Rationality, Efficacy, Tolerability of Empagliflozin Plus Linagliptin Combination for the Management of Type 2 Diabetes Mellitus: A Systematic Review of Randomized Controlled Trials and Observational Studies

Background: Treatment of diabetes mellitus includes more than one drug of different groups, which may lead to a high pill burden and non-adherence to drugs. We have aimed to systematically analyze the clinical efficacy, safety, and pharmacoeconomic cost-effectiveness of the fixed-dose combination of empagliflozin plus a linagliptin in Type-2 Diabetes mellitus (T2DM) patients. Methods: A literature search of PubMed/MEDLINE, SCOPUS, Google Scholar, and EMBASE was performed using the MeSH terms and/or keywords“((Single-pill combination) OR ((Fixeddose combination) OR (Combination therapy)) AND (Empagliflozin add on-to Linagliptin) OR (Empagliflozin combined with Linagliptin) OR ((Combination of Empagliflozin and Linagliptin)” from the inception to February 2021. Results: Search results were found in a total of 13 clinical studies. After removing duplicates and studies not according to inclusion criteria, a total of eight clinical studies (Randomized controlled trials: 7; Observational cohort studies: 1) were included (n=7491). A significant reduction in the primary endpoint, the mean changes in baseline HbA1c at the end of 24 weeks and/or 52 weeks was found in the empagliflozin plus a linagliptin combination group in all included studies. In addition, significant efficacy was seen in decreasing the secondary endpoints such as the mean change in the fasting plasma glucose, systolic and diastolic blood pressure (DBP), and body weight with fewer adverse events than the adverse effects with either drug alone. Conclusion: After reviewing findings from the available clinical studies of the combination of empagliflozin plus linagliptin, we conclude that the combination is effective, safe, tolerable, and rationale cost effective compared to placebo and either drug alone for the management of T2DM in patients with inadequate glycemic control with metformin alone, patients with intolerance to metformin, increased baseline HbA1c, patients with overweight or obesity and diabetic hypertensive, CHF, atherosclerotic cardiovascular disease, and renal dysfunction patients. Future randomized controlled trials in a larger number of T2DM patients with or without CHF and renal failure patients are recommended.