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Keywords:

  • glycaemic control;
  • type 2 diabetes

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Aims

To compare the efficacy and safety of once-daily prandial lixisenatide with placebo in type 2 diabetes mellitus (T2DM) insufficiently controlled by pioglitazone ± metformin.

Methods

This randomized, double-blind study included a 24-week main treatment period and a ≥52-week variable extension period. Patients were randomized 2 : 1 to receive lixisenatide 20 µg once daily or placebo. The primary endpoint was change in glycated haemoglobin (HbA1c) at week 24.

Results

In total, 484 patients were randomized: 323 to lixisenatide; 161 to placebo. After 24 weeks, lixisenatide once daily significantly improved HbA1c (−0.56% vs. placebo; p < 0.0001) and increased the proportion of patients achieving HbA1c <7% compared with placebo (52.3% vs. 26.4%, respectively; p < 0.0001) and significantly improved fasting plasma glucose (−0.84 mmol/l vs. placebo; p < 0.0001). There was a small decrease in body weight with lixisenatide once daily and a small increase with placebo, with no statistically significant difference between the two groups. Overall, lixisenatide once daily was well tolerated, with a similar proportion of treatment-emergent adverse events (TEAEs) and serious TEAEs between groups (lixisenatide: 72.4% and 2.5%; placebo: 72.7% and 1.9%). Symptomatic hypoglycaemia rates were also relatively low in both groups (lixisenatide 3.4% and placebo 1.2%), with no severe episodes. Lixisenatide continued to be efficacious and well tolerated during the variable extension period.

Conclusions

Lixisenatide once daily significantly improved glycaemic control with a low risk of hypoglycaemia, and was well tolerated over 24 weeks and during the long-term, double-blind extension period in patients with T2DM insufficiently controlled on pioglitazone ± metformin.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Patients with type 2 diabetes mellitus (T2DM) often require multiple glucose-lowering agents in order to maintain glycaemic control as their disease progresses. However, a number of currently available treatment options are associated with hypoglycaemia (e.g. sulphonylureas or insulin) and/or weight gain (e.g. sulphonylureas, thiazolidinediones or insulin) [1-3]. Consequently, therapies are needed for combination strategies that allow multiple aspects of metabolic control, while minimizing the risk of hypoglycaemia and avoiding weight gain.

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are a class of subcutaneously injected glucose-lowering agents that have become an established treatment option in T2DM [4]. In general, these agents are associated with a low propensity to cause hypoglycaemia and have been shown to have beneficial effects on weight [5], making them particularly suitable for a range of combination regimens for the treatment of patients with T2DM. These patients are frequently obese and elderly, hence weight gain and hypoglycaemia are important concerns.

Lixisenatide is a once-daily prandial GLP-1RA for the treatment of T2DM that has been granted marketing authorisation by the European Medicines Agencies in February 2013 and is currently under review by the US Food and Drug Administration [6-10]. The structure of lixisenatide is based on exendin-4 [11], a natural GLP-1 receptor agonist derived from the salivary glands of the Gila monster, which shares 53% homology with human GLP-1 [12]. Lixisenatide differs in structure from exendin-4 in the deletion of a proline residue and the addition of six lysine residues at the C terminus [11].

Phase III studies have evaluated the benefits of lixisenatide 20 µg once daily (QD) as monotherapy or in combination with other glucose-lowering therapies, including oral agents and/or basal insulin [10, 13-17]. These studies show that lixisenatide is associated with significant improvements in glycated haemoglobin (HbA1c), with a marked reduction in postprandial plasma glucose levels, a beneficial effect on body weight and a favourable tolerability profile [10, 13-17].

GetGoal-P was a phase III, placebo-controlled study investigating the efficacy and safety of lixisenatide once daily as add-on therapy to pioglitazone with or without metformin. The main objective of this study was to assess the efficacy of lixisenatide once daily on glycaemic control in comparison with placebo in patients with T2DM as an add-on treatment to pioglitazone with or without metformin, in terms of absolute HbA1c reduction over a period of 24 weeks.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Study Design

GetGoal-P was a phase III, randomized, double-blind, placebo-controlled, two-arm, parallel-group, multicentre, multinational study. The study was conducted at 150 centres in 13 countries (Austria, Canada, France, Germany, Greece, Guatemala, India, Mexico, Peru, Puerto Rico, Romania, Turkey and the USA) between September 2008 and June 2011. The study included a 2-week screening period, a 1-week single-blind placebo run-in period, a 24-week main double-blind treatment and a variable double-blind extension period of at least 52 weeks, which ended when the last randomized patient had completed 76 weeks of treatment.

The study was approved by the relevant institutional review boards or ethics committees and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients gave written informed consent to participate in the study. An independent Data Monitoring Committee supervised conduct of the study. Possible allergic events were adjudicated in a blinded manner by the external Allergic Reaction Assessment Committee (ARAC). The study was registered with clinicaltrials.gov (NCT00763815).

Study Population

Adults with T2DM for at least 1 year and who were treated with pioglitazone at a stable dose of ≥30 mg/day with or without metformin for at least the previous 3 months, and with a HbA1c measurement of ≥7.0% and ≤10.0%, were eligible for inclusion. For patients who were receiving metformin, a stable dose (≥1.5 g/day) had to be maintained for at least 3 months prior to screening. The main exclusion criteria included use of oral or injectable glucose-lowering agents other than pioglitazone and metformin within 3 months prior to the time of screening; fasting plasma glucose (FPG) at screening >250 mg/dl (13.9 mmol/l); history of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery or inflammatory bowel disease; end-stage renal disease and/or dialysis for patients treated only with pioglitazone and for patients treated with metformin in addition to pioglitazone, creatinine >1.4 mg/dl in women or >1.5 mg/dl in men; history of allergic reaction to any GLP-1RAs; and clinically relevant history of gastrointestinal disease, with prolonged nausea and vomiting during the previous 6 months.

Randomization and Blinding

Participants were randomized in a 2 : 1 ratio to receive either lixisenatide once daily or matching placebo. Lixisenatide and placebo were packaged in accordance with the randomized treatment kit number list. Corresponding treatment numbers were allocated using an interactive voice response system according to a predefined randomization list. Lixisenatide was administered in a two-step dose-increase regimen (10 µg QD for 1 week, 15 µg QD for 1 week, followed by the maintenance dose of 20 µg QD, if tolerated). If the target dose of 20 µg QD was not tolerated, the study treatment could be reduced to 15 µg QD, then, if necessary, to 10 µg QD. Lixisenatide and placebo were administered subcutaneously within 1 h before breakfast. Participants also continued on their established doses of pioglitazone with or without metformin. The study was double blind with regard to active and placebo treatments; however, the study drug volume was not blinded. Participants were stratified by screening values of HbA1c (<8%, ≥8%) and metformin use at screening (yes/no). Rescue therapy was permitted from baseline to week 8 if FPG was repeatedly (at least 3 times) >15.0 mmol/l (270 mg/dl); from week 8 to 12 if FPG was >13.3 mmol/l (240 mg/dl); from week 12 to 24 if FPG was >11.1 mmol/l (200 mg/dl) or HbA1c >8.5%; and during the extension period if FPG was >10.0 mol/l (180 mg/dl) or HbA1c >8%.

Efficacy and Safety Assessments

The primary efficacy endpoint was the absolute change in HbA1c from baseline to week 24 for the modified intent-to-treat (mITT) population. The percentage of patients reaching HbA1c ≤6.5% and <7.0% were also assessed. The secondary efficacy measures included change in FPG, body weight, β-cell function [assessed by the homeostatic model assessment of β-cell function (HOMA-β)], percentage of patients requiring rescue therapy from baseline to week 24 and fasting plasma insulin (FPI). All efficacy parameters were assessed during the main 24-week period and descriptively during the extension period.

The mITT population consisted of all randomized patients who received at least one dose of double-blind investigational product and had both a baseline and at least one post-baseline assessment of any primary or secondary efficacy parameters.

The safety population comprised all randomized patients exposed to at least one dose of double-blind investigational product. Safety and tolerability were assessed based on systematic adverse event (AE) and serious AE reporting and other specific safety information, including symptomatic hypoglycaemia and severe symptomatic hypoglycaemia. Symptomatic hypoglycaemia was defined as an event with clinical symptoms with either plasma glucose <3.3 mmol/l (60 mg/dl) or prompt recovery after oral carbohydrate administration, intravenous glucose or glucagon injection if no plasma glucose measurement was available. Severe symptomatic hypoglycaemia was defined as symptomatic hypoglycaemia in which the patient required the assistance of another person, and which was associated either with a plasma glucose level <2.0 mmol/l (36 mg/dl) or, if no plasma glucose measurement was available, with prompt recovery with oral carbohydrate, intravenous glucose or glucagon injection. The safety data was assessed during the 24-week, double-blind treatment period, as well as during the double-blind variable extension period.

Statistical Analyses

The primary endpoint was analysed during the main 24-week, on-treatment period using an analysis of covariance (ancova) model. Randomization was stratified by screening HbA1c (<8.0%, ≥8.0%) and metformin use (yes, no). In case of a missing week 24 measurement, a last observation carried forward (LOCF) approach was used to account for missing data by taking the last available post-baseline, on-treatment HbA1c measurement (before the introduction of rescue therapy) as the HbA1c value at week 24. Provided that the primary variable was shown to be statistically significant at α = 0.05, secondary efficacy endpoints could be analysed according to the following order of prioritization: (i) change in FPG; (ii) change in body weight; (iii) change in β-cell function, assessed by HOMA-β; (iv) percentage of patients requiring rescue therapy; (v) change in FPI. Continuous secondary efficacy variables were also analysed by ancova. For both the primary and the continuous secondary variable, differences between lixisenatide and placebo and two-sided 95% confidence intervals (CIs), as well as p values, were estimated within the framework of ancova. Categorical secondary efficacy variables were analysed using a Cochran–Mantel–Haenszel method stratified on randomization strata. Efficacy endpoints during the variable extension period were evaluated by descriptive statistics.

A sample size of 450 participants (300 in the lixisenatide group and 150 in the placebo group) was calculated as sufficient to detect a difference of 0.5% in the absolute change in HbA1c from baseline to week 24 between lixisenatide and placebo, with a power of 96%. This approach assumed a common standard deviation (SD) of 1.3% at a 5% significance level.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Study Population

Of 906 participants screened, 496 entered the single-blind, placebo run-in period and 484 were randomized to receive either lixisenatide once daily (n = 323) or placebo (n = 161) in addition to ongoing pioglitazone therapy with or without metformin (figure 1). Approximately half of the patients were enrolled in North America. Demographic and baseline characteristics were generally well matched between the two study groups (Table 1). At baseline, roughly two-thirds of the patients (67.6%) were obese [body mass index (BMI) ≥30 kg/m2], with a median BMI of 33.6 and 33.7 kg/m2 in the lixisenatide and placebo groups, respectively. The median daily dose of pioglitazone at baseline was 30 mg in both treatment groups (Table 1). At screening, 81% of patients in both treatment groups were using metformin, with a median duration of 3.4 years and a median daily dose of 2000 mg. All 484 randomized patients were exposed to study treatment and included in the safety analyses. Five patients (lixisenatide n = 3, placebo n = 2) were excluded from mITT for efficacy analysis due to lack of post-baseline efficacy data. The majority of patients (89% lixisenatide, 85% placebo) completed the 24-week main treatment period (figure 1). In addition, 348 patients (74% lixisenatide, 68% placebo) completed the variable double-blind extension period. At the end of treatment, approximately 92% of patients reached and stayed on the lixisenatide maintenance dose of 20 µg QD.

image

Figure 1. Patient disposition at week 24. *Patients completed the 24-week main double-blind treatment period.

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Table 1. Demographic and baseline characteristics (safety population)
Demographic variableLixisenatide (n = 323)Placebo (n = 161)
  1. BMI, body mass index; FPG, fasting plasma glucose; FPI, fasting plasma insulin; HbA1c, glycated haemoglobin; SD, standard deviation.

Sex (male/female), %53/4751/49
Race (Caucasian/Black/Asian/other), %85/4/4/782/6/5/8
Age, years (mean ± SD)56.0 ± 9.555.3 ± 9.5
Duration of diabetes, years (mean ± SD)8.1 ± 5.48.1 ± 5.6
Weight, kg (mean ± SD)92.9 ± 22.996.7 ± 25.6
BMI, kg/m2 (mean ± SD)33.7 ± 6.734.4 ± 7.0
HbA1c, % (mean ± SD)8.1 ± 0.98.1 ± 0.8
FPG, mmol/l (mean ± SD)9.1 ± 2.29.1 ± 2.2
FPI, pmol/l (mean ± SD)63.3 ± 57.766.1 ± 48.1
Duration of pioglitazone treatment, years (mean ± SD)1.7 ± 2.01.8 ± 2.5
Daily dose of pioglitazone, mg (%)
≥30–< 4574.978.3
≥4525.121.7
Metformin use (%)8181

Efficacy During the 24-week Treatment Period

Lixisenatide once daily significantly reduced HbA1c versus placebo at week 24 (figure 2A). In the lixisenatide group, HbA1c was reduced from 8.1 ± 0.9% at baseline to 7.1 ± 1.0% at week 24 (LOCF), whereas HbA1c was reduced from 8.1 ± 0.8% to 7.6 ± 1.0% in the placebo group. The least squares (LS) mean difference in HbA1c reduction at week 24 for lixisenatide versus placebo was −0.56% [95% CI (−0.73,–0.39); p < 0.0001]. There was no difference in the reduction of HbA1c with lixisenatide versus placebo according to metformin use at screening [LS mean difference (95% CI) was −0.55% (−0.75, –0.36) and −0.57% (−0.97, –0.17) for patients using and not using metformin at screening, respectively]. There were no relevant effects due to race, ethnicity, age, gender, BMI or baseline HbA1c on the mean change in HbA1c. A significantly higher percentage of patients achieved the HbA1c targets of <7.0% and ≤6.5% in the lixisenatide group compared with placebo (52.3% vs. 26.4% achieved HbA1c <7%; 28.9% vs. 10.1% reached HbA1c ≤6.5%; p < 0.0001 for both; figure 2B).

image

Figure 2. Glycated haemoglobin (HbA1c) levels during treatment with lixisenatide versus placebo. (A) LS mean change (± SE) in HbA1c from baseline at week 24 (based on week 24 LOCF analysis of HbA1c). (B) Percentage of patients achieving HbA1c goals ≤6.5% and <7.0% at week 24. (C) Change in HbA1c from baseline to week 76. Baseline and mean values over time are given for the as-observed population, in addition to the LOCF analysis at week 24 and the EOS analysis. Values are mean ± SE. *p values for lixisenatide-treated patients versus placebo-treated patients. EOS, end of study; HbA1c, glycated haemoglobin; LOCF, last observation carried forward; LS, least squares; SE, standard error.

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Mean (± SD) FPG was reduced from 9.1 ± 2.2 mmol/l at baseline to 8.0 ± 2.3 mmol/l at week 24 in the lixisenatide once-daily group, and from 9.1 ± 2.2 to 8.8 ± 2.3 mmol/l in the placebo group (figure 3A, B). The reduction in FPG from baseline was significantly greater with lixisenatide compared with placebo (figure 3A), with a LS mean difference of −0.84 mmol/l [95% CI (−1.21,–0.47); p < 0.0001].

image

Figure 3. Fasting plasma glucose (FPG) levels during treatment with lixisenatide versus placebo. (A) LS mean change in FPG from baseline at week 24 (based on week 24 LOCF analysis of FPG). (B) Change in mean FPG ± SE from baseline to week 76. FPG values are given for the as-observed population, in addition to the LOCF analysis at week 24 and the EOS analysis. *p values for lixisenatide-treated patients versus placebo-treated patients. EOS, end of study; LOCF, last observation carried forward; LS, least squares; SE, standard error.

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There was a small decrease in body weight with lixisenatide (−0.2 kg LS mean change) and a small increase with placebo (+0.2 kg). LS mean difference in body weight change at week 24 for lixisenatide versus placebo was not statistically significant [−0.41 kg; 95% CI (−1.03, 0.20); p = 0.1864]. For patients using metformin at screening, the LS mean difference in body weight was −0.54 kg [95% CI (−1.23, 0.14)] compared with +0.13 kg [95% CI (−1.27, 1.53)] for patients who were not using metformin.

Additional Secondary Efficacy Parameters at Week 24

On the basis of the pre-specified stepwise testing strategy for adjustment of multiplicity, analyses of additional secondary efficacy endpoints were performed for exploratory purpose only, and no statistical significance was calculated.

β-Cell function was assessed by HOMA-β. LS mean change in HOMA-β from baseline to week 24 was similar in the two treatment groups (6.72 and 6.98 in the lixisenatide and placebo groups, respectively); LS mean difference for lixisenatide versus placebo was–0.25 (95% CI: –6.579, 6.070).

Fewer patients on lixisenatide required rescue therapy at week 24 (3.8% vs. 11.3% on placebo).

The LS mean decrease in FPI from baseline to week 24 was greater in the lixisenatide group compared with placebo [−10.36 pmol/l from a baseline (± SD) of 62.7 ± 56.9 for lixisenatide vs. −1.01 pmol/l from a baseline of 68.1 ± 49.3 pmol/l for placebo]. The LS mean difference for lixisenatide versus placebo was −9.36 pmol/l [95% CI (−16.59, –2.12)].

Safety and Tolerability During the 24-week Treatment Period

The overall incidence of AEs and serious AEs, as well as the incidence of AEs leading to permanent discontinuation of study treatment, are outlined in Table 2. One patient in the placebo group had a severe acute myocardial infarction that led to death. Another patient in the placebo group died due to an AE of severe general physical health deterioration following a duodenal ulcer perforation, which occurred after discontinuation of placebo. The most commonly reported AEs in the lixisenatide group were gastrointestinal in nature, mostly nausea that was often mild or moderate in intensity, usually improved without therapy and only led to discontinuation of study treatment in a small number of patients (n = 6; 1.9%) (Table 2). In the lixisenatide group, the greatest number of events related to nausea was observed during the first week of treatment and the week following each increase in dose.

Table 2. Adverse events during the 24-week treatment period (safety population)
Type of TEAE, n (%)Lixisenatide (n = 323)Placebo (n = 161)
  1. AE, adverse event; TEAE, treatment-emergent adverse event.

  2. a

    Acute myocardial infarction.

  3. b

    Another patient in the placebo group died due to an AE of severe general physical health deterioration that started after the patient discontinued treatment.

  4. c

    As defined in the methods.

Any TEAE234 (72.4)117 (72.7)
Any serious TEAE8 (2.5)3 (1.9)
Death01 (0.6)a,b
Any TEAE leading to treatment discontinuation21 (6.5)8 (5.0)
Gastrointestinal disorders (any)118 (36.5)46 (28.6)
Nausea76 (23.5)17 (10.6)
Diarrhoea23 (7.1)17 (10.6)
Vomiting22 (6.8)6 (3.7)
Symptomatic hypoglycaemiac11 (3.4)2 (1.2)
Severe hypoglycaemiac00

The overall incidence of symptomatic hypoglycaemia was similar in both groups (Table 2) and no cases were considered to be severe according to the protocol-defined criteria.

A total of nine events from seven patients [six (1.9%) lixisenatide-treated patients and one (0.6%) placebo-treated patient] were adjudicated as an allergic reaction by ARAC during the 24-week treatment period. Four of these events in two patients in the lixisenatide group were adjudicated as possibly related to treatment: one patient with allergic dermatitis and one patient with angioedema, anaphylactic reaction and allergic conjunctivitis.

Injection-site reactions were reported in 20 patients [13 (4.0%) in the lixisenatide group and seven (4.3%) in the placebo group]. None of the reactions were serious or led to permanent treatment discontinuation.

Efficacy, Safety and Tolerability During the Variable Extension Period

The beneficial effect of lixisenatide on glycaemic control was maintained during the variable extension period. At week 76, HbA1c was reduced from baseline (± SE) by 1.1 ± 0.1 in the lixisenatide group (n = 194) compared with 0.6 ± 0.1 in the placebo group (n = 71; figure 2C). Mean HbA1c at week 76 was 6.9% ± 0.1 versus 7.3% ± 0.1 for the lixisenatide and placebo groups, respectively. In total, 58.8% of lixisenatide-treated patients and 38.0% of placebo-treated patients reached and maintained HbA1c targets of <7%, whereas 35.6% and 21.1% reached targets of ≤6.5%. FPG reduction was generally greater with lixisenatide compared with placebo (figure 3B). Mean changes in body weight from baseline at week 76 were similar in the lixisenatide and placebo groups (0.88 vs. 0.86 kg, respectively).

Lixisenatide continued to be well tolerated throughout the variable extension period. At the end of the whole on-treatment period, including the extension phase, the total proportion of AEs/serious AEs was 87.9/7.7% and 83.2/9.3% in the lixisenatide and placebo groups, respectively, with 9.3% of patients receiving lixisenatide and 7.5% of patients receiving placebo discontinuing treatment due to AEs. The most common AE in the lixisenatide group continued to be related to gastrointestinal disorders (48.3% vs. 38.5% in the placebo group), with no discernible increase in the incidence of nausea, vomiting or diarrhoea during the variable extension period (nausea: 26.0% vs. 13.7%; vomiting: 8.0% vs. 5.0%; diarrhoea: 10.8% vs. 14.3% at week 76 in the lixisenatide group compared with the placebo group, respectively). The incidence of symptomatic hypoglycaemia in the lixisenatide and placebo groups was 7.1% and 4.3%, respectively, which corresponded to 4.7 and 3.1 patients with events per 100 patient-years. There were no cases of severe hypoglycaemia occurring by the end of the on-treatment period.

A total of 12 patients reported 19 events that were adjudicated as an allergic reaction by ARAC during the whole treatment period [nine patients (2.8%) in the lixisenatide group and 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 30 patients by the end of the variable extension period (6.8% in the lixisenatide group and 5.0% in the placebo group); none of the reactions were serious or severe in intensity, or led to permanent treatment discontinuation.

A total of four patients [two (0.6%) receiving lixisenatide, and two (1.2%) receiving placebo] had protocol-defined events of increased lipase or amylase reported during the whole treatment period. No confirmed diagnoses of pancreatitis were reported in either treatment group. Nine patients (2.8%) in the lixisenatide group and four (2.5%) in the placebo group had calcitonin levels ≥20 ng/l (which was the cut-off for mandatory reporting according to the protocol). None of the events reported were considered to be severe or were diagnosed with an underlying thyroid C-cell disease; one of the events in the placebo group was considered as serious (i.e. medically important).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

The results of this phase III, placebo-controlled trial of the GLP-1RA lixisenatide show that lixisenatide, at a once-daily dose of 20 µg, significantly improves glycaemic control in patients insufficiently controlled on pioglitazone therapy (with or without metformin) and is well tolerated. Furthermore, the long-term extension data showed that the efficacy and tolerability of lixisenatide was maintained at the end of an on-treatment period lasting up to at least week 76. Efficacy and tolerability variables were also well maintained in the placebo group during the variable extension period.

At week 24, lixisenatide once daily significantly reduced HbA1c compared with placebo (LS mean difference −0.56%, p < 0.0001), and enabled significantly more patients to achieve the HbA1c targets of <7.0% and ≤6.5%. Lixisenatide treatment was also associated with reductions in FPG and FPI and a decreased need for rescue therapy compared with placebo.

In addition, lixisenatide QD was associated with a small reduction in body weight at week 24 compared with a small mean weight gain among those who received placebo. The difference in body weight change between treatment groups did not reach statistical significance, which contrasts with data from other studies of lixisenatide [9, 13], and may be related to the common finding of weight gain with thiazolidinediones [2, 3]. During this study, lixisenatide was taken in combination with pioglitazone and, for 80% of participants, with metformin. For those patients also receiving metformin, the difference in body weight change between lixisenatide-treated and placebo-treated patients was greater compared with those who did not receive metformin.

The beneficial effects on glycaemic control of combined lixisenatide and pioglitazone treatment can be explained by the different mechanisms of action of these two compounds. Pioglitazone increases tissue sensitivity to insulin [18, 19] but does not increase insulin secretion from pancreatic β-cells, whereas lixisenatide augments glucose-dependent insulin secretion [20]. Lixisenatide delays gastric emptying and decreases postprandial glucose, which complements the effects of pioglitazone on FPG. The combination of both therapies can also reduce or suppress the weight gain currently associated with pioglitazone therapy [2, 3]. Lixisenatide has been examined in a number of different treatment settings, including in combination with insulin glargine [16, 17]. In these studies, lixisenatide was shown to significantly improve glycaemic control and counteract the weight gain associated with insulin therapy.

The observed benefits of the combination of lixisenatide once daily and pioglitazone (with or without metformin) were achieved with a favourable tolerability profile. The most frequent AEs associated with lixisenatide were gastrointestinal in nature and occurred mainly during the initial weeks of treatment. The addition of lixisenatide once daily to pioglitazone therapy was associated with a low incidence of symptomatic hypoglycaemia throughout the entire treatment period. Thus, combining lixisenatide with one or two other agents that also have a low propensity to induce hypoglycaemia (i.e. pioglitazone and/or metformin) may be a valuable option to improve glycaemic control in patients who are prone to hypoglycaemia and are not achieving HbA1c targets with these oral agents alone.

The results of this study are consistent with, and extend the results of, previously reported phase III studies of lixisenatide in patients with T2DM, either untreated [14] or inadequately controlled on metformin alone [13, 15, 21], on sulphonylurea therapy with or without metformin [9], and on basal insulin plus oral agents [10, 16, 17]. Taken together, the results of these studies show improved glycaemic control, beneficial effects on body weight, limited risk of hypoglycaemia and good overall tolerability, indicating that lixisenatide once daily may be an effective treatment option in tailoring treatment to the needs of individual patients.

In conclusion, lixisenatide once daily significantly improved glycaemic control with a limited risk of hypoglycaemia, and was well tolerated over 24 weeks and during the variable extension period in patients with T2DM insufficiently controlled on pioglitazone, with or without metformin.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Data from this study were presented in poster form at the 72nd Annual Meeting of the American Diabetes Association, 8–12 June, 2012, Philadelphia, PA, USA. The authors thank all of the investigators, coordinators and patients who took part in this study. Editorial assistance was provided to the authors by Helen Brereton, PhD, of Medicus International and funded by Sanofi.

Conflict of Interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

M. P. has received research support and honoraria for consulting services from a number of pharmaceutical companies, including Sanofi. R. G. has received research support or honoraria from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly & Company, GlaxoSmithKline, Janssen, Merck, Novo Nordisk and Sanofi. E. N. and I. M.-B. are employees of Sanofi. H. G. is a consultant for Sanofi. R. A has received research support and/or consulting honoraria from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi and Takeda. M. P. was involved in the coordination of the study and led the writing of the manuscript. R. G. critically reviewed and approved the manuscript. E. N. has significantly contributed to protocol development, medical supervision and reporting of results. I. M.-B. has significantly contributed to medical supervision and reporting of results. H. G. has significantly contributed to the statistical analyses and reporting of results. R. A. was involved in the clinical performance of the study, analysis and discussion of results, and the preparation of the manuscript.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References
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