Introduction
Type 2 diabetes (T2D) is a chronic and progressive disease associated with microvascular and macrovascular complications leading to increased morbidity and mortality [
1,
2].
Glycemic control is the key goal in the management of T2D, with targets of glycated hemoglobin (HbA
1c) < 7.0% (53 mmol/L) or ≤ 6.5% (48 mmol/mol) defined in treatment guidelines [
3‐
6]. Despite clear clinical guidelines for achieving glycemic control in patients with T2D [
3,
7,
8], glycemic control remains suboptimal in many patients with T2D receiving insulin treatment. For example, in patients with T2D receiving basal insulin across Europe and the US, it has been estimated that 78.1% and 72.2% had inadequate glycemic control 3 and 24 months post-initiation [
9]. There is significant clinical inertia in the initiation and intensification of insulin therapy among patients with poor glycemic control, and it has been estimated that only one-third achieve glycemic control 3 years after the initiation of basal insulin [
10]. For patients who are inadequately controlled on basal insulin, treatment options include the intensification of insulin therapy by adding either rapid-acting bolus insulin, another oral anti-diabetic medication (OAD), or injectable glucagon-like peptide-1 receptor agonists (GLP-1 RAs) [
3,
6,
7].
GLP-1 RAs are incretin mimetics that improve glycemic control with a favorable effect on body weight and a low incidence of hypoglycemia [
11,
12]; GLP-1 RAs improve glycemic control when used at different stages along the T2D treatment cascade [
3,
7,
13]. The differing mechanism of actions mean that GLP-1 RAs can complement basal insulin therapy for the management of day-to-day blood glucose control without incurring the increased risk of hypoglycemia and weight gain associated with the addition of a bolus insulin [
13]. As such, it has been suggested that the combination treatment of a GLP-1 RA and basal insulin allows achievement of the goals of anti-diabetic therapy: robust glycemic control without an increase in hypoglycemia and weight gain [
14,
15]. Combination therapy with GLP-1 RAs and basal insulin is also more effective when compared to other anti-diabetic treatment regimens [
14].
Semaglutide is a new once-weekly GLP-1 analogue available at either a 1.0 mg or 0.5 mg dose. The clinical efficacy of once-weekly semaglutide has been extensively studied in the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) clinical trial program, for which data from seven global phase 3 trials have been published [
16‐
22]. Specifically, the efficacy and safety of once-weekly semaglutide as an add-on to basal insulin (± OADs) has been investigated in the SUSTAIN 5 clinical trial [
20]. In this trial, once-weekly semaglutide (+ basal insulin ± metformin) provided a superior reduction in HbA
1c levels and body weight compared with placebo (+ basal insulin ± metformin) and allowed a significantly greater proportion of patients to achieve target HbA
1c levels [
20].
Given the number of treatment options available for the management of T2D, it is important for decision makers to understand the relative clinical benefits of all treatment options to allow for an informed treatment decision. So far, no head-to-head trials between once-weekly semaglutide and other GLP-1 RAs in patients inadequately controlled on basal insulin (± OADs) have been conducted. As each GLP-1 RA may demonstrate unique advantages and disadvantages, it is important to understand the relative efficacy and safety of each GLP-1 RA [
23]. The aim of the current study was to conduct a systematic literature review (SLR) and network meta-analysis (NMA) to assess the relative efficacies and safety of GLP-1 RAs as an add-on to basal insulin (± OADs) in the treatment of T2D.
Methods
The trials included across the analyses were derived from a SLR, for which the methodology has been reported in Witkowski et al. [
24] (while the search strategy and PICOS criteria have been previously presented in the sister publication within this journal, they are replicated in Tables S1 and Table S2 of the Electronic supplementary material, ESM, for convenience). Briefly, searches of databases (MEDLINE
®, Embase, and the Cochrane Library; see Table S1 of the ESM) and conference proceedings were performed via Ovid on April 5, 2016 (updated in October 3, 2016 and August 16, 2017). Studies were then screened independently by two reviewers against the PICOS (population, interventions, comparators, outcomes, study design) selection criteria for inclusion in the SLR (Table S2 of the ESM).
An NMA was performed to compare the efficacy and safety of GLP-1 RAs in patients with T2D. In the analysis, the primary intervention of interest was once-weekly semaglutide (0.5 mg and 1.0 mg) and the primary comparators of interest were all other licensed doses of GLP-1 RAs approved for the treatment of T2D—liraglutide once-daily (QD), dulaglutide once-weekly (QW), exenatide twice-daily (BID), exenatide QW, lixisenatide QD, and albiglutide QW; despite a withdrawal notice, albiglutide is included as the reason for withdrawal was not related to the safety of the medicine [
25]. In order to reduce variability between the populations across the different trials, the definition of the add-on to basal insulin population was aligned as closely as possible with the population included in SUSTAIN 5—patients inadequately controlled on basal insulin (100% received basal insulin) with or without metformin (approximately 83% of patients also received metformin). As relatively few trials have been conducted in patients inadequately controlled on basal insulin ± metformin, trials with patients inadequately controlled on basal insulin with up to two OADs were included for feasibility assessment. All trials identified in the SLR were examined for data on at least one outcome of interest, and the ability to form a best-case connected network was assessed. The feasibility of generating evidence networks for each of the 20 outcomes of interest outlined in the PICOS criteria of the SLR (Table S2 of the ESM) was then examined. All studies included in the NMA were assessed for risk of bias using a seven-criteria checklist as approved by the National Institute of Health and Care Excellence (NICE) [
26].
Statistical Analysis
As previously described in the sister publication, analyses of continuous outcomes (using a normal likelihood, identity link, shared parameter model) and dichotomous outcomes (using a binomial likelihood [assuming a normal distribution], logit link model) considered feasible for assessment were implemented on WinBUGS (MRC Biostatistics Unit, Cambridge, UK [
27]) using a Bayesian framework with the inclusion of vague prior distributions, and three Markov Monte Carlo chains. Both fixed-effects (FE) and random-effects (RE) models were run for each outcome and the model with the best fit (based on the deviance information criterion [DIC] and the average posterior residual deviance) was used. All NMAs were formally assessed for inconsistency using Bucher’s method (as outlined by the NICE Technical Support Document 4) [
28]; briefly, the inconsistency assessment with Bucher’s method compares direct and indirect (NMA) estimates, and the difference between these estimates is a measure of inconsistency.
Model convergence (assessed using standard diagnostic methods for evaluating convergence) inferences were made from data obtained by sampling for a further 20,000 iterations using all the samples. If models failed to converge, the feasibility of a Bucher indirect comparison was considered. Bucher indirect comparisons were calculated in STATA 13 (release 13, 2013; StataCorp. LP, College Station, TX, USA) using the “indirect” command [
29]. The results of the NMA are presented as mean treatment differences or odds ratios (ORs) and an associated 95% credible interval (CrI). Unless the CrI excludes the null value (for treatment differences) or 1 (for ORs), it is assumed that there is no difference. Two ranking outcomes, median rank and the surface under the cumulative ranking curve (SUCRA), are also presented.
Finally, this article does not contain any new studies with human or animal subjects performed by any of the authors.
Discussion
The objective of this study was to demonstrate the efficacy and safety of once-weekly semaglutide vs other GLP-1 RAs in patients with T2D inadequately controlled on basal insulin (± OADs). The analyses demonstrated that once-weekly semaglutide 1.0 mg was associated with significantly greater reductions in HbA1c and body weight vs all other GLP-1 RAs. This was reflected in a SUCRA score of 100%, indicating that once-weekly semaglutide 1.0 mg is the most efficacious treatment within these networks. Additional analyses showed that the significantly greater reductions in HbA1c and body weight with once-weekly semaglutide 1.0 mg are also supported by significant improvements in FPG and significantly higher odds of achieving the HbA1c targets of < 7% and ≤ 6.5% compared with other GLP-1 RAs. The analyses also demonstrated that once-weekly semaglutide 0.5 mg can provide significantly greater reductions in HbA1c vs the majority of GLP-1 RA comparators. The increased efficacy of once-weekly semaglutide was not at the expense of reduced tolerability, as the GI-related side effects of nausea, vomiting, and diarrhea were comparable between once-weekly semaglutide and other GLP-1 RA comparators.
This is the first NMA to assess the efficacy and safety of once-weekly semaglutide as an add-on to basal insulin in patients with T2D vs other GLP-1 RAs. To our knowledge, no other study has performed a comparative analysis of GLP-1 RAs as an add-on to basal insulin; however, previous systematic reviews and meta-analyses have assessed the efficacy and safety of GLP-1 RAs compared with other anti-diabetic treatments in this population. In a systematic review of studies assessing the safety and efficacy of GLP-1 RAs (exenatide, liraglutide, lixisenatide) as an add-on to basal insulin, the majority of studies reported beneficial effects of such a combination compared with other treatment regimens [
15]. In a meta-analysis comparing the efficacy and safety of a combination of GLP-1 RAs and basal insulin vs other anti-diabetic treatment regimens, the combination of a GLP-1 RA and basal insulin yielded a greater mean reduction in HbA
1c and body weight by − 0.44% and − 3.22 kg, respectively, and a greater likelihood of patients achieving a HbA
1c level < 7% [
14].
In this NMA, once-weekly semaglutide 1.0 mg was the most clinically effective GLP-1 RA for achieving glycemic targets and reducing HbA
1c, FPG, and body weight in patients who are receiving basal insulin. This was supported by SUCRA scores which indicated that once-weekly semaglutide is the most clinically efficacious in the evidence network. However, it is important that an increase in efficacy does not come at the expense of an increase in AEs. The most frequent AEs linked with GLP-1 RA therapy are GI-related (e.g., nausea, vomiting, and diarrhea); however, these AEs are thought to be dose dependent and can decline over time [
45,
46]. In a NMA investigating the relative frequencies of GI-related AEs in association with various GLP-1 RAs (excluding semaglutide), it was demonstrated that taspoglutide (now withdrawn), albiglutide and lixisenatide were most commonly associated with nausea and vomiting, while lixisenatide and liraglutide ranked first and second for the incidence of diarrhea [
45]. In our analysis, the risk of GI-related AEs with once-weekly semaglutide was similar to all other GLP-1 RA comparators, suggesting that the increased efficacy of once-weekly semaglutide vs other GLP-1 RAs is not associated with a higher risk of AEs.
The strengths of this study include the quality and homogeneity of trials included across the networks. All included data were derived from a SLR, ensuring that all evidence was captured for the analyses. Furthermore, the NMAs were performed according to previously published guidelines [
28,
47‐
50], and the sensitivity analyses confirmed the robustness of the results and conclusions. This study was also subject to some limitations. Firstly, there was heterogeneity in the time points reported in the individual studies, which was addressed by using the well-established approach of applying a time window to the analyses [
51‐
53]. Secondly, although the risk of publication bias in this analysis was considered low, four of the publications included across these analyses were open-label studies, which can introduce performance bias. Lastly, an analysis to assess the risk of hypoglycemia with once-weekly semaglutide (in combination with insulin) compared with other GLP-1 RAs was not feasible. In general, GLP-1 RAs can complement basal insulin therapy without the increased risk of hypoglycemia associated with basal–bolus insulin therapy [
13]; often, the addition of GLP-1 RAs allows for the insulin dose to be reduced, decreasing the risk of hypoglycemia and weight gain [
15,
54]. Furthermore, in a meta-analysis assessing the efficacy and safety of GLP-1 RAs as an add-on to basal insulin vs basal insulin with or without rapid-acting insulin, insulin with GLP-1 RA was associated with a significantly lower risk of hypoglycemia compared with treatment intensification with a rapid-acting insulin [
55]. For once-weekly semaglutide, the data from SUSTAIN 5 [
20] suggest that the addition of once-weekly semaglutide 0.5 or 1.0 mg to basal insulin is not associated with a significant increase in hypoglycemia compared with placebo (data unpublished). Therefore, it is likely that once-weekly semaglutide will not increase the risk of hypoglycemia when added to basal insulin; however, comparative data with other GLP-1 RAs are required.