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☆
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.
References (28)
- et al.
Guideline for management of postmeal glucose
Nutrition, Metabolism, and Cardiovascular Diseases
(2008) - et al.
A stepwise approach to insulin therapy in patients with type 2 diabetes mellitus and basal insulin treatment failure
Endocrine Practice
(2011) - et al.
Postprandial glucose regulation: new data and new implications
Clinical Therapeutics
(2005) - et al.
Impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes Importance of postprandial glycemia to achieve target HbA1c levels
Diabetes Research and Clinical Practice
(2007) Standards of medical care in diabetes–2008
Diabetes Care
(2008)Insulin therapy for management of type 2 diabetes mellitus: strategies for initiation and long-term patient adherence
Journal of the American Osteopathic Association
(2011)The glucose triad and its role in comprehensive glycaemic control: current status, future management
International Journal of Clinical Practice
(2010)- et al.
Psychological insulin resistance: overcoming barriers to starting insulin therapy
The Diabetes Educator
(2006) - et al.
Telecare provides comparable efficacy to conventional self-monitored blood glucose in patients with type 2 diabetes titrating one injection of insulin glulisine-the ELEONOR study
Diabetes Technology & Therapeutics
(2012) Authorization from the Committee for Medicinal Products for Human Use (CHMP)
Meta-analysis of individual patient data in randomised trials of self monitoring of blood glucose in people with non-insulin treated Type 2 diabetes
BMJ
A propensity score matched comparison of different insulin regimens 1 year after beginning insulin in people with Type 2 diabetes
Diabetes, Obesity & Metabolism
Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)
Diabetologia
Introducing a simplified approach to insulin therapy in type 2 diabetes: a comparison of two single-dose regimens of insulin glulisine plus insulin glargine and oral antidiabetic drugs
Diabetes, Obesity & Metabolism
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2021, Nutrition, Metabolism and Cardiovascular DiseasesCitation Excerpt :However, in clinical practice, it is often very difficult to appropriately titrate insulin, due to hypoglycemia, weight gain, and patients’ compliance. This has been observed in clinical trials as well: all studies in which treatment intensification by basal insulin was compared with treatment intensification by GLP-1 receptor agonists, failed to demonstrate superiority of insulin treatment [27,28]. Patients treated with GLP-1 receptor agonists achieved at least the same HbA1c reduction as patients treated with basal insulin, but with less hypoglycemic events and less weight gain.
Intensification of Basal Insulin Therapy with Lixisenatide in Patients with Type 2 Diabetes in a Real-World Setting: The BASAL-LIXI Study
2018, Current Therapeutic Research - Clinical and ExperimentalAddition of once daily prandial lixisenatide to basal insulin therapy in patients with type-2 diabetes results in a reduction of HbA1c as an effect of postprandial glucose lowering
2017, Diabetes and Metabolic Syndrome: Clinical Research and ReviewsCitation Excerpt :This was accompanied by a 3.8 mmol/l (68 mg/dl) greater decrease in PPG levels and a 1.3 kg greater decrease in body weight. Raccah et al. analysed data from 5 randomised controlled trials comparing treatments with basal insulin and the GLP-1 receptor agonist or short acting prandial insulin [15]. Both combinations resulted in similar reductions in HbA1c levels, but lixisenatide treatment was associated with lower risks of hypoglycaemia and weight gain.
Basal insulin treatment intensification in patients with type 2 diabetes mellitus: A comprehensive systematic review of current options
2017, Diabetes and MetabolismCitation Excerpt :At week 8, mean HbA1c was comparable in all treatment arms and ranged from 6.1% to 6.2% [56]. Raccah et al. [55] assessed the efficacy of lixisenatide plus basal insulin vs RAIs plus basal insulin in a propensity-score-matched analysis of data extracted from five 24-week RCTs. This analysis found that patients in the lixisenatide arm were almost twice as likely to achieve composite endpoints, comprising HbA1c < 7%, no weight increase and no documented hypoglycaemia, compared with the RAI arm (29.2% vs 15.3%; P = 0.0046).
Options for intensification of basal insulin in type 2 diabetes: Premeal insulin or short-acting GLP-1 receptor agonists?
2015, Diabetes and MetabolismCitation Excerpt :According to these encouraging results, adding a short-acting, prandial GLP-1 RA to the treatment of T2D patients still uncontrolled despite basal insulin and OADs now represents a promising strategy, and could constitute a worthwhile alternative to insulin intensification with basal-plus and basal-bolus regimens. Indirect comparisons derived from five randomized trials show that lixisenatide offers a safe and effective therapeutic alternative to enhanced basal insulin treatments, improving glucose control without weight gain and with less risk of hypoglycaemia than a once-daily meal-time rapid-acting insulin [45]. Although direct comparisons are as yet limited, the available data suggest that adding a prandial GLP-1 RA results in a similar or greater reduction of HbA1c, weight loss instead of weight gain and a lower risk of hypoglycaemic episodes compared with the addition of once-daily up to thrice-daily meal-time rapid-acting insulin analogues [36,40,44].
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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.