SYSTEMATIC REVIEW. Introduction. X. Xue, 1 Z. Ren, 1 A. Zhang, 2 Q. Yang, 3 W. Zhang, 4 F. Liu 1,4

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1 SYSTEMATIC REVIEW Efficacy and safety of once-weekly glucagon-like peptide-1 receptor agonists compared with exenatide and liraglutide in type 2 diabetes: a systemic review of randomised controlled trials X. Xue, 1 Z. Ren, 1 A. Zhang, 2 Q. Yang, 3 W. Zhang, 4 F. Liu 1,4 SUMMARY Background: Once-weekly glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promising results in the treatment of type 2 diabetes. Herein, we compared the efficacy and safety of once-weekly GLP-1RAs with exenatide and liraglutide separately. Methods: We systematically surveyed the pertinent literature using various databases. The randomised controlled trials that compared once-weekly GLP-1RAs with exenatide and liraglutide in type 2 diabetes were included. Our main end-points were control of glycaemia, body weight, hypoglycaemia and gastrointestinal adverse events (AEs). Results: Our analysis included eight trials involving 5531 patients. Exenatide-long-acting release (LAR), dulaglutide and taspoglutide were more effective than twice-daily exenatide in reducing glycosylated haemoglobin A1c (HbA1c) and fasting blood glucose (FBG) levels and achieving HbA1c targets (< 7.0% and 6.5%). Liraglutide was as effective as dulaglutide and more effective than exenatide-lar and albiglutide in controlling glycaemia. With regard to the effectiveness in decreasing body weight, exenatide-lar, dulaglutide and taspoglutide were similar to exenatide whereas exenatide-lar, dulaglutide and albiglutide were inferior to liraglutide. Once-weekly GLP-1RAs, exenatide and liraglutide resulted in a similar incidence of hypoglycaemia and of gastrointestinal, serious, or other AEs. Conclusions: Once-weekly GLP-1RAs were more effective in controlling glycaemia and equally effective in decreasing body weight than twice-daily exenatide but were inferior to liraglutide in controlling these two parameters (dulaglutide was similar with liraglutide in controlling glycaemia). Once-weekly GLP-1RAs, exenatide and liraglutide had a similar risk of causing AEs. Review criteria Once-weekly GLP-1RAs have shown very promising results in preclinical and clinical trials. This metaanalysis included data from all randomised controlled trials that compared once-weekly GLP-1RAs with exenatide and liraglutide in type 2 diabetes. Message for the clinic There are significant differences between onceweekly GLP-1RAs, exenatide and liraglutide in controlling glycaemia and decreasing body weight. Until now, Liraglutide might be best GLP-1RA in controlling these two parameters. 1 Department of Endocrinology, Tengzhou Central People s Hospital, Shandong, China 2 Zaozhuang Science and Technology College, Shandong, China 3 Department of Medicine, Maternal and Child Care Service Centre of Tengzhou City, Shandong, China 4 Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Freiburg, Germany Correspondence to: Fupeng Liu, Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Hugstetter Strasse 55, Freiburg, Germany Tel.: Fax: Liufupengsdu@126.com Xianzhong Xue and Zhongfa Ren contributed equally to this research. Introduction Type 2 diabetes is a common and complex metabolic disorder characterised by progressive hyperglycaemia and a high risk of microvascular and macrovascular complications (1 4). Achieving the control of glycaemia and reducing the levels of glycosylated haemoglobin A1c (HbA1c) reduces the risk of long-term microvascular and possibly macrovascular involvement. Optimal treatment of diabetes should address both the control of glycaemia and comorbidities such as obesity, hypertension, and dyslipidemia (5,6). First-line treatments for type 2 diabetes generally include the administration of oral antihyperglycaemic medications and, unless contraindicated, metformin (7,8). However, despite treatment, control of glycaemia becomes more and more ineffective with time and consequently more advanced therapy is required to maintain glycaemic targets (9,10). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of injectable antidiabetic drugs with multiple glucoregulatory effects, including enhancement of glucose-dependent insulin secretion, suppression of inappropriately elevated postprandial glucagon secretion, and slowing of gastric emptying (11 13). In addition to improving the control of glycaemia, they also counteract other diabetes-associated conditions, including obesity, hypertension, and hyperlipidaemia (14,15). GLP-1RAs are widely used as second-line treatments after failure of one or more oral antidiabetic drugs (16,17). Examples of older GLP- 1RAs commonly used in clinical practice include twicedaily exenatide and once-daily liraglutide. Many once-weekly GLP-1RAs have been developed by amino acid substitutions, structural modifications, Disclosure The authors have no financial conflict of interest to declare.. doi: /ijcp

2 650 Once-weekly GLP-1RAs vs. exenatide and liraglutide and novel preparation methods. Several of them have shown very promising results in preclinical and clinical trials. A recent systematic review evaluated the efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonists for the management of type 2 diabetes (18). However, they have not focused on the comparison of once-weekly GLP-1RAs vs. exenatide and liraglutide, and it is not very suitable to pool different once-weekly GLP-1RAs together directly. So, we further performed this systemic review comparing the clinical efficacy and safety of once-weekly GLP-1RAs to exenatide and liraglutide. Methods Search strategy and selection criteria This study was designed according to the guidelines of the 2009 Preferred Reporting Items for Systematic Reviews and Meta-analysis statement (19). We selected relevant studies published before 1 October 2015, by searching the MEDLINE ( nlm.nih.gov/pubmed), EMBASE ( and Cochrane Library ( databases using the following search terms in the titles and abstracts (and also in combination with MESH terms): glucagon-like peptide-1 receptor agonist OR exenatide OR liraglutide OR albiglutide OR taspoglutide OR dulaglutide OR lixisenatide OR semaglutide. The study type was limited to randomised controlled trial (RCT) in MEDLINE and EMBASE. No language restriction was used. Unpublished clinical trials were not included in this systematic review. Study selection and data extraction An RCT was considered eligible if the following criteria were met: (i) adult patients with type 2 diabetes were studied; (ii) once-weekly GLP-1RAs, exenatide, and liraglutide were compared; (iii) the intervention duration was at least 12 weeks and (iv) the presence of more than 60 samples in each arm. The exclusion criteria were as follows: (i) observational and retrospective studies; (ii) non-clinical studies and (iii) lack of information about the outcomes that we analysed. Three reviewers selected the potentially publications and assessed the quality of the studies included using the Cochrane risk tool as previous study (15). We extracted the following data from each selected study: study design, baseline measurements, type of intervention, trial sponsors and reporting of the outcomes that we analysed. Statistical analysis We compared the effects of once-weekly GLP-1RAs with exenatide and liraglutide, with no restriction on treatment history. The main outcome was the change in HbA1c level after intervention relative to baseline. The other outcomes assessed were: (i) proportion of participants who achieved an HbA1c target of < 7.0% or 6.5% at the end of intervention; (ii) change in fasting blood glucose (FBG) level between baseline and end of intervention; (iii) change in body weight between baseline and end of intervention; (iv) number of participants with hypoglycaemic episodes; (v) incidence of total, serious and gastrointestinal adverse events (AEs). The pooled outcomes were calculated as either weighted mean difference (WMD, change from baseline) or risk ratio (RR) with 95% confidence intervals (CIs). Standard deviation was calculated from the sample size and the standard error if not reported in the study. I² testing was performed to assess the magnitude of the heterogeneity between the studies, and values greater than 50% indicated moderate-to-high heterogeneity (20). Inverse variance statistical method and random effects analysis model were used to calculate the pooled effect size. To evaluate the influence of each study on the overall effect size, sensitivity analyses were conducted using the leave-one-out method, i.e. by removing one study at a time and repeating the analysis. As a rule of thumb, tests for funnel plot asymmetry should be used only when there are at least 10 studies included in the meta-analysis, because when there are fewer studies the power of the tests is too low to distinguish chance from real asymmetry. So, we have not tested the publication bias in our meta-analysis. All analyses were performed using RevMan software version 5.1 (Nordic Cochrane Centre, Copenhagen, Denmark). Results Search results and study characteristics We identified 1280 studies in the MEDLINE, EMBASE and Cochrane Library databases. Eight RCTs involving 5531 patients were included in our analysis. The study selection process is shown in Figure 1. Five of the eight trials compared once-weekly GLP-1RAs [exenatide-lar (21 23), taspoglutide (24), and dulaglutide (25)] with exenatide 10 lg b.i.d. and three trials compared [exenatide-lar (26), albiglutide(27), and dulaglutide (28)] with liraglutide 1.8 mg q.d. Treatment backgrounds were oral antidiabetic agents (six RCTs) (23 28), and no drugs or oral antidiabetic agents (2 RCTs) (21,22). The mean baseline level of HbA1c was 8.3% (range of ), the mean baseline body mass index was 32.2 kg/m² ( ), and the mean duration of diabetes was 7.6 years ( ). Other characteristics of the 8 RCTs are shown in Table 1.

3 Once-weekly GLP-1RAs vs. exenatide and liraglutide 651 Figure 1 Study selection process Assessment of the risk of bias Seven trials of the eight RTCs were randomised and open-label, indicating that patients and investigators were unmasked to treatment (21 24,26 28). Six trials provided a detailed description of random sequence generation (23 28), six described their methods of allocation concealment (21,24 28), and 5 included blinding of outcome assessments (21,22,24,25,28). The rate of withdrawal for all RCTs was 14.2% (range of %). Analysis of variance (21,22,24), covariance (25,27) or mixed models analysis (23,26,28) was used to assess changes in the HbA1c levels. The risk of bias is summarised and shown in Figures S1 and S2, respectively. Efficacy HbA1c and FBG Comparisons with exenatide. Three trails compared exenatide-lra 2 mg q.w. with exenatide 10 lg b.i.d (21 23). The pooled analysis showed that onceweekly exenatide reduced the mean HbA1c levels more than did exenatide injected twice a day (WMD, 0.46; 95% CI, 0.69 to 0.23; p < 0.01) and increased the proportion of patients who achieved HbA1c levels < 7.0% (RR, 1.52; 95% CI, ; p < 0.01) or 6.5% (RR, 1.65; 95% CI, ; p = 0.02) to a greater extent. Once-weekly exenatide also reduced the mean FBG levels more than did twice-daily exenatide (WMD, 0.83; 95% CI, 1.08 to 0.58; p < 0.01; I 2 = 0%). When the trial by Blevins et al. (21) was excluded, the proportion of patients who achieved HbA1c levels 6.5% became non-significant. All the other results were robust and not affected by any single study included in the analysis. (The detailed results change of HbA1c, change of FBG, patients achieving HbA1c < 7.0%, and patients achieving HbA1c 6.5% were shown in Figures 2, 3, S3, and S4, respectively). Wysham et al. compared dulaglutide with exenatide for 52 weeks (25). Compared with exenatide 10 lg b.i.d., the least square mean changes from baseline were superior for dulaglutide 1.5 mg q.w. ( 0.56%%; p < 0.01) and dulaglutide 0.75 mg q.w. ( 0.27%; p < 0.01). Dulaglutide 1.5 mg q.w. and 0.75 mg q.w. increased the proportion of patients who achieved HbA1c levels < 7.0% (71%, 59% vs. 49%; p < 0.01 for both comparisons) or 6.5% (57%, 48% vs. 35%; p < 0.01 for both comparisons) to a greater extent. At 52 weeks, dulaglutide arms produced greater changes in FBG from baseline compared with exenatide (p < 0.01 for both comparisons). Rosenstock et al. compared taspoglutide with exenatide for 52 weeks (24). Taspoglutide 10 mg q.w. and 20 mg q.w. were significantly superior to exenatide 10 lg b.i.d. in the reduction in HbA1c (estimated difference of 0.22%; p < 0.01, and 0.25%; p < 0.01, for taspoglutide 10 and 20 mg, respectively). Taspoglutide reduced FBG to a greater extent than did exenatide (estimated difference of 0.31 [ 0.62 to 0.01; p = 0.05], and 0.34 [ 0.64 to 0.03; p = 0.03], for taspoglutide 10 and 20 mg, respectively). Comparisons with liraglutide. Dungan et al. compared dulaglutide 1.5 mg q.w. with liraglutide 1.8 mg q.d (28). Dulaglutide showed no significant advantage in decreasing the mean HbA1c and FBG (estimated difference of 0.06% [95% CI, 0.19 to 0.07], and 0.03 [95% CI, 0.32 to 0.25], for HbA1c and FBG, respectively). Moreover, no significant differences were observed in the proportion of patients who achieved HbA1c levels < 7.0% (68% vs. 68%; p = 0.93) and 6.5% (55% vs. 51%; p = 0.36). Pratley et al. evaluated the efficacy of albiglutide 50 mg q.w. with liraglutide 1.8 mg q.d (27). Liraglutide was superior in decreasing the mean HbA1c and FBG [estimated difference of 0.21% (95% CI, 0.08 to 0.34), and 0.46 (95% CI, 0.14 to 0.78), for HbA1c and FBG, respectively] and increased the proportion of patients who achieved

4 652 Once-weekly GLP-1RAs vs. exenatide and liraglutide Table 1 Characteristics of randomised controlled trials included in the systemic review Author Year NCT Number Duration of intervention Treatment background Final Interventions Patients number Sponsor Men (%) Age (year) BMI (kg/m²) HbA1c (%) Diabetes duration (year) Drucker DJ (22) weeks Drug naive, or on one or more oral antidiabetic agents Blevins T (21) weeks Drug naive, or with a stable oral antidiabetic agents Ji L (23) weeks Inadequately controlled with oral antihyperglycaemic medications Rosenstock J (24) weeks Overweight inadequately controlled on metformin a thiazolidinedione Wysham C (25) weeks Treated with metformin and pioglitazone. Buse JB (26) weeks Treated with lifestyle modification and oral antihyperglycaemic drugs Dungan KM (28) weeks Receiving a stable dose of metformin at least for 3 months Pratley RE (27) weeks Inadequate glycaemic control on oral antidiabetic agents E-LAR 2 mg q.w. 148 AstraZeneca E 10 lg b.i.d. 147 E-LAR 2 mg q.w. 129 AstraZeneca; Eli Lilly E 10 lg b.i.d. 123 and Company E-LAR 2 mg q.w. 340 AstraZeneca; Eli Lilly E 10 lg b.i.d. 338 and Company T 10 mg q.w. 384 Hoffmann-La Roche T 20 mg q.w. 392 E 10 lg b.i.d. 373 D 0.75 mg q.w. 280 Eli Lilly and Company D 1.5 mg q.w. 279 E 10 lg b.i.d. 276 E-LAR 2 mg q.w. 461 AstraZeneca; Eli Lilly L 1.8 mg q.d. 450 and Company D 1.5 mg q.w. 299 Eli Lilly and Company L 1.8 mg q.d. 300 A 50 mg q.w. 404 GlaxoSmithKline L 1.8 mg q.d. 408 E-LAR, exenatide long acting release; E, exenatide; L, liraglutide; A, albiglutide; D, dulaglutide; T, taspoglutide.

5 Once-weekly GLP-1RAs vs. exenatide and liraglutide 653 Figure 2 Forest plot of weighted mean difference in change in HbA1c from baseline HbA1c levels < 7.0% (52% vs. 42%; p < 0.01) or 6.5% (28% vs. 20%; p < 0.01) to a greater extent. Buse et al. evaluated the efficacy of exenatide-lar 2 mg q.w. and liraglutide 1.8 mg q.d (26). Similar to the comparison between liraglutide and albiglutide, liraglutide was superior in decreasing the mean HbA1c and FBG [estimated difference of 0.21% (95% CI, 0.08 to 0.33), and 0.36 (95% CI, 0.05 to 0.66), for HbA1c and FBG, respectively] and increased the proportion of patients who achieved HbA1c levels < 7.0% (60% vs. 53%; p = 0.02) to a greater extent. Body weight A pooled analysis from three trials indicated that the effectiveness of exenatide-lar in decreasing body weight was similar to that of exenatide 10 lg b.i.d. (WMD, 0.02; 95% CI, 1.16 to 1.19; p < 0.98) (21 23). Similarly, dulaglutide 1.5 mg, taspoglutide 10 mg, and taspoglutide 20 mg q.w. did not decrease body weight compared with exenatide (24,25). By contrast, liraglutide 1.8 mg q.d. significantly decreased body weight compared with exenatide-lar (26), dulaglutide 1.5 mg (28) and albiglutide 10 mg q.w. (27) (detailed results are shown in Figure 4). Safety Severe hypoglycaemia was very rare, and only two patients who received 10 lg of exenatide twice a day were affected (25). The incidence of minor hypoglycaemia was also very low in patients who received exenatide once weekly (6.8%) and exenatide or liraglutide (8.9%). Pooled results of five trials showed that once-weekly GLP-1RAs significantly decreased the incidence of minor hypoglycaemia compared with exenatide 10 lg b.i.d. (RR, 0.67; 95% CI, ; p < 0.01; I 2 = 0%) (21 25). However, this advantage became non-significant when exenatide-lar (21 23), dulaglutide (25) and taspoglutide (24) were compared with exenatide separately. Exenatide-LAR (26), dulaglutide (28) and albiglutide (27) caused no difference in the incidence of minor hypoglycaemia compared with liraglutide 1.8 mg q.d.

6 654 Once-weekly GLP-1RAs vs. exenatide and liraglutide Figure 3 Forest plot of weighted mean difference in change in FBG from baseline Once-weekly GLP-1RAs did not increase the incidence of serious AEs (RR, 0.97; 95% CI, ; p = 0.78; I 2 = 5%) or other (not including serious) AEs (RR, 0.98; 95% CI, ; p = 0.37; I 2 = 47%) (21 28). These results were robust and not affected by the types of once-weekly GLP-1RAs and by the comparison with exenatide or liraglutide. In general, there was no difference in the incidence of gastrointestinal AEs between once-weekly GLP-RAs and exenatide or liraglutide, although several trials indicated that exenatide-lar was superior to liraglutide in causing nausea, diarrhoea, vomiting, and dyspepsia (26), albiglutide was superior to liraglutide in causing nausea (27), and liraglutide was superior to taspoglutide in causing nausea and vomiting (24). The events examined were nausea (RR, 0.80; p = 0.25) (21 28), diarrhoeal (RR, 1.06; p = 0.64) (21 28), vomiting (RR, 0.83; p = 0.44) (21 28), dyspepsia (RR, 0.93; p = 0.73) (22,24 28) and constipation (RR, 1.22, p = 0.29) (22 28). All these results were robust and not affected by any single study. Discussion Our study assessed the clinical efficacy and safety of once-weekly GLP-1RAs compared with exenatide and liraglutide in patients with type 2 diabetes who were drug-naive or inadequately controlled via oral antihyperglycaemic medication. Patient data from eight RCTs were examined. We found that exenatide-lar, dulaglutide and taspoglutide were more effective than twice-daily exenatide in reducing HbA1c and FBG levels and achieving HbA1c targets (< 7.0% and 6.5%). However, liraglutide was as effective as dulaglutide and more effective than exenatide-lar and albiglutide in controlling glycaemia. Previous studies showed that once-daily liraglutide caused a greater reduction in HbA1c and FBG levels than did twice-daily exenatide in indirect or head-to-head clinical trials (29 34). Therefore, the significantly different results obtained in the comparisons between exenatide and liraglutide primarily reflect their different hypoglycaemic effects. Exenatide-LAR, dulaglutide and taspoglutide did not reduce body weight to a greater extent than did exenatide. However, exenatide-lar, albiglutide and dulaglutide were inferior to liraglutide in decreasing body weight. In the safety analysis, once-weekly GLP-1RAs showed a tendency to decrease the incidence of minor hypoglycaemia compared with exenatide, and in the overall analysis, they did not increase the incidence of gastrointestinal, serious or other AEs.

7 Once-weekly GLP-1RAs vs. exenatide and liraglutide 655 Figure 4 Forest plot of weighted mean difference in change in body weight from baseline Furthermore, once-weekly GLP-1RAs can significantly reduce the patients pain, resulting in better compliance. Patients who switched from short-acting to once-weekly GLP-1RAs reported significant improvements in their quality of life (35). Although most of the included studies were published in high-impact journals, this systemic review has some limitations. First, all RCTs included in our analysis were sponsored by the pharmaceutical industry, and most were open-label owing to different injection frequencies. Second, the RCTs included in our analysis ranged in duration from 24 weeks to 52 weeks (mean of 30 weeks); therefore, whether our findings apply to patients who received once-weekly GLP-RAs for longer periods is unknown. Third, the use of different types of once-weekly GLP-RAs in our analysis resulted in significant heterogeneity, especially in comparison with liraglutide. For this reason, we conducted this analysis by directly comparing the efficacy of GLP-1 RAs. In addition, Ji et al. (23) and Pratley et al. (27) reported HbA1c targets of 7.0% and < 6.5%, respectively. For consistency with other trials, we believe that these values are similar to those used in our study (< 7.0% and 6.5%, respectively). This may influence the validity of our conclusions. In conclusion, exenatide-lar, dulaglutide and taspoglutide were more effective in controlling glycaemia and similarly effective in decreasing body weight compared with twice-daily exenatide. By contrast, liraglutide was superior to exenatide-lar, dulaglutide, and albiglutide in decreasing body weight, and superior to exenatide-lar and albiglutide in controlling glycaemia. In addition, once-weekly exenatide and liraglutide had a similar risk of causing AEs. Acknowledgement None. Funding Fupeng Liu would like to acknowledge the support from The China Scholarship Council.

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