Effect of intensive insulin therapy on β-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial

Summary

Background

Early intensive insulin therapy in patients with newly diagnosed type 2 diabetes might improve β-cell function and result in extended glycaemic remissions. We did a multicentre, randomised trial to compare the effects of transient intensive insulin therapy (continuous subcutaneous insulin infusion [CSII] or multiple daily insulin injections [MDI]) with oral hypoglycaemic agents on β-cell function and diabetes remission rate.

Methods

382 patients, aged 25–70 years, were enrolled from nine centres in China between September, 2004, and October, 2006. The patients, with fasting plasma glucose of 7·0–16·7 mmol/L, were randomly assigned to therapy with insulin (CSII or MDI) or oral hypoglycaemic agents for initial rapid correction of hyperglycaemia. Treatment was stopped after normoglycaemia was maintained for 2 weeks. Patients were then followed-up on diet and exercise alone. Intravenous glucose tolerance tests were done and blood glucose, insulin, and proinsulin were measured before and after therapy withdrawal and at 1-year follow-up. Primary endpoint was time of glycaemic remission and remission rate at 1 year after short-term intensive therapy. Analysis was per protocol. This study was registered with ClinicalTrials.gov, number NCT00147836.

Findings

More patients achieved target glycaemic control in the insulin groups (97·1% [133 of 137] in CSII and 95·2% [118 of 124] in MDI) in less time (4·0 days [SD 2·5] in CSII and 5·6 days [SD 3·8] in MDI) than those treated with oral hypoglycaemic agents (83·5% [101 of 121] and 9·3 days [SD 5·3]). Remission rates after 1 year were significantly higher in the insulin groups (51·1% in CSII and 44·9% in MDI) than in the oral hypoglycaemic agents group (26·7%; p=0.0012). β-cell function represented by HOMA B and acute insulin response improved significantly after intensive interventions. The increase in acute insulin response was sustained in the insulin groups but significantly declined in the oral hypoglycaemic agents group at 1 year in all patients in the remission group.

Interpretation

Early intensive insulin therapy in patients with newly diagnosed type 2 diabetes has favourable outcomes on recovery and maintenance of β-cell function and protracted glycaemic remission compared with treatment with oral hypoglycaemic agents.

Funding

973 Programme from the Chinese Government, the Natural Science Foundation of Guangdong Province Government, Novo Nordisk (China), and Roche Diagnostics (Shanghai).

Introduction

The UK Prospective Diabetes Study1, 2 has shown that β-cell function progressively deteriorates over time in people with type 2 diabetes mellitus, irrespective of lifestyle and existing pharmacological interventions. Notwithstanding, continued effort has been directed toward β-cell preservation or rejuvenation in an attempt to change or at least delay the natural course of type 2 diabetes.³ Other studies have indicated that, in newly diagnosed patients, short-term intensive insulin therapies that target overall glycaemic control, such as multiple daily insulin injections (MDI) and continuous subcutaneous insulin infusion (CSII), could improve β-cell function and result in extended remissions in which only diet was needed to maintain normoglycaemia.3, 4, 5, 6, 7, 8 The results of our previous study⁷ also suggest that the improvement of β-cell function, especially the restoration of the first-phase insulin secretion, could be responsible for the remission. Still unclear, however, is whether this disease-modifying effect is due to insulin therapy itself or the effects of simply eliminating glucotoxicity by achieving excellent glycaemic control, and which kind of initiation of early intensive therapy would be more beneficial.

We therefore did a multicentre, randomised, parallel-group trial to assess the efficacy of short-term intensive insulin therapy (including MDI and CSII) compared with oral hypoglycaemic agents on glycaemic control, remission rate, and β-cell function in patients with newly diagnosed type 2 diabetes. Several indicies were used for assessment of β-cell insulin-secretory capacity, including: HOMA B, which represents basal β-cell function; the first-phase insulin secretion after a glucose challenge, which represents the acute insulin response; and the ratio of plasma proinsulin to immunoreactive insulin (PI/IRI), which indicates β-cell secretory quality.⁹