Once-daily prandial lixisenatide versus once-daily rapid-acting insulin in patients with type 2 diabetes mellitus insufficiently controlled with basal insulin: analysis of data from five randomized, controlled trials

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Abstract

Aims

To compare the efficacy and safety of lixisenatide (LIXI), a once-daily prandial glucagon-like peptide-1 (GLP-1) receptor agonist, as add-on to basal insulin (Basal + LIXI) versus once-daily rapid-acting insulin (Basal + RAI) in patients with type 2 diabetes mellitus (T2DM).

Methods

Data were extracted from five randomized controlled trials assessing the efficacy and safety of basal insulin + insulin glulisine (n = 3) or basal insulin + LIXI (n = 2). Patients in the Basal + LIXI cohort were matched to patients in the Basal + RAI cohort using propensity score matching.

Results

In the matched population, Basal + LIXI was twice as likely to reach composite outcomes of glycated haemoglobin (HbA1c) < 7% and no symptomatic hypoglycaemia compared with the Basal + RAI group (odds ratio [OR]: 1.90; 95% confidence interval [CI]: 1.01, 3.55; P = 0.0455), as well as HbA1c < 7% and no severe hypoglycaemia (OR: 1.97; 95 CI: 1.06, 3.66; P = 0.0311). Furthermore, Basal + LIXI was more than twice as likely to reach HbA1c < 7%, no weight gain and no symptomatic hypoglycaemia (OR: 2.58; 95% CI: 1.23, 5.40; P = 0.0119).

Conclusions

Both basal + LIXI and Basal + RAI improved glycaemic control in patients with T2DM with inadequate glycaemic control on basal insulin. Basal + LIXI offers an effective therapeutic option to advance basal insulin therapy, improving glucose control without weight gain and with less risk of hypoglycaemia than prandial insulin.

Introduction

Basal insulin is an important tool for the treatment of type 2 diabetes mellitus (T2DM) as it improves glycaemic control within therapeutic glycated haemoglobin (HbA1c) levels (HbA1c < 7%) in most patients with T2DM (American Diabetes, 2008, Ryden et al., 2007). However, owing to progressive diminution of insulin secretory capacity, patients who receive basal insulin therapy do not always achieve glycaemic targets, or may experience suboptimal glycaemic control over time, thus requiring additional therapeutic interventions (Barag, 2011, Davis and Renda, 2006, Raccah, 2008, Raccah et al., 2007). Glycaemic targets for patients with T2DM have traditionally been focused on reducing HbA1c, with an emphasis on fasting plasma glucose (FPG) (Nathan et al., 2006). However, control of FPG alone is not always sufficient for control of HbA1c, as both FPG and postprandial glucose (PPG) contribute to overall HbA1c levels (Ceriello, 2010). PPG appears to contribute more to overall hyperglycaemia as HbA1c levels decrease, making control of PPG particularly important in patients with relatively modest elevations of HbA1c, or in patients on basal insulin therapy when no further improvement in FPG is feasible (Ceriello et al., 2008, Leiter et al., 2005, Monnier et al., 2007, Riddle et al., 2011, Woerle et al., 2007).

There is currently an unmet need for additional therapeutic options for patients treated with basal insulin who do not meet HbA1c targets due to elevated PPG, despite relatively well-controlled FPG levels. These patients have traditionally been treated with the addition of rapid-acting insulin (RAI) therapy to target PPG excursions. In many patients, a Basal-Plus regimen, consisting of the addition of a once-daily RAI to basal insulin at the main meal, is sufficient to restore acceptable glycaemic control (Davidson et al., 2011, Del Prato et al., 2012, Lankisch et al., 2008, Owens et al., 2011). The once-daily RAI dose can be titrated to reduce PPG without affecting basal insulin action, although the basal dose may require adjustment according to the presence of hypoglycaemia (Rosenstock, 2004).

Lixisenatide (LIXI) is a once-daily prandial glucagon-like peptide-1 (GLP-1) receptor agonist that is indicated for the treatment of T2DM as add-on to oral antidiabetic drugs (OADs) or basal insulin regimens (European Medicines Agency, 2013). The current analysis evaluated the efficacy and safety of once-daily prandial lixisenatide as add-on to basal insulin (Basal + LIXI) compared with once-daily RAI as add-on to basal insulin (Basal + RAI) using data from randomized controlled trials (RCTs). Analysis of individual patient data is increasingly used as a valuable method for evaluating treatment outcomes in diabetes (Farmer et al., 2012, Freemantle et al., 2013). Recent studies also suggest that propensity score matching provides an effective tool for comparing treatment regimens in patients with diabetes and can reduce treatment selection bias between groups (Freemantle et al., 2013, Wang et al., 2013).

Section snippets

Data source

The Sanofi clinical trial database was searched for RCTs with a 24–26-week randomized phase, conducted in Europe and North America, and that included subjects with T2DM randomized to either insulin glulisine as add-on to basal insulin or lixisenatide as add-on to basal insulin regimens. Individual patient-level data were pooled and data from all trials had to include baseline and endpoint HbA1c measurements. Five RCTs assessing the efficacy and safety of lixisenatide or RAI added to basal

Participants

Of the 1184 patients included in the unmatched population, 519 were treated with basal insulin and a once-daily injection of lixisenatide (Basal + LIXI), and 665 were treated with basal insulin plus a once-daily injection of rapid-acting prandial insulin (Basal + RAI). Of the patients selected in the matched population, 144 patients were in the Basal + LIXI group and 144 patients in the Basal + RAI group (Table 2). In the unmatched population, there were significant differences in baseline

Discussion

The objective of this analysis was to explore an additional therapeutic option to the Basal-Plus treatment concept by comparing the efficacy and safety outcomes with Basal + LIXI versus Basal + RAI regimens in patients with T2DM. The current analysis showed that the use of either Basal + LIXI or Basal + RAI treatment regimens can result in improved glycaemic control for patients with T2DM who have inadequate glycaemic control on basal insulin treatment. However, patients on Basal + LIXI treatment were

Acknowledgments

The study was supported by Sanofi. Editorial support was provided by Medicus International London (UK) and funded by Sanofi.

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    Conflicts of Interest: Denis Raccah is a member of advisory boards and a speaker at symposia for Sanofi, Novo Nordisk, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Bristol-Myers Squibb, Novartis, and Medtronic. Jay Lin is an employee of Novosys Health, which received funding from Sanofi. Edward Wang, Maeva Germé and Riccardo Perfetti are employees of Sanofi. Riccardo Bonadonna has served on scientific advisory boards and received honoraria or consulting fees and been a speaker at symposia for Sanofi Aventis, Merck Sharp & Dohme, Eli Lilly, Bristol-Myers Squibb, and Amgen. Pedro de Pablos-Velasco has served on scientific advisory boards and received honoraria or consulting fees or grants/research support from antidiabetic agents manufacturers, AstraZeneca, Takeda and Novartis, along with speaker fees from Merck Sharp & Dohme, Sanofi Aventis, GlaxoSmithKline, Pfizer, and Roche. Ronan Roussel has served on scientific advisory boards and received honoraria or consulting fees or grants/research support from insulin and GLP-1 receptor agonist manufacturers Eli Lilly, GlaxoSmithKline, Novo Nordisk, and Sanofi. Julio Rosenstock has served on scientific advisory boards and received honoraria or consulting fees or grants/research support from insulin and GLP-1 receptor agonist manufacturers, Amylin, Eli Lilly, GlaxoSmithKline, Hoffmann-La Roche, Novo Nordisk, and Sanofi.

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