Efficacy and safety of empagliflozin and linagliptin in fixed-dose combination compared with empagliflozin for Type 2 Diabetes Mellitus: Protocol for a systematic review and meta-analysis
Creators: name: Pachito, Daniela
name: Bagattini, Angela
Publisher: name: Open Science Framework
Year: 2022
Subjects: subject: Medicine and Health Sciences

description: Efficacy and safety of empagliflozin and linagliptin in fixed-dose combination compared with empagliflozin for Type 2 Diabetes Mellitus: Protocol for a systematic review and meta-analysis 1 - Objective To assess the effectiveness and safety of empagliflozin and linagliptin in fixed-dose combination compared with empagliflozin for individuals with DM2. 2 - Methods 2.1 Eligibility criteria 2.1.1 Types of participants Individuals with Type 2 Diabetes Mellitus. 2.1.2 Types of interventions Empagliflozin and linagliptin in combination, as add-on therapy to metformin or sulfonylureas, or as a first-line therapy, regardless of dosage or treatment duration. 2.1.3 Types of comparators Empagliflozin, as add-on therapy to metformin or sulfonylureas, or as a first-line therapy, regardless of dosage or treatment duration. 2.1.4 Types of outcomes measures Primary outcomes are: • HbA1c levels; • hypoglycemic events. Secondary outcomes are: • Fasting blood glucose; • Microvascular complications (e.g., diabetic retinopathy, peripheral neuropathy); • Macrovascular complications (e.g., myocardial infarction, stroke); • Mortality from cardiovascular diseases; • Mortality from any cause; • Serious adverse events, including death, life-threatening events, hospitalization, disability or permanent damage, congenital anomaly/birth defect, required Intervention to prevent permanent impairment, or other important medical events that may jeopardize the patient;1 • Mild adverse events. 2.1.5 Timing We will consider short-, medium- and long-term treatment. Short-term will be defined as treatment lasting up to one month. Medium-term treatment will be defined by treatment lasting longer than one month and up to six months. Long-term treatment duration will be defined as treatment for more than six months. 2.1.6 Types of study designs Randomized controlled trials (RCTs) with parallel design and individual allocation. Cross-over randomized controlled trials will be included under the condition that data for the first phase is provided in separate. Non-randomized studies or quasi-randomized studies will not be included. Table 1 Research question according to the PICOTS framework Population Individuals with Type 2 Diabetes Mellitus Intervention Empagliflozin and linagliptin in combination, as add-on therapy to metformin or sulfonylureas, or as a first-line therapy, regardless of dosage or treatment duration Comparator Empagliflozin, as add-on therapy to metformin or sulfonylureas, or as a first-line therapy, regardless of dosage or treatment duration Outcome measures Primary outcomes: • HbA1c levels • Hypoglycemic events Secondary outcomes: • Fasting blood glucose; • Microvascular complications; • Macrovascular complications; • Mortality from cardiovascular diseases; • Mortality from any cause; • Serious adverse events; • Mild adverse events. Timing Short-, medium- and long-term follow up Study design Randomized controlled trials 2.2 Search methods for identification of studies 2.2.1 Electronic searches We aim to identify all relevant RCTs, regardless of language or publication status (published, unpublished, in press, or in progress). We will search the following sources, from inception to the search date: • Medical Literature Analysis and Retrieval System Online (Medline) via PubMed; • Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; • Embase via Elsevier; • Latin American and Caribbean Health Science Information Database (LILACS). In addition, we will search the following trials registries: • US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov). The search strategy for MEDLINE via PubMed is presented in Appendix 1 and will be adapted for use in the other databases. 2.2.2 Searching other resources We will screen the reference lists of relevant published reviews and primary studies to identify RCTs that we may not have been identified by our electronic searches. We will search relevant manufacturers’ web sites for study information. 2.3 Selection of studies The Rayyan software will be used to screen our search results in two stages2. At a first stage, at least two reviewers will independently screen titles and abstracts identified by our search to identify studies that appear relevant after excluding duplicates. In the second stage, full texts of all potentially relevant studies will be retrieved to assess the study eligibility. In both stages, disagreements will be solved by a third reviewer. We will record the reasons for exclusion at the second stage in the 'Characteristics of excluded studies' table and we will record the selection process in sufficient detail to complete the PRISMA flowchart. 2.4 Data extraction Two reviewers will independently extract data from all included studies, using a structured data collection form considering the following information. • Methods: study design, total duration of study, study setting, withdrawals, and date of study; • Participants: number of participants, mean age, age range, gender, diagnostic criteria, comorbidities medication before study; • Interventions and comparators: dose, frequency, concomitant medications; • Outcomes: primary and secondary outcomes specified and collected, instruments used for outcome measure and reported time points; • Notes: funding for studies and conflicts of interest of trial authors. We will resolve any disagreement during the stage of data extraction by consensus. One reviewer will contact authors if reported data is insufficient. 2.5 Assessment of risk of bias in included studies Two reviewers will independently evaluate the studies regarding the methodological quality by using validated instruments according to the study design, such as Cochrane Risk of Bias tool for randomized trials (RoB 2.0)3. Disagreements on assessments will be resolved by consulting a third reviewer. We will judge each potential source of bias as 'low', 'some concerns', or 'high risk of bias', based on answers to the signaling questions. We will summarize the risk of bias judgements across different trials for each of the domains listed, with a justification for their judgements in the 'Risk of bias' table. We will assess risk of bias according to the following domains: 1. bias arising from the randomization process; 2. bias due to deviations from intended interventions; 3. bias due to missing outcome data; 4. bias in measurement of the outcome; and 5. bias in selection of the reported result. We will consider the overall risk of bias for each result assessed to be the least favorable assessment across the domains of bias3 . We will address special issues in the risk of bias tool for cross-over trials as proposed in the Cochrane Handbook4. 2.6 Measures of treatment effect We will meta-analyze odds ratios for dichotomic outcome data and mean differences or standardized mean differences for continuous outcome data. 2.7 Unit of analysis issues The unit of analysis will be the individual. We will not include studies in which clusters of participants were randomized as opposed to randomization being performed at the participant level. If cross-over studies are included, only data related to the first phase of the study will be included in meta-analysis. 2.8 Dealing with missing data If standard errors are reported as the variance measure, we will calculate the respective standard deviations. We will not impute missing standard deviations from other studies or perform any other type of imputation. 2.9 Assessment of reporting biases To detecting and correcting for publication bias, we will try to reduce their potential impact by ensuring a comprehensive search for eligible studies and evaluate in independent pairs. Furthermore, we will use a funnel plot to help to explore the publication bias for meta-analysis with more than ten studies. 2.10 Data synthesis Results will be reported in compliance with all items of the extension of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Statement, developed specifically to network meta-analyses5. The same applies to the other sections of the systematic review. Decisions of including studies in meta-analyses will be made provided the studies are homogeneous from the methodological and clinical perspective4. We will therefore not pool results of studies with different treatment durations (e.g., results for short-term treatment will not be combined to results of long-term treatment). Meta-analysis will be performed by applying the random-effects model. 2.11 Subgroup analysis Subgroup analysis will be performed to account for age and concomitant cardiovascular disease as possible effect modifiers. Aged individuals will be defined as 65 years old or over. Cardiovascular disease will be defined as coronary heart disease; strokes and transient ischaemic attack; peripheral arterial disease; and aortic disease.6 2.12 'Summary of findings' table The main findings of the systematic review and meta-analysis will be presented in the ‘Summary of Findings’ table produced with the software GRADEpro GTD7. We will assess the certainty of evidence for each outcome and will rate the certainty of evidence as high, moderate, low, very low. 2.13 Sensitivity analysis We intend to perform sensitivity analysis by excluding studies with high risk of bias. Results from random-effects model and fixed-effect model will also be compared. References: 1. U.S. Food and Drug Administration (FDA). What is a Serious Adverse Event? https://www.fda.gov/safety/reporting-serious-problems-fda/what-serious-adverse-event (2016). 2. Ouzzani, M. et al. Rayyan—a web and mobile app for systematic reviews. Syst. Rev. 5, 210 (2016). 3. Sterne, J. A. C. et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 366, l4898 (2019). 4. Higgins, J. et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.0. www.training.cochrane.org/handbook (2019). 5. Hutton, B. et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: Checklist and explanations. Ann. Intern. Med. 162, 777–784 (2015). 6. National Health Service. Cardiovascular disease. https://www.nhs.uk/conditions/cardiovascular-disease/ (2018). 7. McMaster University. GRADEpro GDT: GRADEpro Guideline Development Tool [Software]. (2015). 8. Salanti, G., Del Giovane, C., Chaimani, A., Caldwell, D. M. &amp; Higgins, J. P. T. Evaluating the Quality of Evidence from a Network Meta-Analysis. PLoS One 9, e99682 (2014). 9. Nikolakopoulou, A. et al. CiNeMA: An approach for assessing confidence in the results of a network meta-analysis. PLoS Med. 17, 1–19 (2020). Appendix 1 – Search Strategy for MEDLINE via PubMed #1 "Diabetes Mellitus, Type 2"[Mesh] OR (Diabetes Mellitus) OR (Diabetes Mellitus, Noninsulin-Dependent) OR (Diabetes Mellitus, Ketosis-Resistant) OR (Diabetes Mellitus, Ketosis Resistant) OR (Ketosis-Resistant Diabetes Mellitus) OR (Diabetes Mellitus, Non Insulin Dependent) OR (Diabetes Mellitus, Non-Insulin-Dependent) OR (Non-Insulin-Dependent Diabetes Mellitus) OR (Diabetes Mellitus, Stable) OR (Stable Diabetes Mellitus) OR (Diabetes Mellitus, Type II) OR NIDDM OR (Diabetes Mellitus, Noninsulin Dependent) OR (Diabetes Mellitus, Maturity-Onset) OR (Diabetes Mellitus, Maturity Onset) OR (Maturity-Onset Diabetes Mellitus) OR (Maturity Onset Diabetes Mellitus) OR MODY OR (Diabetes Mellitus, Slow-Onset) OR (Diabetes Mellitus, Slow Onset) OR (Slow-Onset Diabetes Mellitus) OR (Type 2 Diabetes Mellitus) OR (Noninsulin-Dependent Diabetes Mellitus) OR (Noninsulin Dependent Diabetes Mellitus) OR (Maturity-Onset Diabetes) OR (Diabetes, Maturity-Onset) OR (Maturity Onset Diabetes) OR (Type 2 Diabetes) OR (Diabetes, Type 2) OR (Diabetes Mellitus, Adult-Onset) OR (Adult-Onset Diabetes Mellitus) OR (Diabetes Mellitus, Adult Onset) #2 "Linagliptin"[Mesh] OR linagliptin OR Tradjenta OR Trayenta OR Trajenta #3 "empagliflozin" [Supplementary Concept] OR empagliflozin OR Jardiance OR Glyxambi OR (empagliflozin AND linagliptin) #4 #2 OR #3 #5 (randomized controlled trial[Publication Type] OR (randomized[Title/Abstract] AND controlled[Title/Abstract] AND trial[Title/Abstract])) #6 #1 AND #4 AND #5