Pharmacological profile, efficacy and safety of lixisenatide in type 2 diabetes mellitus

Abstract

Introduction: The global prevalence of type 2 diabetes mellitus (T2DM) is rapidly increasing and is associated with a high risk of microvascular and macrovascular complications. Although some glucose-lowering therapies are associated with hypoglycemia and weight gain, glucagon-like peptide-1 (GLP-1) receptor agonists represent a significant advance in the treatment of T2DM, as they provide effective glycemic control with a low incidence of hypoglycemia and a beneficial effect on body weight, as well as potential improvements in cardiovascular outcomes.

Areas covered: This article evaluates the pharmacological and clinical profile of the once-daily prandial GLP-1 receptor agonist lixisenatide for the treatment of T2DM.

Expert opinion: Once-daily prandial lixisenatide has been evaluated in an extensive clinical trials program, in which it was shown to have a favorable safety and tolerability profile, and to effectively improve metabolic control. The unique pharmacological properties of lixisenatide clearly differentiate it from other GLP-1 receptor agonists. As a once-daily agonist with a high affinity for the GLP-1 receptor, lixisenatide improves overall glycemic control, with particularly strong effects on postprandial plasma glucose levels. These attributes encourage the application of lixisenatide in those patients with extensive postprandial glucose excursions, or in combination with other antidiabetic drugs that have prevailing effects on fasting glucose levels.

Keywords::

• glucagon-like peptide-1 receptor agonist
• lixisenatide
• type 2 diabetes mellitus

1. Introduction

Inadequate glycemic control in patients with type 2 diabetes mellitus (T2DM) is associated with a risk for developing macrovascular and microvascular complications [1]. Cardiovascular disease (CVD) is the primary cause of death in patients with T2DM [2] and may reduce life expectancy by up to 10 years [3]. Furthermore, CVD accounts for a substantial component of healthcare expenditure associated with T2DM [4,5]. Although improved glycemic control goes some way to curb the risk of developing CVD, there are a number of other contributing factors [6]. Therefore, glucose-lowering agents that confer additional cardiovascular protection are of particular clinical relevance.

Problems associated with standard glucose-lowering therapies include weight gain (sulfonylureas, insulin, meglitinides, thiazolidinediones), hypoglycemia (sulfonylureas, insulin, meglitinides) and a need for multiple injections (insulin) [7,8], all of which highlight the need for alternative treatments. Incretin therapies represent a substantial advance in antidiabetic treatment, as they are rarely associated with severe hypoglycemia [9]. They can be broadly categorized into dipeptidyl peptidase-IV (DPP-IV) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. Although DPP-IV inhibitors appear to be weight-neutral, GLP-1 receptor agonists have been demonstrated to have a beneficial effect on body weight [10-12].

Native GLP-1 is secreted in anticipation of a meal and in response to food ingestion, and has been demonstrated to enhance insulin secretion and suppress glucagon release. GLP-1 has been shown to improve pancreatic beta-cell function, delay gastric emptying, promote satiety and confer a protective effect on the cardiovascular system [13-17]. In addition to these beneficial effects on the cardiovascular risk profile, there are preliminary reports indicating beneficial effects on diabetic nephropathy and psoriasis [18,19]. Native GLP-1, however, is rapidly degraded by the protease DPP-IV and would therefore require continual infusion to provide a therapeutic benefit for T2DM.

GLP-1 receptor agonists mimic many of the biological actions of endogenous GLP-1, but benefit from extended half-lives [10,20]. They can be characterized as being short-acting or long-acting agents, based on their pharmacokinetic profile. Short-acting GLP-1 receptor agonists predominantly have an effect on postprandial plasma glucose (PPG), whereas long-acting agents primarily affect fasting plasma glucose (FPG). Historically, FPG has always been an important target in achieving normoglycemia, yet PPG is increasingly recognized for its significant contribution to overall glycemic control and to the development of diabetes-related complications [21,22]. As a result, PPG is now accepted to be a crucial therapeutic target for improving glycemic control in patients with T2DM.

The first marketed GLP-1 receptor agonist was the short-acting agent exenatide immediate release (IR), which has a mean half-life of 2.4 h and is given as a twice-daily (BID) subcutaneous injection [23]. Exenatide is a synthetic version of exendin-4, a natural GLP-1 receptor agonist that is derived from the salivary glands of the Gila monster and that shares 53% homology with human GLP-1 [24]. Currently marketed long-acting agents include liraglutide and exenatide long-acting release (LAR). Liraglutide, which shares 97% homology with human GLP-1, has a half-life of 11 – 13 h and is suitable for once-daily (QD) subcutaneous injection [25]. Exenatide-LAR is composed of microspheres encapsulating the exenatide peptide, and is suitable for once-weekly subcutaneous injection [26]. This article summarizes the pharmacological and clinical profile of the once-daily prandial GLP-1 receptor agonist lixisenatide (Box 1) [27] for the treatment of T2DM.

Box 1. Drug summary.

Drug name	Lixisenatide
Phase	Approved in Europe and Japan; under review in the United States
Indication	T2DM
Pharmacology description	Glucagon-like peptide-1 receptor agonist
Route of administration	Subcutaneous injection
Chemical formula	H2N–HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGP SSGAPPSKKKKKK–CONH2
Pivotal trial(s)	[35,41]

2. Profile of lixisenatide

2.1 Introduction to the compound

Lixisenatide is a once-daily prandial GLP-1 receptor agonist that is administered 20 µg QD by subcutaneous injection. It has a distinct structure and pharmacokinetic profile [27] that confers a unique duration of action, efficacy and safety profile compared with the other GLP-1 receptor agonists [20].

2.2 Chemical structure

Lixisenatide is a 44-amino-acid peptide based on exendin-4, which differs in structure through the deletion of a proline residue and the addition of six lysine residues at the C terminus. The amino-acid sequence for lixisenatide is shown in Figure 1.

Figure 1. Structure of lixisenatide. The amino-acid sequence for lixisenatide and native human GLP-1. The amino acids highlighted in dark grey represent differences in the structure of lixisenatide compared with native GLP-1. Dipeptidyl peptidase-IV (DPP-IV) rapidly cleaves and inactivates native GLP-1 at the indicated site.

2.3 Pharmacokinetic and pharmacodynamic profile

Lixisenatide is recommended for once-daily dosing, despite its relatively short half-life, owing to its high affinity for the GLP-1 receptor. Preclinical studies in Chinese hamster ovary (CHO) cells overexpressing human GLP-1 receptor have demonstrated that lixisenatide has a median inhibitory concentration (IC₅₀) for the GLP-1 receptor of 1.43 nM, which is approximately four-fold greater than that of native GLP-1 [28]. Radiolabelling studies suggest that the binding affinity of lixisenatide is higher than that of exenatide or liraglutide, although no direct comparison has been made [20,29].

Lixisenatide is thought to undergo renal filtration and proteolytic degradation. A Phase I, open-label study demonstrated that lixisenatide clearance was not significantly altered in patients with mild or moderate renal function (creatinine clearance 50 – 80 ml/min) compared with patients with normal function. In contrast, clearance was reduced by ∼30% in patients with severe renal impairment (creatinine clearance < 30 ml/min) [30].

A Phase II, 28-day, dose-escalation study assessed the effects of 5 – 20 µg lixisenatide QD or BID, in combination with metformin and/or sulfonylurea, in 64 patients with T2DM [31]. Mean apparent clearance (CL/F) was 21 – 29 L/h. Mean area under the curve (AUC) and peak plasma concentration (C_max) were demonstrated to increase in a dose-dependent manner (at 20 µg QD, AUC was 847.8 h·pg/ml and C_max was 187.2 pg/ml). At the 20 µg dose, the median time to maximal concentration (t_max) was 1.25 h for both the once-daily and twice-daily regimens. In contrast, the half-life (t_1/2) was slightly affected by the frequency of dosing, with a median t_1/2 of 2.8 and 3.2 h with once-daily and twice-daily administration, respectively, at the 20 µg dose.

2.4 Clinical trials program

The efficacy, safety and tolerability of lixisenatide once-daily was examined in the Phase III ‘GetGoal' program, which comprised 11 randomized controlled studies and involved > 5000 adults with T2DM. So far, nine of these trials have been published (Table 1), including the effects of lixisenatide once-daily in monotherapy [32], with oral antidiabetic agents (OADs; metformin, sulfonylureas or thiazolidinediones) [33,34], or basal insulin glargine [35-37], as well as in direct comparison with exenatide [38]. In addition, lixisenatide was directly compared with liraglutide in a randomized, Phase II study [39]. The evidence from the GetGoal program demonstrates that lixisenatide once-daily effectively lowers blood glucose levels, predominantly by reducing PPG. Lixisenatide's postprandial effect is predominantly pronounced for the first meal following injection. However, a recent study has shown that once-daily lixisenatide in the morning reduces PPG levels throughout the day. Further, the reduction in PPG at least after breakfast was attributable to a delay in gastric emptying [40].

Table 1. Summary of the Phase III GetGoal clinical trials.

Study	N *	Main study period (weeks)	Background treatment	HbA1c (%) Δ, p value	PPG (mmol/l) Δ, p value	FPG (mmol/l) Δ, p value	LS mean change in weight (kg)		^‡Symptomatic hypoglycemia (%)		^§Severe hypoglycemia (%)		Any AE (%)		Any serious AE (%)
							LIXI	PBO/Comp	LIXI	PBO/Comp	LIXI	PBO/Comp	LIXI	PBO/Comp	LIXI	PBO/Comp
GetGoal-Mono 1-step: 2-step: [32]	361	12	None	–0.7, p < 0.0001 –0.5, p < 0.0001	–5.5, p < 0.0001 –4.5, p < 0.0001	–1.1, p < 0.0001 –0.9, p < 0.0001	∼ –2 ∼ –2	∼ –2	0.8 2.5	1.6	0 0	0	54.6 52.5	45.1	0 0.8	4.1
GetGoal-M AM: PM: [33]	680	24	MET	–0.5, p < 0.0001 –0.4, p < 0.0001	–4.5, p < 0.0001 NR	–0.9, p < 0.0001 –0.6, p = 0.0046	–2.0 –2.0	–1.6	2.4 5.1	0.6	0 0	0	69.4 69.4	60.0	2.0 3.1	1.2
GetGoal-F1 1-step: 2-step: [41]	482	24	MET	–0.5, p < 0.0001 –0.4, p < 0.0001	NR	–0.7, p = 0.0007 –0.7, p = 0.0004	–2.6^# –2.7^#	–1.6	1.9 2.5	0.6	0	0	67.7 70.8	65.6	3.1 4.3	2.5
GetGoal-X^¶ [38]	634	24	MET	0.2, 95% CI: 0.03 – 0.30	NR	0.2, 95% CI: –0.05 – 0.52	–3.0	–4.0	2.5	7.9	0	0	69.5	72.2	2.8	2.2
GetGoal-P [34]	484	24	PIO ± MET	–0.6%, p < 0.0001	NR	–0.8, p < 0.0001	–0.2	0.2	3.4	1.2	0	0	72.4	72.7	2.5	1.9
GetGoal-S [42]	859	24	SU ± MET	–0.7, p < 0.0001	–6.0, p < 0.0001	–0.6, p < 0.0001	–1.8^#	–0.9	15.3	12.3	0.2	0	68.3	61.1	3.5	5.6
GetGoal- L-Asia [35]	311	24	Basal insulin ± SU	–0.9, p < 0.0001	–7.8, p < 0.0001	–0.7, p = 0.0187	–0.4	0.1	42.9	23.6	0	0	89.0	70.1	6.5	5.7
GetGoal-L [37]	495	24	Basal insulin ± MET	–0.4%, p = 0.0002	–3.8, p < 0.0001	–0.1, p = 0.7579	–1.8^#	–0.5	26.5	21.0	1.2	0	73.5	68.3	3.7	4.2
GetGoal- Duo1 [36]	446	24	Basal insulin + MET ± TZDs	–0.3, p < 0.0001	–3.2, p < 0.0001	–0.1, p = 0.5142	0.3^#	1.2	20.2	11.7	0.4	0	79.8	68.2	7.6	4.5

*Number of randomized patients.

^‡Event with clinical symptoms with either plasma glucose < 3.3 mmol/l or prompt recovery after oral carbohydrate administration.

^§Symptomatic hypoglycemia that required the assistance of another person.

^¶Comparator was exenatide immediate release.

^#Statistically significant reduction in body weight versus placebo.

Δ, LS mean difference versus placebo/comparator; AEs, adverse events; AM, morning injection of lixisenatide; Comp, comparator; FPG, fasting plasma glucose; HbA_1c, glycated hemoglobin; LIXI, lixisenatide; LS, least squares; MET, metformin; NR, not reported; PBO, placebo; PIO, pioglitazone; PM, evening injection of lixisenatide; PPG, postprandial glucose; SU, sulfonylurea; TZD, thiazolidinediones.

2.4.1 Lixisenatide monotherapy

The effect of lixisenatide once-daily administered as monotherapy was evaluated in a 12-week, randomized, double-blind study (GetGoal-Mono) [32]. A total of 361 patients with T2DM were assigned to receive lixisenatide or placebo in a one-step or two-step dose-increase regimen. Lixisenatide treatment significantly reduced glycated hemoglobin (HbA_1c) levels (least squares (LS) mean difference vs placebo: –0.5% (2-step) and –0.7% (1-step); p < 0.0001) and enabled a significantly higher proportion of patients to achieve HbA_1c ≤ 6.5 (31.9% (2-step) and 25.4% (1-step) vs 12.5% with placebo; p < 0.01) and HbA_1c < 7% (52.2% (2-step) and 46.5% (1-step) vs 26.8% with placebo; p < 0.01). There was a highly statistically significant reduction in PPG levels with lixisenatide (–4.5 (2-step) and –5.5 (1-step) vs –0.7 mmol/l with placebo; p < 0.0001). FPG levels were significantly decreased in lixisenatide-treated patients (LS mean change vs placebo: –0.9 mmol/l (2-step); p < 0.001 and –1.1 mmol/l (1-step); p < 0.0001).There was a reduction in body weight of ∼2 kg in all groups, with no significant difference between lixisenatide and placebo. Lixisenatide was generally well tolerated, with no significant differences between the 2-step and 1-step dose regimens (adverse events (AEs): 52.5% 2-step, 54.6% 1-step vs 45.1% placebo; serious AEs: 0.8% 2-step, 0.0% 1-step vs 4.1% placebo). In total, eight patients in the lixisenatide group and one patient in the placebo group discontinued treatment during the study due to a treatment-emergent AE (TEAE; 4.2% 2-step, 2.5% 1-step vs 0.8% placebo), mostly due to gastrointestinal (GI) events. The most common AEs in the lixisenatide group were GI in nature, with nausea being the most frequent AE (lixisenatide combined 22.1% vs placebo 4.1%). Nausea events were generally mild-to-moderate in intensity and were reported more frequently during the first 3 weeks of treatment, with a reduced occurrence from Week 7 to the end of treatment. There was also a higher incidence of vomiting in the lixisenatide group compared with the placebo group (7.1% lixisenatide combined vs 0.0% placebo). Symptomatic hypoglycemia occurred in 1.7% of patients in the lixisenatide group compared with 1.6% in the placebo group, with no severe episodes. There were no reports of suspected pancreatitis during the study. Injection-site reactions were reported by 4.6% of patients in the lixisenatide group and none in the placebo group, with no serious or severe events reported.

2.4.2 Lixisenatide in combination with metformin

Lixisenatide treatment in combination solely with metformin was assessed in three studies: GetGoal-M, GetGoal-F1 and GetGoal-X. GetGoal-M was a randomized, double-blind, 24-week study in 680 patients comparing morning (AM) and evening (PM) doses of lixisenatide versus placebo [33]. Both the lixisenatide morning and evening doses significantly reduced HbA_1c levels compared with placebo (LS mean change: –0.9% AM, –0.8% PM vs –0.4% with placebo), and enabled almost twice as many patients to achieve an HbA_1c level of < 7% (43% AM or 41% PM vs 22% with placebo). Lixisenatide significantly reduced FPG compared with placebo (p < 0.005). The lixisenatide AM group also significantly decreased PPG versus the placebo AM regimen (LS mean difference: –4.5 mmol/l; p < 0.0001). Body weight was reduced in all groups, with no significant difference between lixisenatide and placebo (–2 vs –1.6 kg, respectively). Lixisenatide was well tolerated, with a comparable number of AEs and serious AEs between the groups (AEs: 69.4% AM, 69.4% PM vs 60.0% with placebo; serious AEs: 2.0% AM, 3.1% PM vs 1.2% with placebo). Discontinuations due to AEs were reported in 7.1% of patients in the lixisenatide AM group and in 5.5% of patients in the lixisenatide PM group, compared with 1.2% in the placebo group. The most common TEAE in the lixisenatide group was nausea (22.7% AM, 21.2% PM vs 7.6% with placebo), which generally occurred more frequently during the first 5 – 6 weeks. The majority of nausea events were mild-to-moderate in intensity, with no serious TEAEs reported. Vomiting occurred in 9.4% (AM) and 13.3% (PM) of patients in the lixisenatide group versus 2.9% of patients in the placebo group. Diarrhea was reported for 10.6% of both lixisenatide regimens compared with 8.8% of patients in the placebo group. Symptomatic hypoglycemia occurred in 2.4% (AM) and 5.1% (PM) of patients in the lixisenatide group, compared with 0.6% in the placebo group. There were no severe episodes.

GetGoal-F1 was a randomized, double-blind, placebo-controlled, 24-week study that compared lixisenatide administered in a 1-step or 2-step dose-increase regimen in 482 patients with T2DM [41]. Lixisenatide was demonstrated to significantly reduce HbA_1c levels at Week 24 (p < 0.0001) and enabled a significantly higher proportion of patients to achieve HbA_1c ≤ 6.5% and < 7% (p < 0.001). Significant improvements in FPG and body weight were associated with lixisenatide treatment compared with placebo. The overall incidence of AEs was 70.8% (2-step), 67.7% (1-step) versus 65.6% (placebo), with serious AEs reported in 4.3% (2-step), 3.1% (1-step) versus 2.5% (placebo) of patients. There was one AE leading to death, which occurred in the lixisenatide 1-step group. Discontinuations due to AEs occurred in 8.1% of patients in the 2-step group, and 5.6% of patients in the 1-step group, compared with 2.5% of patients in the placebo group. The most frequent AE reported with lixisenatide was nausea (35.4% (2-step) and 26.1% (1-step) vs 4.4% with placebo) and vomiting (15.5% (2-step) and 11.8% (1-step) vs 0% with placebo). There was no significant difference in the incidence of symptomatic hypoglycemia in the lixisenatide groups compared with placebo (2.5% (2-step) and 1.9% (1-step) vs 0.6%, respectively), and no cases of severe hypoglycemia.

The GetGoal-X randomized, open-label study directly compared lixisenatide once-daily treatment with exenatide twice-daily treatment, in patients with T2DM inadequately controlled on metformin [38]. A total of 634 patients were randomized to receive lixisenatide 20 μg QD (n = 318) or exenatide 10 μg BID (n = 316). Lixisenatide achieved its primary outcome of noninferiority in HbA_1c reduction from baseline at Week 24. Both the proportion of patients achieving HbA_1c < 7.0% and the level of FPG reduction were comparable between the two groups. Mean body weight decreased from baseline in both groups (94.5 to 91.7 kg with lixisenatide vs 96.7 to 92.9 kg with exenatide). The incidence of AEs and serious AEs were similar between lixisenatide and exenatide groups (AEs: 69.5% vs 72.2%; serious AEs: 2.8% vs 2.2%, for lixisenatide and exenatide, respectively). There were two deaths during the study – one in the lixisenatide group and one in the exenatide group. Discontinuations due to AEs were slightly lower in the lixisenatide group (10.4% vs 13.0% with exenatide) and were mainly due to GI events. Overall GI tolerability appeared to be slightly better for lixisenatide compared with exenatide, with fewer patients experiencing nausea (24.5% vs 35.1%, respectively). Vomiting occurred in 10.1% of patients in the lixisenatide group compared with 13.3% of patients in the exenatide group. Lixisenatide treatment was associated with a significantly lower incidence of symptomatic hypoglycemia, with six-fold fewer hypoglycemic events compared with exenatide. There were no cases of severe hypoglycemia. A higher proportion of patients in the lixisenatide group tolerated the targeted maintenance dose of 20 μg/day (93% vs 83% with exenatide). A total of 0.9% of patients in the lixisenatide group had injection-site reactions that led to discontinuation of study treatment, none of which were serious or considered severe by the investigator. No allergic reactions adjudicated as possibly related to treatment were reported in either of the treatment groups. A TEAE of blood calcitonin of ≥ 20 ng/l was reported for 0.3% of patients in each treatment group, with none of the events being serious or considered to be severe by the investigator, and no events of calcitonin ≥ 50 ng/l were reported. No clinically relevant changes in creatinine, aspartate aminotransferase and alanine aminotransferase were observed in either treatment group. No cases of pancreatitis were reported.

2.4.3 Lixisenatide in combination with pioglitazone

GetGoal-P assessed lixisenatide treatment in combination with pioglitazone with or without metformin [34]. In this 24-week, double-blind study, 484 patients were randomized to receive either lixisenatide 20 µg QD (n = 323) or placebo (n = 161). Lixisenatide significantly reduced HbA_1c compared with placebo (LS mean difference: –0.6%; p < 0.0001) and enabled a significantly higher proportion of patients to achieve HbA_1c ≤ 6.5% (28.9% vs 10.1% with placebo) and < 7% (52% vs 26% with placebo). Lixisenatide was associated with a significant improvement in FPG (LS mean difference: –0.8 mmol/l vs placebo; p < 0.0001). There was a small reduction in body weight with lixisenatide (–0.2 kg) and a small increase with placebo (+0.2 kg), with no significant difference between the groups. The incidence of AEs and serious AEs was 72.4% and 2.5% with lixisenatide versus 72.7% and 1.9% with placebo, respectively. There were two deaths in the study, both in the placebo group. The most commonly reported AEs in the lixisenatide group were GI in nature, mostly nausea (23.5% vs 10.6% with placebo). Events of nausea were generally mild-to-moderate in intensity and usually occurred during the first week of treatment and in the week following each increase in dose. Diarrhea occurred in 7.1% of patients in the lixisenatide group versus 10.6% in the placebo group, with vomiting reported for 6.8% versus 3.7%, respectively. The occurrence of symptomatic hypoglycemia was low in both groups (3.4% with lixisenatide vs 1.2% with placebo), with no severe episodes being reported. Events of allergic reaction were reported for nine patients (2.8%) in the lixisenatide group versus three patients (1.9%) in the placebo group. Of these, three patients (0.9%) in the lixisenatide group reported five events that were adjudicated as possibly related to treatment. Injection-site reactions were reported for 6.8% of patients in the lixisenatide group and 5.0% in the placebo group, none of which were serious or severe in intensity, or led to permanent treatment discontinuation. No confirmed diagnoses of pancreatitis were reported in either treatment group.

2.4.4 Lixisenatide in combination with sulfonylurea

The efficacy and safety of lixisenatide in combination with sulfonylurea with or without metformin was assessed in a 24-week, randomized, double-blind, placebo-controlled study (GetGoal-S) [42]. A total of 859 patients with T2DM were assigned to receive either lixisenatide 20 μg QD (n = 573) or placebo (n = 286) in a 2-step dose-increase regimen. Lixisenatide treatment was associated with a significant reduction in HbA_1c (–0.9% vs –0.1% with placebo; p < 0.0001) and enabled a significantly higher proportion of patients to reach HbA_1c < 7% (36.4% vs 13.5%; p < 0.0001). Patients treated with lixisenatide had significant decreases in PPG and FPG levels (p < 0.0001 for both), and experienced a significant reduction in body weight (–1.8 vs –0.9 kg with placebo; p < 0.0001). The overall incidence of AEs was 68.3% with lixisenatide versus 61.1% with placebo, with serious AEs reported for 3.5% versus 5.6% of patients, respectively. AEs leading to discontinuation of treatment occurred in 9.8% of patients in the lixisenatide group compared with 4.9% of patients in the placebo group. There was a higher incidence of AEs relating to GI events in the lixisenatide group, mainly nausea (25.3% vs 7.0% with placebo) and vomiting (8.7% vs 3.5% with placebo). The incidence of symptomatic hypoglycemia was 15.3% with lixisenatide compared with 12.3% with placebo. There was one case (0.2%) of severe hypoglycemia in the lixisenatide group and none in the placebo group.

2.4.5 Lixisenatide treatment in combination with basal insulin

The effects of lixisenatide treatment in combination with basal insulin glargine were evaluated in three separate studies: GetGoal-L-Asia, GetGoal-L and GetGoal-Duo1. GetGoal-L-Asia was a 24-week, randomized, double-blind, placebo-controlled study in Asian patients with T2DM inadequately controlled on basal insulin with or without sulfonylurea [35]. A total of 311 patients from Japan, the Republic of Korea, Taiwan and the Philippines were randomized to receive either lixisenatide (n = 154) or placebo (n = 157). Lixisenatide treatment significantly reduced HbA_1c levels compared with placebo (LS mean difference vs placebo: –0.9%; p < 0.0001) and enabled a significantly higher proportion of patients to achieve HbA_1c ≤ 6.5% (17.8% vs 1.3%) and < 7% (35.6% vs 5.2%). Notable reductions in PPG levels were reported with lixisenatide treatment versus placebo (LS mean difference: –7.8 mmol/L, p < 0.0001). A possible explanation for the marked improvements in HbA_1c and PPG levels observed in this study may be the difference in the pathophysiology of T2DM in Asian people, which is characterized by reduced insulin secretion rather than insulin resistance [43], as well as a GLP-1 deficiency [44]. FPG and glucose excursions were also significantly improved with lixisenatide versus placebo. Mean changes in body weight were small, with no significant differences between the two groups (LS mean change: –0.4 kg with lixisenatide vs +0.1 kg with placebo, p = 0.0857). AEs were reported for 89.0% of patients in the lixisenatide group versus 70.1% of patients in the placebo group. Serious AEs occurred in 6.5% of patients treated with lixisenatide and 5.7% of patients receiving placebo. A higher proportion of patients discontinued treatment due to AEs in the lixisenatide group (9.1% vs 3.2% with placebo), which were mainly GI in nature. There was a higher incidence of nausea and vomiting in the lixisenatide group compared with the placebo group (nausea: 39.6% vs 4.5%; vomiting: 18.2% vs 1.9%). The incidence of symptomatic hypoglycemia was higher in the lixisenatide group compared with placebo (42.9% vs 23.6%), but was similar between groups in patients not receiving sulfonylureas (32.6% vs 28.3%). There were no episodes of severe hypoglycemia reported. No pancreatitis was reported during this study. Injection-site reactions were reported for two patients (1.3%) in each of the treatment groups, with none of these reactions considered serious or severe or leading to treatment discontinuation. Seven possible allergic reactions were reported during the study (five events in the lixisenatide group and two events in the placebo group), with one of these events (urticaria, in the lixisenatide group) adjudicated as an allergic reaction possibly related to study medication.

In GetGoal-L, 495 patients (predominantly Caucasian (78%)) with T2DM inadequately controlled on basal insulin with or without metformin, were randomized 2:1 to receive either lixisenatide or placebo for 24 weeks [37]. Lixisenatide treatment significantly improved HbA_1c levels at Week 24 (–0.4% vs placebo) and enabled a significantly higher proportion of patients to reach target HbA_1c levels of < 7% (28% vs 12% with placebo; p < 0.0001). PPG levels were significantly lower in the lixisenatide group compared with the placebo group at Week 24 (–3.8 mmol/l vs placebo; p < 0.0001). Reductions in body weight (–1.3 kg vs placebo; p < 0.0001) and insulin dosage (–3.7 units/day vs placebo; p = 0.012) were more marked in patients treated with lixisenatide. TEAEs occurred in 73.5% of patients in the lixisenatide group compared with 68.3% of patients in the placebo group, with serious TEAEs reported for 3.7% versus 4.2% of patients, respectively. There was one TEAE leading to death in the lixisenatide group. A total of 7.6% of lixisenatide-treatment patients and 4.8% of placebo-treated patients had a TEAE leading to discontinuation. The most frequent AEs with lixisenatide were GI in nature (40.2% vs 20.4% with placebo). Nausea occurred in 26.2% versus 8.4% of patients in the lixisenatide and placebo groups, respectively. The incidence of hypoglycemia was 28% with lixisenatide compared with 22% with placebo. Four patients (1.2%) in the lixisenatide group, and no patients in the placebo group, experienced severe hypoglycemia. Injection-site reactions were reported for four patients (1.2%) in the lixisenatide group compared with one patient (0.6%) in the placebo group. None of these events were considered severe by the investigator and no participant discontinued as a result. The occurrence of events adjudicated as allergic reactions was 1.5% in the lixisenatide group and 1.8% in the placebo group, three of which were considered to be possibly related to treatment (two events in the lixisenatide group vs one event in the placebo group). No confirmed cases of acute pancreatitis were reported.

GetGoal-Duo1 evaluated the effects of lixisenatide in combination with titrated basal insulin glargine in patients with T2DM inadequately controlled on metformin with or without sulfonylureas/thiazolidinediones [36]. Sulfonylurea treatment was discontinued during the screening phase, after which insulin glargine was titrated during a 12-week run-in phase. Patients with a FPG of 80 – 100 mg/dl who had an HbA_1c ≥ 7 and ≤ 9% were then randomized to lixisenatide (n = 223) or placebo (n = 223) for 24 weeks, during which time insulin glargine titration continued. Lixisenatide significantly reduced HbA_1c compared with placebo (LS mean difference: –0.3%; p < 0.0001), and enabled more patients to achieve HbA_1c < 7.0% (56% vs 39% with placebo). PPG levels were significantly improved in the lixisenatide group compared with the placebo group. There was a beneficial effect on body weight with lixisenatide treatment (LS mean difference vs placebo: –0.9 kg; p = 0.0012), despite insulin glargine titration. TEAEs occurred in 79.8% of patients in the lixisenatide group compared with 68.2% of patients in the placebo group, with serious TEAEs reported for 7.6% versus 4.5%, respectively. There were two TEAEs leading to death during the study, both in the placebo group. The most common AEs in the lixisenatide group were GI events, with a higher incidence of nausea and vomiting versus placebo (nausea: 27.4% vs 4.9%; vomiting: 9.4% vs 1.3%, respectively). Two participants in the lixisenatide group (0.9%) and one in the placebo group (0.4%) had an allergic reaction adjudicated as possibly related to study treatment. Fifteen patients (6.7%) in the lixisenatide group and five (2.2%) in the placebo group had injection-site reactions; two patients treated with lixisenatide discontinued for this reason. One patient in the placebo group had a TEAE of pancreatitis, compared with none in the lixisenatide group.

2.4.6 Lixisenatide versus liraglutide (Phase II study)

Lixisenatide once-daily (n = 77) was directly compared with liraglutide once-daily (n= 71) in a 28-day, randomized, open-label, Phase II study in patients with T2DM insufficiently controlled on metformin [39]. The primary endpoint was change in PPG from baseline to Day 28. Lixisenatide significantly reduced PPG compared with liraglutide (mean change in ΔAUC_0:30–4:30h: –12.6 vs –4.0 h·mmol/l, respectively; mean difference vs liraglutide: –8.6 h.mmol/l; p < 0.0001). Maximum PPG excursion also significantly decreased in the lixisenatide group (mean difference vs liraglutide: –2.5 mmol/l; p < 0.0001). FPG and HbA_1c were reduced in both treatment groups, but with a significantly greater effect with liraglutide (FPG: –0.3 vs –1.3 mmol/l, p < 0.0001; HbA_1c: –0.3 vs –0.5%, p < 0.01 with lixisenatide and liraglutide, respectively). Glucagon levels were lower with lixisenatide compared with liraglutide (mean difference: –21.4 h·ng/l; p < 0.05). The frequency of AEs was 58% for lixisenatide versus 73% for liraglutide, with no serious AEs reported during the study. AEs leading to treatment discontinuation occurred in 2.6% of patients in the lixisenatide group versus 2.8% in the liraglutide group. There was a lower incidence of GI disorders in the lixisenatide group (36.4% vs 46.5% with liraglutide). The frequency of nausea was similar between the two groups (22.1% with lixisenatide versus 22.5% with liraglutide), with a lower incidence of diarrhea in patients taking lixisenatide (2.6% vs 15.5% with liraglutide). There were no events of symptomatic hypoglycemia in either group.

2.4.7 Lixisenatide treatment in elderly patients

The effect of once-daily lixisenatide treatment in elderly (aged ≥ 65 years; n = 612) and very elderly (aged ≥ 75 years; n = 59) patients was evaluated in a pooled analysis of six Phase III studies (GetGoal-Mono, -M, -F1, -S, -L and -L-Asia) [45]. Lixisenatide was effective and well tolerated in elderly and very elderly patients. HbA_1c reductions were comparable in patients aged ≥ 65 years compared with patients aged < 65 years, with significantly greater reductions versus placebo in both age categories. The lixisenatide safety profile was comparable regardless of age (overall AEs: 72% (≥ 65 years) vs 69% (< 65 years) and 73% (≥ 75 years) and 69% (< 75%); GI events: 43% (≥ 65 years) vs 41% (< 65 years) vs 46% (≥ 75 years) vs 41% (< 75%)). There was no relevant difference in the incidence of symptomatic hypoglycemia between the different age groups. These results are particularly relevant as, owing to improved life expectancy, the number of elderly people with T2DM is increasing. Furthermore, owing to the increased number of comorbidities typically observed in elderly patients with T2DM, the efficacy and tolerability profile of lixisenatide may be particularly suitable for this patient group.

2.5 Beyond glycemic control

In addition to its role in lowering blood glucose levels, lixisenatide has a number of interesting properties that may be beneficial in the treatment of T2DM (Table 2). The data in this section is a combination of in vivo, in vitro, animal and human data.

Table 2. Biological actions of native GLP-1 and lixisenatide.

Biological effect	Native GLP-1	Lixisenatide
Postprandial glucose	Reduced [89]	Markedly reduced [32,33,35,42]
Fasting plasma glucose	Reduced [90]	Moderately reduced [32-35,41,42]
Glucagon secretion	Reduced [90]	Reduced [39]
Gastric emptying	Delayed but with tachyphylaxis [70]	Delayed [40,69]
Body weight	Beneficial effect [91]	Beneficial effect [36,37,41,42]
Pancreatic beta-cell protection	Increased [92]	Increased [85,88]
Pancreatic beta-cell insulin mRNA expression	Increased [93]	Increased [28]
Glucose-stimulated insulin secretion	Increased [94]	Increased [86]
Biphasic insulin responses	Restored [95]	Restored [86,87]
Cardioprotection	Increased [15,46]	Increased [39,53,54,88]

GLP-1, glucagon-like peptide-1.

2.5.1 Cardioprotective effect

GLP-1 acts through a distinct heptahelical G-protein-coupled receptor, which has been located in beta-cells and the GI tract, as well as in the nervous system, heart, vascular smooth muscle cells, endothelial cells and macrophages [46-49]. GLP-1 appears to modulate a wide range of physiological effects, not only regulating blood glucose and metabolic control, but also directly affecting several cardiovascular pathways that are involved in atherogenesis (Figure 2). The binding of GLP-1 to the GLP-1 receptor in the myocardium leads to an increase in the production of cyclic adenosine monophosphate (cAMP) and the activation of protein kinase A (PKA), which results in an increase in glucose uptake and the inotropic effects in myocardial tissue. GLP-1 knockout mice exhibit reduced resting heart rate, elevated left ventricular and diastolic pressure and increased left ventricular thickness compared with normal controls [46]. In agreement with these findings, treatment with GLP-1 or GLP-1 receptor agonists was found to improve left ventricular function [15,50] and to reduce circulating levels of brain natriuretic peptide BNP; a biomarker for heart failure [51,52].

Figure 2. GLP-1-mediated regulation of atherogenesis. GLP-1 directly targets endothelial cells, smooth muscle cells and macrophages to potentially reduce atherosclerotic plaque development.

Lixisenatide has been shown to protect against myocardial ischemia-reperfusion (I/R)-induced injury ex vivo, in Langendorff-perfused isolated rat hearts. In this study, I/R-induced injury was reduced by almost 40% with lixisenatide treatment compared with placebo [53]. In an in vivo study performed in male Wistar rats, the effects of chronic lixisenatide treatment on cardiovascular outcomes were investigated, following I/R-induced injury of the left coronary artery [54]. Lixisenatide significantly reduced I/R-induced injury by improving diastolic function, reducing myocardial relaxation and decreasing lung weight (a measure of congestion) compared with control. Lixisenatide treatment also significantly decreased ventricular wall thickness and lowered plasma BNP levels.

Compared with liraglutide, lixisenatide may differentiate with some effects on myocardial physiology [39]. Supine heart rate decreased with lixisenatide by 3.6 beats per minute (bpm) and increased with liraglutide by 5.3 bmp over the 28-day treatment period (mean difference (95% CI): 8.9 bpm (–12.2, –5.6)), which is consistent with previous reports of an increase in heart rate with liraglutide [55]. The mechanism underlying the differential effects on heart rate of these two agents remains elusive and requires further investigation.

There is increasing evidence of the direct effects of GLP-1 on endothelium and vascular smooth muscle cells (Figure 2) [46,56-58]. In human vascular endothelial cells, GLP-1 receptor agonist treatment has been shown to cause endothelial nitric oxide synthase (eNOS) phosphorylation and potentiated eNOS activity, with increased nitric oxide (NO) production [59]. In healthy nondiabetic subjects, GLP-1 enhanced the endothelium-mediated increase in forearm blood flow [56]. In patients with T2DM and coronary artery disease, infusion of GLP-1 increased flow-mediated vasodilatation in the brachial artery, affirming a NO-dependent mechanism of GLP-1 in the vascular system [60]. Treatment with GLP-1 receptor agonists has been consistently demonstrated to reduce blood pressure [61-65]. Interestingly, the reduction of blood pressure in most studies occurred before weight reduction could be achieved. The mechanisms beyond the blood pressure-lowering effects of GLP-1 are still unclear, but in addition to changes in the release of adipokines from the adipose tissue, these may be attributed to direct vasodilatory effects [46] and renal natriuretic effects [66]. A recent metaanalysis assessing the cardiovascular outcomes of patients with T2DM treated with GLP-1 receptor agonists in clinical trials up to November 2010 revealed a significantly lower rate of major cardiovascular events in GLP-1 receptor agonist-treated patients compared with placebo-treated patients [67]. It remains unclear, however, whether this reduction in cardiovascular morbidity was due to direct myocardial effects or to improvements in glycemic control.

Taken together, these studies indicate that both GLP-1 and lixisenatide may have additional cardiovascular benefits beyond their effects on glycemic control. Clinical studies investigating these CV effects are currently ongoing and include the Phase III ELIXA trial, which is due for completion in May 2014 [68]. This randomized, double-blind, placebo-controlled study aims to assess whether lixisenatide treatment can improve cardiovascular outcomes in up to 6000 patients with T2DM, who have recently experienced an acute coronary syndrome (ACS) event.

2.5.2 Slowing of gastric emptying

Several studies have demonstrated that lixisenatide delays gastric emptying, which is a key mechanism in PPG reduction. In normoglycemic dogs, lixisenatide was shown to decrease plasma glucose excursions by up to 73% compared with control treatment. Paracetamol absorption was also significantly reduced with lixisenatide treatment, corresponding to a delay in gastric emptying [69].

Lixisenatide has also been shown to delay gastric emptying within a clinical setting [40]. In a 28-day double-blind study, patients with T2DM were randomized to lixisenatide (n = 19) or placebo (n = 22) in combination with up to two OADs. Lixisenatide was shown to significantly delay gastric emptying compared with placebo, which was accompanied by a significant reduction in PPG. In contrast to long-acting agents, the effects of delayed gastric emptying with short-acting agonists do not appear to be subject to tachyphylaxis [70].

2.5.3 Protective effect on pancreatic beta-cells

T2DM is a progressive disease associated with deteriorating beta-cell function. An early laboratory marker for beta-cell dysfunction is an increase in circulating proinsulin levels. Although a disproportionate increase in the release of insulin and proinsulin indicates beta-cell dysfunction, elevated absolute proinsulin levels are associated with an increased risk for cardiovascular events in diabetic and nondiabetic subjects [71-76]. Beta-cell workload increases after the ingestion of carbohydrate-containing meals, and recent studies suggest that an increase in proinsulin levels after beta-cell stimulation with an oral glucose load might be a more sensitive method to characterize beta-cell function [77,78]. Several clinical studies have shown an improvement in the proinsulin/insulin ratio during treatment with GLP-1 receptor agonists [79,80] and DPP-IV inhibitors [81-83]. Recently, treatment with a DPP-IV inhibitor was shown to improve the proinsulin/insulin ratio and to lower the postprandial release of intact proinsulin in patients with T2DM, whereas treatment with a sulfonylurea worsened beta-cell function and increased the postprandial secretion of intact proinsulin [84].

In vitro studies in the pancreatic beta-cell line INS-1 have demonstrated that lixisenatide is able to reduce cytokine- or fatty-acid-induced apoptotic activity by 50 – 60% [85]. The protective effect of lixisenatide was further enhanced when used in combination with insulin analogs (in particular, insulin glargine), with apoptotic activity reduced by approximately 80%.

Lixisenatide was demonstrated to improve first-phase insulin secretion in a rodent model of diabetes [86], as well as in healthy and diabetic subjects [87]. In addition, lixisenatide was shown to reduce proinsulin levels compared with placebo treatment, in patients with T2DM inadequately controlled on sulfonylurea in the GetGoal-S study [88].

2.5.4 Increased insulin mRNA expression and hormone secretion

A 90-day in vivo study in diabetic db/db mice has demonstrated that lixisenatide treatment is associated with increased pancreatic insulin mRNA expression compared with vehicle-control-treated mice [28]. In a study performed in the isolated pancreas of normoglycemic Wistar rats [86], lixisenatide treatment was shown to significantly augment glucose-stimulated insulin secretion compared with saline control, whereas insulin secretion was unaffected at low glucose levels.

3. Conclusions

Lixisenatide is a once-daily prandial GLP-1 receptor agonist for the treatment of T2DM. Lixisenatide has a unique pharmacokinetic and pharmacodynamic profile compared with the other GLP-1 receptor agonists. Despite its relatively short half-life, lixisenatide is suitable for once-daily dosing, partly due to its high affinity for the GLP-1 receptor as well as its ability to delay gastric emptying.

Clinical studies evaluating the effects of once-daily lixisenatide in monotherapy or in combination with OADs (metformin, sulfonylureas, thiazolidinediones) or basal insulin glargine demonstrate that lixisenatide improves glycemic control, is generally well tolerated and has a fairly low incidence of hypoglycemia. In addition, lixisenatide appears to have a beneficial effect on body weight, as it is either associated with no weight gain or weight loss.

Lixisenatide potentially has a number of additional benefits beyond glycemic control for the treatment of T2DM, including delayed gastric emptying, which is a key mechanism in PPG reduction. In contrast to long-acting agents, lixisenatide-mediated slowing of gastric emptying is not subject to tachyphylaxis, which occurs due to sustained activation of the GLP-1 receptor. Lixisenatide may also provide a protective effect to the cardiovascular system. As CVD is the main cause of death among patients with T2DM, the results of the ELIXA cardiovascular trial investigating lixisenatide treatment in patients with T2DM after ACS (due to be completed in 2014) will be of particular interest [68]. Furthermore, preclinical and preliminary clinical data suggest that lixisenatide may protect pancreatic beta-cells and improve insulin secretory response patterns, resulting in the restoration of first- and second-phase insulin secretion, as well as reduced proinsulin levels.

In summary, lixisenatide is a promising addition to the treatment armamentarium for patients with T2DM. Lixisenatide has proven efficacy in a variety of patient subpopulations, as well as an acceptable tolerability profile. It offers the potential for a range of unique additional health benefits, as well as convenient administration owing to its once-daily dosing regimen.

4. Expert opinion

Incretin-based therapies such as DPP-IV inhibitors and GLP-1 receptor agonists have become an essential part of the pharmacological treatment for T2DM. In addition to providing effective metabolic control without increasing hypoglycemic events, treatment with GLP-1 receptor agonists has been shown to reduce body weight and to improve the overall cardiovascular risk profile in patients with T2DM.

GLP-1 acts through a distinct heptahelical G-protein-coupled receptor, which has been located not only in beta-cells and the GI tract, but also in several other cell systems that are not involved in metabolic regulation [46-49]. GLP-1 appears to have distinct, physiological effects on endothelium and vascular smooth muscle cells. In both healthy nondiabetic subjects and patients with T2DM, GLP-1 was shown to improve the endothelium-mediated increase in forearm blood flow, affirming a NO-dependent mechanism of GLP-1 [56]. In addition, treatment with GLP-1 or GLP-1 receptor agonists seems to improve left ventricular function and protect myocardial tissue in ischemia reperfusion models [15,50].

T2DM is a progressive disease that is characterized by a steady decline in beta-cell function. A loss of first-phase insulin release following the ingestion of a meal and an increase in the release of intact proinsulin are early markers of deteriorating beta-cell function, preceding an overall breakdown in the synthetic capacity of the beta-cell with the development of relative insulin deficiency. Several clinical studies have shown an improvement in the release of insulin and a decline in the proinsulin/insulin ratio following treatment with a GLP-1 receptor agonist [79,80] or DPP-IV inhibitor [81-83]. Overall, these studies indicate an improvement in the functional capacity of the beta-cell during GLP-1-based treatments. Whether GLP-1 also improves beta-cell survival by increasing the differentiation of new beta-cells or decreasing their rate of apoptosis in humans is still a matter of debate. In addition to its effects on beta-cell function, GLP-1 appears to interact with alpha cells in the pancreatic islet, by suppressing the postprandial release of glucagon without affecting the glucagon response during hypoglycemia. As shown in Figure 3, GLP-1-based treatments seem to restore overall islet-cell function by improving the regulation of glucagon and insulin secretion from alpha- and beta-cells.

Figure 3. Restoration of islet-cell function by glucagon-like peptide-1 (GLP-1). GLP-1 reduces islet-cell dysfunction by a number of mechanisms, including increasing insulin secretion from pancreatic beta-cells and restoring first-phase insulin secretory patterns. GLP-1 has also been shown to improve the proinsulin/insulin ratio, which is an early marker of beta-cell dysfunction.

Lixisenatide is a once-daily GLP-1 receptor agonist, which has been evaluated in a broad clinical study program. In these studies, lixisenatide was shown to have a favorable safety and tolerability profile and to improve metabolic control in monotherapy, as well as in combination with a number of different antidiabetic drugs. Treatment with lixisenatide improved blood glucose control without increasing the risk of hypoglycemia. In addition, lixisenatide had a beneficial effect on body weight in the majority of patients.

The unique pharmacological properties of lixisenatide clearly differentiate the molecule from other GLP-1 receptor agonists. As a once-daily agent with a high affinity to the GLP-1 receptor, it improves overall glycemic control, with especially strong effects on PPG excursions. Lixisenatide's postprandial effect is predominantly pronounced for the first meal following injection, but continues to be sustained throughout the day [40]. These attributes encourage the application of lixisenatide in those patients with extensive postprandial glucose excursions, or in combination with other antidiabetic drugs that have prevailing effects on fasting glucose levels, such as long-acting insulin analogs. Ongoing trials, such as the ELIXA study, will provide further information on the overall effects of lixisenatide on the cardiovascular risk profile and mortality.

Declaration of interest

T Forst has received advisory and speaker honoraria from Sanofi. A Pfützner has received research grants, travel support, consultancy fees and/or speaker fees during the last five years from the following pharmaceutical companies with products related to the content of this article: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Novartis, NovoNordisk and Sanofi. This paper was supported by Sanofi. Editorial support was provided by H Brereton from Medicus International (London, UK).

Notes