Search for the glycated hemoglobin target minimizing mortality among people with type 2 diabetes with rare incidence of treatment-related severe hypoglycemia – Epidemiologic analysis of J-DOIT3 randomized controlled trial
9 affiliations
- 1Department of Diabetes, Metabolism and Endocrinology, Ichikawa Medical Center, International University of Health and Welfare, Chiba, Japan.
- 2Department of Endocrinology and Diabetes, Saitama Medical University, Saitama, Japan.
- 3Diabetes Research Center, Japan Institute for Health Security, Tokyo, Japan.
- 4Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
- 5Okachimachi Ohisama Clinic, Tokyo, Japan.
- 6Center for Digital Transformation for Health, Kyoto University School of Medicine, Kyoto, Japan.
- 7Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
- 8Department of Integrated Science and Engineering for Sustainable Society, Chuo University, Tokyo, Japan.
- 9Toranomon Hospital, Tokyo, Japan.
Abstract
Objectives: In recent years, with the considerable changes in the therapeutic armamentarium for diabetes, the incidence of hypoglycemia events, especially severe hypoglycemia events, associated with drug treatment in people with diabetes has markedly decreased. We were prompted to evaluate the threshold for each intervention target, especially glycemic control, associated with a minimized risk of the macrovascular complications of diabetes in this setting. Methods: In the Japan Diabetes Optimal Integrated Treatment study for 3 major risk factors of cardiovascular diseases (J-DOIT3) conducted by us previously, we recruited 2542 participants and assigned them to a conventional therapy group (n = 1271) and an intensive therapy group (n = 1271; two ineligible participants were removed from all analyses afterwards), and the incidence of severe hypoglycemia events was low in both groups (7 in the intensive therapy group and 4 in the conventional therapy group during a median 8.5 years’ follow-up). Towards the objective of this study, we undertook a landmark analysis with a landmark time-point of 1 year after the baseline of the J-DOIT3 study. Then, using the updated mean values of the glycated hemoglobin (HbA1c), systolic blood pressure, and LDL-cholesterol and HDL-cholesterol levels, we determined the optimal levels of each of these variables associated with the lowest hazard ratios for outcomes, including the primary and cardiovascular outcomes. Results: For glycemic control, our results revealed no clear lower threshold of the glycated hemoglobin associated with the lowest risk of myocardial infarction or all-cause mortality; for other risk factors, it might be an important treatment target to maintain the LDL-cholesterol levels at below 80 mg/dL to minimize the risk of stroke. Conclusions: The present analysis suggested that the treatment target for HbA1c to minimize the risk of all-cause mortality in participants with diabetes with a low incidence of severe hypoglycemia episodes could be < 6.5% (ClinicalTrials.gov, number NCT00300976).
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BibTeX
@article{noda2026search,
title = {{Search for the glycated hemoglobin target minimizing mortality among people with type 2 diabetes with rare incidence of treatment-related severe hypoglycemia – Epidemiologic analysis of J-DOIT3 randomized controlled trial}},
author = {Mitsuhiko Noda and Kohjiro Ueki and Takayoshi Sasako and Naoki Ishizuka and Kana Miyake and Kengo Miyoshi and Tomohisa Aoyama and Yukiko Okazaki and Yasuo Ohashi and Toshimasa Yamauchi and Takashi Kadowaki and J-DOIT3 Study Group},
journal = {PLOS One},
year = {2026},
month = oct,
doi = {10.1371/journal.pone.0360295},
url = {https://doi.org/10.1371/journal.pone.0360295},
note = {CC BY},
}
RIS
TY - JOUR
TI - Search for the glycated hemoglobin target minimizing mortality among people with type 2 diabetes with rare incidence of treatment-related severe hypoglycemia – Epidemiologic analysis of J-DOIT3 randomized controlled trial
AU - Mitsuhiko Noda
AU - Kohjiro Ueki
AU - Takayoshi Sasako
AU - Naoki Ishizuka
AU - Kana Miyake
AU - Kengo Miyoshi
AU - Tomohisa Aoyama
AU - Yukiko Okazaki
AU - Yasuo Ohashi
AU - Toshimasa Yamauchi
AU - Takashi Kadowaki
AU - J-DOIT3 Study Group
PY - 2026
DA - 2026/10/23
JO - PLOS One
DO - 10.1371/journal.pone.0360295
UR - https://doi.org/10.1371/journal.pone.0360295
AB - Objectives: In recent years, with the considerable changes in the therapeutic armamentarium for diabetes, the incidence of hypoglycemia events, especially severe hypoglycemia events, associated with drug treatment in people with diabetes has markedly decreased. We were prompted to evaluate the threshold for each intervention target, especially glycemic control, associated with a minimized risk of the macrovascular complications of diabetes in this setting. Methods: In the Japan Diabetes Optimal Integrated Treatment study for 3 major risk factors of cardiovascular diseases (J-DOIT3) conducted by us previously, we recruited 2542 participants and assigned them to a conventional therapy group (n = 1271) and an intensive therapy group (n = 1271; two ineligible participants were removed from all analyses afterwards), and the incidence of severe hypoglycemia events was low in both groups (7 in the intensive therapy group and 4 in the conventional therapy group during a median 8.5 years’ follow-up). Towards the objective of this study, we undertook a landmark analysis with a landmark time-point of 1 year after the baseline of the J-DOIT3 study. Then, using the updated mean values of the glycated hemoglobin (HbA1c), systolic blood pressure, and LDL-cholesterol and HDL-cholesterol levels, we determined the optimal levels of each of these variables associated with the lowest hazard ratios for outcomes, including the primary and cardiovascular outcomes. Results: For glycemic control, our results revealed no clear lower threshold of the glycated hemoglobin associated with the lowest risk of myocardial infarction or all-cause mortality; for other risk factors, it might be an important treatment target to maintain the LDL-cholesterol levels at below 80 mg/dL to minimize the risk of stroke. Conclusions: The present analysis suggested that the treatment target for HbA1c to minimize the risk of all-cause mortality in participants with diabetes with a low incidence of severe hypoglycemia episodes could be < 6.5% (ClinicalTrials.gov, number NCT00300976).
SN - 1932-6203
ER -