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. 2020 May 21;19(1):545–550. doi: 10.1007/s40200-020-00544-x

The comparison of efficacy and safety between different doses of empagliflozin in insulin-treated type 1 diabetes mellitus patients: a systematic review and meta-analysis protocol

Sumanta Saha 1,✉, Sujata Saha 2
PMCID: PMC7270238  PMID: 32550206

Abstract

Objectives

The proposed review aims to compare the efficacy and safety profile of empagliflozin 25 mg with its lower dosages and placebo, respectively, in insulin-treated type 1 diabetes mellitus (T1DM) patients.

Methods

Double-blinded randomized controlled trials comparing the above outcomes will be searched primarily in three electronic databases (PubMed, Embase, and Scopus) and eligible trials will be included in the proposed review. Then, from the trials recruited in the review, data of the study design, participants, interventions compared, and outcomes of interest will be extracted. Subsequently, the trials’ risk of bias will be assessed using the Cochrane Collaboration’s tool. The meta-analysis will be conducted with a fixed-effect or a random-effect model to estimate the mean differences (weighted or standardized) and risk ratios for the efficacy and safety-related comparable outcome data, respectively. Statistical heterogeneity will be assessed by the p-value of chi-squared statistics and I2 statistics and explained by subgroup analysis and meta-regression. Publication bias will be assessed by funnel plots and Egger’s test. The sensitivity analysis will repeat the meta-analysis for respective outcomes using assumptions alternative to that used in the preliminary meta-analysis and by dropping each study at a time.

Results

A narrative reporting will ensue if a meta-analytic comparison is not possible.

Conclusions

Based on the contemporary literature, the proposed review will synthesize the evidence on how the efficacy and safety profile of high dose empagliflozin varies with its lower doses and placebo, respectively, in insulin-treated T1DM patients.

Keywords: Empagliflozin; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 1; Treatment Outcome; Adverse effects

Introduction

Type 1 diabetes mellitus (T1DM) is a clinical condition characterized by hyperglycemia [1, 2]. This hyperglycemia occurs due to the autoimmune destruction of insulin-producing pancreatic beta cells and plays a vital role in the pathogenesis of diabetic complications [3]. The anabolic hormone insulin plays following key roles in the human body - allows glucose to enter muscles and fat cells, stimulates the liver to store glucose as glycogen and synthesize fatty acids, stimulates amino acid uptake, restricts the breakdown the adipose tissue fat cells, and stimulates the uptake of potassium into cells [1]. Due to the lack of insulin production, T1DM patients are at risk of life-threatening diabetic ketoacidosis [4, 5]. The primary treatment of T1DM patients is life-long insulin replacement [1].

However, sole dependence on insulin can compromise the quality of life of these patients due to the required multiple daily insulin injections and their associated need for self-monitoring of blood glucose [6, 7]. Besides, insulin therapy alone does not always achieve adequate glycemic control [8] and patients who require it in large doses due to long-standing T1DM are prone to develop complications from it [6]. Oral adjunct therapies may help to limit such inconveniences and complications associated with insulin therapy by decreasing the frequency and dosage of insulin administration.

In this regard, empagliflozin may be a potential future oral insulin adjunct therapy for efficient glycemic control in T1DM patients. The benefit of the drug is established in type 2 diabetes mellitus (T2DM) patients and has been contemporarily tested in T1DM patients in various clinical trials for their effects on health [3, 9–11]. However, before approving its use in T1DM patients, the efficacy and safety profile of this drug needs to be proven.

Empagliflozin is a sodium-glucose cotransporter-2 inhibitor (SGLT2i) with a molecular weight of 450.91 g/mol and the chemical structure of C23H27ClO7 [12]. SGLT2is are phlorizin based compounds that remove glucose from the blood by inhibiting its reabsorption in the kidney [2, 6, 13, 14]. Physiologically, the transport protein sodium-glucose cotransporter-2 is responsible for reabsorbing nearly 90% of the filtered glucose [14]. Empagliflozin is particularly beneficial as it is ideal for once-daily dosing due to its relatively prolonged half-life (of 10–12 h) [6, 12]. Additionally, it does not produce any major metabolites (undergoes glucuronidation) [12]. Currently, the U.S. Food and Drug Administration approves empagliflozin’s use in the treatment of T2DM patients only [12, 15]. As an adjunct to diet and exercise management in T2DM patients, empagliflozin has been proven to be beneficial in achieving glycemic control and decreasing the risk of cardiovascular death (compared to placebo) [16]. The following are the chief adverse reactions noted in empagliflozin treated T2DM patients - hypotension, ketoacidosis, impaired renal function, urinary tract infection, genital mycotic infections, hypoglycemia (when concurrently used with insulin), elevated low-density lipoprotein [15, 16]. However, in T1DM patients, the efficacy and safety profile of SGLT2is’ (including empagliflozin’s) are not yet established and the U.S. Food and Drug Administration currently does not endorse SGLT2is’ use in T1DM patients [2, 17]. The daily dosing of empagliflozin in T2DM patients varies between 10 and 25 mg [15] and depending on this variation, the urinary glucose excretion threshold of empagliflozin also varies (increases by 18-fold and 11-fold with the 25 mg and 10 mg dosing, respectively) [12].

Such differences in pharmacokinetic properties of the drug has been noted in T1DM patients too when used along with insulin. Studies have primarily tested empagliflozin’s effect (as an insulin additive) on T1DM patients in the following doses − 2.5 mg, 10 mg, and 25 mg [3, 9, 10, 18, 19]. In T1DM patients, the renal threshold drops to a negligible value with the 25 mg and 10 mg dosages and to almost 53 mg/dl and 13 mg/dl with the 1 mg and 2.5 mg dosages, respectively [19]. However, it is not clear if the efficacy and safety profile differ between a large and low dose empagliflozin in T1DM patients. Contemporarily, several review articles studied the efficacy and safety of SGLT2is in T1DM patients [2, 6, 26–29, 8, 13, 20–25] [30]; however, best known to us, none have compared these between different doses of empagliflozin in insulin-treated T1DM patients. Furthermore, when the review papers made a meta-analytic comparison in this milieu, the findings were neither empagliflozin specific (pooled data primarily from one empagliflozin-related trial; except one, that compared between large dose empagliflozin and placebo) [30] nor SGLT2i specific, due to frequent incorporation of a drug that inhibits both SGLT1 and SGLT2 receptors [20, 21, 26–29, 31].

Henceforth, to address this evidence gap in T1DM, our proposed review aims to compare the efficacy and safety of megadose empagliflozin with its lower doses and placebo, respectively.

Methods

The proposed review has been registered with the PROSPERO (registration no. CRD42019135844) [32].

The inclusion criteria of the proposed review include the following points: (1) Study design: Double-blinded parallel arm (any number of arm) randomized controlled trials of any duration. (2) Participants: Adult (18 years or older) T1DM patients on insulin therapy. The diagnosis of T1DM and the insulin therapy’s dosage, regimen, and route of administration will be accepted as per the trialists. (3) Compared intervention groups: The trials should compare the outcomes depicted below in daily 25 mg empagliflozin tablet recipients with those receiving a lower dose of the drug or placebo every day.

For efficacy, the primary outcomes of interest will be glycemic control (HbA1c (%)), fasting plasma glucose levels (mmol/l), and 24-hour urine glucose excretion (gm/24 hours). The secondary efficacy associated outcomes will involve total insulin dose requirement per week (U/Kg), body weight (Kg), systolic blood pressure (mmHg), diastolic blood pressure (mmHg), total cholesterol (mmol/L), high-density lipoprotein (mmol/L), low-density lipoprotein (mmol/L), and triglycerides (mmol/L).

The safety associated main outcomes of interest will be diabetic ketoacidosis, urinary tract infection, limb amputation, renal impairment, Fournier’s gangrene, bone fracture, genital infection, and volume depletion related side effects. These safety outcomes will be accepted when it is reported in the trial participants who have taken at least one dose of the respective test drug. To be eligible for inclusion, a trial should report any one of these primary outcomes.

Regarding the safety profile, the adjunct outcome of interest will be the frequency of trial participants who discontinued treatment due to adverse effects. However, these accessory outcomes will not comprise of the inclusion criteria.

Following are the exclusion criteria: (1) Trial participants diagnosed with any other type of diabetes mellitus except T1DM like T2DM, gestational diabetes mellitus, and maturity onset diabetes of the young. (2) T1DM patients treated with any other blood glucose lowering medication besides empagliflozin and insulin. (3) Studies conducted on animals. (4) Study design other that mentioned in the above inclusion criteria e.g., single arm trials, cross over design or observational design.

To recruit randomized controlled trials matching the afore-mentioned eligibility criteria, title and abstract of the research papers published in English language will be searched in the electronic databases (PubMed, Embase, and Scopus) with no restriction to date. An additional search will be done in the references section of the publications that will be read in full text.

A draft of the PubMed database search strategy is presented here. The search will use the following search terms: “sodium-glucose cotransporter” OR “Sodium-Glucose Transporter 2 Inhibitors” OR Empagliflozin OR Jardiance OR SGLT* OR “SGLT2-inhibitors” OR “SGLT2 inhibitors” OR “insulin-dependent diabetes mellitus” AND “type 1” OR type-1 OR “juvenile-onset diabetes” AND efficacy OR benefit* OR effective* AND “safety” OR “tolerance” OR “adverse event” OR “side effect.” The subsequent MeSH terms will also be used: “Diabetes Mellitus, type 1,” “Insulin-Dependent Diabetes Mellitus 1,” “glucosides/administration and dosage,“ “Glucosides / adverse effects,” “sodium-glucose transporter 2 inhibitors/administration and dosage,“ “Sodium-Glucose Transporter 2 Inhibitors / adverse effects,” “benzhydryl compounds/administration and dosage,“ “benzhydryl compounds/administration and dosage,“ and “benzhydryl compounds/adverse effects.“ To narrow down the search output to clinical trials, the filters, “Clinical Trial” and “Randomized Controlled Trial,” will be applied. This database search will be done by the first author.

Once the search results are available they will be uploaded to the Rayyan [33] systematic reviews software. After excluding the duplicates, the authors will independently scan through the titles and abstracts of the papers and then collate their findings. Papers seeming to meet this review’s eligibility criteria will be read in full text. An entire manuscript reading will also follow when a decision of inclusion or exclusion can’t be made affirmatively by reading the title and abstract only. If more than one trial source data from the same study population, for any particular outcome, one that followed participants for a longer duration will be included in this review.

From the respective trials, the authors will first extract the data independently (on study design, study population, interventions compared, and outcomes of interest) and consecutively contrast these with each other. The study design-related data will include information on - randomization, number of intervention arms, number of study centers where the trial was conducted, duration of the trials, participant consent, ethical clearance, funding, and trial identification number. The following participant characteristics will be gathered from the trials: the diagnosis of type of diabetes, frequency of participants in respective intervention groups, mean age of the participants, duration of diabetes mellitus, and nations from where the participants originated. Besides, the TIDM classification (into immune-mediated or idiopathic type) of study participants will be abstracted from the reviewed trials [34, 35].

Pertaining to the interventions compared, their dosages and regimen will be noted. Finally, for efficacy, any or all of the following data will be collected (when available) - baseline mean, change from baseline mean values, and follow-up means along with their respective statistical comparisons (within or between group), standard deviation and standard errors will be collected. For the drug’s safety, data related to the number of individuals in the respective treatment arms experiencing the side effects of interest will be collected.

During the review, all discrepancies in opinion among the authors will be resolved by discussion. A third-party opinion will be sought if the authors are unable to resolve a conflict in opinion after discourse.

Thereafter, using the Cochrane Collaboration’s tool we will independently assess the risk for the selection bias, performance bias, detection bias, attrition bias, reporting bias, and other biases, and categorize it as high risk, low risk or unclear risk (when it doesn’t not meet the low or high risk classification) [36]. Subsequently, we will match our findings and resolve any discrepancy in opinion by discourse. If a trial is at a high risk of bias, it will not be included in the meta-analysis. Here we describe how each risk of bias component will be assessed. The selection bias’s judgement will be based on information pertaining to the random sequence generation mechanism and how the allocation of different interventions to the participants in the different intervention arms were concealed from the trialists. The judgement for performance bias will be made based on information about the blindness of participants and assessors to the interventions. The outcome assessors’ blindness to the intervention received in the respective treatment arms will be used to determine the detection bias. The attrition bias and reporting bias will be evaluated from the missingness of the outcome data and deviation of the reported results from the trialists’ pre-defined intentions, respectively.

A meta-analysis will be performed when at least two studies with comparable outcome data are available [36]. A decision of using a random-effect or fixed-effect model will be based on the clinical non-uniformity or uniformity among the trials (like diverseness in the trial’s population, investigators, and clinical settings), and not based on a pre-determined statistical heterogeneity. For the efficacy-related outcome data, post intervention endpoint mean data and their standard deviations (SD) will be used in meta-analysis (inverse-variance method) to estimate the weighted mean difference or standardized mean difference. If these data are not available, we will try to obtain it from the trialists. If still not obtainable, we will use the mean changes from baseline data and impute its SD change using a correlation coefficient of 0.5.

Regarding the safety-associated data (dichotomous data), the meta-analysis will determine the risk ratio using the inverse-variance method or the DerSimonian and Laird method. A trial will be excluded from meta-analysis when an adverse outcome does not happen in either of its compared intervention groups. However, if it occurs in any one of these groups, data from that trial will be included in the meta-analysis, and 0.5 will be added to each cell of the 2 × 2 cell. For all meta-analyses, the statistical significance will be determined at a p-value < 0.05 and 95% confidence interval.

Heterogeneity will be assessed during meta-analysis using the p-value of chi-squared statistics and I2 statistics. The p-value of chi-squared statistics will be considered significant if the p-value is < 0.1 [36]. Based on the I2 values of 0–40%, 30–60%, 50–90%, and 75–100% the heterogeneity will be classified as unimportant, moderate, substantial, and considerable, respectively [36].

Depending upon the number of trials available for meta-analysis, publication bias of each outcome will be assessed. Egger’s test and funnel plots will be used if 10 or more trials are included in the meta-analysis. When < 10 trials are available, only funnel plots will be used.

Subgroup analysis and meta-regression will ensue to explain any statistical inconsistency observed during a meta-analysis involving at least 10 trials. Such analyses will be done if estimated glomerular filtration rate (eGFR) of the trial participants can be obtained. For the subgroup analysis, trials will be dichotomized based on eGFR value - below 45 mL/min/1.73 m2 versus those with eGFR equal to or above this value. Such dichotomization is planned because evidence from T2DM patients suggest that for starting empagliflozin an optimum eGFR (i.e., 45 mL/min/1.73 m2) is required and at this eGFR no dose adjustment is generally needed [15]. Besides, when there are substantial socio-demographic, geographic, and clinical diversity within or between the trials, subgroup analysis will be conducted using such variables.

The last analytic component will include a sensitivity analysis which is described here. Depending on the model (fixed-effect or random-effect) used in the preliminary meta-analysis, the analysis will be repeated using an alternative model. Additionally, meta-analysis for the respective outcomes will be repeated by dropping a study each time. Moreover, if SD changes for the mean changes from baseline are imputed in the above state way, the meta-analysis will be repeated using the correlation coefficients of 0.3 and 0.8, respectively. Meta-analysis data will be prepared and conducted in Microsoft’s Excel software and Stata statistical software, version 16.0 (StataCorp, College Station, Texas, USA), respectively.

If a meta-analysis is not possible for an outcome due to the lack comparable outcome data, we will report it narratively.

Trialists will be contacted when the components of risk of bias remain unclear despite discourse among the authors and when the endpoint means (and their SDs) are not specified by the trialists for efficacy related outcomes. Two emails, one week apart, will be sent to the trialists for these purposes. If no reply is received after 14 days from the first email contact, we will follow the steps depicted above. Finally, for statistically significant summary estimates obtained by meta-analysis, we will grade the quality of evidence using the GRADE approach [37].

Discussion

We begin by discussing the plausible implications of the proposed review. Physicians treating the T1DM patients might benefit by getting some insight on how the efficacy and safety profile of 25 mg empagliflozin vary from its lower dosages and placebo, respectively, in concomitant insulin users. Besides, the synthesized evidence from our proposed review may help future trialists to identify the potential areas of evidence gap in this context and aid them in planning trials more appropriately. Finally, health authorities concerned about the prospects of empagliflozin’s use in T1DM patients may find this proposed review useful in understanding the efficacy and safety of the trade-offs between the mega dose (25 mg) of empagliflozin with its lower dosages and placebo, respectively.

Next, we compare our proposed review with the existing review articles in this milieu. We could find only one systematic review and meta-analysis that compared the efficacy of the large dose empagliflozin with placebo in terms of glycemic control and blood pressure in insulin-treated T1DM patients with optimum kidney functioning [30]. It found that 25 mg empagliflozin was beneficial for glycemic control than the placebo; although, the systolic and diastolic blood pressure did not vary between the compared interventions [30]. Compared to it [30], our proposed review will compare the safety profile abreast of efficacy in insulin-treated T1DM patients, irrespective of their renal function, between 25 mg empagliflozin recipients and its lower dose and placebo recipients, respectively. Regarding the safety profile, a recent systematic review and meta-analysis found that SGLT2is (compared to placebo recipients) increase the risk of diabetic ketoacidosis and genital infection in insulin-treated T1DM patients [38]. However, unlike our proposed review, it’s findings are not specific to empagliflozin or its particular dosages [38].

The proposed review is expected to have the following strengths. It will perhaps be one of the preliminary studies to compare the efficacy and side effects profile of high dose (25 mg) empagliflozin with its lower dosages and placebo, respectively, in insulin-treated T1DM patients. Besides, the findings of the suggested review are likely to be rigorous since these will be based on double-blinded randomized controlled trials, which are considered as the highest level of epidemiological evidence. Additionally, its flexible way of synthesizing data, either, qualitatively and (or) quantitatively will improve the scope of reporting data pertinent to all outcomes of interest that are reported in the trials. Aside from that, the different methods of sensitivity analysis proposed here will be helpful in determining the strength of the preliminary meta-analytic findings.

Despite these strengths, our review might be susceptible to few weaknesses. Since it will not be including literature published in a non-English language, the database search is likely to be less exhaustive. Furthermore, as the intended review will accept the insulin regimens as per the trialists, any role played by insulin on the efficacy and safety of the tested interventions will be inextricable from those of the tested interventions.

Conclusions

The proposed systematic review and meta-analysis will compare the efficacy and safety profile of 25 mg empagliflozin with its lower doses and placebo, respectively, in double-blinded randomized controlled trials in insulin-treated T1DM patients.

Author contributions

SS1 planned and designed this protocol and also prepared the first and final draft of this manuscript. SS2 edited the first draft prepared by SS1.

Funding information

No funding was received for this protocol. This paper is an independent work of the authors and is not related to their affiliated institutions.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Footnotes

Submission statement

This manuscript is solely submitted to the Journal of Diabetes & Metabolic Disorders. We have not submitted this paper in part or full to any other journal.

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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