Short-term intensive insulin therapy in type 2 diabetes mellitus: a systematic review and meta-analysis

Summary

Background

Studies have shown that, when implemented early in the course of type 2 diabetes mellitus, treatment with intensive insulin therapy for 2–3 weeks can induce a glycaemic remission, wherein patients are able to maintain normoglycaemia without any anti-diabetic medication. We thus did a systematic review and meta-analysis of interventional studies to assess the effect of short-term intensive insulin therapy on the pathophysiological defects underlying type 2 diabetes mellitus (pancreatic β-cell dysfunction and insulin resistance) and identify clinical predictors of remission.

Methods

We identified studies published between 1950 and Nov 19, 2012, which assessed the effect of intensive insulin therapy on β-cell function or insulin resistance, or both, or assessed long-term drug-free glycaemic remission in adults aged 18 years or older with newly diagnosed type 2 diabetes mellitus. We calculated pooled estimates by random-effects model. This study is registered with International Prospective Register of Systematic Reviews, number CRD42012002829.

Findings

We identified 1645 studies of which seven fulfilled inclusion criteria (n=839 participants). Five studies were non-randomised. A pooled analysis of the seven studies showed a post-intensive insulin therapy increase in Homeostasis Model Assessment of β-cell function as compared with baseline (1·13, 95% CI 1·02 to 1·25) and a decrease in Homeostasis Model Assessment of Insulin Resistance (–0·57, −0·84 to −0·29). In the four studies that assessed glycaemic remission (n=559 participants), the proportion of participants in drug-free remission was about 66·2% (292 of 441 patients) after 3 months of follow-up, about 58·9% (222 of 377 patients) after 6 months, about 46·3% (229 of 495 patients) after 12 months, and about 42·1% (53 of 126 patients) after 24 months. Patients who achieved remission had higher body-mass index than those who did not achieve remission (1·06 kg/m², 95% CI 0·55 to 1·58) and lower fasting plasma glucose (–0·59 mmol/L, 95% CI −1·11 to −0·07) at baseline.

Interpretation

Short-term intensive insulin therapy can improve the underlying pathophysiology in early type 2 diabetes mellitus, and thus might provide a treatment strategy for modifying the natural history of diabetes.

Funding

None.

Introduction

Type 2 diabetes mellitus is a complex metabolic disorder, the pathophysiology of which is driven by two main defects: target-cell resistance to the activity of insulin (insulin resistance) and insufficient secretion of insulin by the pancreatic β cells to compensate for this peripheral tissue resistance (β-cell dysfunction).¹ Its natural history is characterised by the progressive deterioration of β-cell function over time, a pathological process that occurs irrespective of lifestyle and existing pharmacological interventions.2, 3 As a result, the typical clinical course of this disease consists of the sequential addition of anti-diabetic drugs over time, followed ultimately by insulin therapy when functional β-cell capacity deteriorates to the point at which glycaemic control can no longer be achieved without exogenous insulin supplementation.⁴ At this point in the progressive course of type 2 diabetes mellitus, insulin therapy is generally continued indefinitely thereafter.

In recent years, temporary administration of short-term intensive insulin therapy early in the course of type 2 diabetes mellitus has been a strategy of interest.⁵ Indeed, 2–3 weeks of intensive insulin therapy can induce a so-called glycaemic remission wherein patients are subsequently able to maintain normal glucose levels without any antidiabetic medication. Furthermore, studies⁶ have shown that this drug-free glycaemic remission can last up to 2 years in many patients, suggesting that short-term intensive insulin therapy could provide a strategy for modifying the natural history of the disease.⁶

Despite these promising results, the evidence base for early use of short-term intensive insulin therapy in type 2 diabetes mellitus remains scarce at this time, and data from individual studies might not be sufficient to show modification of the underlying pathophysiological changes or support the implementation of this therapy in clinical care. Thus, we did a systematic review and meta-analysis of interventional studies to determine (1) whether short-term intensive insulin therapy leads to improvement in β-cell function and insulin resistance in patients with newly diagnosed type 2 diabetes mellitus, and (2) whether baseline characteristics exist that can differentiate patients who will achieve glycaemic remission following short-term intensive insulin therapy from those who will not.