ArticlesOnce-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
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 A1c 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 A1c concentrations initially with oral hypoglycaemic agents, secondary failure (haemoglobin A1c >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 A1c, 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 A1c concentrations,26, 27, 28, 29 whereas others have shown that postprandial blood glucose concentrations are a better predictor of haemoglobin A1c 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.
Section snippets
Patients
The study was undertaken at 69 study sites across Europe and Australia between June 25, 2003, and May 31, 2005. Male and female patients were eligible for enrolment if they were aged between 18 and 75 years, had type 2 diabetes mellitus for 1 year or more with haemoglobin A1c concentrations between 7·5% and 10·5%, were on oral hypoglycaemic agents (excluding alpha-glucosidase inhibitors) for at least 6 months with stable doses for 3 months or more before study entry, had fasting blood glucose
Results
Figure 1 shows the trial profile. 412 patients were in the intention-to-treat population (204 in insulin glargine group and 208 in insulin lispro group). A total of 35 patients were excluded owing to major protocol deviations during the study (figure 1); thus the per-protocol population consisted of 377 patients (186 in insulin glargine group and 191 in insulin lispro group), who were included in our analyses.
Table 1 shows the demographics and baseline characteristics of the per-protocol and
Discussion
Our results suggest that treatment with once-daily insulin glargine is non-inferior to three-times daily insulin lispro in achieving overall glycaemic control as represented by haemoglobin A1c in patients with type 2 diabetes mellitus that is poorly controlled by oral hypoglycaemic agents. We noted similar significant reductions in haemoglobin A1c over the 44-week treatment period in both groups.
In practice, monotherapy fails to achieve or maintain the glycaemic target of haemoglobin A1c of 7%
References (48)
- et al.
Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study
Diabetes Res Clin Pract
(1995) - et al.
Efficacy comparison between preprandial and postprandial insulin aspart administration with dose adjustment for unpredictable meal size
Clin Ther
(2004) - et al.
Treatment regimen determines the relationship between depression and glycemic control
Diabetes Res Clin Pract
(2005) - et al.
Therapy in type 2 diabetes: insulin glargine vs. NPH insulin both in combination with glimepiride
Arch Med Res
(2006) - et al.
Negative binomial meta-regression of combined HbA1c and hypoglycemia outcomes across eleven phase III and IV studies of insulin glargine compared NPH insulin in Type 1 and Type 2 diabetes
Clin Ther
(2007) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)
Lancet
(1998)- et al.
Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study
BMJ
(2000) Standards of medical care in diabetes—2006
Diabetes Care
(2006)Global guideline for type 2 diabetes
(2005)- et al.
Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes
Diabetologia
(2006)
United Kingdom Prospective Diabetes Study (UKPDS). 13: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years
BMJ
Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group
JAMA
Hypoglycaemia: the limiting factor in the glycaemic management of type I and type II diabetes
Diabetologia
Evaluation of alternative strategies for optimizing glycemia: progress to date
Am J Med
Psychological insulin resistance in patients with type 2 diabetes
Diabetes Care
Hypoglycaemia, the most feared complication of insulin therapy
Diabete Metab
Treatment of the patient with diabetes: importance of maintaining target HbA(1c) levels
Curr Med Res Opin
Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro
Diabetes
Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique
Diabetologia
Time-action profile of the long-acting insulin analog insulin glargine (HOE901) in comparison with those of NPH insulin and placebo
Diabetes Care
Comparison of pharmacokinetics and dynamics of the long-acting insulin analogs glargine and detemir at steady state in type 1 diabetes: a double-blind, randomized, crossover study
Diabetes Care
The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients
Diabetes Care
Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. HOE 901/3002 Study Group
Diabetes Care
Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for type 2 diabetes
Diabetes Care
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These authors contributed equally