Diabetes Ther (2018) 9:1233–1251 https://doi.org/10.1007/s13300-018-0428-y ORIGINAL RESEARCH A Systematic Literature Review and Network Meta- Analysis Comparing Once-Weekly Semaglutide with Other GLP-1 Receptor Agonists in Patients with Type 2 Diabetes Previously Receiving Basal Insulin . . . . Michal Witkowski Lars Wilkinson Neil Webb Alan Weids Divina Glah Hrvoje Vrazic Received: March 16, 2018 / Published online: April 30, 2018 The Author(s) 2018 Data at 24 ± 4 weeks were extracted for efﬁcacy ABSTRACT and safety outcomes (feasible for analysis in an NMA), including the change from baseline in Introduction: Once-weekly semaglutide is a glycated hemoglobin (HbA ), body weight, and 1c glucagon-like peptide-1 (GLP-1) analogue that is systolic blood pressure, and the incidence of currently available as 1.0 mg and 0.5 mg dose nausea, vomiting, and diarrhea. Data were syn- for the treatment of type 2 diabetes (T2D). thesized using a NMA and a Bayesian framework. Currently, no head-to-head trial investigating Results: In total, eight studies were included once-weekly semaglutide as an add-on to basal across the base-case analyses. The results insulin vs other GLP-1 receptor agonists (GLP-1 demonstrate that once-weekly semaglutide RAs) is available. The aim of this study was to 1.0 mg was associated with signiﬁcantly greater conduct a network meta-analysis (NMA) to reductions in HbA (- 0.88% to - 1.39% vs 1c assess the efﬁcacy and safety of once-weekly comparators) and weight (- 1.49 to - 4.69 kg vs semaglutide vs other GLP-1 RAs in patients with comparators) and similar odds of experiencing T2D inadequately controlled on basal insulin. nausea, vomiting, or diarrhea vs all GLP-1 RA Methods: A systematic literature review was comparators. Once-weekly semaglutide 1.0 mg performed to identify all trials of GLP-1 RAs as an was also equally effective at reducing systolic add-on to basal insulin in patients with T2D. blood pressure compared with liraglutide 1.8 mg. Once-weekly semaglutide 0.5 mg signiﬁcantly Enhanced Digital Features To view enhanced digital reduced HbA vs the majority of other GLP-1 1c features for this article go to https://doi.org/10.6084/ RAs, except liraglutide 1.8 mg QD. The odds of m9.ﬁgshare.6106613. experiencing nausea were signiﬁcantly lower Electronic supplementary material The online with once-weekly semaglutide 0.5 mg compared version of this article (https://doi.org/10.1007/s13300- with all GLP-1 RA comparators. 018-0428-y) contains supplementary material, which is available to authorized users. Conclusion: Once-weekly semaglutide 1.0 mg as an add-on to basal insulin is likely to be the M. Witkowski N. Webb (&) A. Weids most efﬁcacious GLP-1 RA for reducing HbA 1c DRG Abacus, Bicester, Oxfordshire, UK and weight from baseline after 6 months of e-mail: firstname.lastname@example.org treatment. The efﬁcacy of once-weekly semaglutide is not associated with a signiﬁcant L. Wilkinson H. Vrazic Novo Nordisk A/S, Søborg, Denmark increase in the incidence of gastrointestinal side-effects vs other GLP-1 RAs. D. Glah Funding: Novo Nordisk. Novo Nordisk Ltd., Gatwick, UK 1234 Diabetes Ther (2018) 9:1233–1251 Keywords: Basal insulin; GLP-1 receptor treatment of a GLP-1 RA and basal insulin agonist; Glycemic control; HbA ; Network allows achievement of the goals of anti-diabetic 1c meta-analysis; Semaglutide; Systematic review; therapy: robust glycemic control without an Systolic blood pressure; Type 2 diabetes; Weight increase in hypoglycemia and weight gain [14, 15]. Combination therapy with GLP-1 RAs and basal insulin is also more effective when INTRODUCTION compared to other anti-diabetic treatment reg- imens . Type 2 diabetes (T2D) is a chronic and pro- Semaglutide is a new once-weekly GLP-1 gressive disease associated with microvascular analogue available at either a 1.0 mg or 0.5 mg and macrovascular complications leading to dose. The clinical efﬁcacy of once-weekly increased morbidity and mortality [1, 2]. semaglutide has been extensively studied in the Glycemic control is the key goal in the Semaglutide Unabated Sustainability in Treat- management of T2D, with targets of glycated ment of Type 2 Diabetes (SUSTAIN) clinical trial hemoglobin (HbA ) \ 7.0% (53 mmol/L) or 1c program, for which data from seven global B 6.5% (48 mmol/mol) deﬁned in treatment phase 3 trials have been published [16–22]. guidelines [3–6]. Despite clear clinical guideli- Speciﬁcally, the efﬁcacy and safety of once- nes for achieving glycemic control in patients weekly semaglutide as an add-on to basal insu- with T2D [3, 7, 8], glycemic control remains lin (± OADs) has been investigated in the SUS- suboptimal in many patients with T2D receiv- TAIN 5 clinical trial . In this trial, once- ing insulin treatment. For example, in patients weekly semaglutide (? basal insulin ± met- with T2D receiving basal insulin across Europe formin) provided a superior reduction in HbA 1c and the US, it has been estimated that 78.1% levels and body weight compared with placebo and 72.2% had inadequate glycemic control 3 (? basal insulin ± metformin) and allowed a and 24 months post-initiation . There is sig- signiﬁcantly greater proportion of patients to niﬁcant clinical inertia in the initiation and achieve target HbA levels . 1c intensiﬁcation of insulin therapy among Given the number of treatment options patients with poor glycemic control, and it has available for the management of T2D, it is been estimated that only one-third achieve important for decision makers to understand glycemic control 3 years after the initiation of the relative clinical beneﬁts of all treatment basal insulin . For patients who are inade- options to allow for an informed treatment quately controlled on basal insulin, treatment decision. So far, no head-to-head trials between options include the intensiﬁcation of insulin once-weekly semaglutide and other GLP-1 RAs therapy by adding either rapid-acting bolus in patients inadequately controlled on basal insulin, another oral anti-diabetic medication insulin (± OADs) have been conducted. As each (OAD), or injectable glucagon-like peptide-1 GLP-1 RA may demonstrate unique advantages receptor agonists (GLP-1 RAs) [3, 6, 7]. and disadvantages, it is important to under- GLP-1 RAs are incretin mimetics that stand the relative efﬁcacy and safety of each improve glycemic control with a favorable GLP-1 RA . The aim of the current study was effect on body weight and a low incidence of to conduct a systematic literature review (SLR) hypoglycemia [11, 12]; GLP-1 RAs improve and network meta-analysis (NMA) to assess the glycemic control when used at different stages relative efﬁcacies and safety of GLP-1 RAs as an along the T2D treatment cascade [3, 7, 13]. The add-on to basal insulin (± OADs) in the treat- differing mechanism of actions mean that GLP- ment of T2D. 1 RAs can complement basal insulin therapy for the management of day-to-day blood glucose METHODS control without incurring the increased risk of hypoglycemia and weight gain associated with The trials included across the analyses were the addition of a bolus insulin . As such, it derived from a SLR, for which the methodology has been suggested that the combination Diabetes Ther (2018) 9:1233–1251 1235 has been reported in Witkowski et al.  (while risk of bias using a seven-criteria checklist as the search strategy and PICOS criteria have been approved by the National Institute of Health and previously presented in the sister publication Care Excellence (NICE) . within this journal, they are replicated in Tables S1 and Table S2 of the Electronic sup- Statistical Analysis plementary material, ESM, for convenience). Brieﬂy, searches of databases (MEDLINE , As previously described in the sister publication, Embase, and the Cochrane Library; see Table S1 analyses of continuous outcomes (using a normal of the ESM) and conference proceedings were likelihood, identity link, shared parameter performed via Ovid on April 5, 2016 (updated in model) and dichotomous outcomes (using a October 3, 2016 and August 16, 2017). Studies binomial likelihood [assuming a normal distri- were then screened independently by two bution], logit link model) considered feasible for reviewers against the PICOS (population, inter- assessment were implemented on WinBUGS ventions, comparators, outcomes, study design) (MRC Biostatistics Unit, Cambridge, UK ) selection criteria for inclusion in the SLR using a Bayesian framework with the inclusion of (Table S2 of the ESM). vague prior distributions, and three Markov An NMA was performed to compare the efﬁ- Monte Carlo chains. Both ﬁxed-effects (FE) and cacy and safety of GLP-1 RAs in patients with random-effects (RE) models were run for each T2D. In the analysis, the primary intervention of outcome and the model with the best ﬁt (based on interest was once-weekly semaglutide (0.5 mg the deviance information criterion [DIC] and the and 1.0 mg) and the primary comparators of average posterior residual deviance) was used. All interest were all other licensed doses of GLP-1 NMAs were formally assessed for inconsistency RAs approved for the treatment of T2D—liraglu- using Bucher’s method (as outlined by the NICE tide once-daily (QD), dulaglutide once-weekly Technical Support Document 4) ; brieﬂy, the (QW), exenatide twice-daily (BID), exenatide inconsistency assessment with Bucher’s method QW, lixisenatide QD, and albiglutide QW; compares direct and indirect (NMA) estimates, despite a withdrawal notice, albiglutide is inclu- and the difference between these estimates is a ded as the reason for withdrawal was not related measure of inconsistency. to the safety of the medicine . In order to Model convergence (assessed using standard reduce variability between the populations diagnostic methods for evaluating convergence) across the different trials, the deﬁnition of the inferences were made from data obtained by add-on to basal insulin population was aligned as sampling for a further 20,000 iterations using all closely as possible with the population included the samples. If models failed to converge, the in SUSTAIN 5—patients inadequately controlled feasibility of a Bucher indirect comparison was on basal insulin (100% received basal insulin) considered. Bucher indirect comparisons were with or without metformin (approximately 83% calculated in STATA 13 (release 13, 2013; Sta- of patients also received metformin). As rela- taCorp. LP, College Station, TX, USA) using the tively few trials have been conducted in patients ‘‘indirect’’ command . The results of the inadequately controlled on basal NMA are presented as mean treatment differ- insulin ± metformin, trials with patients inade- ences or odds ratios (ORs) and an associated quately controlled on basal insulin with up to 95% credible interval (CrI). Unless the CrI two OADs were included for feasibility assess- excludes the null value (for treatment differ- ment. All trials identiﬁed in the SLR were exam- ences) or 1 (for ORs), it is assumed that there is ined for data on at least one outcome of interest, no difference. Two ranking outcomes, median and the ability to form a best-case connected rank and the surface under the cumulative network was assessed. The feasibility of generat- ranking curve (SUCRA), are also presented. ing evidence networks for each of the 20 out- Finally, this article does not contain any new comes of interest outlined in the PICOS criteria of studies with human or animal subjects per- the SLR (Table S2 of the ESM) was then examined. formed by any of the authors. All studies included in the NMA were assessed for 1236 Diabetes Ther (2018) 9:1233–1251 patients, which may inﬂuence the relative RESULTS treatment effects ). It was therefore decided that these studies should be excluded from the Identiﬁed Publications base-case analysis in order to limit the clinical heterogeneity of the NMA, yielding a total of A total of 107 publications reporting on 75 eight studies; however, the impact of excluding unique trials were included within the SLR those trials was to be explored in sensitivity (Table S3 of the ESM) as demonstrated in the analyses. sister article within this journal; the PRISMA diagram is replicated in Fig. S1 of the ESM. Of NMA Results these 75 trials, 12 trials were considered to be relevant for inclusion in the current analysis [20, 30–40]. All 12 trials considered in the NMA For the analysis, outcome-speciﬁc evidence networks were possible for 10 of the 20 out- formed a connected network. It should be noted that the insulin lispro arms from Diamant et al. comes of interest assessed for feasibility; note that it was not feasible to perform an analysis of  and HARMONY-6  were deemed to be similar enough to combine into a single treat- the incidence of hypoglycemia as no connected network could be formed. Of the eight trials ment node. The 12 trials were next examined for time points for which data were available for considered in the base-case analysis, all trials at least one outcome (Fig. S2 in the ESM). All 12 reported data on the change from baseline in trials (100%) reported on an at least one out- HbA , the proportion of patients achieving 1c come of interest between 20 and 28 weeks. HbA \ 7% and B 6.5%, fasting plasma glucose 1c Based on this, it was decided to analyze each (FPG), weight, and the incidence of nausea, outcome at 24 ± 4 weeks (approximately vomiting, and diarrhea; only two trials (LIRA- ADD2BASAL  and SUSTAIN 5 ) reported 6 months) of treatment—it was assumed that the level of response to treatment within the change from baseline in systolic blood pressure (SBP), and three trials (GetGoal-Duo 2 4 weeks of the target week was unlikely to vary considerably. Overall, the majority of trials , GetGoal-L , and SUSTAIN 5 ) reported the proportion of patients achieving (75%) reported at either 24 or 26 weeks (range week 23–28) in the analysis at 24 ± 4 weeks. C 5% weight loss. The evidence networks are The study design and patient characteristics shown in Fig. 1. of 12 trials are presented in Table 1. Overall, the The FE model was preferred for all outcomes risk of bias across the 12 studies was considered analyzed in the base case; no important differ- to be low; however, the highest risk of bias ences between the FE and RE models were across the studies was associated with elements observed in terms of DIC and average posterior residual deviance (Table S4 of the ESM). How- of study blinding and omissions (Figure S3 in the ESM). In total, eight trials were deemed ever, the NMA for the change from baseline in SBP was unstable and failed to converge. As sufﬁciently homogeneous to combine for anal- ysis, while four studies were identiﬁed as outlined in the methodology, a Bucher indirect comparison was therefore performed for this potential outliers due to study design and patient characteristics: the GetGoal-Duo 1 trial outcome.  screened patients who were newly initiated The results of the NMA are presented as on basal insulin and were only included in the treatment differences or ORs (once-weekly study if they were uncontrolled after 12 weeks; semaglutide vs comparator) in Fig. 2a–h (the full matrix of relative treatment effects results the GetGoal-O trial  was conducted exclu- sively in elderly patients; and both the GetGoal- are shown in Tables S12–S20 of the ESM). The associated treatment ranks (SUCRA and median L-C trial  and the GetGoal L-Asia trial  were conducted primarily ([ 85%) in an Asian rank) are presented, where available, in Tables 2 and 3. population (GLP-1 RAs are known to be more effective in Asian patients than in Caucasian Diabetes Ther (2018) 9:1233–1251 1237 Table 1 Study design and patient characteristics of trials included in the NMA Trial Number Randomized Background therapy Prior therapy Females, n (%) Mean age, Mean baseline weight, Mean Mean baseline Treatment of treatment with 2/1 years (SD) kg (SD) baseline duration of duration, weeks patients OADs, n (%) HbA ,% diabetes, years (total trial 1c (SD) (SD) duration) AWARD-9 : 150 DULA 1.5 mg IGlar ± MET 134 (89.3)/ 65 (43.3) 60.2 (9.5) 93.3 (17.5) 8.4 (0.9) 13 (7.5) 28 (31) QW NR phase 3, double- blind, parallel 150 Placebo 131 (87.3)/ 62 (41.3) 60.6 (10.1) 92.6 (17.1) 8.3 (0.8) 13.3 (7.7) trial, NR 40 sites globally Buse et al. : 123 Placebo IGlar ± MET ± PG 97/8 (7) 44 (36) 59 (10) 93.4 (21.2) 8.5 (0.96) 12 (7) (30) phase 3, double- 138 EXE 10 lg 93/23 (17) 67 (49) 59 (9) 95.4 (20.4) 8.32 (0.85) 12 (7) blind, parallel BID trial, 59 sites globally Diamant et al. 312 ILispro starting IGlar ? MET ± SU NR/99 (38) 130 (49.4296577946768) 59.4 (9.3) 89.4 (17) 8.2 (0.9) 11 (8, 15) 30 (44) : dose phase 3, open- 24.6 U QD label, parallel changing to trial, dose 42.1 U QD 108 sites globally 315 EXE 10 lg NR/85 (34) 119 (48.1781376518219) 59.5 (9.6) 91.1 (16.6) 8.3 (1) 12 (8, 17) BID GetGoal-Duo 1 223 Placebo IGlar ? MET ± PG or RG 196 (87.9)/27 110 (53.7) 56 (10) 86.8 (20.4) 7.6 (0.5) 8.7 (5.8) 24 (38.5) ; (12) phase 3, open- 223 LIXI 20 lg 196 (87. 92)/ 114 (53.7) 56 (10) 87.3 (21.8) 7.6 (0.5) 9.6 (6) label, parallel QD 27 (12) trial, 140 sites, 25 countries 1238 Diabetes Ther (2018) 9:1233–1251 Table 1 continued Trial Number Randomized Background therapy Prior therapy Females, n (%) Mean age, Mean baseline weight, Mean Mean baseline Treatment of treatment with 2/1 years (SD) kg (SD) baseline duration of duration, weeks patients OADs, n (%) HbA ,% diabetes, years (total trial 1c (SD) (SD) duration) GetGoal-Duo 2 298 LIXI 20 lg IGlar ± MET NR 160 (53.7) 59.8 (8.6) 90.1 (17.4) 7.8 (0.6) 11.89 (6.43) 26 (38) : QD phase 3, open- 298 IGlar QD IGlar ± MET NR 163 (54.7) 60.2 (8.6) 88.4 (15.9) 7.7 (0.6) 12.33 (6.75) label, parallel 298 IGlu TID IGlar ± MET NR 166 (55.7) 59.4 (9.5) 90 (17.2) 7.8 (0.6) 12.41 (6.8) trial, 199 sites globally GetGoal-L : 167 Placebo IGlar/IDet/NPH ± MET NR (78)/NR 85 (50.9) 57 (10) 88.9 (20.8) 8.4 (0.8) 12.4 (6.3) 24 (25) phase 3, double- 329 LIXI 20 lg NR (80)/NR 182 (55.5) 57 (10) 87.1 (20) 8.4 (0.9) 12.5 (7) blind, parallel QD trial, 111 sites globally GetGoal-L-Asia 154 LIXI 20 lg IGlar/IDet/NPH 108 (70.1)/ 85 (55.2) 58.7 (10.2) 65.93 (13) 8.54 (0.73) 13.7 (7.7) 24 (27) : QD NR ± SU phase 3, double- 157 Placebo 111 (70.7)/ 77 (49.0) 58 (10.1) 65.6 (12.47) 8.52 (0.78) 14.1 (7.7) blind, parallel NR trial, 57 sites in multiple Asian countries Diabetes Ther (2018) 9:1233–1251 1239 Table 1 continued Trial Number Randomized Background therapy Prior therapy Females, n (%) Mean age, Mean baseline weight, Mean Mean baseline Treatment of treatment with 2/1 years (SD) kg (SD) baseline duration of duration, weeks patients OADs, n (%) HbA ,% diabetes, years (total trial 1c (SD) (SD) duration) GetGoal-L-C 224 LIXI 20 lg IGlar/IDet/NPH ± MET NR 119 (53.1) 53.9 (9.9) 74.2 (14.1) 7.9 (0.66) 10.3 (6.1) 24 (34) : QD phase 3, double- 224 Placebo NR 126 (56.2) 56.2 (9.1) 74.6 (13.3) 7.9 (0.70) 10.2 (6.2) blind, parallel trial, 51 sites in multiple Asian countries GetGoal-O : 176 LIXI 20 lg BI ± OADs ± SU ± MET NR 84 (46.7) 74.0 (4.0) 80.8 (14.5) 8.1 (0.7) 13.6 (7.3) 24 (28) QD phase 3, double- blind, parallel 174 Placebo NR 84 (48.3) 74.4 (3.8) 80.1 (16.8) 8.1 (0.7) 14.6 (7.9) trial, 73 sites globally HARMONY-6 292 ALBI 30 mg IGlar ± MET ± TZDs 203 (71.2)/18 153 (54) 54.8 (9.1) 92.5 (21.5) 8.5 (0.9) 11 (7) 52 : QW (6) phase 3, open- 294 ILispro 195 (69.4)/19 145 (52) 56.3 (8.9) 91.6 (21) 8.4 (0.9) 11 (6) label, parallel (7) trial, 210 sites globally 1240 Diabetes Ther (2018) 9:1233–1251 Table 1 continued Trial Number Randomized Background therapy Prior therapy Females, n (%) Mean age, Mean baseline weight, Mean Mean baseline Treatment of treatment with 2/1 years (SD) kg (SD) baseline duration of duration, weeks patients OADs, n (%) HbA ,% diabetes, years (total trial 1c (SD) (SD) duration) LIRA- 225 Placebo BI (IGlar or IDet) ± MET (93.3)/NR 89 (39.6) 57.5 (11.1) 91.9 (19.3) 8.3 (0.9) 12.1 (6.8) 26 (29) ADD2BASAL 226 LIRA 1.8 mg (92)/NR 105 (46.7) 59.3 (9.2) 90.2 (20) 8.2 (0.8) 12.1 (7.1) : QD phase 3, double- blind, parallel trial, 76 sites globally SUSTAIN 5 : 132 SEMA 0.5 mg BI ± MET NR/NR 58 (43.9) 59.1 (10.3) 92.7 (range 50.4, 162.8) 8.36 (0.83) 12.91 (7.59) 30 (43) QW phase 3a, double- blind, parallel 131 SEMA 1.0 mg NR/NR 54 (41.2) 58.5 (9.0) 92.5 (range 48.5, 165.6) 8.31 (0.82) 13.74 (7.82) trial QW 133 Placebo NR/NR 62 (46.6) 58.8 (10.9) 89.9 (range 47.5, 157.3) 8.42 (0.88) 13.30 (7.98) ALBI albiglutide, BG biguanide, BI basal insulin, BID twice daily, DULA dulaglutide, EXE exenatide, HbA glycated hemoglobin, IDet insulin detemir, IGlar insulin glargine, ILispro insulin lispro, LIRA liraglutide, LIXI lixisenatide, 1c MET metformin, NPH neutral protamine Hagedorn (isophane insulin), NR not reported, OAD oral anti-diabetic drug, PG pioglitazone, QD once daily, QW once weekly, RG rosiglitazone, SD standard deviation, SEMA semaglutide, SITA sitagliptin, SU sulfonylureas, TZD thiazolidinediones Diabetes Ther (2018) 9:1233–1251 1241 evidence network for the change from baseline in HbA is shown in Fig. 1a. Once-weekly 1c semaglutide 1.0 mg was associated with a sig- niﬁcantly greater reduction in HbA vs all GLP- 1c 1 RA comparators included in the analysis (Fig. 2a, Table S12 of the ESM). Furthermore, based on the 0.3 percentage-points margin for clinical superiority suggested by the FDA  and European Medicines Agency (EMA; ), the improvements in HbA achieved with 1c once-weekly semaglutide 1.0 mg were clinically meaningful vs all primary comparators. The analysis also suggested that once-weekly semaglutide 0.5 mg can provide signiﬁcantly greater reductions in HbA vs all GLP-1 RA 1c comparators except liraglutide 1.8 mg QD. An additional sensitivity analysis using the same statistical approach as in the base-case analysis was performed to validate the legitimacy of excluding four trials [33, 36–38] from the base- case analysis on the basis of heterogeneity. The evidence network for the sensitivity analysis is shown in Fig. S4 of the ESM. The results of the analysis demonstrate that the inclusion of the outlier trials had little impact on the results and the overall interpretation of the analysis (Table S21 of the ESM). NMAs were also feasible for the proportion of patients with HbA levels \ 7% or HbA level 1c 1c B 6.5% using the same evidence network as shown in Fig. 1a. Data supporting these analy- Fig. 1 Evidence networks for all outcomes. Blue nodes ses are shown in Table S6 of the ESM. In line indicate a primary intervention of interest, orange nodes with the results seen for change from baseline in indicate a primary comparator of interest, and gray nodes HbA , analysis of the proportion of patients 1c indicate a secondary comparator. a The evidence network achieving HbA targets showed that once- 1c for the change from baseline in HbA , weight, and FPG, 1c weekly semaglutide 1.0 mg had signiﬁcantly the proportions of patients with HbA \ 7% or B 6.5%, 1c higher odds of achieving a HbA level\ 7% vs 1c and the incidence of nausea, vomiting, and diarrhea. b The all GLP-1 RA comparators (Fig. 2b, Table S13 of evidence network for the change from baseline in SBP. the ESM). Once-weekly semaglutide 0.5 mg also c The evidence network for the proportion of patients demonstrated signiﬁcantly higher odds of with C 5% weight loss. ALBI albiglutide, BID twice-daily, achieving a HbA level \ 7% vs all GLP-1 RA 1c DULA dulaglutide, EXE exenatide, IGlu insulin glulisine, comparators, except liraglutide 1.8 mg QD, to ILispro insulin lispro, LIRA liraglutide, LIXI lixisenatide, which it was comparable. Once-weekly QD once-daily, QW once-weekly, SEMA semaglutide, TID semaglutide 1.0 mg had higher odds of achiev- thrice-daily ing a HbA level B 6.5% vs the majority of GLP- 1c 1 RA comparators, except liraglutide 1.8 mg, to which it was comparable; once-weekly Glycemic Control semaglutide 0.5 mg had similar odds vs all GLP- All eight trials considered in the base-case 1 RA comparators (Fig. 2c, Table S14 of the analysis reported data on the change from ESM). baseline in HbA (Table S5 of the ESM). The 1c 1242 Diabetes Ther (2018) 9:1233–1251 Fig. 2 Forest plots of the NMA results—once-weekly baseline in FPG, e change from baseline in weight, and the semaglutide 0.5 or 1.0 mg vs comparator. Treatment incidence of f nausea, g vomiting, and h diarrhea. ALBI differences are considered signiﬁcant when the 95% CrI albiglutide, BID twice-daily, CrI credible interval, DULA excludes the null value. Odds ratios are considered dulaglutide, EXE exenatide, FPG fasting plasma glucose, signiﬁcant when the 95% CrI excludes 1. The NMA HbA glycated hemoglobin, LIRA liraglutide, LIXI lixise- 1c results are presented as Forest plots for a change from natide, NMA network meta-analysis, QD once-daily, QW baseline in HbA , b proportion of patients achieving once-weekly 1c target HbA \ 7% or c HbA B 6.5%, d change from 1c 1c Diabetes Ther (2018) 9:1233–1251 1243 Fig. 2 continued 1244 Diabetes Ther (2018) 9:1233–1251 Fig. 2 continued A NMA was also performed for FPG using the 3). In line with the interpretation of SUCRA same evidence network as shown in Fig. 1a scores , this indicates that once-weekly (Table S7 of the ESM). In line with the results semaglutide 1.0 mg is the most efﬁcacious achieved relating to reductions in HbA , the treatment within these networks. Despite the 1c analysis of the change from baseline in FPG absence of lower-dose variants of the GLP-1 RA demonstrated that once-weekly semaglutide comparators from the analyses (e.g., dulaglutide 1.0 mg and 0.5 mg were both associated with 0.75 mg QW, exenatide 5 lg BID), once-weekly signiﬁcantly greater reductions in FPG com- semaglutide 0.5 mg ranked highly in the anal- pared with the majority of GLP-1 RA compara- ysis of these glycemic outcomes, achieving tors, except dulaglutide 1.5 mg, to which they median ranks of 2–3 and SUCRA scores of were comparable (Fig. 2d, Table S15 of the 80–90% (Tables 2, 3). ESM). Across these analyses, once-weekly semaglu- Weight tide 1.0 mg was the highest ranked GLP-1 RA, All eight trials included in the base-case anal- achieving a median rank of 1 and a SUCRA score ysis reported data for the change from baseline of 100% across all glycemic outcomes (Tables 2, in body weight (Table S8 of the ESM). The Diabetes Ther (2018) 9:1233–1251 1245 Table 2 SUCRA results Comparator CFB in HbA CFB in FPG CFB in weight Nausea (%) Vomiting (%) Diarrhea (%) 1c HbA <7% HbA ≤6.5% ≥ 5% weight loss 1c 1c (%) (%) (%) (%) (%) (%) Semaglutide 0.5 mg QW 80 70 20 90 90 90 80 80 70 Semaglutide 1.0 mg QW 100 100 100 100 100 100 50 50 10 Albiglutide 30 mg QW 70 50 60 20 30 60 70 20 Dulaglutide 1.5 mg QW 60 60 40 80 70 0 0 30 Exenatide 10 μg BID 50 30 40 60 80 20 40 40 Insulin glulisine QD 20 20 20 50 20 40 90 60 90 Insulin glulisine TID 30 60 70 40 10 0 100 50 100 Insulin lispro 40 30 30 10 0 10 100 70 Liraglutide 1.8 mg 80 80 90 0 90 30 20 40 Lixisenatide 20 μg QD 20 30 30 50 50 60 40 10 60 Placebo 0 0 0 50 30 20 70 90 80 The highest and second highest SUCRA values of the primary comparators per outcome are highlighted in green and blue, respectively. The calculation of SUCRA scores for the change from baseline in SBP was not possible as the analysis was performed via a Bucher indirect comparison only BID twice-daily, CFB change from baseline, CrI credible interval, FPG fasting plasma glucose, HbA glycated hemoglobin, 1c QD once-daily, QW once-weekly, SBP systolic blood pressure, SUCRA surface under the cumulative ranking, TID thrice- daily Secondary comparators Table 3 Median ranks Comparator CFB in HbA CFB in FPG CFB in weight Nausea Vomiting Diarrhea 1c HbA <7% HbA ≤6.5% ≥ 5% weight 1c 1c loss Semaglutide 0.5 mg QW 2 (2, 3) 2 (2, 3) 3 (2, 7) 2 (1, 3) 4 (2, 6) 2 (2, 4) 3 (1, 3) 4 (2, 8) 9 (3, 11) Semaglutide 1.0 mg QW 1 (1, 1) 1 (1, 1) 1 (1, 2) 1 (1, 2) 1 (1, 1) 1 (1, 2) 6 (5, 9) 6 (4, 10) 10 (5, 11) Albiglutide 30 mg QW 4 (3, 7) 6 (4, 10) 5 (3, 10) 9 (4, 10) 8 (6, 10) 9 (5, 11) 5 (4, 10) 4 (2, 9) Dulaglutide 1.5 mg QW 5 (4, 8) 5 (4, 9) 7 (4, 10) 3 (2, 5) 4 (2, 5) 11 (6, 11) 11 (5, 11) 8 (4, 11) Exenatide 10 μg BID 6 (4, 8) 8 (5, 10) 7 (4, 10) 5 (4, 8) 3 (2, 5) 9 (7, 11) 7 (4, 10) 7 (5, 10) Insulin glulisine QD 9 (6, 11) 9 (5, 10) 9 (5, 10) 6 (4, 10) 9 (7, 10) 4 (4, 6) 2 (1, 3) 5 (1, 10) 2 (1, 6) Insulin glulisine TID 8 (4, 10) 5 (4, 8) 4 (2, 8) 7 (4, 10) 10 (7, 11) 6 (4, 6) 1 (1, 3) 6 (2, 10) 1 (1, 2) Insulin lispro 7 (5, 10) 8 (5, 10) 8 (4, 10) 10 (6, 10) 11 (9, 11) 10 (7, 11) 1 (1, 3) 4 (1, 8) Liraglutide 1.8 mg 3 (2, 3) 3 (2, 4) 2 (1, 4) 11 (10, 11) 2 (2, 4) 8 (5, 11) 9 (5, 11) 7 (4, 11) Lixisenatide 20 μg QD 9 (8, 10) 8 (5, 10) 8 (4, 10) 6 (4, 9) 6 (5, 7) 3 (1, 3) 7 (5, 9) 10 (7, 11) 5 (3, 9) Placebo 11 (10, 11) 11 (11, 11) 11 (11, 11) 6 (4, 9) 8 (7, 10) 5 (4, 6) 4 (4, 5) 2 (1, 4) 3 (2, 5) The highest and second highest median ranks of the primary comparators per outcome are highlighted in green and blue, respectively. The calculation of median ranks for the change from baseline in SBP was not possible as the analysis was performed via a Bucher indirect comparison only BID twice-daily, CFB change from baseline, CrI credible interval, FPG fasting plasma glucose, HbA glycated hemoglobin, 1c QD once-daily, QW once-weekly, SBP systolic blood pressure, TID thrice-daily Secondary comparators evidence network for the change in body results showed that once-weekly semaglutide weight was the same as for the outcomes of 1.0 mg was associated with a signiﬁcantly glycemic control presented in Fig. 1a. The greater reduction in body weight vs all GLP-1 1246 Diabetes Ther (2018) 9:1233–1251 Table 4 Matrix of results for the change from baseline in SBP Treatment difference: treatment A (row) vs treatment B (column), mmHg (95% CI) Green shaded cells indicate a signiﬁcantly greater reduction (improvement) from baseline in the outcome with treatment A vs treatment B where the 95% CrI excludes the null value Red shaded cells indicate a signiﬁcantly greater increase (worsening) from baseline in the outcome with treatment A vs treatment B where the 95% CrI excludes the null value CFB change from baseline, CI conﬁdence interval, QD once-daily, QW once-weekly, SBP systolic blood pressure These two estimates are indirect comparisons. All remaining estimates in this matrix are trial-level direct comparisons RA comparators (Fig. 2e, Table S16 of the ESM). weekly semaglutide and liraglutide 1.8 mg QD Furthermore, once-weekly semaglutide 1.0 mg was possible (Fig. 1b). This analysis suggests that achieved a median rank of 1 and a SUCRA the change in SBP with once-weekly semaglu- score of 100%, indicating that this treatment is tide 1.0 mg was comparable with liraglutide 1.8 the most efﬁcacious option for a reduction in mg in this population. In contrast, the change body weight within the network (Tables 2, 3). in SBP with liraglutide 1.8 mg QD was more Overall, once-weekly semaglutide 0.5 mg was effective than once-weekly semaglutide 0.5 mg broadly comparable to all GLP-1 RA compara- (Table 4). tors. An additional sensitivity analysis, per- formed to validate the legitimacy of excluding Adverse Events four trials [33, 35–38]fromthe base-case It is important to consider whether the analysis (Fig. S4 of the ESM), showed that the improved efﬁcacy of once-weekly semaglutide inclusion of the outlier trials had little impact vs other GLP-1 RA comparators is at the expense on the results and interpretation of the anal- of an increase in adverse events (AEs). The most ysis (Table S21 of the ESM). A NMA was also common AEs associated with the GLP-1 RA class possible for the proportion of patients compared with other anti-diabetic drug classes achieving C 5% weight loss using data from are gastrointestinal (GI)-related . In this three trials (GetGoal-Duo 2 , GetGoal-L NMA, it was feasible to analyze three GI-related , and SUSTAIN 5 ; Table S9); however, AEs: nausea, vomiting, and diarrhea. The data lixisenatide 20 lg QD was the only GLP-1 RA included in the base-case analysis of these out- available for comparison (Fig. 1c). Overall, comes are shown in Table S11 of the ESM and once-weekly semaglutide 1.0 mg and 0.5 mg the evidence network (the same for each out- had comparable odds of achieving C 5% come) is presented in Fig. 1a. Overall, once- weight loss vs lixisenatide 20 lgQD(TableS17 weekly semaglutide 1.0 mg was associated with of the ESM). similar odds of nausea, vomiting, or diarrhea vs all GLP-1 RA comparators (Fig. 2f–h, Systolic Blood Pressure Tables S18–S20 of the ESM). Once-weekly Only two trials (LIRA-ADD2BASAL  and semaglutide 0.5 mg was associated with similar SUSTAIN 5 ) reported data on the change odds of vomiting or diarrhea; however, the risk from baseline in SBP and were included in an of nausea with once-weekly semaglutide 0.5 mg indirect comparison (Table S10 of the ESM). was signiﬁcantly lower vs all other GLP-1 RA Therefore, only a comparison between once- comparators. Diabetes Ther (2018) 9:1233–1251 1247 - 0.44% and - 3.22 kg, respectively, and a DISCUSSION greater likelihood of patients achieving a HbA 1c level\ 7% . The objective of this study was to demonstrate In this NMA, once-weekly semaglutide the efﬁcacy and safety of once-weekly 1.0 mg was the most clinically effective GLP-1 semaglutide vs other GLP-1 RAs in patients with RA for achieving glycemic targets and reducing T2D inadequately controlled on basal insulin HbA , FPG, and body weight in patients who 1c (± OADs). The analyses demonstrated that are receiving basal insulin. This was supported once-weekly semaglutide 1.0 mg was associated by SUCRA scores which indicated that once- with signiﬁcantly greater reductions in HbA 1c weekly semaglutide is the most clinically efﬁ- and body weight vs all other GLP-1 RAs. This cacious in the evidence network. However, it is was reﬂected in a SUCRA score of 100%, indi- important that an increase in efﬁcacy does not cating that once-weekly semaglutide 1.0 mg is come at the expense of an increase in AEs. The the most efﬁcacious treatment within these most frequent AEs linked with GLP-1 RA ther- networks. Additional analyses showed that the apy are GI-related (e.g., nausea, vomiting, and signiﬁcantly greater reductions in HbA and 1c diarrhea); however, these AEs are thought to be body weight with once-weekly semaglutide dose dependent and can decline over time 1.0 mg are also supported by signiﬁcant [45, 46]. In a NMA investigating the relative improvements in FPG and signiﬁcantly higher frequencies of GI-related AEs in association with odds of achieving the HbA targets of\ 7% and 1c various GLP-1 RAs (excluding semaglutide), it B 6.5% compared with other GLP-1 RAs. The was demonstrated that taspoglutide (now analyses also demonstrated that once-weekly withdrawn), albiglutide and lixisenatide were semaglutide 0.5 mg can provide signiﬁcantly most commonly associated with nausea and greater reductions in HbA vs the majority of 1c vomiting, while lixisenatide and liraglutide GLP-1 RA comparators. The increased efﬁcacy of ranked ﬁrst and second for the incidence of once-weekly semaglutide was not at the diarrhea . In our analysis, the risk of GI-re- expense of reduced tolerability, as the GI-re- lated AEs with once-weekly semaglutide was lated side effects of nausea, vomiting, and similar to all other GLP-1 RA comparators, sug- diarrhea were comparable between once-weekly gesting that the increased efﬁcacy of once- semaglutide and other GLP-1 RA comparators. weekly semaglutide vs other GLP-1 RAs is not This is the ﬁrst NMA to assess the efﬁcacy and associated with a higher risk of AEs. safety of once-weekly semaglutide as an add-on to The strengths of this study include the quality basal insulin in patients with T2D vs other GLP-1 and homogeneity of trials included across the RAs. To our knowledge, no other study has per- networks. All included data were derived from a formed a comparative analysis of GLP-1 RAs as an SLR, ensuring that all evidence was captured for add-on to basal insulin; however, previous sys- the analyses. Furthermore, the NMAs were per- tematic reviews and meta-analyses have assessed formed according to previously published the efﬁcacy and safety of GLP-1 RAs compared guidelines [28, 47–50], and the sensitivity anal- with other anti-diabetic treatments in this popu- yses conﬁrmed the robustness of the results and lation. In a systematic review of studies assessing conclusions. This study was also subject to some the safety and efﬁcacy of GLP-1 RAs (exenatide, limitations. Firstly, there was heterogeneity in liraglutide, lixisenatide) as an add-on to basal the time points reported in the individual stud- insulin, the majority of studies reported beneﬁcial ies, which was addressed by using the well- effects of such a combination compared with established approach of applying a time window other treatment regimens . In a meta-analysis to the analyses [51–53]. Secondly, although the comparing the efﬁcacy and safety of a combina- risk of publication bias in this analysis was con- tion of GLP-1 RAs and basal insulin vs other anti- sidered low, four of the publications included diabetic treatment regimens, the combination of across these analyses were open-label studies, a GLP-1 RA and basal insulin yielded a greater which can introduce performance bias. Lastly, an mean reduction in HbA and body weight by 1c analysis to assess the risk of hypoglycemia with 1248 Diabetes Ther (2018) 9:1233–1251 once-weekly semaglutide (in combination with Editorial and Other Assistance. Editorial insulin) compared with other GLP-1 RAs was not assistance in the preparation of this manuscript feasible. In general, GLP-1 RAs can complement was provided by Katrin Nather of DRG Abacus. basal insulin therapy without the increased risk The systematic literature review was conducted of hypoglycemia associated with basal–bolus by Steve Kanters of Precision Xtract. Both were insulin therapy ; often, the addition of GLP-1 funded by Novo Nordisk. RAs allows for the insulin dose to be reduced, Authorship. All named authors meet the decreasing the risk of hypoglycemia and weight International Committee of Medical Journal gain [15, 54]. Furthermore, in a meta-analysis Editors (ICMJE) criteria for authorship for this assessing the efﬁcacy and safety of GLP-1 RAs as manuscript, take responsibility for the integrity an add-on to basal insulin vs basal insulin with or of the work as a whole, and have given ﬁnal without rapid-acting insulin, insulin with GLP-1 approval to the version to be published. RA was associated with a signiﬁcantly lower risk of hypoglycemia compared with treatment Disclosures. Lars Wilkinson is an employee intensiﬁcation with a rapid-acting insulin . of Novo Nordisk. Divina Glah is an employee of For once-weekly semaglutide, the data from and shareholder in Novo Nordisk. Hrvoje Vrazic SUSTAIN 5  suggest that the addition of once- is an employee of and shareholder in Novo weekly semaglutide 0.5 or 1.0 mg to basal insulin Nordisk. Neil Webb is an employee of DRG is not associated with a signiﬁcant increase in Abacus. Michal Witkowski is an employee of hypoglycemia compared with placebo (data DRG Abacus. Alan Weids is an employee of DRG unpublished). Therefore, it is likely that once- Abacus. weekly semaglutide will not increase the risk of hypoglycemia when added to basal insulin; Compliance with Ethics Guidelines. This however, comparative data with other GLP-1 RAs article does not contain any new studies with are required. human or animal subjects performed by any of the authors. CONCLUSION Data Availability. The datasets generated and/or analyzed during the current study are Overall, once-weekly semaglutide 1.0 mg as an available from the corresponding author on add-on to basal insulin is the most efﬁcacious reasonable request. GLP-1 RA in terms of reductions in HbA and 1c body weight from baseline after 6 months of Open Access. This article is distributed treatment. Once-weekly semaglutide 0.5 mg is under the terms of the Creative Commons also efﬁcacious in reducing HbA compared with 1c Attribution-NonCommercial 4.0 International the majority of GLP-1 RA comparators in the License (http://creativecommons.org/licenses/ analysis. The increased efﬁcacy of once-weekly by-nc/4.0/), which permits any noncommercial semaglutidevsother GLP-1 RA comparatorswas use, distribution, and reproduction in any not associated with an increase in GI-related AEs. medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and ACKNOWLEDGEMENTS indicate if changes were made. Funding. The study and article processing charges were funded by Novo Nordisk. 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Published: Apr 30, 2018