The development and benefits of metformin in various diseases

doi:10.1007/s11684-023-0998-6

Frontiers of Medicine

2023, Vol. 17

Issue (3): 388-431 https://doi.org/10.1007/s11684-023-0998-6

本期目录

The development and benefits of metformin in various diseases

Ying Dong¹, Yingbei Qi^1,⁵, Haowen Jiang¹, Tian Mi¹, Yunkai Zhang^1,², Chang Peng^1,², Wanchen Li^1,², Yongmei Zhang^1,⁵, Yubo Zhou^1,⁷(

), Yi Zang^1,^3,⁵(

), Jia Li^1,^2,^4,^5,⁶(

)

¹. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
². University of Chinese Academy of Sciences, Beijing 100049, China
³. Lingang Laboratory, Shanghai 201203, China
⁴. Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266237, China
⁵. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
⁶. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China
⁷. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China

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Abstract：

Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety, low cost, and outstanding hypoglycemic effect clinically. The mechanisms underlying these benefits are complex and still not fully understood. Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin, leading to reduced ATP production and activation of AMP-activated protein kinase (AMPK). Meanwhile, many novel targets of metformin have been gradually discovered. In recent years, multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes. Herein, we summarized the benefits of metformin in four types of diseases, including metabolic associated diseases, cancer, aging and age-related diseases, neurological disorders. We comprehensively discussed the pharmacokinetic properties and the mechanisms of action, treatment strategies, the clinical application, the potential risk of metformin in various diseases. This review provides a brief summary of the benefits and concerns of metformin, aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research. Although there have been countless studies of metformin, longitudinal research in each field is still much warranted.

Key words： metformin metabolism cancer aging neurological disorder

收稿日期: 2022-12-23 出版日期: 2023-07-28

Corresponding Author(s): Yubo Zhou,Yi Zang,Jia Li

引用本文:

. [J]. Frontiers of Medicine, 2023, 17(3): 388-431.
Ying Dong, Yingbei Qi, Haowen Jiang, Tian Mi, Yunkai Zhang, Chang Peng, Wanchen Li, Yongmei Zhang, Yubo Zhou, Yi Zang, Jia Li. The development and benefits of metformin in various diseases. Front. Med., 2023, 17(3): 388-431.

链接本文:

https://academic.hep.com.cn/fmd/CN/10.1007/s11684-023-0998-6
https://academic.hep.com.cn/fmd/CN/Y2023/V17/I3/388

Tab.1

Fig.1

Fig.2

Title (NCT No.)	Phases	Tumor type	Drug	Status
The Effect of Metformin on Breast Cancer Patients (NCT04559308)	Phase 2	Breast cancer	Metformin, doxorubicin, cyclophosphamide, paclitaxel	Unknown
Evaluation of the Effect of Metformin on Metastatic Breast Cancer as Adjuvant Treatment (NCT04143282)	Phase 2	Breast cancer	Metformin, chemotherapy	Completed
Advanced Lung Cancer Treatment With Metformin and Chemo-Radiotherapy (NCT02115464)	Phase 2	Lung cancer	Metformin, cisplatin	Terminated
Role of Adding Metformin to Neoadjuvant Chemotherapy in Patients With Breast Cancer (NCT04170465)	Phase 2	Breast cancer	Metformin, doxorubicin, cyclophosphamide, paclitaxel	Unknown
Metformin-Docetaxel Association in Metastatic Hormone-refractory Prostate Cancer (NCT01796028)	Phase 2	Prostate cancer	Metformin, docetaxel	Completed
Study of Metformin With Carboplatin/Paclitaxel Chemotherapy in Patients With Advanced Ovarian Cancer (NCT02312661)	Phase 1	Epithelial ovarian cancer	Metformin, carboplatin, paclitaxel	Completed
Metformin Combined With Chemotherapy for Pancreatic Cancer (NCT01210911)	Phase 2	Pancreatic cancer	Metformin, gemcitabine, erlotinib	Completed
Safety and Efficacy of Metronomic Cyclophosphamide, Metformin and Olaparib in Endometrial Cancer Patients (NCT02755844)	Phases 1 and 2	Endometrial cancer	Metformin, olaparib, cyclophosphamide	Completed
Combination Chemotherapy With or Without Metformin Hydrochloride in Treating Patients With Metastatic Pancreatic Cancer (NCT01167738)	Phase 2	Pancreatic cancer	Metformin, capecitabine, csplatin, epirubicin, gemcitabine	Terminated
Neoadjuvant FDC With Melatonin or Metformin for Locally Advanced Breast Cancer (NCT02506777)	Phase 2	Breast cancer	Metformin, fluoruracil, doxorubicin, cyclophosphamide, melatonin	Unknown
Metformin Plus Irinotecan for Refractory Colorectal Cancer (NCT01930864)	Phase 2	Colorectal cancer	Metformin, irinotecan	Unknown
Metformin in Children With Relapsed or Refractory Solid Tumors (NCT01528046)	Phase 1	Solid tumors	Metformin, vincristine, irinotecan, temozolomide	Active, not recruiting
Metformin Plus Paclitaxel for Metastatic or Recurrent Head and Neck Cancer (NCT01333852)	Phase 2	Head and neck neoplasms	Metformin, paclitaxel	Terminated
Metformin Plus Modified FOLFOX 6 in Metastatic Pancreatic Cancer (NCT01666730)	Phase 2	Metastatic pancreatic cancer	Metformin, oxaliplatin, leucovorin, fuorouracil	Completed
Metformin Combined With Gemcitabine as Adjuvant Therapy for Pancreatic Cancer After Curative Resection (NCT02005419)	Phase 2	Pancreatic cancer	Metformin, gemcitabine	Completed
Paclitaxel and Carboplatin With or Without Metformin Hydrochloride in Treating Patients With Stage III, IV, or Recurrent Endometrial Cancer (NCT02065687)	Phases 2 and 3	Endometrial cancer	Metformin, carboplatin, paclitaxel	Active, not recruiting
Myocet + Cyclophosphamide + Metformin Vs Myocet + Cyclophosphamide in 1st Line Treatment of HER2 Neg. Metastatic Breast Cancer Patients (NCT01885013)	Phase 2	Breast cancer	Metformin, myocet, cyclophosphamide	Completed
Dose-finding Study of Metformin With Chemoradiation in Locally Advanced Head and Neck Squamous Cell Carcinoma (NCT02325401)	Phase 1	Head and neck squamous cell carcinoma	Metformin, cisplatin	Completed
NeoMET Study in Neoadjuvant Treatment of Breast Cancer (NCT01929811)	Phase 2	Breast cancer	Metformin, docetaxel, epirubicin, cyclophosphomide	Terminated
Chemotherapy and Radiation Therapy With or Without Metformin Hydrochloride in Treating Patients With Stage III Non-small Cell Lung Cancer (NCT02186847)	Phase 2	Non small cell lung cancer	Metformin, carboplatin, paclitaxel	Active, not recruiting
Treatment of Patients With Advanced Pancreatic Cancer After Gemcitabine Failure (NCT01971034)	Phase 2	Pancreatic cancer	Metformin, paclitaxel	Completed
Study of Paclitaxel, Carboplatin and Oral Metformin in the Treatment of Advanced Stage Ovarian Carcinoma (NCT02437812)	Phase 2	Ovarian carcinoma	Metformin, paclitaxel, carboplatin	Unknown
Oxidative Phosphorylation Targeting In Malignant Glioma Using Metformin Plus Radiotherapy Temozolomide (NCT04945148)	Phase 2	Glioblastoma	Metformin, temozolomide	Not yet recruiting
Metformin in Combined With Cisplatin Plus Paclitaxel With Advanced Esophageal Squamous Cell Carcinoma (NCT03833466)	Phase 2	Esophageal squamous cell carcinoma	Metformin, paclitaxel, cisplatin	Unknown
Study on Low Dose Temozolomide Plus Metformin or Placebo in Patient With Recurrent or Refractory Glioblastoma (NCT03243851)	Phase 2	Glioblastoma	Metformin, temozolomide	Completed
Comparison of Melatonin or Metformin and Dacarbazine Combination Versus Dacarbazine Alone in Disseminated Melanoma (NCT02190838)	Phase 2	Melanoma	Metformin, dacarbazine, melatonin	Terminated
Vincristine, Dexamethasone, Doxorubicin, and PEG-asparaginase (VPLD) and Metformin for Relapsed Childhood Acute Lymphoblastic Leukemia (ALL) (NCT01324180)	Phase 1	Acute lymphoblastic leukemia	Metformin, Vincristine, dexamethasone, asparaginase, doxorubicin	Completed
Temozolomide, Memantine Hydrochloride, Mefloquine, and Metformin Hydrochloride in Treating Patients With Glioblastoma Multiforme After Radiation Therapy (NCT01430351)	Phase 1	Glioblastoma	Metformin, temozolomide	Active, not recruiting
Metformin + Cytarabine for the Treatment of Relapsed/Refractory AML (NCT01849276)	Phase 1	Acute myeloid leukemia	Metformin, cytarabine	Terminated

Tab.2

Title (NCT No.)	Phases	Tumor type	Drug	Status
Study of Erlotinib and Metformin in Triple Negative Breast Cancer (NCT01650506)	Phase 1	Breast cancer	Metformin, erlotinib	Completed
Randomized Trial of Neo-adjuvant Chemotherapy With or Without Metformin for HER2 Positive Operable Breast Cancer (NCT03238495)	Phase 2	Breast cancer	Metformin, taxotere, carboplatin, herceptin, pertuzumab	Recruiting
Temsirolimus in Combination With Metformin in Patients With Advanced Cancers (NCT01529593)	Phase 1	Advanced cancers	Metformin, temsirolimus	Active, not recruiting
Study of Safety and Efficacy of Dapagliflozin + Metformin XR Versus Metformin XR in Participants With HR + , HER2-, Advanced Breast Cancer While on Treatment With Alpelisib and Fulvestrant (NCT04899349)	Phase 2	Breast cancer	Metformin, alpelisib, fulvestrant	Recruiting
A Study of Liposomal Doxorubicin + Docetaxel + Trastuzumab + Metformin in Operable and Locally Advanced HER2 Positive Breast Cancer (NCT02488564)	Phase 2	Breast cancer	Metformin, doxorubicin, docetaxel, trastuzumab	Completed
Modulation of Response to Hormonal Therapy With Lapatinib and/or Metformin in Patients With Metastatic Breast Cancer (NCT01477060)	Phase 2	Breast cancer	Metformin, lapatinib	Terminated
Lapatinib With Sirolimus or Metformin (NCT01087983)	Phase 1	Advanced cancers	Metformin, lapatinib	Completed
Study to Evaluate the Effect of Metformin in the Prevention of HG in HR[+]/HER2[–] PIK3CA-mut Advanced BC Patients (NCT04300790)	Phase 2	Breast cancer	Metformin, alpelisib, fulvestrant, letrozole, exemestane	Active, not recruiting
A Pharmacokinetic Interaction Study Between Apatinib and Rosuvastatin or Metformin in Solid Tumor Subjects (NCT04428086)	Phase 1	Solid tumor	Metformin, apatinib	Completed
An Efficacy and Safety Study of Erdafitinib (JNJ-42756493) in Participants With Urothelial Cancer (NCT02365597)	Phase 2	Urothelial cancer	Metformin, erdafitinib	Recruiting
Combination of Metformin With Gefitinib to Treat NSCLC (NCT01864681)	Phase 2	Non small cell lung cancer	Metformin, gefitinib	Completed
Metformin And Chloroquine in IDH1/2-mutated Solid Tumors (NCT02496741)	Phases 1 and 2	IDH1/2-mutated solid tumor	Metformin, chloroquine	Completed
Metformin, Nelfinavir, and Bortezomib in Treating Patients With Relapsed and/or Refractory Multiple Myeloma (NCT03829020)	Phase 1	Multiple myeloma	Metformin, bortezomib, nelfinavir	Recruiting
A Phase I/II Trial of Vemurafenib and Metforminto Melanoma Patients (NCT01638676)	Phases 1 and 2	Melanoma	Metformin, vemurafenib	Recruiting
Study of Dabrafenib, Trametinib and Metformin for Melanoma Patients (NCT02143050)	Phases 1 and 2	Melanoma	Metformin, dabrafenib, trametinib	Recruiting
Study of Metformin Plus Paclitaxel/Carboplatin/Bevacizumab in Patients With Adenocarcinoma (NCT01578551)	Phase 2	Lung adenocarcinoma	Metformin, paclitaxel, carboplatin, bevacizumab	Terminated
Paxalisib With a High Fat, Low Carb Diet and Metformin for Glioblastoma (NCT05183204)	Phase 2	Glioblastoma	Metformin, paxalisib	Not yet recruiting
Metformin in Combination With Standard Induction Therapy for Large B cell Lymphoma (NCT02531308)	Phase 2	Diffuse large B cell lymphoma	Metformin, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone, pegfilgrastim	Terminated

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