Safety and tolerability of empagliflozin and linagliptin combination therapy in patients with type 2 diabetes mellitus: a pooled analysis of data from five randomized, controlled clinical trials

ABSTRACT

Objectives

The fixed-dose combination of empagliflozin and linagliptin, two glucose-lowering drugs prescribed for type 2 diabetes mellitus, has demonstrated good tolerability in phase III clinical trials. To further evaluate the safety profile of this combination, the data from these trials were pooled and analyzed.

Methods

This was a post-hoc pooled analysis of five randomized, double-blind, clinical trials of the empagliflozin/linagliptin fixed-dose combination. Data for adverse events and laboratory parameters were evaluated.

Results

The analysis included 2895 patients: 1410, 1015, and 470 receiving the empagliflozin/linagliptin combination, empagliflozin monotherapy, and linagliptin monotherapy, respectively. Overall, the incidence of adverse events with the empagliflozin/linagliptin combination was similar to that with empagliflozin or linagliptin alone. Fewer than 2% of patients experienced hypoglycemia, and its incidence was similar across treatment groups. Genital infections occurred in more patients receiving empagliflozin/linagliptin (3.0%) or empagliflozin monotherapy (5.1%) than in those receiving linagliptin monotherapy (1.9%). No cases of Fournier’s gangrene, diabetic ketoacidosis, or pemphigoid occurred, and no clinically relevant mean changes in laboratory parameters were noted.

Conclusion

The safety profile of the fixed-dose combination of empagliflozin and linagliptin was similar to the individual monotherapies. No new safety signals were identified.

KEYWORDS:

• Type 2 diabetes mellitus
• dipeptidyl-peptidase IV inhibitors
• empagliflozin
• linagliptin
• patient safety
• sodium-glucose transporter 2 inhibitors

Acknowledgments

The authors thank the physicians and patients who participated in the clinical trials analyzed in this manuscript.

Author contributions

All authors participated in the interpretation of study results, and in the drafting, critical revision, and approval of the final version of the manuscript. All authors agree to be accountable for all aspects of this work.

Role of the sponsor

The Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance was involved in the study design, data collection, data analysis, and preparation of the manuscript.

Declaration of interest

H. Watada has received grants from Kowa, Sanofi, Yakult, Eli Lilly, Novartis, Sanwa Kagaku Kenkyusho, Abbott Japan, Astellas Pharma, Boehringer Ingelheim, Daiichi Sankyo, Dainippon Sumitomo Pharma, Pfizer, Kissei Pharma, Kyowa Hakko Kirin, Mitsubishi Tanabe Pharma, Merck Sharp & Dohme, Novo Nordisk, Ono Pharmaceutical, Teijin, Taisho-Toyama, and Souiken; and has received personal fees from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Dainippon Sumitomo Pharma, Eli Lilly, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Novo Nordisk, Ono Pharmaceutical, Sanofi, Sanwa Kagaku Kenkyusho, Kyowa Hakko Kirin, Terumo Corp, Fuji Film, and Takeda. T. Yamauchi has received grants from Mitsubishi Tanabe Corporation, Takeda Pharmaceutical Co. Ltd., Novo Nordisk Co. Ltd., Astellas Pharm Inc., AstraZeneca K.K., Ono Pharmaceutical Co. Ltd., Novartis International AG, Nippon Boehringer Ingelheim Co. Ltd., Kyowa Kirin Co. Ltd., Kowa Pharmaceutical Company Ltd., Merck Sharp & Dohme Co., Sanofi K. K. Shionogi&Co. Ltd., Daiichi Sankyo Co. Ltd., Tosoh Corporation, Sanwa Chemistry Laboratory Co. Ltd., NTT DOCOMO INC, Mitsubishi Corporation Life Sciences Limited, AeroSwitch, Nipro Corporation; and has received personal fees from Johnson & Johnson Co. Ltd., Mitsubishi Tanabe Corporation, Medtronic Japan Co. Ltd., Takeda Pharmaceutical Co. Ltd., Novo Nordisk Co. Ltd., Astellas Pharm Inc., AstraZeneca K.K., Ono Pharmaceutical Co. Ltd., Novartis International AG, Nippon Boehringer Ingelheim Co. Ltd., Kyowa Kirin Co. Ltd., Kowa Pharmaceutical Company Ltd., Merck Sharp & Dohme Co., Sanofi K. K., Sanwa Kagaku Kenkyusho Co. Ltd., Shionogi&Co. Ltd., Daiichi Sankyo Co. Ltd., Taisho Pharmaceutical Co. Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co. Ltd., Sanwa Chemistry Laboratory Co. Ltd., Sumitomo Dainippon Pharma Co. Ltd., FUJIFILM Toyama Chemical Co. Ltd., DOJINDO LABORATORIES. F. Yamamoto, A. Taniguchi, and A. Yasui are employees of Nippon Boehringer Ingelheim Co. Ltd. L. Yarush is an employee of Boehringer Ingelheim Pharmaceuticals, Inc. C. Heilmann is an employee of Boehringer Ingelheim International GmbH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are an Editor in Chief for Taylor and Francis Publishing. A reviewer on this manuscript has disclosed that they are an employee of Janssen research and development. A reviewer on this manuscript has disclosed that they have received research support from Boehringer Ingelheim in the past.

Data availability

The sponsor of the clinical trials (Boehringer Ingelheim) is committed to responsible sharing of clinical study reports, related clinical documents, and patient-level clinical study data. Researchers are invited to submit inquiries via the following website (https://trials.boehringer-ingelheim.com).

Trial registration

The trials included in this pooled analysis are registered at ClinicalTrials.gov (CT.gov identifiers: NCT01422876, NCT01734785, NCT01778049, NCT02453555, NCT02489968)

Additional information

Funding

The studies that provided data for this analysis were sponsored by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. Medical writing assistance was provided by Giles Brooke, PhD CMPP, of Elevate Scientific Solutions during the preparation of this manuscript, and was funded by Nippon Boehringer Ingelheim Co. Ltd.