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Effect of linagliptin, a dipeptidyl peptidase-4 inhibitor, compared with the sulfonylurea glimepiride on cardiovascular outcomes in Asians with type 2 diabetes: subgroup analysis of the randomized CAROLINA® trial

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Abstract

Objective

Linagliptin, a dipeptidyl peptidase-4 inhibitor, recently demonstrated cardiovascular (CV) safety versus placebo in Asians with advanced type 2 diabetes mellitus (T2DM) in the CARMELINA® trial. We assessed its CV safety compared with the sulfonylurea glimepiride in Asians with relatively early T2DM in the CAROLINA® trial.

Methods

Based on prespecified and post hoc subgroup analyses of the multinational CAROLINA® trial in which adults with relatively early T2DM and elevated CV risk were randomized to linagliptin or glimepiride added to usual care, we analyzed data for participants from Asian countries. This included the primary outcome defined as time to first CV death, non-fatal myocardial infarction, or non-fatal stroke [three-point major adverse cardiovascular events (3P-MACE)].

Results

Of the 6033 participants, 933 (15.5%) were from Asia. During a median follow-up of 6.2 years, 3P-MACE occurred in 9.5% and 11.1% of the linagliptin and glimepiride groups, respectively (hazard ratio [HR] 0.85; 95% confidence interval [CI] 0.57–1.26]), consistent with the overall population (HR 0.98; 95% CI 0.84–1.13; P = 0.17 for treatment by region interaction). Similarly, there were no significant differences between groups for other outcomes, including CV death (HR 0.73; 95% CI 0.38–1.38), non-CV mortality (HR 0.76; 95% CI 0.37–1.57) and hospitalization for heart failure (HR 0.89; 95% CI 0.36–2.19). Hypoglycemia adverse events occurred in 13.1% of linagliptin patients versus 42.1% of glimepiride patients (HR 0.25; 95% CI 0.19–0.33; P < 0.0001) despite similar glycemic control. Body weight was slightly lower with linagliptin relative to glimepiride: weighted average mean difference over 256 weeks of − 1.82 kg (95% CI − 2.28 to − 1.35).

Conclusions

In Asian patients, linagliptin demonstrated similar CV safety to glimepiride with a markedly lower rate of hypoglycemia and modestly lower weight.

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Acknowledgements

The CAROLINA® trial was funded by the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Giles Brooke, PhD, CMPP, of Elevate Scientific Solutions during the preparation of this manuscript.

Author information

Authors and Affiliations

  1. Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan

    Takashi Kadowaki

  2. Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China

    Guang Wang

  3. Dallas Diabetes Research Center at Medical City and University of Texas Southwestern Medical Center, Dallas, TX, USA

    Julio Rosenstock

  4. Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, Gifu, Japan

    Daisuke Yabe

  5. Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Kobe, Japan

    Daisuke Yabe

  6. Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan

    Daisuke Yabe

  7. Department of Endocrinology and Metabolism, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Yongde Peng

  8. Internal Medicine 1, Faculty of Medicine, Shimane University, Shimane, Japan

    Keizo Kanasaki

  9. Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan

    Keizo Kanasaki

  10. Department of Endocrinology, Chinese People’s Liberation Army General Hospital, Beijing, China

    Yiming Mu

  11. Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

    Michaela Mattheus & Annett Keller

  12. Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan

    Tomoo Okamura

  13. Boehringer Ingelheim Norway KS, Asker, Norway

    Odd Erik Johansen

  14. Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Aachen, Germany

    Nikolaus Marx

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  1. Takashi Kadowaki
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Corresponding author

Correspondence to Takashi Kadowaki.

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Conflict of interest

TK reports consulting/lecture fees from Abbott, Asahi Mutual Life Insurance, Astellas Pharma Inc., AstraZeneca KK, Bayer, Boehringer Ingelheim, Cosmic, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Fujifilm, FUJIREBIO, Johnson & Johnson Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kowa Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Medical Review, Medscape Education, Medtronic Sofamor Danek, Mitsubishi Tanabe Pharma Corporation, MSD, Musashino Foods, Nipro, Novartis International AG, Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi S.A., SANWA KAGAKU KENKYUSHO CO., LTD., Sumitomo Dainippon, Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited., and Terumo; grants from Astellas Pharma Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD, Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi S.A., Sumitomo Dainippon, Taisho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Company Limited.; contracted research from AstraZeneca KK and Takeda Pharmaceutical Company Limited.; joint research from Daiichi Sankyo Company, Limited.; endowed chair from Asahi Mutual Life Insurance, Boehringer Ingelheim, Kowa Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD, Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd, and Takeda Pharmaceutical Company Limited. JR has served on scientific advisory boards and received honoraria or consulting fees from Eli Lilly, Sanofi, Novo Nordisk, Janssen, AstraZeneca, Boehringer Ingelheim, and Intarcia; he has also received grants/research support from Merck, Pfizer, Sanofi, Novo Nordisk, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Genentech, Janssen, Lexicon, Boehringer Ingelheim, and Intarcia. DY has received consulting or speaker fees from MSD KK, Novo Nordisk Pharma Ltd. and Taisho Toyama Pharmaceutical Co. Ltd., and clinically commissioned/joint research grants from Taisho Toyama Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., Novo Nordisk Pharma Ltd., Arklay Co. Ltd. and Terumo Co. Ltd. KK has received lecture fees from Boehringer Ingelheim, Eli Lilly and Sanofi. Boehringer Ingelheim, Mitsubishi Tanabe Pharma and Ono Pharmaceutical contributed to establishing the Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, and is under contract for consultancy with Boehringer Ingelheim. GW, YP, YM have no conflicts to disclose. MM, AK, TO, and OEJ are employees of Boehringer Ingelheim. NM is funded by the German Research Foundation SFB TRR 219 (projects M-03 and M-05); reports giving lectures for and receiving honoraria from Amgen, Boehringer Ingelheim, Sanofi-Aventis, Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Lilly, Novo Nordisk; receiving unrestricted research grants from Boehringer Ingelheim; serving as an advisor for Amgen, Bayer, Boehringer Ingelheim, Sanofi-Aventis, Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Novo Nordisk; serving in trial leadership for Boehringer Ingelheim and Novo Nordisk; and declining all personal compensation from pharmaceutical and device companies.

Ethical standards

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and/or with the Helsinki Declaration of 1964 and later versions.

Human rights statement

This research involves human participants. This report was limited to the Asian population from the CAROLINA® trial (ClinicalTrials.gov Identifier, NCT01243424). The study protocol was approved by the institutional review board or independent ethics committee from each site (approval numbers: not applicable) and all patients provided written informed consent before entering the trial. Full details of the approval process are provided in previous publications [19, 21].

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Informed consent or substitute for it was obtained from all patients for being included in the study.

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Kadowaki, T., Wang, G., Rosenstock, J. et al. Effect of linagliptin, a dipeptidyl peptidase-4 inhibitor, compared with the sulfonylurea glimepiride on cardiovascular outcomes in Asians with type 2 diabetes: subgroup analysis of the randomized CAROLINA® trial. Diabetol Int 12, 87–100 (2021). https://doi.org/10.1007/s13340-020-00447-5

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