Triple fixed-dose combination empagliflozin, linagliptin, and metformin for patients with type 2 diabetes

Abstract

Objectives: Fixed-dose combination (FDC) therapy can improve outcomes in type 2 diabetes (T2D). We evaluated the bioequivalence of 2 doses of an FDC of extended-release metformin (metformin XR), empagliflozin, a sodium-glucose co-transporter 2 inhibitor, and linagliptin, a dipeptidyl peptidase-4 inhibitor, versus corresponding free tablet combinations. Methods: Two randomized, open-label, two-way crossover studies in healthy adults compared: 2 FDC tablets of empagliflozin 5 mg/linagliptin 2.5 mg/metformin XR 1000 mg (Study 1; N = 30), 1 FDC tablet of empagliflozin 25 mg/linagliptin 5 mg/metformin XR 1000 mg (Study 2; N = 30) versus corresponding dose of free combinations. Subjects received study medication under fed conditions; washout was ≥35 days between treatments. Primary endpoints: area under the plasma concentration-time curve (AUC) from time 0 to last quantifiable data point for empagliflozin and metformin; AUC from time 0 to 72 hours for linagliptin, and peak plasma concentration (C max) for empagliflozin, linagliptin, and metformin. Bioequivalence was defined as adjusted geometric mean ratios (FDC: free combination) and two-sided 90% confidence intervals (CIs) of AUC and C max for each component within 80.00-125.00%. Results: Study 1: 27/29 and 28/30 treated participants were included in the pharmacokinetic analysis for the FDC and free combination periods, respectively. Study 2: 29/29 treated participants were included in the pharmacokinetic analysis for both periods. The adjusted geometric mean ratios of FDCs to their respective free tablet combinations and two-sided 90% CIs were all within the predefined range. The shapes of the mean plasma concentration-time profile of empagliflozin, linagliptin, and metformin XR were similar for subjects in the FDC and free combination groups in both studies. No serious adverse events were reported. Conclusion: The evaluated doses of empagliflozin/linagliptin/metformin XR FDC tablets were bioequivalent to the corresponding free combinations. Based on these two bioequivalence studies and existing phase 3 data, the FDA has recently approved this triple FDC to improve glycemic control in adults with T2D. PLAIN LANGUAGE SUMMARY: Study supports the convenience of empagliflozin, linagliptin, and metformin XR in 1 tablet as new treatment for type 2 diabetes What is the purpose of this summary? • This summary is to help you understand findings from recent research. • This summary is about 2 studies that are part of a larger group of studies with these medications. Researchers look at many studies to understand whether a medication works, how it works, and whether it is safe to prescribe to patients. What is known? • People with type 2 diabetes often need several medicines to control their blood sugar. • Some people find it difficult to take a lot of different tablets, and some people may not want to. This can lead to difficulties with managing type 2 diabetes. • Combining medicines into 1 tablet may help make it easier to take the treatment and to manage type 2 diabetes, wh...

Effect of metformin monotherapy and dual or triple concomitant therapy with metformin on glycemic control and lipid profile management of patients with type 2 diabetes mellitus

“…Previous studies have also suggested that the lipid-reducing efficiency of linagliptin or metformin may be lower than that of dapagliflozin (20) and a placebo (21). The different effects of monotherapy, dual therapy, and triple therapy with metformin on the lipid profiles of patients with T2DM in this study are largely consistent with the results of previous studies (22)(23)(24). In our study, triple therapy reduced the lipid profile as effectively as linagliptin dual therapy did, there were also significant differences when compared with metformin monotherapy.…”

“…Previous studies reported that combination therapy with empagliflozin, linagliptin, and metformin (22) or dapagliflozin, saxagliptin, and metformin (27) produced considerable glucose-lowering effects in patients with T2DM. In a 52week study, reductions in HbA1c with empagliflozin plus linagliptin therapy were superior to those with the joint use of either empagliflozin or linagliptin with metformin (28).…”

New Validated Stability-Indicating Rp-HPLC Method for the Simultaneous Determination of Metformin Hydrochloride, Linagliptin and Empagliflozin in Bulk and Pharmaceutical Dosage Forms

“…Fixed-dose combinations (FDCs) of metformin HCl, empagliflozin and linagliptin are a new option in adults with type 2 DM to improve glycemic control [10]. FDCs are effective choices for patients needing glucose lowering with multiple agents, with advantages of reducing pill burden, low risk of weight gain, and hypoglycemia as compared to monotherapy [11,12].…”

Novel UV Spectroscopic Methods for Simultaneous Assessment of Empagliflozin, Linagliptin and Metformin in Ternary Mixture

“…Trijardy XR ® consisting of empagliflozin, linagliptin, and metformin hydrochloride formulated as tablets (extended release) is a fixed-dose combination that improves glycemic control in individuals with diabetes mellitus (type 2) if given in conjunction with controlled diet and regular workout. [9][10][11] Literature survey disclosed numerous analytical approaches for the assessment of EPZ, LGT and MTH independently and in combined dosage form by means of UV spectrophotometry, [12][13] HPLC, [14][15][16][17][18][19][20] HPTLC. [21][22][23][24] Moreover, few methods were described for the estimation of EPZ, LGT and MTH in combined formulation/synthetic mixture using HPLC, [25][26][27][28][29] and HPTLC.…”