Comparative efficacy and safety of lixisenatide combined with basal insulin versus ISPOR insulin regimens in the treatment of patients with type 2 diabetes mellitus inadequately controlled by basal insulin: a systematic review and network meta-analysis Sep 8-11, 2018 Peng Men1, Shuli Qu2, Wenting Luo2, Yanjun Liu3, Chaoyun Li4, Suodi Zhai1* Tokyo, Japan 1 Department of Pharmacy, Peking University Third Hospital, Beijing, China; 2 Real World Insights, IQVIA, China ; 3 Columbia University Mailman School of Public Health, NY, USA; 4 Health Economics & Outcome Research, Sanofi, Shanghai, China

INTRODUCTION RESULTS, continued • Change in HbA1c from baseline: • Lixisenatide is a once-daily, short-acting, selective glucagon like peptide-1 agonist (GLP-1 RA) for the treatment of ─ HbA1c reduction for Lixisenatide combined with basal insulin was comparable to premix, basal plus, and basal type 2 diabetes mellitus (T2DM). The efficacy and tolerability of lixisenatide, as add-on therapy to basal insulin, has bolus (Figure 2). been demonstrated in patients inadequately controlled by basal insulin in several randomized controlled trials (RCTs).1-3 Figure 2: HbA1c change from baseline (%) • According to local and international guidelines 4-6 and clinical practices, in addition to lixisenatide added on to basal insulin, intensified premixed insulin (premix) and basal insulin plus prandial insulin with the main meal (basal plus) or progressively covering all meals (basal-bolus) are also recommended for the treatment of T2DM patients inadequately controlled by basal insulin. • Limited head-to-head comparisons are reported for lixisenatide combined with basal insulin versus other intensified insulin regimens. In the absence of direct evidence, indirect and mixed comparisons can provide useful insights to support clinical and policy decision-makings. • Change in FPG from baseline: ─ FPG reduction for Lixisenatide combined with basal insulin was comparable to premix, basal plus and basal OBJECTIVE bolus (Figure 3). Figure 3: FPG change from baseline (mmol/l) To assess the relative efficacy and tolerability of lixisenatide combined with basal insulin, compared to premix, basal plus and basal bolus for the treatment of patients with T2DM inadequately controlled by basal insulin.

METHODS • Change in body weight from baseline: • Systematic Literature Review (SLR) ─ Lixisenatide combined with basal insulin showed statistically significant reduction in body weight compared with premix, basal plus, and basal bolus (Figure 4). ─ A SLR was conducted in PubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI) and Wanfang databases from January 1998 to January 2018 in accordance with the PRISMA7. Only RCTs published Figure 4: Body weight change from baseline (kg) in English and Chinese were included. ─ RCTs that investigated lixisenatide combined with basal insulin, premix, basal plus and basal bolus for the treatment of T2DM patients inadequately controlled by basal insulin for ≥24 weeks were identified. ─ Outcomes of interest included change in HbA1c, FPG and body weight from baseline, as well as percentage of patients experiencing at least one symptomatic hypoglycemic episode (incidence) and event per patient-year of symptomatic hypoglycemia. • Network Meta-analyses (NMA) ─ Networks were based on treatment-specific nodes. • Incidence and event per patient-year of symptomatic hypoglycemia: ─ Selection of a fixed-effect versus random-effect model was based on the deviance information criterion (DIC), ─ The incidence of symptomatic hypoglycemia for lixisenatide combined with basal insulin was significantly lower which measured the relative goodness of fit between models. compared with premix and basal bolus, and was comparable to basal plus (Figure 5(A)). ─ NMA was applied to calculate the relative risk (RR) or mean difference (MD) with 95% credibility interval (95%Crl) ─ As shown in Figure 5(B), the event per patient-year of symptomatic hypoglycemia for lixisenatide combined with within a Bayesian framework using STATA® software, version 13.0. basal insulin was lower compared with premix, and was comparable to basal plus and basal bolus. RESULTS Figure 5: Incidence and event per patient-year of symptomatic hypoglycaemia • Systematic Literature Review (A) Incidence ─ Eight RCTs met the inclusion criteria and were included for this study 1-3, 8-12. ─ Overall risk of bias was observed to be low across 8 studies, which was considered appropriate for quantitative analysis. ─ The baseline characteristics of included trials were shown in Table 1. Table 1: Baseline characteristics of included trials

Treatment Randomised Age BMI HbA1c T2DM Study Name duration Interventions (B) Event per patient-year population (yr) (kg/m2) (%) duration (yr) (week) BIAsp 30 + metformin Ligthelm 24 280 52.7 33.8 9.0 11.2 2011 Glargine + metformin +/- secretagogues Insulin glargine + gluisine (1 shot) Vora 2015 24 334 61.6 31.2 8.6 12.9 Insulin aspart/aspart protamine 30/70 Insulin lispro protamine suspension 75% and insulin lispro 25% + Tinahones 24 metformin +/- pioglitazone 478 57.5 29.6 8.6 11.7 MD= mean difference; RR=rate ratio; 95% CrI=95% credibility interval 2014 Glargine and lispro (1 shot) + metformin +/- pioglitazone Lispro mix 50/50 DISCUSSION Rosenstock 24 374 54.7 34.5 8.9 11.0 2008 glargine + lispro (3 shots) • HbA1c and FPG serve as surrogate markers of glycemic control and are key risk indicators for diabetes-associated microvascular and macrovascular complications and mortality 13. This study suggested that lixisenatide combined with Lixisenatide 20 μg + basal insulin +/- basal insulin has comparable glucose control capability to premix, basal plus and basal bolus. Yang 2018 24 metformin 448 55.0 27.7 7.9 10.3 Placebo + basal insulin +/- metformin • Choice of treatment is not solely based on efficacy, side effects such as weight gain and hypoglycemia that commonly Lixisenatide 20 μg + basal insulin +/- associated with insulin treatments could significantly diminish patients’ quality of life 14,15. It is reported that lixisenatide Riddle 2013 24 metformin 496 57.0 32.1 8.4 12.5 combined with basal insulin significantly reduce body weight, accompanied by less risk of hypoglycemia. Placebo + basal insulin +/- metformin • Limitations: 1) lack of raw data for pooling some outcomes such as PPG and severe hypoglycemia; 2) Slight Lixisenatide 20 μg + basal insulin +/- differences across studies in titration duration, mean dosage use, etc. To assess the influences of inconsistent sulfonylurea Seino 2012 24 311 58.4 25.3 8.5 13.9 variables, sensitivity analyses were performed, whose results showed no significant changes. Placebo + basal insulin +/- sulfonylurea lixisenatide 20 μg +/- metformin insulin gluisine once daily +/- Rosenstock CONCLUSIONS 26 metformin 894 59.8 32.2 7.9 12.2 2016 insulin gluisine thrice daily +/- metformin • Lixisenatide combined with basal insulin seemed to be • Network Meta-analyses similar in HbA1c reduction with significant greater weight ─ Figure 1 shows the different treatment regimens investigated in the eights studies, and how this network of evidence is connected. loss compared to premix, basal plus and basal bolus, Figure 1: Network of evidences accompanied by significant lower hypoglycaemia risk versus premix and basal bolus and comparable hypoglycaemia risk Vora 2015 to basal plus. Tinahones 2014 Basal Plus Premix REFERENCES 1. Riddle M C, et al. Diabetes care, 2013; 36(9):2489-2496. 2. Yang, et al. Diabetes Obes Metab, 2018; 20 (2): 335-343. 3. Seino, et al. Diabetes Obes Metab ,2012; 14 (10): 910-917. Ligthelm 2011 4. Chinese Diabetes Society. Chin J Diabetes Mellitus. 2018; 10(1): 4-67. 5. International Diabetes Federation Guideline Development Group. Diabetes research and clinical practice. 2014; 104 (1) : 1-52. 6. American Diabetes Association. Standards of medical care in diabetes—2018[J]. Diabetes Care, 2018; 41(Supplement 1): S86-S104 Placebo 7. Moher, et al. Annals of internal medicine. 2009; 151 (4): 264-269. 8. Ligthelm R et al. Endocrine Practice. 2010;17(1):41-50. Rosenstock 2016 Rosenstock 2008 9. Rosenstock J, et al. Diabetes Care. 2016; 39(8):1318-1328 10. Rosenstock J et al. Diabetes Care. 2008; 31(1):20-5. 11. Tinahones F, et al. Diabetes, Obesity and Metabolism. 2014;16(10):963-970. 12. Vora J, et al. Diabetes, Obesity and Metabolism. 2015;17(12):1133-1141. Riddle 2013 13. Kim JI et al. Diabetologia. 2005; 48: Suppl 1: A33 14. Gilet H et al. Value in Health. 2012; 15(8): 1036-1041. Seino 2012 15. Aravind SR. Curr Med Res Opin. 2014; 30(7):1275-1278. Yang 2018 Lixisenatide + Basal Bolus CONTACT basal insulin Suodi Zhai, Department of Pharmacy, Peking University Third Hospital, No. 49, Huayuan North Road, Haidian District, Beijing, 100083. Rosenstock 2016 E-mail: [email protected] DISCLOSURE No potential conflict of interest was reported by the authors. Basal Plus: one basal insulin injection and one pre-prandial short-acting insulin injection per day; Basal Bolus: one basal insulin injection and three short-acting insulin injections per day; SOURCE OF FUNDING Placebo: basal insulin This study was sponsored by Sanofi China.