Optimizing glycemic control: lixisenatide and basal insulin in combination therapy for the treatment of Type 2 diabetes mellitus

Abstract

Despite availability of new treatments for patients with Type 2 diabetes mellitus (T2DM), optimal management of glycemic control remains challenging. Treatment with basal insulin can improve HbA_1c, but may not be sufficient to control postprandial plasma glucose (PPG) levels. Both fasting plasma glucose (FPG) and PPG levels contribute to overall glycemic control. In patients with moderate hyperglycemia, PPG excursions have a greater contribution to overall hyperglycemia, with this contribution being greatest when HbA_1c is approximately 7–8% . Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been designed to restore and maintain GLP-1 levels and attenuate PPG excursions. GLP-1RAs that predominantly affect PPG may complement the FPG lowering provided by basal insulin, possibly improving overall glycemic control without additional weight gain and with limited incidence of hypoglycemia. Lixisenatide as an add-on to basal insulin lowers PPG levels, improves HbA_1c control and has a beneficial effect on weight in T2DM patients.

Keywords::

• basal insulin
• GLP-1 receptor agonist
• lixisenatide
• Type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) has reached epidemic proportions, with the number of patients with T2DM expected to increase by 50% over the next 20 years [101]. Despite the availability of new treatments for the management of T2DM, optimal management of glycemic control remains a challenge [2,3]. When oral antihyperglycemic agents and lifestyle modifications are no longer capable of maintaining glycemic control, the addition of basal insulin can restore glycated hemoglobin (HbA_1c) to 7.0% for 50–60% of patients with T2DM [2,4–6]. However, addition of basal insulin may not always achieve glycemic targets, when postprandial hyperglycemia is an issue [4,7], and is commonly associated with weight gain and a higher incidence of hypoglycemia.

The incretin hormone glucagon-like peptide-1 (GLP-1) has been found to enhance insulin secretion in β-cells (Figure 1). GLP-1 receptor agonists (GLP-1RAs) have been designed to restore and maintain incretin GLP-1 hormone levels and attenuate postprandial plasma glucose (PPG) excursions, allowing an extended duration of action and consequently improving glucose tolerance with low risk of hypoglycemia [8,9]. In addition, they have the ability to support β-cell number and function and control PPG levels; thus, GLP-1RAs, when used in combination with basal insulin, may help to improve overall glycemic control without additional weight gain and with a lower incidence of hypoglycemia than other therapeutic options [9–11].

An important consideration in the overall management of T2DM is the control and prevention of hyperglycemia as it is believed to increase the risk of both microvascular complications and macrovascular disease, such as coronary heart disease [12]. The addition of a GLP-1RA to basal insulin treatment results in a lowering of both fasting plasma glucose (FPG) and PPG levels, which may reduce the risk of hyperglycemia and hence cardiovascular (CV) risk. Furthermore, several studies demonstrate that PPG is an independent risk factor for CV events, and may be a stronger predictor of CV disease and all-cause mortality than FPG [13]. Therefore, PPG is now recognized as an important therapeutic target for improving glycemic control in patients with T2DM [14].

Overview of the clinical landscape

Patients with T2DM are initially treated with oral antihyperglycemic medications and lifestyle changes to achieve glycemic control. When glycemic control maintenance fails, patients receive basal insulin and, often, prandial insulin. This treatment intensification brings with it an increased risk of hypoglycemia and weight gain.

Figure 1. Glucagon-like peptide-1 fundamental mechanisms.

An alternative treatment strategy is the addition of a short-acting prandial GLP-1RA. GLP-1RAs release insulin only in the context of hyperglycemia and hence have a low propensity to cause hypoglycemia. Through their action in delaying gastric emptying and increasing satiety, GLP-1RAs may induce weight loss, and they have been shown to increase insulin secretion and decrease glucagon secretion [15].

Currently, several GLP-1RAs are available or in late-stage development. These agents may be classified by their pharmacokinetic properties as either short-acting or long-acting GLP-1RAs, which may provide other non-glycemic-related advantages. GLP-1RAs are also associated with delayed gastric emptying, inhibiting postprandial glucagon secretion and appetite suppression [16]. Through the stimulation of insulin secretion, GLP-1RAs reduce PPG levels and lower the risk of hypoglycemia, as well as having a beneficial effect on patient weight stability [10]. In addition, some GLP-1RAs may have a prandial effect on glucose excursions.

Long-acting GLP-1RAs

Long-acting GLP-1RAs – such as liraglutide, albiglutide, dulaglutide and exenatide long-acting release (LAR) – lower blood glucose levels through stimulation of insulin secretion and reduction of glucagon levels. They have an average half-life of 12 h to several days [15]. Exenatide LAR is available in some markets and is based on a formulation that encapsulates exenatide in microspheres made of poly (D,L-lactic-co-glycolic acid), and administered as a once weekly injection [17]. Liraglutide is a GLP-1RA with a half-life of about 12 h given as a once daily (q.d.) injection [18].

Long-acting GLP-1RAs stimulate fasting insulin secretion, and predominantly reduce FPG levels, glucagon secretion and body weight [15]. Modest reductions in postprandial hyperglycemia have been reported with long-acting GLP-1 RAs, but because of their non-prandial properties they have minimal impact on gastric emptying over long-term use, due to tachyphylaxis [15,19]. The impact of all action of GLP-1RAs on gastric emptying appears to be determined by repeated dosing. As such, even long-acting GLP-1RAs have a sustained effect on slowing the gastric emptying, but the magnitude of this effect diminishes with time [19,20].

Short-acting GLP-1RAs

Currently available short-acting prandial GLP-1RAs, such as exenatide and lixisenatide, predominantly lower PPG levels and insulin concentrations via retardation of gastric emptying, which depends on the baseline rate of gastric emptying. The resistance of prandial GLP-1RAs to cleavage by dipeptidyl peptidase-4 (DPP-4) confers a plasma half-life of 2–4 h [15]. Owing to their short half-life, the effects of prandial GLP-1RAs on FPG are less pronounced than those of long-acting agents. Therefore, prandial GLP-1RAs lead to a substantial delay of gastric emptying, and a blunting of PPG excursions, consequently acting as an effective prandial therapy. The delayed gastric emptying effect makes prandial GLP-1RAs compatible for use with basal insulin [21]. Exenatide is available in some markets, has a half-life of 2 h and is administered as a twice daily (b.i.d.) injection [3]. Lixisenatide will be discussed in detail in this article.

GLP-1RAs & CV variables

Glycemic control and the prevention of CV comorbidities remain key unmet needs in the treatment of T2DM. Patients with T2DM have a greater incidence of CV disease than the general population [22]. Clinical evidence suggests that GLP-1 may improve lipid profiles and other biomarkers of CV disease [12]. Studies have shown that prandial and long-acting GLP-1RAs may have differing CV influence: short-acting GLP-1RAs have shown either no or a small effect on heart rate (0–2 bpm), whereas long-acting GLP-1RAs produced a moderate increase (2–5 bpm) [15,23,24]. Both long- and short-acting GLP-1RAs reduce blood pressure. A recent study showed that treatment with GLP-1RAs exenatide and liraglutide reduced systolic blood pressure and diastolic blood pressure by 1–5 mmHg compared with insulin, glimepiride and placebo in patients with T2DM [25].

Introduction to the drug

GLP-1RAs have become an established therapeutic option in the treatment of T2DM and are now recommended in combination as part of two-drug and three-drug diabetes treatment options.

Lixisenatide is one of four GLP-1RAs that are clinically available, and is a q.d. prandial GLP-1RA for the treatment of T2DM. Lixisenatide as monotherapy, in combination with one or two OADs and in combination with basal insulin therapy, produced significant improvements in overall glycemia, with a particularly prominent effect on PPG levels [26–28].

Chemistry

Lixisenatide is a 44-amino-acid molecule (amino-acid sequence: H₂N-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-CONH₂) and is based on exendin-4, which has been modified by the addition of six additional Lys residues at the C-terminal and the deletion of one Pro residue in order to prevent immediate physiological degradation by DPP-4 (Figure 2) [8,29].

Figure 2. Chemical structure of lixisenatide and other GLP-1RAs.

Pharmacodynamics

Lixisenatide improved first-phase insulin response by sevenfold and second-phase insulin response by threefold when compared with placebo in patients with T2DM [30]. When lixisenatide was given as monotherapy, the mean 2 h PPG and 2 h glucose excursions were significantly improved from baseline (4.5–5.5 mM vs 0.7 mM) compared with placebo [30]. Moreover, lixisenatide as an add-on to metformin reduced levels of 2 h post-meal glucose, glucagon, insulin, C-peptide and pro-insulin compared with placebo [30].

Pharmacokinetics & metabolism

The pharmacokinetic profiles of 5–20 µg lixisenatide q.d. or b.i.d. were assessed in combination with metformin and/or sulfonylurea and showed that the mean apparent clearance (CL/F) was 21–29 l/h, whereas at the 20 µg dose, the median time to maximal concentration (t_max) was 1.3 h for both the q.d. and b.i.d. regimens. The study showed that the mean area under the curve (AUC) and peak plasma concentration (C_max) increased in a dose-dependent manner (at 20 µg q.d., AUC was 847.8 h·pg/ml and C_max was 187.2 pg/ml). The half-life (t_1/2) varied with the frequency of dosing, with a median t_1/2 of 2.8 and 3.2 h with q.d. and b.i.d. administration, respectively, at the 20 µg dose [31]. Other studies showed that proteolytic degradation of lixisenatide takes place in the renal tubules after being filtered by the kidneys [32]. In addition, lixisenatide exhibited dose-dependent pharmacokinetics, with levels reaching peak plasma concentrations within 1.3–2.3 h, suggesting that it may be suitable for q.d. dosing [31].

Clinical efficacy

Overall glycemic control consists of reaching targets in combined parameters of PPG, FPG and HbA_1c. Previous GLP-1RAs exhibited good efficacy in lowering HbA_1c and controlling FPG levels while reducing body weight [33]. Because of their effect on lowering body weight without increasing hypoglycemia, liraglutide and exenatide LAR are effective in combination with basal insulin [6]. Lixisenatide improves HbA_1c levels and enables a greater proportion of patients to achieve HbA_1c <7% [34]. In addition, lixisenatide has a beneficial effect on weight, with a limited risk of hypoglycemia and due to the slowing of gastric emptying, markedly reduces PPG levels. Altogether, lixisenatide may be an effective treatment option in combination with basal insulin.

Phase I & Phase II studies [102]

Lixisenatide was evaluated in Phase I and Phase II trials (Table 1).

Table 1. Summary of lixisenatide in Phase I and Phase II trials.

Trial	Phase	Patients (n)	Outcome	Ref.
Randomized, placebo-controlled, crossover clinical trial evaluating the interaction of lixisenatide (10 μg sc) on the absorption of concomitantly administered oral acetaminophen or oral contraceptive	I	40	Lixisenatide significantly reduced the absorption rate (lowering Cmax by 48–71% and prolonging Tmax by 2–3.5 h), but did not significantly affect the extent of absorption (AUC), indicating delayed gastric emptying	[53]
Lixisenatide vs placebo evaluating the dose-dependent effect on plasma glucose	I	28	Plasma glucose levels were reduced relative to placebo	[102]
Evaluation of efficacy of lixisenatide in T2DM patients as add on to metformin and/or SU therapy	II	64	Lixisenatide significantly reduced baseline plasma glucagon AUC and HbA1c levels compared with placebo	[102]
Evaluation of efficacy of lixisenatide in T2DM patients insufficiently controlled by metformin monotherapy	II	542	Lixisenatide vs placebo significantly and dose-dependently reduced mean HbA1c levels from baseline (−0.28 – [−0.57%]) with q.d. dosing and (−0.47 – [−0.69%]) with b.i.d. dosing	[54]

AUC: Area under the curve; C_max: Maximum concentration of drug; HbA_1c: Glycated hemoglobin; sc: Subcutaneous; SU: Sulfonylurea; T2DM: Type 2 diabetes mellitus; T_max: Amount of time that a drug is present at the maximum concentration.

Phase III studies

The GetGoal clinical trial program was a set of 11 trials that investigated the safety and efficacy of lixisenatide in patients with T2DM (Table 2), in lixisenatide as monotherapy (GetGoal-Mono), as an add-on therapy to metformin (GetGoal-F1, GetGoal-X), sulfonylureas (GetGoal-S) and pioglitazones (GetGoal-P) (Table 2) [27,35,36]. The program began in 2008 and has enrolled more than 5000 patients globally. Three of the trials from the GetGoal program consisted of 24-week, randomized, placebo-controlled, Phase III trials designed to investigate the efficacy and safety of lixisenatide in combination with basal insulin: GetGoal-L, -L-Asia and -Duo-1 [27,36,37].

Table 2. Summary of GetGoal Phase III clinical trial program.

Trial	Comparator	Participants	Duration(weeks)	Primary outcome	Secondary outcome	Status
GetGoal-Mono	LIXI vs PCB (1-step and 2-step titration)	361 adults previously untreated with antidiabetic agents	12	Change in HbA1c from baseline	Changes in body weight, FPG, 2-h PPG	Completed
GetGoal-F1	LIXI + MET vs PCB + MET (1-step and 2-step)	482 adults previously treated with MET	24	Change in HbA1c from baseline	Changes in body weight, FPG	Completed
GetGoal-S	LIXI + SU vs PCB + PCB	859 adults previously treated with SU	24	Change in HbA1c from baseline	Changes in body weight, FPG, 2-h PPG	Completed
GetGoal-L	LIXI + basal insulin vs PCB + basal insulin	495 adults previously treated with basal insulin	24	Change in HbA1c from baseline	Changes in body weight, FPG, change from baseline in insulin doses	Completed
GetGoal-P	LIXI + PIO vs PCB + PIO	484 adults previously treated with PIO	24	Change in HbA1c from baseline	Changes in body weight, FPG, fasting plasma insulin	Completed
GetGoal-X	LIXI + MET vs EXE + MET	634 adults previously treated with MET	24	Noninferiority in HbA1c reduction from baseline	Changes in body weight, FPG, quality of life	Completed
GetGoal-M	LIXI (morning or evening dose) + MET vs PCB + MET	680 adults previously treated with MET	24	Change in HbA1c from baseline	Changes in body weight, FPG, 2-h PPG	Completed
GetGoal-Mono Japan	Open-label LIXI (1-step and 2-step titration)	66 adults not treated with antidiabetes agents	52	Safety measures	Changes in HbA1c and FPG from baseline	Completed
GetGoal-L-Asia	LIXI + basal insulin vs PCB + basal insulin	311 adults previously treated with basal insulin ± SU	24	Change in HbA1c from baseline	Change from baseline in body weight, FPG, insulin doses	Completed
GetGoal-Duo-1	Insulin glargine + LIXI vs insulin glargine + PCB	446 adults with HbA1c 7–10% despite oral therapy	24 (with a 12-week insulin glargine run-in period)	Change in HbA1c from baseline	Changes in body weight, 2-h PPG	Completed
GetGoal-M-Asia	LIXI + MET ± SU vs PCB + MET ± SU	380 adults previously treated with MET or MET + SU	24	Change in HbA1c from baseline	Changes in body weight, FPG, 2-h PPG	Completed

EXE: Exenatide; FPG: Fasting plasma glucose; HbA_1c: Glycated hemoglobin; LIXI: Lixisenatide; MET: Metformin; PCB: Placebo; PIO: Pioglitazone; PPG: Postprandial plasma glucose; SU: Sulfonylurea.

Reproduced with permission from [29].

GetGoal-L

In GetGoal-L, the efficacy and safety of lixisenatide 20 µg q.d. as an add-on therapy to basal insulin was investigated in 495 patients inadequately controlled on a combination of basal insulin ± metformin. Lixisenatide significantly reduced HbA_1c vs placebo and increased the proportion of patients achieving HbA_1c <7% (28.0 vs 12.0% for placebo; p < 0.0001). Significant improvements in 2-h PPG after a standardized breakfast were seen with lixisenatide vs placebo (LS mean difference of −3.8 mmol/l; 95% CI: −4.7 to −2.9; p < 0.0001). Lixisenatide reduced body weight compared with placebo (LS mean difference of −1.3 kg; p < 0.0001). A decrease in insulin dose at study end was seen with lixisenatide compared with placebo (−5.6 U vs −1.9 U; p = 0.012). The incidence of symptomatic hypoglycemia was comparable between groups (27.7% for lixisenatide vs 21.6% for placebo), whereas four cases of severe hypoglycemia occurred in the lixisenatide group (1.2%) compared with none in the placebo group (0.0%) [14,28].

GetGoal-L-Asia

GetGoal-L-Asia evaluated lixisenatide 20 µg q.d. vs placebo in 311 Asian patients not achieving glycemic control with basal insulin with or without a sulfonylurea. Lixisenatide significantly improved HbA_1c (LS mean difference vs placebo –0.9%; p < 0.0001) and the proportion of patients achieving HbA_1c <7% (35.6 vs 5.2%; p < 0.0001) and HbA_1c ≤6.5% (17.8 vs 1.3%; p < 0.0001) was greater compared with placebo. In addition, the 2-h PPG and glucose excursion was reduced with lixisenatide compared with placebo. In this Asian study population, mean changes in body weight were small, but there was a trend to weight decreases with lixisenatide, with no statistically significant differences between lixisenatide and placebo (LS mean change: −0.4 kg vs +0.1 kg, respectively; 95% CI: −0.93 to −0.06; p = 0.0857). Symptomatic hypoglycemia was similar in patients not receiving sulfonylureas, but was more frequent with lixisenatide vs placebo (32.6 vs 28.3%) [37].

GetGoal-Duo-1

GetGoal-Duo-1 assessed 446 patients inadequately controlled on oral antihyperglycemic medications who were treated with lixisenatide 20 µg q.d. In this study, insulin glargine was systemically titrated in patients during a run-in period of 12 weeks. Subsequently, patients who successfully achieved a FPG level of ≤7.8 mmol/l and HbA_1c of 7.0–9.0% were randomized to either lixisenatide 20 µg q.d. or placebo for 24 weeks with continuation of basal insulin treatment. Lixisenatide significantly reduced HbA_1c vs placebo (LS mean difference: −0.3%; 95% CI: 0.5 to −0.2; p < 0.0001).

The proportion of patients achieving HbA_1c <7% was higher compared with placebo (56 vs 39%, respectively). After a standardized breakfast, lixisenatide significantly improved 2-h PPG (LS mean difference: 3.2; 95% CI: −3.95 to −2.37; p < 0.0001) and FPG increased slightly from baseline for both lixisenatide and placebo (LS mean difference: −0.1; 95% CI: −0.5 to 0.2; p = 0.5142). Lixisenatide had a favorable effect on body weight (LS mean difference vs placebo: −0.9 kg; p = 0.0012); after randomization, body weight increased by 1.2 kg in the placebo group and 0.3 kg in the lixisenatide group. A total of 20.2% of patients experienced symptomatic hypoglycemia with lixisenatide vs 11.7% for placebo [38].

Lixisenatide vs other GLP-1RAs

In a Phase III, open-label, non-inferiority trial of lixisenatide vs short-acting exenatide IR in patients inadequately controlled on metformin (GetGoal-X), glycemic control was comparable between lixisenatide and exenatide IR. After 24 weeks, mean FPG and the proportion of subjects achieving HbA_1c <7.0% were comparable between both treatment groups. The incidence of nausea and vomiting was lower with lixisenatide compared with exenatide (24.5 vs 35.1% and 10 vs 13%, respectively). In addition, three-times fewer patients experienced symptomatic hypoglycemia (eight patients [2.5%] vs 25 patients [7.9%]) and six-times fewer patients experienced symptomatic hypoglycemic events with lixisenatide vs exenatide [39].

In a 28-day, randomized, open-label, parallel-group, multicenter pharmacodynamics study, lixisenatide produced a significantly greater reduction in PPG (AUC) during a morning meal test vs pre-breakfast, when compared with liraglutide. Patients receiving lixisenatide experienced significant decreases in postprandial insulin, C-peptide (vs an increase with liraglutide), glucagon and had better gastrointestinal (GI) tolerability vs liraglutide [40].

A recent meta-analysis assessed the efficacy and safety of lixisenatide in 1198 patients with T2DM treated with lixisenatide compared with placebo. A significant number of patients receiving lixisenatide as an add-on to basal insulin ± oral antihyperglycemic medications achieved HbA_1c <7% compared with placebo (odds ratio [OR]: 3.67 [1.64, 8.19]; p = 0.002), were 2.5-times as likely to achieve HbA_1c <7% with no documented hypoglycemia compared with placebo (OR: 2.65 [1.30, 5.38]; p = 0.007), and were 2.5-times as likely to achieve HbA_1c <7% with no documented symptomatic hypoglycemia and no weight gain compared with placebo (OR: 2.65 [1.48, 4.70]; p = 0.0009) [41]. In a pooled analysis of GetGoal-L, GetGoal-L-Asia and GetGoal-Duo-1 studies, postprandial hyperglycemia was reduced more with lixisenatide compared with placebo at 24 weeks (p < 0.0001). Where persisting postprandial hyperglycemia is an issue, lixisenatide may complement the effect of basal insulin control in T2DM, decreasing HbA_1c mainly by reducing postprandial hyperglycemia [42].

Safety & tolerability

Side effects related to GLP-1RAs are GI in nature, specifically nausea. The main safety concern with GLP-1RA usage is pancreas safety [43].

Safety of short-acting GLP-1RAs

GI side effects have been reported in studies of lixisenatide as an add-on therapy to basal insulin.

In the GetGoal-Duo-1 study, nausea and vomiting (27.4 and 9.4% vs 4.9 and 1.3% for placebo, respectively) were the most common GI adverse events (AEs). In the GetGoal-L study, nausea, vomiting and diarrhea occurred in 26.2, 8.2 and 7.3% of patients with lixisenatide compared with 8.4, 0.6 and 5.4% with placebo, respectively. Most reports of nausea in the GetGoal-L study occurred in the first 2 months of treatment in both groups. In the GetGoal-L-Asia study, nausea and vomiting were reported in 39.6 and 18.2% vs 4.5 and 1.9% for lixisenatide and placebo, respectively. Reports of deaths and serious events are rare with GLP-1RAs as an add-on to basal insulin, and the incidence of serious AEs in lixisenatide, exenatide and placebo were similar [44]. The most common AEs in one study of exenatide vs placebo were nausea (12.0 vs 2.0%; p = 0.037), vomiting (8.0 vs 0.0%; p = 0.031) and headache (4.0 vs 4.0%) [45]. There have been no reports of pancreatitis with lixisenatide [103].

Safety of long-acting GLP-1RAs

Therapies with long-acting GLP-1RAs appear to have slightly lower GI side effects compared with short-acting GLP-1RAs [11]. In one randomized, multicenter, double-blind, parallel-group study, the incidence of GI AEs in subjects receiving albiglutide 30 mg weekly was less (29.0%) than that observed for the highest biweekly (54.3%) and monthly doses (55.9%) of albiglutide or exenatide [46]. In a randomized, placebo-controlled, double-blind study of overweight patients with T2DM, nausea occurred in 13.6% of those in the dulaglutide group compared with 7.6% in the placebo group [47]. One study examining the US FDA database of reported AEs from 2004 to 2009 found evidence of increased risk of pancreatitis with exenatide and cautioned about long-term use [48]. The FDA warns that both GLP-1RAs and DDP-4 inhibitors should be stopped if patients develop signs of pancreatitis, and should be used with caution in patients with a history of the disease [104]. In addition, liraglutide and exenatide once-weekly carry a black box warning for thyroid cancer risk.

Regulatory affairs

Lixisenatide was granted marketing authorization in February 2013 by the European Medicines Agency and is under consideration by other markets, including the US FDA [105,106].

Conclusion

This review provides an overview of the q.d. prandial GLP-1RA lixisenatide as an add-on to basal insulin for use in glycemic control optimization. Although the efficacy of available treatments for the management of T2DM continues to improve, the need for glycemic control remains a challenge. Addition of basal insulin to the treatment therapy may help to reduce FPG levels but has a limited effect on PPG levels. However, PPG plays a significant role in glycemic control and in the complications of diabetes. With the action of basal insulin on FPG, the addition of a short-acting GLP-1RA provides a complementary effect on overall glycemic control. The combination of GLP-1RAs and basal insulin may help to optimize glycemic control without contributing to increased side effects of hypoglycemia and weight gain and may have a positive effect on CV by improving lipid profiles, decreasing blood pressure and other mechanisms. Short-acting prandial GLP-1RAs (exenatide, lixisenatide) and long-acting GLP-1RAs (albiglutide, dulaglutide, exenatide-LAR and liraglutide) lower blood glucose levels. Long-acting GLP-1RAs, in particular, reduce FPG, whereas short-acting GLP-1RAs reduce PPG levels. Modest reductions in postprandial hyperglycemia have also been reported with long-acting GLP-1RAs, but unlike short-acting GLP-1RAs, they have minimal impact on gastric emptying over long-term use, due to tachyphylaxis. Lixisenatide, once-daily, prandial GLP-1RA as an add-on to basal insulin therapy, lowers PPG levels, improves HbA_1c control and has a beneficial effect on body weight, while limiting the risk of hypoglycemia with an acceptable safety/benefit ratio in patients with T2DM. Therefore, lixisenatide added on to basal insulin improves overall glycemic control in patients with T2DM.

Expert commentary

The incretin family – specifically, GLP-1RAs – have been shown to effectively improve glycemia with minimal impact on the AEs typically seen with rapid-acting insulin and sulphonylureas, such as hypoglycemia and weight gain. Long-acting GLP-1RAs have the additional benefit of lowering the likelihood of GLP-1-specific AEs such as nausea and vomiting, but they have reduced efficacy on PPG. PPG response is directly related to the extent of gastric emptying delay, and tachyphylaxis generally results in the use of longer-acting GLP-1RAs. The decision to use short- or long-acting GLP-1RAs partly depends on the T2DM disease profile, as the contribution of FPG and PPG hyperglycemia to overall glycemic control changes with the degree of hyperglycemia. In patients with moderately uncontrolled T2DM, PPG excursions contribute more to overall hyperglycemia, especially when HbA_1c is approximately 7–8% [1]. For patients where FPG is the primary treatment goal, long-acting non-prandial GLP-1RAs may be more suitable, whereas short-acting prandial GLP-1RAs have a stronger reducing effect on PPG levels owing to their effect on delaying gastric emptying. Thus, short-acting prandial GLP-1RAs may be more suitable for moderate degrees of hyperglycemia, whereas long-acting non-prandial GLP-1RAs may be more effective in patients with severe hyperglycemia [49]. The q.d. prandial GLP-1RA lixisenatide may have the dual benefit of being a long-acting agent, allowing q.d. injection and a lower side-effect profile, while also providing rapid onset of action. The rapid onset may help to avoid tachyphylaxis, thereby maintaining the beneficial impact on delaying gastric emptying, improving PPG and having a beneficial effect on body weight.

Five-year view

In 2012, more than US$471 billion were spent on healthcare for diabetes, with the cost of healthcare for patients with T2DM expected to rise by an additional 25% between 2035 and 2045. The relative economic burden of the disease can be expected to increase by 40–50% [50], and CV disease accounts for nearly 70% of morbidity and mortality in patients with T2DM [51]. Therefore, achieving and maintaining optimal glycemic control is vital in reducing macrovascular complications associated with T2DM.

The q.d. prandial GLP-1RA lixisenatide as an add-on therapy to basal insulin has been shown to lower HbA_1c in T2DM patients, and also has a beneficial effect on weight, thereby improving patients’ likelihood of avoiding complications of diabetes.

The GetGoal-Duo-1 study examined the efficacy and safety of lixisenatide in patients with HbA_1c that is still elevated after initiation of insulin glargine. Another upcoming study (GetGoal-Duo-2) will compare lixisenatide with rapid-acting insulin glulisine as an add-on to basal insulin therapy. The study will focus on HbA_1c reduction effects and body weight change at week 26 in patients with T2DM not adequately controlled on insulin glargine ± metformin, and may further highlight the potential role that lixisenatide may play as an add-on to basal insulin therapy [107].

An upcoming study (RISE Adult Medication Study; NCT01779362) is investigating the role of therapy using basal insulin and a GLP-1RA in adults presenting with prediabetes [108]. Future models of prescribing for patients with T2DM include the addition of basal insulin for patients already receiving GLP-1RAs who have suboptimal control of T2DM due to the development of β-cell failure [16]. Another area of interest is the potential for innovation in the delivery system for insulin/GLP-1 receptor analog combinations in order to reduce the potential complexity of these regimens [52]. Finally, the incretin class of therapies appears to have positive effects on surrogates of CV disease. To date, trials investigating the effect of lixisenatide on CV outcomes have been animal based. However, the upcoming ELIXA trial (NCT01147250) is designed to evaluate CV outcomes in patients with T2DM after acute coronary syndrome during treatment with lixisenatide [109].

Key issues

• • Optimal glycemic management has yet to be achieved for all Type 2 diabetes mellitus (T2DM) patients.

• • Both fasting plasma glucose and postprandial plasma glucose (PPG) levels contribute to overall glycemic control.

• • In cases where oral antidiabetic drugs and lifestyle modifications are no longer capable of maintaining glycemic control, addition of basal insulin can restore HbA_1c to 7.0% for 50–60% of patients with T2DM.

• • Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) have been designed to restore and maintain incretin GLP-1 hormone levels and attenuate PPG excursions [9].

• • The effect of GLP-1RAs in dual therapy with basal insulin may improve overall glycemic control without additional weight gain and with less hypoglycemia.

• • Four GLP-1RAs are currently available for the treatment of T2DM: exenatide twice daily; a long-acting formulation, once weekly; liraglutide q.d.; and q.d. prandial lixisenatide [30].

• • Lixisenatide is a once daily prandial GLP-1RA for the treatment of T2DM.

• • Lixisenatide as an add-on to basal insulin therapy lowers PPG levels, improves HbA_1c control and has a beneficial effect on weight in patients with T2DM, and has been shown to reduce the risk of hypoglycemia without the serious side effect of pancreatitis.

Financial & competing interests disclosure

R Aronson has received research support and/or consulting honoraria from Sanofi-Aventis, Novo Nordisk, Eli Lilly and Takeda. 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.

Editorial support was provided by Judith Leavy, Medicus International (London, UK) and funded by Sanofi-Aventis.

Notes