Study design

This post hoc pooled analysis used clinical trial data extracted from the intent-to-treat subpopulation of patients with T2D who participated in standardized meal tests (measured 2 h after a standard liquid breakfast) as part of the 24-week, phase 3, randomized, double-blind, placebo-controlled, 2-arm parallel-group, multicenter GetGoal-L ({“type”:”clinical-trial”,”attrs”:{“text”:”NCT00715624″,”term_id”:”NCT00715624″}}NCT00715624) [16], GetGoal-Duo1 ({“type”:”clinical-trial”,”attrs”:{“text”:”NCT00975286″,”term_id”:”NCT00975286″}}NCT00975286) [17], and GetGoal-L Asia ({“type”:”clinical-trial”,”attrs”:{“text”:”NCT00866658″,”term_id”:”NCT00866658″}}NCT00866658) [18] trials; all trials are registered at ClinicalTrials.gov. These were the 3 trials that evaluated the efficacy and safety of adding lixisenatide to basal insulin therapy in patients with T2D inadequately controlled on basal insulin, with or without OADs (metformin [MET], thiazolidinediones [TZD], or sulfonylurea [SU]). GetGoal-L enrolled patients from 15 countries who were inadequately controlled (HbA1c = 53–86 mmol/mol [7.0–10.0%]) on an existing, stable dose of basal insulin therapy for ≥3 months with or without MET [16]. Patients in GetGoal-L Asia were from Japan, Republic of Korea, Taiwan, and the Philippines. These patients were on existing basal insulin therapy with or without a SU. Patients in GetGoal-Duo 1 were from 25 countries and were inadequately controlled (HbA1c 53–86 mmol/mol [7.0–10.0%]) on existing OAD therapy. If present, SU therapy was discontinued, and patients were initiated on basal insulin therapy with or without MET or a TZD during the run-in phase. After the 12-week run in, patients with an HbA1c ≥ 53 mmol/mol (≥ 7.0%) to ≤75 mmol/mol (≤ 9.0%) and FPG ≤ 7.8 mmol/L (≤ 140 mg/dL) were randomly assigned to add lixisenatide or placebo [17].

To evaluate the impact of baseline FPG on achieving glycemic control, patients with baseline FPG of < 7 mmol/L (< 126 mg/dL) were categorized as controlled, whereas those with FPG ≥ 7 mmol/L (≥ 126 mg/dL) were categorized as uncontrolled. Patients were further grouped into PPG responders (< 10 mmol/L [< 180 mg/dL]) or non-responders (≥ 10 mmol/L [≥ 180 mg/dL]) at the end of the 24-week treatment period.

Assessments

The primary endpoint was the proportion of patients who achieved PPG < 10 mmol/L (< 180 mg/dL) at Week 24. Secondary endpoints in PPG responders and non-responders with or without controlled FPG levels at baseline were change in mean HbA1c from baseline to Week 24; the percentage of patients with HbA1c < 53 mmol/mol (< 7.0%) at Week 24; body weight change over 24 weeks; and the rate of symptomatic hypoglycemia during the study period (defined as typical symptoms of hypoglycemia accompanied by an SMPG value of ≤60 mg/dL [3.9 mmol/L]). Hypoglycemia was recorded via patient diaries; patients recorded any hypoglycemic events daily, which were passed on to investigators at the next visit.

Statistical analyses

Continuous efficacy assessments were analyzed using analysis of variance carried out by baseline FPG category using last observation carried forward at Week 24, with treatment group and PPG category as fixed effects. Response rates and hypoglycemia rates were analyzed using chi-square tests. Analyses excluded measurements obtained after the use of rescue medication and/or after treatment cessation. Rescue medication of short-acting or rapid-acting insulin was given to patients with a measurement of FPG > 11.1 mmol/L (> 200 mg/dL) or > 75 mmol/mol (HbA1c > 9%), for 3 consecutive days (Weeks 0–8), when changes to diet and study medication did not resolve the high readings. This threshold changed to FPG > 10 mmol/L (> 180 mg/dL) or HbA1c > 69 mmol/mol (> 8.5%) for Weeks 8–24. Results were combined across studies using a fixed-effects meta-analysis with inverse variance weights calculated separately by FPG and PPG categories. All analyses were performed using SAS Version 9.2® [SAS Institute Inc. Cary, NC, USA] or higher.

Patient baseline characteristics

Data from 587 lixisenatide-treated patients and 484 placebo-treated patients were included in this analysis. Baseline characteristics between the 2 treatment groups were comparable. Females made up 53% of patients in the lixisenatide group and 50% in the placebo group. In the lixisenatide versus placebo groups, respectively, mean body weight was 82 kg versus 81 kg, and mean duration of T2D was 11.8 years versus 11.3 years. Mean HbA1c was 65 mmol/mol (8.1%) in both groups.

When baseline variables were examined in the groups stratified by baseline FPG and PPG goal achievement the majority of variables were similar between the groups (Table 1). In the group with controlled FPG, the placebo PPG responders were less likely to be female and had a lower baseline HbA1c (Table ​(Table1).1). Baseline HbA1c was higher in lixisenatide non-responders with uncontrolled FPG than in responders. Both groups of non-responders with controlled FPG at baseline had higher baseline PPG, though there was no differences between the groups with uncontrolled FPG at baseline.

Impact of lixisenatide treatment on PPG target

Significantly more patients who received lixisenatide than those who received placebo achieved the PPG target. In patients with controlled FPG at baseline, 55.1% receiving lixisenatide achieved PPG < 10 mmol/L (< 180 mg/dL), compared with 18.3% in the patients receiving placebo, a difference of 36.8% (P < 0.001) (Fig. 1). Similarly, for patients with uncontrolled FPG at baseline, 48.4% in the lixisenatide group, compared with 10.1% in the placebo group, achieved PPG < 10 mmol/L (< 180 mg/dL), a difference of 38.3% (P < 0.001) (Fig. ​(Fig.11).

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Fig. 1

Percentage of patients who achieved ADA-recommended PPG target < 10 mmol/L (< 180 mg/dL) at Week 24. Abbreviations: ADA American Diabetes Association, FPG fasting plasma glucose, PPG postprandial glucose

Impact of achieving PPG target on other efficacy and safety outcomes

Regardless of baseline FPG status, patients who reached PPG target achieved a significantly greater mean reduction in HbA1c compared with patients who did not reach PPG target. The magnitude of HbA1c change from baseline was similar for patients with controlled and uncontrolled FPG (Fig. 2; Table 2), with greater absolute HbA1c reductions in PPG responders than non-responders. Regardless of whether PPG target was achieved, patients with controlled FPG experienced increased FPG, whereas patients with uncontrolled FPG experienced FPG reductions. Among patients with controlled FPG, the increase was significantly lower in PPG responders, and among patients with uncontrolled FPG the reductions were significantly greater among PPG responders (Table ​(Table2).2). Patients who reached PPG target were also more likely to achieve HbA1c goal < 53 mmol/mol (< 7.0%) compared with patients who did not reach PPG target (Fig. 3).

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Fig. 2

Change in HbA1c from baseline to Week 24. a Patients with controlled baseline FPG. b Patients with uncontrolled baseline FPG. Abbreviations: HbA1c glycated hemoglobin, FPG fasting plasma glucose, PPG postprandial glucose. aP = 0.008. bP < 0.001 for comparison between PPG response categories for both baseline FPG categories; Cochran–Mantel–Haenszel test stratified by study

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Fig. 3

Percentage of patients with controlled (a) and uncontrolled (b) baseline FPG achieving HbA1c < 53 mmol/mol (< 7.0%) at Week 24. Abbreviations: HbA1c glycated hemoglobin, FPG fasting plasma glucose, PPG postprandial glucose. aP < 0.001 for comparison between PPG response categories

There was no significant change in the risk of symptomatic hypoglycemia associated with achieving PPG target (Table ​(Table2).2). Patients who reached PPG target also experienced greater average reductions in body weight compared with those who did not reach PPG target with lixisenatide treatment; in contrast, all the placebo groups showed an increase in body weight (Table ​(Table22).

The authors received writing/editorial support in the preparation of this manuscript provided by Catarina Fernandes, PhD, and Keisha Peters, MSc, of Excerpta Medica, funded by Sanofi US, Inc.

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