Efficacy and safety of lixisenatide in the treatment of Type 2 diabetes mellitus: a review of Phase III clinical data

Abstract

Lixisenatide is a novel glucagon-like peptide-1 receptor agonist developed for the treatment of Type 2 diabetes mellitus (T2DM). In its clinical development program, once-daily lixisenatide has been associated with significant improvements in HbA_1c (change from baseline to week 24: up to -0.92%) and postprandial plasma glucose (PPG; change from baseline to week 24 as add-on to basal insulin: up to -7.96 mmol/l) with beneficial weight effects (change from baseline to week 24: up to -2.0 kg as add-on to oral antidiabetic agents and -1.8 kg as add-on to basal insulin) and a low incidence of severe hypoglycemia (from 0 to 1.2% over 24 weeks). Pharmacodynamic data highlight differences between lixisenatide and other glucagon-like peptide-1 receptor agonists, demonstrating more pronounced effects on PPG than liraglutide, with less frequent dosing and a better tolerability profile than exenatide. Lixisenatide has recently been evaluated in a comprehensive Phase III clinical trial program in patients with T2DM, which included three large-scale studies of once-daily lixisenatide in combination with basal insulin. Lixisenatide has been studied as a monotherapy or oral agent combination, or with insulin. It may become a treatment option for certain patient groups in the near future, including those that are unable to reach target HbA_1c goals despite treatment with basal insulin and a fairly well-controlled fasting plasma glucose, indicating that additional PPG control could be needed. This article reviews clinical data for lixisenatide to date, both as monotherapy and in combination with basal insulin, and discusses the implications of lixisenatide for the management of T2DM.

Keywords::

• basal insulin
• glucagon-like peptide-1
• HbA_1c
• insulin
• lixisenatide
• postprandial glucose
• Type 2 diabetes

Figure 1. Changes in HbA_1c levels following treatment with lixisenatide either as monotherapy (GetGoal-Mono) or in combination with oral antidiabetic drugs (GetGoal-M, GetGoal-F1, GetGoal-S, GetGoal-P).

Standard error values are given where available.

*p < 0.0001 versus placebo.

am: Morning administration; ext.: Extension; MET: Metformin; PIOG: Pioglitazone; pm: Evening administration; q.d.: Once daily; 1s: One-step dosing; 2s: Two-step dosing; SU: Sulfonylurea.

Data taken from [46–50].

Figure 2. Changes in fasting plasma glucose following treatment with lixisenatide either as monotherapy (GetGoal-Mono) or in combination with oral antidiabetic drugs (GetGoal-M, GetGoal-F1, GetGoal-S, GetGoal-P).

Standard error values are given where available.

*p < 0.01 versus placebo; **p < 0.001 versus placebo; ***p < 0.0001 versus placebo.

1s: One-step dosing; 2s: Two-step dosing; am: Morning administration; ext.: Extension; FPG: Fasting plasma glucose; MET: Metformin; PIOG: Pioglitazone; pm: Evening administration; q.d.: Once daily; SU: Sulfonylurea.

Data taken from [46–50].

Figure 3. Changes in 2-h postprandial glucose following treatment with lixisenatide either as monotherapy (GetGoal-Mono) or in combination with oral antidiabetic drugs (GetGoal-M, GetGoal-F1, GetGoal-S).

2-h PPG indicates plasma glucose levels taken 2 h after a standardized meal, at baseline and follow-up. Mean changes from baseline are presented with last observations carried forward. Standard error values are given where available.

*p < 0.0001 versus placebo.

1s: One-step dosing; 2s: Two-step dosing; am: Morning administration; ext.: Extension; MET: Metformin; NR: Not reported; PPG: Postprandial glucose; q.d.: Once daily;

SU: Sulfonylurea.

Data taken from [46–49].

Figure 4. Changes in HbA_1c levels following treatment with lixisenatide in combination with insulin (GetGoal-L, GetGoal-L Asia, GetGoal-Duo 1).

Standard error values are given where available.

*p < 0.0001 versus placebo; **p < 0.001 versus placebo. ^†Following 12-week run-in period.

MET: Metformin; q.d.: Once daily; SU: Sulfonylurea.

Data taken from [52–54].

Figure 5. Changes in 2-h postprandial glucose following treatment with lixisenatide in combination with insulin (GetGoal-L, GetGoal-L Asia, GetGoal-Duo 1).

Two-hour PPG indicates plasma glucose levels taken 2 h after a standardized meal, at baseline and follow-up. Mean changes from baseline are presented with last observations carried forward. Standard error values are given where available.

*p < 0.0001 versus placebo.

MET: Metformin; PPG: Postprandial glucose; q.d.: Once daily; SU: Sulfonylurea.

Data taken from [52–54].

Inadequate glycemic control in patients with Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular disease and both diabetes-related and all-cause mortality, largely due to an increased risk of microvascular and macrovascular disease complications [1–3]. For example, cardiovascular disease is significantly more common in patients with T2DM than in nondiabetic patients, accounting for more than two-thirds of deaths associated with the condition [4]. Consequently, international guidelines recommend targeting HbA_1c levels of <7.0 or ≤6.5% [5–7], which have been shown to reduce the risk of diabetes-related events [8,9].

Elevation of both fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) can contribute to overall HbA_1c levels, although there is some debate on the relative contributions of these factors [10–13]. Clinical studies have verified that targeting PPG can help to optimize HbA_1c [4,14], and the control of FPG alone may not be sufficient to achieve HbA_1c targets in some patients [15]. Consequently, guidelines from the International Diabetes Federation (IDF) recommend therapeutic management that targets both PPG and FPG simultaneously, at any HbA_1c level [101]. Traditionally, dual targeting has been achieved with insulin therapy using a basal insulin to target FPG and a prandial insulin for PPG control, either as part of a basal-bolus or biphasic insulin regimen [16].

Newer classes of drugs are now available for the management of glycemic control, including incretin-based therapies, such as some glucagon-like peptide-1 (GLP-1) analogs, dipeptidyl peptidase-4 (DPP-4) inhibitors and islet amyloid polypeptide (amylin) analogs. Amylin is a hormone secreted by pancreatic β cells in response to nutrient intake, which suppresses postprandial glucagon secretion and regulates gastric emptying and appetite [17]. Long-term studies of the amylin analog pramlintide have demonstrated that it improves postprandial glucose fluctuations and HbA_1c levels, while reducing bodyweight and the requirement for insulin [17,18]. Incretin-based therapies exploit the physiologic effects of activating the GLP-1 receptor, which potentiates insulin secretion, inhibits glucagon release, delays gastric emptying and reduces appetite [19]. Native GLP-1 has a very short elimination half-life due to cleavage by DPP-4 at the alanine residue at position two of the full-length molecule [20] and rapid renal clearance [21]. DPP-4 inhibitors act by slowing down GLP-1 degradation, whereas synthetic GLP-1 receptor agonists have been specifically developed to be DPP-4-resistant [22,23]. In the treatment of T2DM, GLP-1 receptor agonists have been associated with improved control of HbA_1c, with weight loss and a low rate of hypoglycemia [24,25]. These latter features are important, since some patients may experience hypoglycemic events with insulin therapies, and weight gain is a well-documented concern for some patients receiving insulin therapy or some oral antidiabetic drugs (OADs) [26–29]. The weight loss and low rate of hypoglycemia associated with GLP-1 receptor agonists, together with their ability to confer improved glycemic control, allow greater individualization of treatment for patients with T2DM [24,25,30,31].

At present, three GLP-1 receptor agonists are available for the treatment of T2DM: exenatide, exenatide extended release and liraglutide. These agents differ in their pharmacokinetics, dosing frequency and molecular structures [32–34]. Lixisenatide is a new once-daily (q.d.) GLP-1 receptor agonist for the treatment of T2DM and was approved by the EMA in February 2013 [23]. The aims of this article are to review the available efficacy and safety data for lixisenatide, both as monotherapy and in combination with oral drugs and basal insulin, and to discuss the implications that lixisenatide may have for the management and treatment of individuals with T2DM.

Lixisenatide

Lixisenatide is a novel synthetic GLP-1 receptor agonist comprising of a 44-amino acid peptide that differs from exendin-4 by the addition of six lysine residues and the deletion of one proline at the C-terminal [35]. Lixisenatide is a highly potent and selective GLP-1 receptor agonist; its binding affinity is approximately four-times greater than endogenous human GLP-1 (K_i = 1.33 ± 0.22 vs 5.09 ± 1.19 nM, respectively) [35,36].

By binding to the GLP-1 receptor with greater (enhanced) affinity, a GLP-1 receptor agonist may enhance the effects of naturally occurring GLP-1. As with other GLP-1 receptor agonists, the key mechanisms underlying lixisenatide’s efficacy in T2DM result from simulation and enhancement of the effects of endogenous GLP-1, which can be summarized as follows. First, lixisenatide has been shown to preserve pancreatic responsiveness to glucose in both animal and human models in a strictly glucose-dependent manner [35,37,38]. In obese Zucker diabetic fatty rats, progressive impairment of β-cell function and loss of pancreatic response to blood glucose changes occurs, as well as lixisenatide-preserved glucose-stimulated insulin secretion and total insulin secretion to a greater extent than native GLP-1 [38], which is consistent with its enhanced affinity at the GLP-1 receptor. In T2DM patients, lixisenatide enhanced first-phase insulin secretion to intravenous glucose challenge assessed by glucose-stimulated insulin secretion (by 2.8-fold relative to placebo) and second-phase secretion (by 1.6-fold) with corresponding changes seen in insulin (by 6.6-fold in the first phase and threefold in the second phase) [37]. Second, GLP-1 suppresses prandial glucagon production, contributing to normalization of blood glucose [39]. Lixisenatide has been shown to suppress prandial glucagon production in animal models of T2DM [38], and in patients with T2DM it has been suggested that q.d. lixisenatide provides a significantly greater decrease in postprandial glucagon levels than q.d. liraglutide [40]. Third, GLP-1 delays gastric emptying and reduces appetite, thereby promoting weight loss [35,41]. This is postulated to occur via a variety of mechanisms, including GLP-1 interaction with sensory neurons in the GI tract, and stomach distension, which induces transmission of satiety signals to the brain [19]. Preclinical studies have demonstrated that treatment with lixisenatide is associated with reduction in food intake, slowed gastric emptying and promotion of weight loss [35]; the beneficial weight effects of lixisenatide have also been observed clinically [42]. Finally, since GLP-1 only stimulates insulin release when blood glucose levels are elevated, there is a low risk of hypoglycemia with agents that target this system [42,43].

When administered to patients with T2DM, lixisenatide plasma concentrations increase in a dose-dependent manner, reaching a peak concentration (C_max) after 1–2 h [42,44]. The mean area under the curve (AUC) and C_max increase according to dose and frequency of administration [42,44]. The elimination half-life of lixisenatide is approximately 2–4 h [42,44]. At doses of 20 µg q.d. or 10 µg twice-daily (b.i.d.), lixisenatide treatment was shown to significantly improve PPG compared with placebo after breakfast (PPG-AUC_{[0:14 h–4:55 h]}: -381.3 ± 62.9 and -362.9 ± 65.8 for q.d. and b.i.d., respectively; p < 0.0001 for both vs placebo), lunch (PPG-AUC_{[5:14 h–9:55 h]}: -277.5 ± 74.4 and -256.1 ± 75.0; p = 0.0004 and p = 0.0011 vs placebo) and dinner (PPG-AUC_{[10:14 h–14:55 h]}: -179.1 ± 72.4 and -357.5 ± 72.9; p = 0.0162 and p < 0.0001 vs placebo) [42,44].

The dose–response relationship of lixisenatide in T2DM patients inadequately treated with metformin was investigated in a 13-week, randomized, double-blind, placebo-controlled, parallel-group study in which 542 patients with HbA_1c levels ≥7 and <9.0% were treated with lixisenatide doses of 5, 10, 20, or 30 µg q.d. or b.i.d. or placebo [45]. Lixisenatide significantly improved mean HbA_1c levels from baseline to week 13 versus placebo, regardless of dose or dosing regimen (p < 0.01 for all). A target HbA_1c level of <7.0% at study end was achieved by 68% of patients treated with lixisenatide 20 or 30 µg q.d. versus 32% of patients treated with placebo (p < 0.0001). Dose-dependent improvements were observed for FPG, 2-h PPG (after a standardized breakfast meal test) and mean self-monitored seven-point blood glucose levels. In addition, dose-dependent weight changes ranged from -2.0 to -3.9 kg with lixisenatide versus -1.9 kg with placebo. The most frequent adverse event was mild-to-moderate nausea. Overall, lixisenatide 20 µg q.d. demonstrated the most favorable efficacy-to-tolerability ratio [45].

Clinical efficacy

A comprehensive Phase III clinical trial program – entitled GetGoal – evaluated the efficacy and safety/tolerability of lixisenatide, administered as monotherapy and in combination with OADs and basal insulin, in patients with T2DM. Indeed, the GetGoal program represents the most extensive investigation of GLP-1 receptor agonist therapy in combination with basal insulin conducted to date. Data from nine of the GetGoal studies are now available either as peer-reviewed publications or interim reports from congress abstracts (Table 1). This review of lixisenatide’s clinical efficacy and safety/tolerability is based on data from these nine studies and has been compiled using published manuscripts, abstracts and clinical trial databases that are in the public domain.

Lixisenatide monotherapy/oral agent combination studies

A series of Phase III placebo-controlled studies has assessed the efficacy of lixisenatide in improving glycemic control in patients with T2DM when administered either as monotherapy or in combination with an OAD. GetGoal-Mono was a multinational, randomized, double-blind, placebo-controlled study in which patients with T2DM not currently receiving glucose-lowering therapy, and with a HbA_1c measurement of 7–10%, were randomized to receive monotherapy treatment with lixisenatide 20 µg q.d. or placebo, administered using either a one- or two-step dose-increase schedule [46]. With one-step dosing, patients received lixisenatide 10 µg/day for 2 weeks and 20 µg/day thereafter; with a two-step dose increase, they received lixisenatide 10 µg/day for 1 week, 15 µg/day for 1 week and 20 µg/day thereafter. The primary efficacy end point was change in HbA_1c from baseline to week 12 [46]. Four Phase III multicenter, randomized, double-blind, placebo-controlled studies have assessed the ability of lixisenatide 20 µg q.d. to improve glycemic control in patients with T2DM insufficiently controlled with OADs [47–50]. In each of these studies, patients were required to have a baseline HbA_1c of 7–10% and the primary objective was to assess absolute HbA_1c reduction after a treatment period of 24 weeks. In GetGoal-F1, patients with T2DM insufficiently controlled by metformin (≥1.5 g/day) were randomized to receive additional treatment with lixisenatide 20 µg q.d. or placebo, administered using either a one- or two-step dosing schedule (as outlined for GetGoal-Mono) [46,47]. In GetGoal-M, patients with T2DM insufficiently controlled by metformin (≥1.5 g/day) were randomized to receive additional treatment with either lixisenatide 20 µg q.d. or placebo using the two-step dosing schedule described for GetGoal-Mono, administered either in the morning or in the evening [48]. In GetGoal-S, patients with T2DM insufficiently controlled on a sulfonylurea with or without metformin were randomized to receive additional treatment with either lixisenatide 20 µg q.d. or placebo, using the two-step schedule described for GetGoal-Mono [49]. In GetGoal-P, patients with T2DM insufficiently controlled by pioglitazone (≥30 mg/day) with or without metformin were randomized to receive additional treatment with either lixisenatide 20 µg q.d. or placebo [50].

Effect on HbA_1c

Following 12 weeks of treatment as monotherapy in GetGoal-Mono, lixisenatide significantly improved HbA_1c levels compared with placebo whether administered using a one- or two-step dosing schedule (p < 0.0001 for both) (Figure 1). Moreover, significantly more lixisenatide versus placebo patients achieved HbA_1c target levels; at week 12, a target level of ≤6.5% was achieved by 25.4 and 31.9% of patients treated with lixisenatide using a one- or two-step dosing schedule, respectively, compared with 12.5% of patients treated with placebo (p = 0.0095 and p = 0.0005 vs placebo, respectively) and a target level of <7.0% was achieved by 46.5 and 52.2% of patients treated with lixisenatide using a one- or two-step dosing schedule, respectively, compared with 26.8% of patients treated with placebo (p = 0.0013 and p < 0.0001 vs placebo, respectively) [46].

Similarly, in each of the four studies that assessed the efficacy of lixisenatide as an add-on to existing OAD therapy, lixisenatide 20 µg q.d. was shown to be significantly more effective than placebo in reducing HbA_1c levels after 24 weeks of treatment, regardless of the concomitant OAD used, and regardless of whether lixisenatide was administered using a one- or two-step dose increase schedule or administered in the morning or evening (p < 0.0001 for all comparisons vs placebo) (Figure 1).

As in GetGoal-Mono, improvements in glycemic control were not only demonstrated by significant reductions from baseline in HbA_1c compared with placebo, but also by the higher proportions of lixisenatide- versus placebo-treated patients achieving target HbA_1c levels of ≤6.5 and <7.0% at week 24. For example, in GetGoal-P, the proportion of patients achieving an HbA_1c target of <7.0% was 52% for lixisenatide versus 26% for placebo (p < 0.0001) [50].

In addition to these placebo-controlled studies, a head-to-head study assessed the efficacy of lixisenatide versus the GLP-1 receptor agonist exenatide. GetGoal-X was a multicenter, multinational, Phase III, randomized, parallel-group, open-label, noninferiority study in which patients with T2DM inadequately controlled by metformin were randomized to receive additional treatment with either lixisenatide 20 µg q.d. administered in the morning using the two-step titration schedule described for GetGoal-Mono, or exenatide 10 µg b.i.d. administered using a one-step schedule (5 µg b.i.d. for 4 weeks and 10 µg b.i.d. thereafter) [51]. As in the add-on to OAD placebo-controlled studies, the primary efficacy end point was HbA_1c reduction from baseline following 24 weeks of treatment. The study was designed to show noninferiority if the upper limit of the 95% CI of the least square (LS) mean treatment difference was ≤0.4%. At baseline, mean ± standard deviation (SD) HbA_1c levels were 8.6 ± 0.8% in both treatment groups. At week 24, the HbA_1c LS mean ± standard error (SE) changed from baseline was -0.8 ± 0.1% for lixisenatide versus -1.0 ± 0.1% for exenatide and the LS mean treatment difference was 0.2% (95% CI: 0.03–0.30). HbA_1c reduction with lixisenatide was therefore shown to be comparable and noninferior to that achieved with exenatide [51].

Effect on FPG & PPG

Significant improvements in FPG levels are observed when lixisenatide is added to existing OAD therapy (Figure 2). For example, when lixisenatide was added to existing metformin therapy in GetGoal-M, FPG was reduced by -1.2 mmol/l from baseline to week 24 when administered in the morning and by -0.8 mmol/l when administered in the evening compared with -0.3 mmol/l with placebo (p < 0.001 for both lixisenatide groups vs placebo) [48]. When lixisenatide was added to pioglitazone (with or without metformin) in the GetGoal-P study, FPG improved by -1.2 mmol/l from baseline to week 24 compared with -0.3 mmol/l with placebo (p < 0.0001) [50]. Similarly, when added to a sulfonylurea (with or without metformin) in GetGoal-S, lixisenatide improved FPG by -1.0 mmol/l from baseline to week 24 compared with -0.4 mmol/l with placebo (p < 0.0001) [49].

Treatment with lixisenatide provides particularly pronounced and significant reductions in postprandial glycemic control (Figure 3). In GetGoal-Mono, treatment with lixisenatide q.d. <1 h before breakfast resulted in statistically significant improvements in 2-h PPG (after a standardized breakfast meal test) from baseline to week 12 versus placebo, whether administered using one- or two-step dosing (p < 0.0001 for both). Lixisenatide also significantly decreased 2-h glucose excursion (2-h PPG minus plasma glucose 30 min prior to the meal test) versus placebo: at week 12, the LS mean treatment difference was -3.7 mmol/l (95% CI: -4.85 to -2.53) and -3.1 mmol/l (95% CI: -4.3 to -1.9) for lixisenatide administered using a one- and two-step dosing schedule, respectively [46]. Similarly, in GetGoal-S, the LS mean reduction in 2-h PPG with lixisenatide from baseline to week 24 was -6.2 mmol/l compared with -0.2 mmol/l with placebo (p < 0.0001) [49].

Effect on bodyweight

In addition to its beneficial effects on improving glycemic control, treatment with lixisenatide has been shown to result in reductions in bodyweight compared with placebo. In GetGoal-S, lixisenatide reduced bodyweight by -1.8 kg over 24 weeks compared with -0.9 kg with placebo (p < 0.0001) [49]. Lixisenatide also provided reductions in bodyweight compared with placebo in GetGoal-P and GetGoal-M, although the differences were not statistically significant: in GetGoal-P, LS mean change in bodyweight from baseline to week 24 was -0.2 kg with lixisenatide versus +0.2 kg with placebo [50] in GetGoal-M, LS mean change in bodyweight from baseline to week 24 was -2.0 kg with lixisenatide administered in the morning or evening compared with -1.6 kg with placebo [48]. The reductions in bodyweight with placebo in the GetGoal-M and -S studies is notable and may be a reflection of the diet and lifestyle counseling included in the design of the GetGoal studies.

Lixisenatide in combination with insulin

Three Phase III placebo-controlled studies have assessed the efficacy of lixisenatide in combination with basal insulin. GetGoal-L was a multicenter, Phase III, randomized, double-blind, placebo-controlled study in which patients being treated with basal insulin with or without metformin were randomized to lixisenatide 20 µg q.d. or placebo, with a two-step dose increase regimen being administered in the morning [52]. Insulin therapy at baseline was predominantly glargine (50%) or neutral protamine Hagedorn (40%), with a minority of patients receiving detemir; the mean insulin dose at baseline was approximately 55 U/day. In patients with HbA_1c ≤7.5% at screening, the insulin dose was reduced by 20% at randomization to limit hypoglycemia, with the subsequent aim of maintaining stable dosage (titration was only allowed in the event of hypoglycemia). The primary end point was change in HbA_1c from baseline to week 24.

GetGoal-L Asia was a multicenter, Phase III, randomized, double-blind, placebo-controlled study conducted in Japan, Korea, Taiwan and The Philippines, in which patients being treated with basal insulin with or without a sulfonylurea were randomized to lixisenatide 20 µg q.d. (using the two-step dosing schedule described for GetGoal-Mono) or placebo administered in the morning [53]. Approximately 70% of patients received sulfonylurea at screening and basal insulin use comprised glargine (60%), detemir (27%) and neutral protamine Hagedorn (13%). As in GetGoal-L, the insulin dose was reduced by 20% in patients with screening HbA_1c ≤7.5% and thereafter remained stable (±20%), except in the event of hypoglycemia. Similarly, in patients with screening HbA_1c ≤8.0%, the sulfonylurea dose was decreased by ≥25% (or stopped in the case of minimum dosing) in order to decrease the risk of hypoglycemia. As in GetGoal-L, the primary end point was change in HbA_1c from baseline to week 24 [53].

GetGoal-Duo 1 was a multicenter, Phase III, randomized, double-blind, placebo-controlled study in patients with T2DM inadequately controlled on oral agents [54]. Glargine was initiated and titrated over a 12-week run-in phase to achieve an FPG of 4.4–5.6 mmol/l; patients with HbA_1c ≥7 and ≤9% and a mean FPG ≤7.8 mmol/l over the last 7 days of the run-in were then randomized to morning lixisenatide 20 µg q.d. or placebo for 24 weeks (initiated with a two-step dose-increase regimen). Titration of glargine continued during the randomized treatment period, unlike GetGoal-L, GetGoal-L Asia, and studies with exenatide and insulin [55]. Sulfonylurea and glinide therapy was stopped at the initiation of insulin glargine. At randomization, all patients were on metformin and 12% were on a thiazolidinedione. The primary end point was change in HbA_1c from randomization [54].

Effect on HbA_1c

In GetGoal-L, mean ± SD baseline HbA_1c levels were 8.4 ± 0.9% and 8.4 ± 0.8% in the lixisenatide and placebo groups, respectively. By week 24, the LS mean ± SE change in HbA_1c from baseline was -0.7 ± 0.1% with lixisenatide versus -0.4 ± 0.1% with placebo; the LS mean treatment difference was -0.4% (95% CI: -0.6 to -0.2; p = 0.0002) (Figure 4) [52]. The proportion of patients achieving an HbA_1c target of <7.0% was also significantly higher with lixisenatide versus placebo (28 vs 12%; p < 0.001) [52]. The glycemic benefits with lixisenatide were achieved despite a significantly greater reduction in the basal insulin dose versus placebo over 24 weeks (-5.6 vs -1.9 U/day; p = 0.012). Similar improvements in HbA_1c were observed in GetGoal-L Asia: the mean change from baseline was significantly greater, and the proportion of patients achieving targets of <7.0 and ≤6.5% were significantly higher, with lixisenatide versus placebo [53]. In GetGoal-Duo 1, mean HbA_1c decreased during the glargine run-in period from 8.6 to 7.6% and, following randomization, lixisenatide significantly decreased HbA_1c further versus placebo. In addition, more patients treated with lixisenatide versus placebo achieved an HbA_1c target of <7.0% (56 vs 39%, respectively) [54].

Effect on FPG & PPG

FPG was not significantly changed from baseline for patients treated with lixisenatide versus placebo in GetGoal-L and GetGoal-Duo 1 [52,54]. These findings are as expected, since the relatively low FPG values prior to commencement of randomized treatment for patients in these studies indicate that basal insulin was providing adequate control of FPG. However, in GetGoal-L Asia, improvements in FPG from baseline to week 24 were significantly greater with lixisenatide versus placebo (LS mean change ± SD was -0.42 ± 0.31 mmol/l vs +0.25 ± 0.30 mmol/l; p = 0.0187) [53].

Addition of lixisenatide to basal insulin resulted in significant improvements in 2-h PPG and PPG excursions (Figure 5). In GetGoal-L, the LS mean ± SD reduction in 2-h PPG with lixisenatide from baseline to week 24 was -5.5 ± 0.5 mmol/l compared with -1.7 ± 0.5 mmol/l with placebo; the LS mean treatment difference was -3.8 mmol/l (95% CI: -4.7 to -2.9; p < 0.0001) [52]. A significant improvement in 2-h PPG was observed in GetGoal-L Asia (Figure 5), as well as in 2-h glucose excursion: the LS mean change from baseline to week 24 was -7.1 mmol/l with lixisenatide versus +0.1 mmol/l for placebo; the LS mean treatment difference was -7.2 mmol/l (95% CI: -8.3 to -6.2; p < 0.0001) [53]. Similarly, when lixisenatide was administered as add-on therapy to basal insulin and metformin (with or without thiazolidinediones) in GetGoal-Duo 1, a significant improvement in 2-h PPG was observed compared with placebo, equating to LS mean treatment difference at 24 weeks of -3.2 mmol/l (95% CI: -4.0 to -2.4; p < 0.0001) [54]. Reductions in PPG were not as great in the GetGoal-Duo1 study versus the GetGoal-L and GetGoal-L Asia studies, probably because patients in GetGoal-Duo1 had lower PPG at baseline (~13 mmol/l compared with ~16 and 18 mmol/l).

Effect on bodyweight

When added to existing OAD therapy, treatment with lixisenatide in combination with insulin has also been shown to result in beneficial effects on bodyweight. For example, in GetGoal-L, mean ± SD bodyweight at baseline was 87.4 ± 20.0 kg and 89.1 ± 21.0 kg in the lixisenatide and placebo groups, respectively. Following 24-week treatment, the LS mean ± SE change from baseline was -1.8 ± 0.3 kg with lixisenatide versus -0.5 ± 0.3 kg with placebo; the LS mean treatment difference was -1.3 kg (95% CI: -1.8 to -0.7; p < 0.0001) [52]. Mean changes in bodyweight from baseline were small in GetGoal-L Asia, which may be expected in an Asian population with a relatively low baseline bodyweight (66 kg). However, there was still a trend towards weight decrease with lixisenatide versus placebo (LS mean change: -0.4 kg [lixisenatide] vs +0.1 kg [placebo]; 95% CI: -0.93–0.06; p = 0.0857) [53]. In GetGoal-Duo 1, the reduced weight gain for patients on lixisenatide was statistically significant versus placebo (LS mean difference: -0.9 kg; p = 0.0012) [54].

Safety & tolerability

As with other GLP-1 receptor agonists, the most frequently reported adverse events associated with lixisenatide are related to the gastrointestinal (GI) system, including transient, dose-dependent nausea, diarrhea and vomiting [42,56,57]. Of interest, only one case of pancreatitis has so far been reported throughout the clinical trial program [54]. The ongoing ELIXA study (ClinicalTrials.gov identifier: NCT01147250 [102]) aims to evaluate the cardiovascular risk profile of lixisenatide in patients with T2DM who have recently experienced a cardiac event.

Lixisenatide monotherapy/ lixisenatide plus OAD

Hypoglycemia

When administered as a monotherapy, or as an add-on to OAD therapy, lixisenatide does not increase the frequency of hypoglycemia compared with placebo and the reported rates for severe hypoglycemia are very low (Table 2). In GetGoal-X, there were significantly fewer symptomatic hypoglycemic events with lixisenatide compared with exenatide (2.2 vs 6.3%; p < 0.05) (Table 2) [51]. The GetGoal program included a substantial number of elderly patients. Importantly, the safety and tolerability of lixisenatide was shown to be consistent across age groups and the risk of hypoglycemia was found to be low in patients aged ≥65 and ≥75 years, and comparable with younger age groups [58].

GI side effects

As with other GLP-1 receptor agonists [56,57], treatment with lixisenatide is associated with GI side effects, and the GetGoal program consistently demonstrated an increased risk of GI adverse events with lixisenatide versus placebo (Table 3). However, in GetGoal-X, fewer GI adverse events were reported for lixisenatide versus exenatide (43.1 vs 50.6%) and the incidence of nausea was significantly lower for lixisenatide versus exenatide (24.5 vs 35.1%; p < 0.05) (Table 3) [51]. In a 4-week pharmacodynamic study, lixisenatide was also associated with fewer GI events versus liraglutide (36 vs 46%), including diarrhea (2.6 vs 15.5%), although these findings need to be confirmed in larger clinical trials [40].

Lixisenatide in combination with insulin

Hypoglycemia

In GetGoal-L Asia, there was an increased rate of hypoglycemia with lixisenatide plus basal insulin versus placebo plus basal insulin (42.9 vs 23.6% [without requirement for blood glucose measurement <3.3 mmol/l]). The rate of hypoglycemia in patients receiving concomitant sulfonylurea was 47.2 versus 21.6% for lixisenatide and placebo, respectively, despite decreases in sulfonylurea doses at randomization for patients with HbA_1c ≤8%. For patients not receiving concomitant sulfonylurea, the incidence of hypoglycemia was similar in lixisenatide- versus placebo-treated patients (32.6 vs 28.3%) [53]. In GetGoal-L and GetGoal-Duo, the addition of lixisenatide to insulin and OAD therapy resulted in low rates of hypoglycemia, although higher than that observed with placebo (Table 2) [52,54]. It is noteworthy that, in GetGoal-L, no patients received concomitant sulfonylurea, and in GetGoal-Duo 1, sulfonylurea therapy was stopped at randomization. These results may be explained by the effect of sulfonylurea on the glucose dependence of GLP-1. In animal models, administration of a sulfonylurea enables GLP-1 to stimulate insulin secretion even at low glucose levels, whereas GLP-1 alone is ineffective in stimulating insulin below a threshold glucose level of 4.3 mmol/l [59].

GI side effects

Consistent with studies conducted in patients receiving lixisenatide as monotherapy or as add-on to OAD therapy, GetGoal-L, GetGoal-L Asia and GetGoal-Duo demonstrated an increased rate of GI adverse events with lixisenatide versus placebo, when added to insulin therapy (Table 3) [52–54].

Conclusion

The GetGoal Phase III program represents the most extensive investigation of a GLP-1 therapy in combination with basal insulin conducted to date. The data overviewed here demonstrate that, when administered as add-on therapy to basal insulin in patients experiencing inadequate glycemic control, lixisenatide is associated with significant reductions in PPG, resulting in improved overall glycemic control and achievement of HbA_1c targets. When added to basal insulin, lixisenatide treatment also resulted in significant weight loss or neutral weight gain, and low rates of hypoglycemia.

The GetGoal program has also demonstrated that, when administered as monotherapy or concomitantly with OADs, treatment with lixisenatide is associated with marked reductions in PPG, as well as significant reductions in FPG, which contribute towards improved glycemic control, with high proportions of patients achieving optimal HbA_1c targets. Lixisenatide treatment also resulted in reductions in bodyweight relative to treatment with OADs, and was associated with low rates of hypoglycemia and a reduced frequency of GI adverse events compared with exenatide.

A significant proportion of patients treated with basal insulin therapy who have elevated HbA_1c may experience inadequate control of PPG. The data from the GetGoal-L, GetGoal-L Asia and GetGoal-Duo 1 studies suggest that such patients may benefit from additional prandial therapy with a GLP-1 receptor agonist such as lixisenatide. Furthermore, cross-trial comparison of basal bolus insulin versus a basal insulin plus lixisenatide strategy suggests weight benefits and relatively low rates of hypoglycemia with the latter option [52,54]. Therefore, patients with T2DM who are uncontrolled on basal insulin and at risk of hypoglycemia and weight gain may further benefit from the addition of lixisenatide.

In summary, treatment with lixisenatide, which is in late-stage clinical development, has led to optimized glycemic management, including control of PPG excursions in patients who are not achieving target HbA_1c levels with their current therapies, and has been associated with low levels of hypoglycemia and beneficial weight loss. Lixisenatide could be an option for the tailoring and individualizing of treatment for patients with T2DM.

Expert commentary

Data suggest that PPG or FPG excursions can be specifically targeted through choice of shorter- or longer-acting GLP-1 receptor agonists. Although the measurement and targeting of HbA_1c has been the focus of T2DM management for many years, it has become apparent that FPG does not always correlate well with HbA_1c, and recent evidence has pointed to the role of PPG in achieving and maintaining comprehensive glycemic control in T2DM [12]. Studies such as the Treat-to-Target Trial indicate that 50–60% of patients achieve good glycemic control with basal insulin [60], but the natural history of the disease makes it likely that these patients will eventually require additional therapy to control PPG. The remaining, approximately 40% of patients, may require additional PPG control, even soon after basal insulin initiation, as evaluated in the GetGoal-Duo 1 study. Indeed, guidelines from the IDF recommend therapeutic management that aims to control both FPG and PPG [101].

The relative contributions of FPG and PPG to HbA_1c levels have been the subject of considerable recent debate [10,11,13,61]. Initial data indicated that the relative contribution of FPG decreases, while that of PPG increases as HbA_1c levels decrease [10,11]. However, a recent study has provided evidence suggesting that although intensified HbA_1c-lowering therapy changes the relationship of FPG to HbA_1c, the degree to which the contribution of PPG increases might depend on the type of HbA_1c-lowering therapy employed; the change in relative contribution of FPG to HbA_1c appears to be greatest when basal insulin therapy is used [13]. Suggested explanations for the apparent discrepancies in the findings of these studies include methodological differences in the way in which postprandial excursions were measured, the criteria used to define hyperglycemia and/or the type of patients included in the studies [13,61]. On balance, it appears that when patients are treated with OADs alone, the contribution of FPG to HbA_1c is greatest, whereas once basal insulin is initiated, the contribution of PPG becomes of greater importance.

Clinical evaluation consistently shows that the significant reductions in HbA_1c associated with lixisenatide are derived in part from substantial reductions in PPG excursions. In a head-to-head comparison in patients with T2DM, q.d. lixisenatide was shown to have a significantly greater PPG-lowering effect than q.d. liraglutide (-129 vs -41%, respectively) [40], although it should be noted that this was a short-term (4-week) study that focused on pharmacodynamics. By contrast, liraglutide has a more pronounced effect on FPG than PPG, since it has a relatively long elimination half-life [42]. Lixisenatide therefore differs from both liraglutide and exenatide, since it is relatively short-acting and effective in targeting PPG (like exenatide but unlike liraglutide), but only requires q.d. dosing (like liraglutide but unlike exenatide). These characteristics may be a reflection of lixisenatide’s shorter half-life relative to liraglutide (2–4 vs 13 h) and its high affinity for the GLP-1 receptor. No head-to-head data for receptor binding affinities of the GLP-1 receptor agonists are currently available [35,42,44].

A study in patients with T2DM demonstrated that q.d. lixisenatide was associated with significant reductions in the rate of gastric emptying and that reductions in PPG over the course of the study correlated significantly with the rate of slowing of gastric emptying [62]. Slowing of gastric emptying is, therefore, thought to be a key mechanism for improvements in glycemic control associated with lixisenatide [62]. Indeed, it is possible that differences in the effects of the available types of GLP-1 receptor agonist on PPG may result from differences in their propensity to slow gastric emptying. A pilot study conducted in healthy volunteers demonstrated that the delay in gastric emptying induced by administration of synthetic GLP-1 was markedly reduced over time with continuous administration (tachyphylaxis), leading to attenuation of PPG control [63]. Longer-acting GLP-1 receptor agonists, such as liraglutide or once-weekly exenatide, may result in more continuous activation of the GLP-1 receptor and a reduction in their effects on gastric emptying and PPG excursions over time. This is consistent with the glycemic effects of the longer-acting GLP-1 receptor agonists being mediated by more pronounced control of FPG as opposed to PPG [42].

The acceptance of the importance of PPG has important implications for the way in which T2DM is treated, as outlined in treatment guidelines recently published by the IDF, which state that “…particularly in people with HbA_1c levels between 7.0 and 8.0% in whom it is considered clinically appropriate to improve glycemic control, assessing postmeal glucose is warranted and if found to be elevated, blood glucose therapy should preferentially choose an agent which specifically lowers postmeal glucose” [101]. Data from the GetGoal Phase III program demonstrate that treatment with lixisenatide can result in optimized glycemic management via control of PPG in patients who are not achieving target HbA_1c levels with their current therapies. Indeed, lixisenatide has been demonstrated to provide additional PPG control in patients whose FPG is already controlled with basal insulin but whose HbA_1c levels are suboptimal. As such, it provides an important additional treatment option in the management of T2DM, allowing PPG levels to be specifically targeted in accordance with IDF guidelines [101].

In summary, q.d. treatment with lixisenatide is simple and convenient, and can facilitate treatment adjustment for different patient populations, including elderly patients, for whom the risk of hypoglycemia is a concern, and patients who may struggle with weight gain. These features provide greater options for more individualized therapeutic management of patients with T2DM.

Five-year view

The next 5 years up to 2017 will probably see a continuation of the recent focus on individualized treatment according to patients’ specific needs from therapy. The availability of new treatment options, improvements in monitoring and the recognition of subsets of patients with distinct requirements means that the complexity of treatment algorithms is likely to increase, as demonstrated by the 2012 update to the American Diabetes Association/European Association for the Study of Diabetes recommendations [6]. Treatment choice will increasingly be influenced by factors such as patients’ overall glycemic profile rather than HbA_1c values alone. Factors such as hypoglycemic risk associated with age, diet and levels of activity can also be assessed and treatment tailored accordingly to minimize the risk. In this context, the GLP-1 receptor agonists represent a valuable treatment option for T2DM management because of their distinct efficacy and safety profile, which include a low risk of weight gain and hypoglycemia.

Lifestyle changes and metformin therapy are likely to remain as first-line treatment options for T2DM, but for patients failing oral therapy, GLP-1 receptor agonists may be an effective addition for some groups of patients, for whom insulin therapy may be challenging. These subgroups include obese patients for whom additional weight gain represents a problem, or patients at particular risk of hypoglycemia, such as the elderly. Patients with particularly poor glycemic control may also benefit more from the potentially greater efficacy of basal insulin therapy. Analysis of clinical studies has shown that insulin therapy is more effective when initiated earlier in the disease course [64] and physicians must be mindful of the danger of delaying insulin therapy in those patients who require it. Given the effectiveness of basal insulin therapy in the majority of patients [60] and the relative simplicity of adding a GLP-1 receptor agonist to existing basal insulin (as evidenced in the GetGoal program), initiating injectable therapy with a GLP-1 receptor agonist in patients who are not achieving adequate glycemic control on basal insulin due to PPG would appear to be a rational approach for many patients. The relative contribution of FPG and PPG to the overall glycemic profile should be considered when choosing between the different GLP-1 receptor agonists or alternative therapies. Finally, the relative safety profiles of treatment types should also be carefully considered; for example, balancing the benefits of a potential for reduced hypoglycemia with GLP-1 receptor agonists against the higher incidence of GI adverse events.

The combination of GLP-1 receptor agonists with insulin is currently a very active topic of clinical research and is likely to become an important treatment strategy in the clinic over the next 5 years. Basal insulin and GLP-1 receptor agonists have compatible efficacy and safety profiles in terms of the balance between glycemic control, weight gain and risk of hypoglycemia. The GetGoal clinical trial program included a comprehensive assessment of this strategy and demonstrated significant clinical benefits in patients uncontrolled on basal insulin alone. Again, monitoring of patients’ glycemic profile, including relative contributions of FPG and PPG to overall control, will become increasingly important. Currently, strategies for targeting PPG include the addition of prandial insulin to basal insulin [16]. This might be achieved by administering short/rapid-acting insulin analogues before each meal or by b.i.d. administration of premixed insulin [16]. An alternative strategy is to administer a single injection of prandial insulin prior to the meal causing the largest PPG excursion, with additional prandial boluses added over time – known as the basal-plus strategy [16]. An area for research over the next 5 years will be to compare the benefits of GLP-1 receptor agonists versus prandial insulin in patients not optimally controlled with basal insulin.

GLP-1 receptor agonists, such as lixisenatide, have demonstrated efficacy and tolerability in different treatment regimens recommended for the management of T2DM, including as monotherapy, as add-on to OADs and in combination to basal insulin. There will be distinct groups of patients who will benefit from each of these strategies and, in line with a move towards more personalized therapy, further studies and observations from clinical practice are required to guide physicians’ decision-making in this area.

Table 1.  Summary of studies from the Phase III GetGoal clinical program that are included in this review.

Study (year)	Trial	Patients (n)	Patient demographics	Concomitant therapy	Treatment arms	Duration (weeks)^†	Study primary end point	Ref.
Fonseca et al. (2012)	GetGoal-Mono	361	52% male; mean age: 53–54 years; 73% Caucasian; 22% Asian		LIXI 20 µg q.d., one-step LIXI 20 µg q.d., two-step PBO	12	Mean change in HbA1c level (%) from baseline	[46]
Pinget et al. (2012)	GetGoal-P	484	52% male; mean age: 55–56 years; 84% Caucasian	Pioglitazone ± metformin	LIXI 20 µg q.d. PBO	24	Mean change in HbA1c level (%) from baseline	[50]
Bolli (2011)	GetGoal-F1	482	45% male; mean age: 55–58 years; 91% Caucasian	Metformin	LIXI 20 µg q.d., one-step LIXI 20 µg q.d., two-step PBO	24	Mean change in HbA1c level (%) from baseline	[47]
Aronson et al. (2011)	GetGoal-M	680	43% male; mean age: 55 years; 89% Caucasian	Metformin	LIXI 20 µg q.d., two-step, morning LIXI 20 µg q.d., two-step, evening PBO	24	Mean change in HbA1c level (%) from baseline	[48]
Ratner et al. (2011)	GetGoal-S	859	50% male; mean age: 57 years; 52% Caucasian; 45% Asian	Sulfonylurea ± metformin	LIXI 20 µg q.d., two-step PBO	24	Mean change in HbA1c level (%) from baseline	[49]
Rosenstock et al. (2011)	GetGoal-X	634	53% male; mean age: 57 years; 93% Caucasian	Metformin	LIXI 20 µg q.d., two-step, morning Exenatide 10 µg b.i.d.	24	Mean change in HbA1c level (%) from baseline (noninferiority)	[51]
Riddle et al. (2012)	GetGoal-L	493	46% male; mean age: 57–58 years; 77% Caucasian	Basal insulin ± metformin	LIXI 20 µg q.d., morning PBO	24	Mean change in HbA1c level (%) from baseline	[52]
Seino et al. (2012)	GetGoal-L Asia	311	48% male; mean age: 58 years; 100% Asian	Basal insulin ± sulfonylurea	LIXI 20 µg q.d., two-step, morning PBO	24	Mean change in HbA1c level (%) from baseline	[53]
Rosenstock et al. (2012)	GetGoal-Duo	446	50% male; mean age: 56 years; ethnicity not reported	Titrated insulin glargine; metformin ± thiazolidinedione	LIXI 20 µg q.d., morning PBO	24	Mean change in HbA1c level (%) from randomization	[54]

^†Duration over which primary end point was assessed.

b.i.d.: Twice daily; LIXI: Lixisenatide; PBO: Placebo; q.d.: Once daily.

Table 2. Incidence of hypoglycemic events in the GetGoal program (presented as percentage of patients experiencing events).

Study (year)	Concomitant therapy	Treatment arm	Any symptomatic hypoglycemia with BG <3.3 mmol/l (%)	Severe symptomatic hypoglycemia (%)	Ref.
GetGoal-Mono (2012)		LIXI 20 µg q.d., one-step	0.8	0	46]
		LIXI 20 µg q.d., two-step	2.5	0
		PBO	1.6	0
GetGoal-P (2012)	Pioglitazone ± metformin	LIXI 20 µg q.d.	3.4	0	[50]
		PBO	1.2	0
GetGoal-F1 (2011)	Metformin	LIXI 20 µg q.d., one-step	1.9	0	[47]
		LIXI 20 µg q.d., two-step	1.9	0
		PBO	0	0
GetGoal-M (2011)	Metformin	LIXI 20 µg q.d., two-step, morning	2.4	0	[48]
		LIXI 20 µg q.d., two-step, evening	5.1	0
		PBO	0.6	0
GetGoal-S (2011)	Sulfonylurea ± metformin	LIXI 20 µg q.d., two-step	12.2	0.2	[49]
		PBO	8.4	0
GetGoal-X (2011)	Metformin	LIXI 20 µg q.d., two-step, morning	2.2*	0	[51]
		Exenatide 10 µg b.i.d.	6.3	0
GetGoal-L (2012)	Basal insulin ± metformin	LIXI 20 µg q.d., morning	26.5	1.2	[52]
		PBO	21.0	0
GetGoal-L Asia (2012)	Basal insulin ± sulfonylurea	LIXI 20 µg q.d., two-step, morning	38.3	0	[53]
		PBO	20.4	0
GetGoal-Duo 1 (2012)	Titrated insulin glargine; metformin ± thiazolidinedione	LIXI 20 µg q.d., morning	20.2	0.4	[54]
		PBO	11.7	0

*p < 0.05 vs exenatide.

BG: Blood glucose; b.i.d.: Twice daily; LIXI: Lixisenatide; PBO: Placebo; q.d.: Once daily.

Table 3.  Incidence of gastrointestinal adverse events in the GetGoal program (presented as percentage of patients experiencing events).

Study (year)	OAD therapy	Treatment arm	Any GI event (%)	Nausea (%)	Diarrhea (%)	Vomiting (%)	Ref.
GetGoal-Mono (2012)		LIXI 20 µg q.d., one-step	31.9	20.2	NR	6.7	[46]
		LIXI 20 µg q.d., two-step	32.5	24.2	NR	7.5
		PBO	13.9	4.1	NR	0
GetGoal-P (2012)	Pioglitazone ± metformin	LIXI 20 µg q.d.	36.5	23.5	7.1	6.8	[50]
		PBO	28.6	10.6	10.6	3.7
GetGoal-F1 (2011)	Metformin	LIXI 20 µg q.d., one-step	41.6	26.1	6.2	11.8	[47]
		LIXI 20 µg q.d., two-step	47.2	35.4	12.4	15.5
		PBO	21.9	4.4	8.8	0
GetGoal-M (2011)	Metformin	LIXI 20 µg q.d., two-step, morning	36.5	22.7	10.6	9.4	[48]
		LIXI 20 µg q.d., two-step, evening	41.2	21.2	10.6	13.3
		PBO	25.9	7.6	8.8	2.9
GetGoal-S (2011)	Sulfonylurea ± metformin	LIXI 20 µg q.d., two-step	40.9	25.3	8.9	8.7	[49]
		PBO	20.0	7.0	6.7	3.5
GetGoal-X (2011)	Metformin	LIXI 20 µg q.d., two-step, morning	43.1	24.5*	10.4	10.1	[51]
		Exenatide 10 µg b.i.d.	50.6	35.1	13.3	13.3
GetGoal-L (2012)	Basal insulin ± metformin	LIXI 20 µg q.d., morning	40.2	26.2	7.3	8.2	[52]
		PBO	20.4	8.4	5.4	0.6
GetGoal-L Asia (2012)	Basal insulin ± sulfonylurea	LIXI 20 µg q.d., two-step, morning	61.0	39.6	6.5	18.2	[53]
		PBO	14.6	4.5	2.5	1.9
GetGoal-Duo 1 (2012)	Titrated insulin glargine; metformin ± thiazolidinedione	LIXI 20 µg q.d., morning	39.9	27.4	6.7	9.4	[54]
		PBO	16.1	4.9	3.1	1.3

*p < 0.05 vs exenatide.

b.i.d.: Twice daily; GI: Gastrointestinal; LIXI: Lixisenatide; NR: Not reported; OAD: Oral antidiabetic agent; PBO: Placebo; q.d.: Once daily.

Key issues

• • Traditional approaches used to complement basal insulin are often associated with side effects such as weight gain and an increased incidence of hypoglycemia.

• • Glucagon-like peptide-1 (GLP-1) receptor agonists represent an important treatment option for Type 2 diabetes mellitus, providing significant improvements in glycemic control with a low risk of weight gain and hypoglycemia.

• • Lixisenatide is a once-daily GLP-1 receptor agonist in late-stage clinical development; it is associated with enhanced insulin response to glucose and restoration of glucose disposition. Lixisenatide also suppresses glucagon secretion and significantly reduces the rate of gastric emptying.

• • Evidence from a comprehensive Phase III clinical trial program shows that lixisenatide is associated with improved glycemic control in patients failing oral therapy with significant improvements in HbA_1c, fasting plasma glucose and substantial improvements in postprandial glucose (PPG).

• • Lixisenatide is associated with good tolerability including a low risk of hypoglycemia, with the most frequent adverse events being gastrointestinal in nature.

• • Lixisenatide has also been extensively investigated in combination with basal insulin, showing significant improvements in HbA_1c and PPG levels with good tolerability.

• • The combination of basal insulin and a GLP-1 receptor agonist, such as lixisenatide, with PPG control may overcome some of the disadvantages of insulin therapy and could become an important treatment option for certain patient groups.

Financial & competing interests disclosure

D Raccah has been a member of advisory boards and speaker at symposia for Sanofi, Novo Nordisk, Eli Lilly, Merck Serono, Novartis, MSD, Bristol-Myers Squibb and Medtronic. He is associated with the UMR 1260 INRA-University Aix Marseille 1 and 2 unit and leads a clinical and biological research group in diabetes and nutrition in this unit as part of the Institute of Federal Research. Several studies are currently in progress, investigating nutritional status in patients with diabetic gastroparesis; calorimetry and impedance in obese patients; new treatments for Type 2 diabetes and the development of a ‘closed loop’ in the treatment of Type 1 diabetes (that is devices that combine a continuous measurement of glucose and infusion of insulin derived from artificial pancreatic β cells). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

The author would like to thank Frances Gambling BA, Medicus International (London, UK) for her editorial assistance, which was funded by Sanofi-Aventis.