In the absence of head‐to‐head clinical trials directly comparing SGLT inhibitors and metformin in the T1DM population, their efficacy and safety as adjunctive therapies needs examining indirectly. Therefore, our analysis aimed to systematically identify and synthesize phase 3 and phase 4 randomized controlled trials (RCTs) of SGLT inhibitors and metformin as an adjunct to insulin for the treatment of T1DM in adults, using network meta‐analysis (NMA) to compare key efficacy and safety outcomes including HbA1c, weight, total daily insulin dose, hypoglycaemia adverse events (AEs) and DKA AEs.

Patients with T1DM are at risk of diabetic ketoacidosis (DKA), a severe form of insulin deficiency that occurs infrequently with SGLT inhibitor use. 22 While the use of lower SGLT inhibitor doses, blood ketone testing and following sick‐day rules have been suggested as ways for patients with T1DM to independently manage their DKA risk, one study involving 2995 patients with T1DM found that more than 30% did not engage in routine ketone testing. 23 Concerns have also been raised about the costs associated with these tests and potentially inaccurate results. 24 Therefore, to determine the risk–benefit ratio and cost‐effectiveness of SGLT inhibitors in T1DM patients, the DKA risk associated with their use requires further investigation, along with examination of other commonly associated side effects such as urinary tract infections (UTIs). 25 , 26

Sodium‐glucose co‐transporter (SGLT) inhibitors are a class of drugs that have the potential to improve glycaemic control in T1DM patients. 6 , 8 SGLT inhibitors reduce glucose absorption in the small intestine, whereas SGLT inhibitors cause the kidneys to excrete glucose from the body through the urine, thereby increasing glucosuria and lowering blood sugar. 9 The US Food and Drug Administration (FDA) 10 and the European Medicines Agency (EMA) 11 have approved the use of SGLT inhibitors in T2DM. A number of studies have been conducted exploring the therapeutic potential of selective or dual SGLT inhibition to better manage T1DM. 8 , 12 These studies have showed that adjunctive use of SGLT inhibitors can improve glycaemic control without increasing hypoglycaemia, and lower body weight and total daily insulin dose in T1DM patients compared with placebo plus insulin. 13 - 16 Based on these findings, the EMA have approved the SGLT inhibitors, dapagliflozin and sotagliflozin, as an adjunct to insulin for T1DM patients in Europe, 17 , 18 and both dapagliflozin and ipragliflozin have been approved in Japan. 19 , 20 Following the completion of the EASE‐2 and EASE‐3 trials, regulatory options for empagliflozin as an adjunct to insulin in T1DM are now being explored. 21

Therapies used for type 2 diabetes mellitus (T2DM) management, such as metformin, are being used in patients with T1DM, despite not being indicated for this population. However, the REMOVAL study, which investigated metformin in patients with T1DM, failed to meet the primary endpoint of reducing atherosclerosis associated with cardiovascular disease (CVD), and the reductions in HbA1c were not sustained beyond 6 months. 7 Therefore, there is an unmet need in T1DM for alternative adjunctive, glucose‐lowering therapies with an insulin‐independent mechanism of action that aid glycaemic control without increasing the risk of hypoglycaemia or negatively impacting weight.

In 2014, globally there were an estimated 422 million people living with diabetes, of whom 5%‐10% had type 1 diabetes mellitus (T1DM). 1 , 2 T1DM is characterized by deficient insulin production in the pancreas and can develop at any age. T1DM is not currently preventable and the exact cause remains unclear. 1 Patients with T1DM require daily insulin administration in order to regulate their blood glucose levels, with the National Institute of Health and Care Excellence (NICE) recommending a target HbA1c level of ≤6.5%. 3 However, reaching this level of glycaemic control remains a challenge for patients. 4 , 5 Additionally, weight gain and hypoglycaemia associated with insulin administration are major problems in T1DM patients, which probably contribute to an increased risk of cardiovascular events. 6

Where possible, studies were removed in sensitivity analyses if they contributed to heterogeneity when considering clinically meaningful differences in baseline characteristics or trial design, or to assess inconsistency when running the UME models ( Supplementary Material F ). Results of the NMAs are reported as median risk ratios (RRs) for dichotomous outcomes, and mean differences (MDs) for continuous outcomes. Corresponding 95% credible intervals (CrI) are also reported and were used as a framework to report results with the most certainty. Results at this level of certainty are discussed in the paper while all of the results can be found in Supplementary Material G–Supplementary Material J .

The Deviance Information Criterion (DIC) was used to select the best fitting model (FE or RE), where a lower DIC was indicative of a better model fit. The goodness‐of‐fit of each model was also assessed using the total residual deviance. An unrelated mean effects (UME) model was run for the preferred base case model (FE or RE), to test for inconsistency where possible ( Supplementary Material F ). However, UME models could not be run for some outcomes because of a lack of independent loops within the networks. Heterogeneity was assessed through RE model fit and by evaluating the estimate of the between‐study standard deviation.

NMAs were performed according to NICE Decision Support Unit recommendations, with both fixed effects (FE) and random effects (RE) models considered. 30 CFB HbA1c, CFB weight, CFB systolic blood pressure and CFB total daily insulin dose were modelled as continuous outcomes using a normal likelihood and an identity link function. All‐cause discontinuation and number of UTI AEs, DKA AEs, hypoglycaemia AEs, hypoglycaemia SAEs and diarrhoea AEs were dichotomous outcomes and were modelled as binomial endpoints. For binomial data, a generalized linear model with logit link function and binomial likelihood was used. The models were fitted to the data via Bayesian Markov Chain Monte Carlo methods using WinBUGs version 1.4.3. Additional model specifications can be found in Supplementary Material D and Supplementary Material E .

A feasibility assessment determined which efficacy and safety outcomes could be analyzed, exploring study design and baseline characteristics to determine potential sources of heterogeneity between or within trials. Where data were available, Bayesian NMAs were performed for CFB HbA1c, CFB weight, CFB systolic blood pressure, CFB total daily insulin dose, all‐cause discontinuation, UTI AEs, DKA AEs, hypoglycaemia AEs, hypoglycaemia SAEs and diarrhoea AEs. For the REMOVAL and EASE trials, data for CFB total daily insulin dose were converted from international units (IU) or units per kilogram (U/kg) to a percentage.

No language restriction was applied. Studies were eligible for inclusion if they reported relevant efficacy or safety outcomes of phase 3 or phase 4 RCTs of adults with T1DM, receiving SGLT inhibitors or metformin as add‐on to insulin for ≥12 Weeks ( Supplementary Material C ). The authors did not contact the principal investigators in cases where a study met the eligibility criteria but no relevant results were reported, and no further publications were identified. Efficacy outcomes of interest included change from baseline (CFB) in HbA1c, total daily insulin dose, weight, 24‐hour continuous glucose monitoring (CGM), body mass index (BMI), total cholesterol (as well as low‐density lipoprotein [LDL] and high density lipoprotein [HDL] cholesterol) and systolic blood pressure. Safety outcomes such as overall AEs, serious AEs (SAEs), all‐cause discontinuation, DKA AEs, hypoglycaemia AEs, hypoglycaemia SAEs, UTI AEs, genital infection AEs and diarrhoea AEs were also of interest. The search results from electronic databases were independently screened by two reviewers using prespecified inclusion criteria. Disagreements were resolved by consensus.

The systematic literature review (SLR) and subsequent updates were conducted in accordance with a prespecified protocol, and are reported in accordance with the preferred items for systematic reviews and meta‐analysis (PRISMA) guidelines. 27 The NMA is reported in accordance with the PRISMA Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta‐analyses of Health Care Interventions. 28 Readers are encouraged to contact the corresponding author to request a copy of the study protocol.

Sensitivity analyses were performed by removing InTandem3 from the CFB HbA1c, CFB weight and CFB total daily insulin dose networks at Week 24 to 26 because of its shorter lead‐in phase (2 Weeks of placebo run‐in compared with ≥8 Weeks for other studies included in these networks). All base case results for HbA1c and weight were sustained in sensitivity analyses ( Supplementary Material G and Supplementary Material I ), while reductions in total daily insulin dose for empagliflozin (2.5 mg) vs metformin at Week 24 to 26 were not sustained ( Supplementary Material I ). Sensitivity analyses removing InTandem3 from the all‐cause discontinuation networks at Week 24 to 26 gave results that were consistent with the base case analyses ( Supplementary Material H and Supplementary Material J ).

When SGLT inhibitors were compared with metformin for all‐cause discontinuation, a higher risk was observed for metformin at both Week 24 to 26 and Week 52 ( Supplementary Material J ). Few differences were observed for hypoglycaemia, although sotagliflozin (400 mg) resulted in a lower risk of hypoglycaemia SAEs vs both metformin and placebo at Week 52 (RR = 0.35, 95% CrI, 0.14‐0.93 and RR = 0.59, CrI, 0.35‐0.97, respectively; Supplementary Material H and Supplementary Material J ). It was not possible to compare SGLT inhibitors vs metformin for risk of DKA AEs, diarrhoea AEs or UTI AEs as those safety outcomes were not reported in the included metformin studies ( Supplementary Material O ).

When SGLT inhibitors were compared with metformin, the majority of SGLT inhibitors showed greater reductions in HbA1c and weight (Figure 4 ), ranging from −0.16 (95% CrI, −0.34‐0.03) to −0.38 (95% CrI, −0.55‐−0.22) for HbA1c, and from −0.23 (95% CrI, −1.59‐1.13) to −2.18 (95% CrI, −3.41‐−0.94) for weight at Week 24 to 26. At Week 52, the reductions observed for SGLT inhibitors vs metformin ranged from −0.23 (95% CrI, −0.39‐0.06) to −0.34 (95% CrI, −0.50‐−0.18) for HbA1c, and from −1.18 (95% CrI, −3.77‐1.43) to −2.70 (95% CrI, −4.83‐−0.50) for weight. The SGLT inhibitors also resulted in reductions in total daily insulin dose vs metformin at Week 24 to 26, but not at Week 52 ( Supplementary Material I ).

When SGLT inhibitors and metformin were compared with placebo for all‐cause discontinuation, empagliflozin (2.5 and 25 mg) was associated with a lower risk of discontinuation at Week 24 to 26 (RR = 0.53, 95% CrI, 0.29‐0.92 and RR = 0.66, 95% CrI, 0.43‐0.98, respectively), which was sustained for empagliflozin (25 mg) at Week 52 (RR = 0.43, 95% CrI, 0.22‐0.78). Metformin resulted in a higher risk of all‐cause discontinuation vs placebo at Week 24 to 26 (RR = 2.51, 95% CrI, 1.49‐4.11), which was also sustained at Week 52 (RR = 1.69, 95% CrI, 1.12‐2.62; Supplementary Material H ).

Analysis of the safety outcomes showed few differences in risk of UTI AEs across all SGLT treatment groups when compared with placebo at both time points ( Supplementary Material H ). There were also few differences in risk of DKA AEs for all SGLT inhibitors vs placebo, although sotagliflozin showed an increased risk of DKA for 400 mg at Week 24 to 26 (RR = 19.72, 95% CrI, 1.87‐2578.65) and both 200 and 400 mg at Week 52 (RR = 23.03, 95% CrI, 2.48‐670.69 and RR = 30.73, 95% CrI, 3.48‐790.53, respectively) and all comparisons except for empagliflozin (2.5 mg) favoured placebo numerically. In the analysis of diarrhoea AEs vs placebo, the credible intervals crossed 1 with sotagliflozin (400 mg) for risk of event at both the Week 24 (RR = 1.83, 95% CrI, 1.27‐2.68) and Week 52 (RR = 1.75, 95% CrI, 1.10‐2.80) time points. It was not possible to compare metformin vs placebo for risk of DKA AEs, UTI AEs or diarrhoea AEs, as those safety outcomes were not reported in the included metformin studies ( Supplementary Material O ).

The NMAs indicated that all therapies performed better than placebo for the efficacy outcomes analyzed (Figure 3 ). All SGLT inhibitors and metformin led to reductions in HbA1c at Week 24 to 26 vs placebo, although this was not sustained for metformin at Week 52 (MD = −0.03, 95% CrI, −0.15 to 0.09; Supplementary Material G ). When compared with placebo at Week 24 to 26 and Week 52, all SGLT inhibitors and metformin led to reductions in weight. All treatments were also associated with a greater reduction in total daily insulin dose compared with placebo at Week 24 to 26 and Week 52, although for reductions observed in total daily insulin dose for metformin vs placebo, the credible intervals crossed 0. Few differences were observed for metformin vs placebo for CFB total daily insulin dose at either time point. At Week 52, all of the SGLT inhibitors reduced systolic blood pressure compared with placebo ( Supplementary Material G ).

NMAs were conducted for four efficacy outcomes (CFB HbA1c, CFB weight, CFB total daily insulin dose and CFB systolic blood pressure; Figure 2 ), and six safety outcomes (number of patients experiencing UTI AEs, DKA AEs, hypoglycaemia AEs, hypoglycaemia SAEs, diarrhoea AEs and all‐cause discontinuation), each at the Week 24 to 26 and Week 52 time points. CFB 24‐hour CGM, CFB LDL, CFB total cholesterol, overall AEs and overall SAEs were considered, but no analyses were conducted because of a lack of reporting or incompatible outcome definitions. The UME models that were run showed no signs of inconsistency for all NMAs conducted, supporting the comparability of data included in these analyses.

Studies were generally of a high quality, with all studies reporting double‐blinding of treatment allocation and well‐balanced treatment arms in terms of patient demographics and disease characteristics at baseline ( Supplementary Material P ). Randomization methodologies could not be assessed for all studies because of inadequate information. 14 , 33 - 37 The methods of statistical analysis were largely comparable between studies, although only Lund 2008 used a full intention to treat analysis. 38

All studies assessed T1DM patients with inadequate glycaemic control on insulin and had a primary efficacy outcome of CFB in HbA1c, except for the REMOVAL study of metformin, which focused on the reduction of atherosclerosis in T1DM patients at high risk of CVD, as opposed to improving glycaemic control. 7 Various efficacy and safety outcomes were reported across the studies at Week 24 to 26 and Week 52 ( Supplementary Material N and Supplementary Material O ).

All nine studies reporting relevant results were placebo‐controlled and used a double‐blind, parallel, multi‐centre study design to assess dapagliflozin (5 and 10 mg; two studies), 13 , 15 , 31 , 32 sotagliflozin (200 and 400 mg; three studies), 14 , 33 , 34 empagliflozin (2.5, 10, and 25 mg; two studies) 35 - 37 or metformin (2000 mg; two studies) 7 , 38 (Table 1 ). All nine studies had a lead‐in phase, with the length ranging from 2 Weeks 14 to 3 months. 7 The treatment phases within the trials ranged from 24 Weeks 14 to 3 years. 7 Overall trial durations varied across studies, ranging from 26 Weeks 34 - 37 to 3 years and 3 months. 7 Inclusion and exclusion criteria and participant baseline characteristics for the included trials are reported in Supplementary Material L and Supplementary Material M , respectively.

After de‐duplication, the electronic database searches identified 1332 individual records (Figure 1 ). Following title/abstract screening, a total of 58 records were reviewed in full. Thirty‐two records were excluded because of an inappropriate study design, population, intervention or a lack of relevant outcomes ( Supplementary Material K ). Hand‐searching resulted in an additional 38 included records. Three ClinicalTrials.gov records (NCT00145379, NCT02582814, and NCT02897219) met the eligibility criteria but were not included in the SLR as they did not report relevant results and no further publications were identified. Ultimately, 64 records reporting on 12 unique studies were included in this review, with nine studies reporting relevant results.

4 DISCUSSION

This analysis provides a comprehensive overview of current evidence on the use of SGLT inhibitors as an adjunct to insulin in the treatment of T1DM. The SLR was conducted in line with NICE guidelines29 and only prospective RCTs were eligible for inclusion, as these are widely considered the gold standard when evaluating the effectiveness of interventions.39 Further, no language restrictions were applied, reducing the potential for bias towards English‐speaking countries.

The NMAs suggest that adjunctive use of SGLT inhibitors can improve glycaemic control compared with adjunctive metformin or insulin therapy alone in T1DM, while enabling weight loss, and show the efficacy of this class. Lack of glycaemic and weight control are important concerns in T1DM, and the reductions in HbA1c and weight when compared with placebo plus insulin are particularly noteworthy, suggesting that SGLT inhibitors could play a role in reducing cardiovascular risk. While metformin also resulted in decreases in HbA1c at Week 24 to 26, these were not sustained at Week 52, suggesting that metformin may be unsuitable as an adjunct to insulin for long‐term glycaemic control in T1DM. However, the NMA results observed for SGLT inhibitors vs metformin may be subject to bias, as the absence of head‐to‐head trials directly comparing SGLT inhibitors with metformin means that results for SGLT inhibitors vs metformin rely on indirect comparisons only. Further, comparisons with metformin in the Week 24 to 26 CFB HbA1c, CFB weight, CFB total daily insulin dose and risk of all‐cause discontinuation networks were informed by the REMOVAL study only, which had a heterogenous lead‐in phase of 3 months and primarily investigated whether adjunctive metformin therapy reduced atherosclerosis in patients aged >40 years at increased risk for CVD; so the patient characteristics differed to the other included studies.7 However, this study had a large sample size and a 3‐year duration and was considered important to include in this analysis.

We identified some variation in the lead‐in periods across the included studies; InTandem3 had a shorter lead‐in phase consisting of a 2‐Week placebo run‐in and no insulin optimization phase compared with ≥8 Weeks in other studies. As this could potentially bias the NMA results towards a greater improvement from baseline in HbA1c, weight and total daily insulin dose for sotagliflozin (400 mg), InTandem3 was removed in sensitivity analyses, which confirmed the robustness of the base case results in which InTandem3 was included, despite the heterogeneous lead‐in period of 2 Weeks. While Lund 2008 and REMOVAL also had heterogeneous lead‐in periods (1 and 3 months, respectively), those studies could not be removed in sensitivity analyses as they were essential to connect metformin to the Week 24 to 26 and Week 52 networks.

The analysis of safety outcomes resulted in few differences in favour of placebo or metformin, suggesting that SGLT inhibitors have a tolerable safety profile. Although UTI and DKA AEs are important safety concerns in the use of SGLT inhibitors,40 the number of patients experiencing DKA events was low in the SGLT treatment arms; the highest proportion of patients experiencing DKA AEs occurred during the InTandem1 trial with sotagliflozin (400 mg), with eight patients (3.1%) and 11 patients (4.2%) experiencing ≥1 DKA AE at Week 24 and Week 52, respectively.33, 41 The rare nature of DKA AEs in the clinical studies reduced the statistical power for the NMAs, leading to wide credible intervals and limiting the usefulness of the results because of their uncertainty. A further limitation of the AE analyses, including DKA AEs, is that the proportion of patients experiencing ≥1 event were modelled (rather than event rates), which does not capture patients experiencing multiple events or allow for potential differences in the duration of follow‐up at each time point examined, and may therefore inaccurately estimate risk. However, all treatments except for empagliflozin (2.5 mg) were associated with a numerically higher risk of experiencing DKA AEs compared with placebo, with the results for sotagliflozin (200 and 400 mg) at Week 52 having credible intervals that did not cross 1. This result highlights safety concerns of sotagliflozin and corresponds with findings from a meta‐analysis of six trials of sotagliflozin in patients with T1DM, where the drug was shown to increase the risk of DKA AEs, sparking concerns from the FDA and ultimately resulting in their rejection of sotagliflozin as adjunctive therapy in T1DM.16, 42 In light of these results, additional education around DKA risk may be beneficial to ensure signs are recognized and treatment is promptly received, as studies have shown that poor adherence to insulin therapy, along with failure to recognize early metabolic decompensation, are the primary causes of DKA in T1DM patients.13, 43

The increased risk of all‐cause discontinuation for metformin vs SGLT inhibitors and placebo at Week 24 to 26 and Week 52 suggests that treatment with SGLT inhibitors may be better tolerated than metformin in patients with T1DM. In the REMOVAL trial, 59 patients (27%) had discontinued from metformin after 36 months, mainly because of gastrointestinal AEs occurring in 34 patients (16%). This finding is consistent with the drugʼs known safety profile and may help to explain the increased risk of discontinuation; gastrointestinal AEs are listed as a very common side effect for metformin therapy.44 In the Lund 2008 trial of metformin, around 40% of patients in both arms reported gastrointestinal AEs, although very few discontinued from the trial over 52 Weeks.38 Moreover, recent literature in T2DM suggests that 20–30% of patients on metformin experience gastrointestinal AEs, leading to treatment discontinuation in approximately 5% of patients.45, 46 Although the gastrointestinal AE of diarrhoea specifically is a primary safety concern with metformin treatment in T2DM,47 metformin could not be included in the analysis of diarrhoea AEs as this safety outcome was not reported in the included metformin studies.

At Week 24 to 26, the all‐cause discontinuation data for metformin were informed by the REMOVAL trial only, which was heterogeneous because of the longer 3‐month lead‐in phase and primary aim of reducing atherosclerosis, while the metformin data for all‐cause discontinuation were informed by both the REMOVAL trial and Lund 2008 at Week 52.7, 38 REMOVAL had the highest proportion of patient discontinuation overall for any treatment at Week 52 while Lund 2008, a smaller trial with only 100 patients randomized, had the lowest proportion of discontinuation. These conflicting results highlight uncertainty around the performance of metformin in the all‐cause discontinuation NMAs and mean that the results should be interpreted with caution.

The review and analysis must be considered in light of its other limitations, such as the inclusion of prospective RCTs only, meaning that a number of observational studies pertaining to the use of relevant treatments in a real‐world setting will not have been captured. These data would be potentially useful, given the chronic nature of T1DM and the necessity to ensure that the outcomes of clinical trials are representative of those in routine clinical practice. In addition, none of the identified studies provided head‐to‐head evidence of the interventions of interest, limiting the analyses to indirect comparisons, which can be biased because of between‐study heterogeneity. However, a feasibility assessment assessing heterogeneity within each network was carried out, and clinically meaningful sources of heterogeneity were explored in sensitivity analyses where possible. A network meta‐regression to adjust for between‐trial differences was considered but was not carried out because of the small number of studies in the network. In this analysis, the 95% credible intervals, which assess certainty around effect sizes, were used as a framework to prioritize results for discussion, although credible intervals do not provide information on the clinical importance of results. However, a cut‐off is needed to highlight results with the greatest certainty to aid decision‐makers.

Future studies should aim to investigate the long‐term effects of SGLT inhibitors in T1DM, to investigate whether the reductions in HbA1c and weight are sustained beyond 52 Weeks, and to consider these benefits vs the risks of any side effects. Additionally, following the granting of market authorization by the EMA for dapagliflozin in T1DM patients with inadequate glycaemic control and a BMI ≥27 kg/m2, it may be useful to explore other subpopulations that could benefit most from adjunctive use of SGLT inhibitors.17 Overall, these results suggest that SGLT inhibitors are beneficial as an adjunct to insulin in the management of T1DM and can address the unmet need for therapies to improve glycaemic control in this population.