nordisk. L.T. holds shares in NovoNordisk A/S. The authors declare no other conflict of interest.
Acknowledgments
Research nurses Mette Glindorf (Steno Diabetes Center), Pernille Banck-Petersen and Tove Larsen (Hillerød University Hospital), Ewa Romanszuk (Odense University Hospital), Karen Lund (Aarhus University Hospital), Merete Meldgaard (Hvidovre University Hospital) and Solvejg Janssen (Bispebjerg University Hospital) are thanked for their engagement in handling patients and correspondence. The excellent data handling is the work of Birthe Nielsen, Anne-Katrine Holstein and Christina Wieth (All Steno
References (24)
- et al.
Activity of angiotensin-converting enzyme and risk of severe hypoglycaemia in type 1 diabetes mellitus
Lancet
(2001) A review of human and analogue insulin trials
Diabetes Res Clin Pract
(2007)- et al.
Symptomatic hypoglycaemia in 411 type 1 diabetic patients
Diabet Med
(1991) - et al.
Concerns about hypoglycaemia and late complications in patients with insulin-treated diabetes
Eur Diabetes Nurs
(2007) - et al.
Insulin therapy and quality of life. A review
Diabetes Metab Res Rev
(2009) - et al.
Mortality, cardiovascular morbidity and possible effects of hypoglycaemia on diabetic complications
- et al.
Costs of managing severe hypoglycaemia in three European countries
J Med Econ
(2009) - et al.
Evaluating the cost-effectiveness of reduced mild hypoglycemia in subjects with type 1 diabetes treated with insulin detemir or NPH insulin in Denmark, Sweden, Finland and The Netherlands
Diabet Med
(2011) Hypoglycemia in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group
Diabetes
(1997)- et al.
Reduced awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic frequency and associated symptoms
Diabetes Care
(1995)
Frequency and morbidity of severe hypoglycaemia in insulin-treated diabetic patients
Diabet Med
Severe hypoglycaemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection
Diabetes Metab Res Rev
Cited by (55)
Hypoglycemia, insulin resistance, and cardiovascular disease: A possible link
2023, Metabolic Syndrome: From Mechanisms to InterventionsTop-down mass spectrometric immunoassay for human insulin and its therapeutic analogs
2018, Journal of ProteomicsThe potential for improvement of outcomes by personalized insulin treatment of type 1 diabetes as assessed by analysis of single-patient data from a randomized controlled cross-over insulin trial
2017, Diabetes Research and Clinical PracticeCitation Excerpt :The unexpected finding that the pre-study insulin regimen was not a predictor of the superior treatment in the study raises the question whether analog insulin is used optimally in clinical practice. The importance of this question is emphasized by the finding of a higher rate of severe hypoglycemia in subjects treated with analog insulin compared to human insulin in the screening of more than 3800 patients to identify candidates to the study [9]. We have previously suggested that this was most likely caused by confounding by indication as analog insulin in the early post-marketing phase was only reimbursed to patients with documented problematic hypoglycemia [9].
Effect of insulin analogues on frequency of non-severe hypoglycaemia in patients with type 1 diabetes prone to severe hypoglycaemia: The HypoAna trial
2016, Diabetes and MetabolismCitation Excerpt :As a consequence, the majority of non-severe hypoglycaemic events were considered asymptomatic. Accordingly, the 24-h rate of confirmed non-severe symptomatic hypoglycaemias (19.9 events/patient-year) in our present study was considerably lower than the rates reported among non-selected patients, which were in the range of 30 to 100 episodes/patient-year [1–3,12,13,19,20]. As for rates of asymptomatic events, these are potentially grossly underestimated as well, as the study protocol specified only two seven-point SMBG profiles per week and one monthly nocturnal measurement.
Managing hypoglycaemia
2016, Best Practice and Research: Clinical Endocrinology and Metabolism
- ☆
Grant support: This investigator-initiated study was supported by an unrestricted grant from Novo Nordisk A/S.