Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial

Summary

Background

As type 2 diabetes mellitus progresses, oral hypoglycaemic agents often fail to maintain blood glucose control and insulin is needed. We investigated whether the addition of once-daily insulin glargine is non-inferior to three-times daily prandial insulin lispro in overall glycaemic control in adults with inadequately controlled type 2 diabetes mellitus taking oral hypoglycaemic agents.

Methods

In the 44-week, parallel, open study that was undertaken in 69 study sites across Europe and Australia, 418 patients with type 2 diabetes mellitus that was inadequately controlled by oral hypoglycaemic agents were randomly assigned to either insulin glargine taken once daily at the same time every day or to insulin lispro administered three times per day. The primary objective was to compare the change in haemoglobin A_1c from baseline to endpoint (week 44) between the two regimens. Randomisation was done with a central randomisation service. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00311818.

Findings

205 patients were randomly assigned to insulin glargine and 210 to insulin lispro. Mean haemoglobin A_1c decrease in the insulin glargine group was −1·7% (from 8·7% [SD 1·0] to 7·0% [0·7]) and −1·9% in the insulin lispro group (from 8·7% [1·0] to 6·8% [0·9]), which was within the predefined limit of 0·4% for non-inferiority (difference=0·157; 95% Cl −0·008 to 0·322). 106 (57%) patients reached haemoglobin A_1c of 7% or less in the glargine group and 131 (69%) in the lispro group. In the glargine group, the fall in mean fasting blood glucose (−4·3 [SD 2·3] mmol/L vs −1·8 [2·3] mmol/L; p<0·0001) and nocturnal blood glucose (−3·3 [2·8] mmol/L vs −2·6 [2·9] mmol/L; p=0·0041) was better than it was in the insulin lispro group, whereas insulin lispro better controlled postprandial blood glucose throughout the day (p<0·0001). The incidence of hypoglycaemic events was less with insulin glargine than with lispro (5·2 [95% CI 1·9–8·9] vs 24·0 [21–28] events per patient per year; p<0·0001). Respective mean weight gains were 3·01 (SD 4·33) kg and 3·54 (4·48) kg. The improvement of treatment satisfaction was greater for insulin glargine than for insulin lispro (mean difference 3·13; 95% CI 2·04–4·22).

Interpretation

A therapeutic regimen involving the addition of either basal or prandial insulin analogue is equally effective in lowering haemoglobin A_1c. We conclude that insulin glargine provides a simple and effective option that is more satisfactory to patients than is lispro for early initiation of insulin therapy, since it was associated with a lower risk of hypoglycaemia, fewer injections, less blood glucose self monitoring, and greater patient satisfaction than was insulin lispro.

Funding

Sanofi-Aventis.

Introduction

The association between poor glycaemic control and the occurrence of microvascular and, to a lesser extent, macrovascular complications in patients with type 2 diabetes mellitus is well known.1, 2 Glycaemic control, preferably with haemoglobin A_1c concentrations less than 7% (optimally 6·5%), can substantially reduce the risk of such complications³ and is now recommended internationally for clinical practice.4, 5, 6 However, achieving and maintaining such a glycaemic target represents a major challenge when treating patients with type 2 diabetes. Despite decreasing haemoglobin A_1c concentrations initially with oral hypoglycaemic agents, secondary failure (haemoglobin A_1c >7%) occurs in 40–60% of patients after a few years of treatment,2, 7, 8 and supplementary insulin therapy becomes necessary to achieve and sustain good glycaemic control.4, 5, 6

Several barriers exist for the initiation and subsequent optimisation of insulin therapy, including the risk of hypoglycaemia⁹ and concern about daily injections¹⁰ or restrictions to lifestyle.¹¹ For example, the efficacy profiles of intermediate-acting human insulins are often associated with interprandial and nocturnal hypoglycaemia, and can thus hinder the achievement of good metabolic control.9, 12 New insulin analogues, both short acting and long acting, offer the possibility of reducing some of the drawbacks associated with conventional insulin preparations, including hypoglycaemia.¹³

The basal insulin analogue glargine has a long duration of action (about 24 h), with little or no discernible peak in insulin concentration in the blood and a lower variability between patients than there is with neutral protamine Hagedorn (NPH) insulin or ultralente insulin.14, 15, 16, 17 Furthermore, an injection of insulin glargine once a day can confer glycaemic control equivalent to NPH insulin in patients with type 2 diabetes mellitus,18, 19 but with a lower rate of hypoglycaemia.18, 19, 20, 21, 22 The short-acting insulin analogue lispro, which is given three times a day at mealtimes, also compares favourably with NPH insulin in terms of improvements in haemoglobin A_1c, and has similar rates of hypoglycaemia.²³ Until recently, opinion on how or when to start insulin treatment in type 2 diabetes mellitus was divided.⁶ However, combination therapy of oral hypoglycaemic agents with a basal insulin analogue like insulin glargine can be regarded as an effective first choice for introducing insulin as part of a stepwise approach, adapting to the progressive β-cell failure. The introduction of insulin glargine once a day (at bedtime or before breakfast) has several advantages, including a substantial improvement in glycaemic control, fewer episodes of hypoglycaemia than with conventional NPH insulin, a reduction of daily insulin requirements when combined with oral hypoglycaemic agents,18, 19, 20, 21, 22 and less weight gain.²⁴ The United Kingdom Insulin Initiation Study (UKIIS) group²⁵ and the International Diabetes Federation (IDF)⁵ concur with this regimen, which is well accepted in clinical practice.

However, there is ongoing debate as to whether and when it is most beneficial to treat patients: to target postprandial blood glucose concentrations with meal-related insulin, or continue to target fasting blood glucose concentrations with basal insulin that is restricted only by hypoglycaemia. Several studies have shown that fasting blood glucose concentrations correlate equivalently or better with overall glycaemic control on the basis of haemoglobin A_1c concentrations,26, 27, 28, 29 whereas others have shown that postprandial blood glucose concentrations are a better predictor of haemoglobin A_1c values and glycaemic control.23, 30 Monnier and colleagues³¹ provided an explanation for such opposing views by showing that postprandial blood glucose contributes more to glycaemic control in patients with mild or moderate hyperglycaemia than in those with poorly controlled diabetes mellitus, in whom fasting hyperglycaemia is the main contributor to overall hyperglycaemia.

The APOLLO study (A Parallel design comparing an Oral antidiabetic drug combination therapy with either Lantus once daily or Lispro at mealtime in type 2 diabetes patients failing Oral treatment) aimed to establish whether the addition of once-daily insulin glargine targeting fasting blood glucose is non-inferior to three-times daily prandial insulin lispro targeting postprandial blood glucose in overall glycaemic control in adults with inadequately controlled type 2 diabetes mellitus taking oral hypoglycaemic agents. In addition to glycaemic control, patient satisfaction with treatment is an important consideration in deciding between available treatments for this disease. Therefore we investigated whether people given insulin glargine plus oral hypoglycaemic agents were more satisfied with their treatment regimen than were those given insulin lispro plus oral hypoglycaemic agents.