Effect of insulin analogues on risk of severe hypoglycaemia in patients with type 1 diabetes prone to recurrent severe hypoglycaemia (HypoAna trial): a prospective, randomised, open-label, blinded-endpoint crossover trial

Summary

Background

Insulin analogues have been developed to reduce the risk of hypoglycaemia in patients with diabetes who require insulin-based treatment, but their effect on this endpoint in patients with type 1 diabetes complicated by recurrent severe hypoglycaemia is unknown. We compared the occurrence of severe hypoglycaemic episodes in such patients during treatment with insulin analogues or human insulin.

Methods

In this investigator-initiated, prospective, randomised, open-label, blinded-endpoint crossover trial at seven medical centres in Denmark, we recruited patients (aged ≥18 years) with type 1 diabetes (diagnosed for >5 years) who had reported two or more episodes of severe hypoglycaemia in the preceding year. Patients were randomly assigned (1:1) using computer-generated site-specific randomisation lists in blocks of four to treatment with basal-bolus therapy with either analogue insulin (detemir and aspart) or human insulin (human neutral protamine Hagedorn and human regular) in a balanced crossover design. A 1-year plus 1-year treatment period was specified, consisting of two 3-month run-in periods, each followed by a 9-month maintenance period. The primary endpoint was the number of validated episodes of severe hypoglycaemia (defined by need for treatment assistance from others) reported during the maintenance periods, analysed by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00346996.

Findings

Between May 9, 2007, and Oct 30, 2009, 159 patients were randomly assigned. 18 patients discontinued during the first run-in period, leaving 141 patients in the intention-to-treat population. 136 severe hypoglycaemic episodes were reported during treatment with human insulin and 105 episodes were reported during treatment with insulin analogues, resulting in an absolute rate reduction of 0·51 episodes (95% CI 0·19–0·84) per patient-year with insulin analogues. This result corresponds to a relative rate reduction of 29% (95% CI 11–48; p=0·010).

Interpretation

Treatment with insulin detemir and aspart in patients with type 1 diabetes and recurrent severe hypoglycaemia resulted in a clinically significant reduced rate of severe hypoglycaemia compared with human insulin. Patients with the greatest chance of benefitting from improved insulin therapy should be offered treatment with insulin analogues and be included in future trials of new insulins.

Funding

Novo Nordisk A/S.

Introduction

Hypoglycaemia is a common result of an imbalance between insulin action and glucose availability in people with type 1 diabetes. Severe hypoglycaemic events can lead to cognitive disruption, impaired self-care, and dependence on assistance from relatives or bystanders. Such episodes can cause social embarrassment, impair patients' quality of life by imposing restrictions on their daily activities (eg, on job opportunities or obtaining a driver's licence¹), lead to accidents, and contribute to excess mortality.² Severe hypoglycaemia is therefore a major concern both for patients with type 1 diabetes and their relatives,3, 4, 5 and is the main barrier to achieving recommended levels of glycaemic control in these patients.⁶

The frequency of severe hypoglycaemia in the general type 1 diabetic population has only been slightly reduced during the past few decades despite efforts to improve insulin replacement therapy through introduction of basal-bolus regimens,⁷ development of insulin analogues with action profiles resembling physiological insulin secretion patterns, and introduction of insulin delivery by insulin pumps.8, 9, 10, 11, 12, 13, 14 The incidence of severe hypoglycaemia is still above one episode per patient-year and up to one in five patients has recurrent severe hypoglycaemia (ie, more than one episode per year).11, 14, 15

The effect of insulin analogues on glycaemic control has been shown in randomised controlled trials (RCTs), mainly in terms of non-inferiority in treat-to-target trials with parallel-series design, and subsequently confirmed in meta-analyses.16, 17, 18 By contrast, their effect on the risk of severe hypoglycaemia is less clear because RCTs, by specifically excluding patients at high risk of severe hypoglycaemia, are generally underpowered to assess this endpoint, and hypoglycaemic safety endpoints are often less rigorously defined and validated than the main glycaemic endpoints.

The HypoAna trial aimed to investigate whether short-acting and long-acting insulin analogues—specifically insulin aspart and insulin detemir—can reduce the rate of severe hypoglycaemia in comparison with human insulins in patients with type 1 diabetes who are at high risk of such episodes.