The effect of SGLT2 inhibition on prostate cancer: Mendelian randomization and observational analysis using electronic healthcare and cohort data

Jie Zheng; Jieli Lu; Jiying Qi; Qian Yang; Huiling Zhao; Haoyu Liu; Zhihe Chen; Lanhui Huang; Youqiong Ye; Min Xu; Yu Xu; Tiange Wang; Mian Li; Zhiyun Zhao; Ruizhi Zheng; Shuangyuan Wang; Hong Lin; Chunyan Hu; Celine Sze Ling Chui; Shiu Lun Au Yeung; Shan Luo; Olympia Dimopoulou; Padraig Dixon; Sean Harrison; Yi Liu; Jamie Robinson; James Yarmolinsky; Philip Haycock; Jinqiu Yuan; Sarah Lewis; Zhongshang Yuan; Tom R Gaunt; George Davey Smith; Guang Ning; Richard M Martin; Bin Cui; Weiqing Wang; Yufang Bi

doi:10.1016/j.xcrm.2024.101688

The effect of SGLT2 inhibition on prostate cancer: Mendelian randomization and observational analysis using electronic healthcare and cohort data

Cell Rep Med. 2024 Aug 20;5(8):101688. doi: 10.1016/j.xcrm.2024.101688.

Authors

Jie Zheng¹, Jieli Lu², Jiying Qi², Qian Yang³, Huiling Zhao³, Haoyu Liu², Zhihe Chen², Lanhui Huang², Youqiong Ye⁴, Min Xu², Yu Xu², Tiange Wang², Mian Li², Zhiyun Zhao², Ruizhi Zheng², Shuangyuan Wang², Hong Lin², Chunyan Hu², Celine Sze Ling Chui⁵, Shiu Lun Au Yeung⁶, Shan Luo⁶, Olympia Dimopoulou⁷, Padraig Dixon⁸, Sean Harrison⁸, Yi Liu³, Jamie Robinson³, James Yarmolinsky³, Philip Haycock³, Jinqiu Yuan⁹, Sarah Lewis³, Zhongshang Yuan¹⁰, Tom R Gaunt¹¹, George Davey Smith¹¹, Guang Ning², Richard M Martin¹², Bin Cui², Weiqing Wang¹³, Yufang Bi¹⁴

Affiliations

¹ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK. Electronic address: zj12477@rjh.com.cn.
² Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
⁴ Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁵ School of Nursing, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administration Region, China; School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administration Region, China; Laboratory of Data Discovery for Health (D24H), Hong Kong Science Park, Hong Kong Science and Technology Park, Hong Kong Special Administration Region, China.
⁶ School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administration Region, China.
⁷ MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2PS, UK.
⁸ MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK.
⁹ Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518107, China; Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518107, China; Guangzhou Women and Children Medical Center, Guangzhou, Guangdong 510623, China; Division of Epidemiology, the JC School of Public Health & Primary Care, the Chinese University of Hong Kong, Hong Kong.
¹⁰ Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China.
¹¹ MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK; NIHR Biomedical Research Centre at the University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK.
¹² MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administration Region, China; NIHR Biomedical Research Centre at the University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK. Electronic address: richard.martin@bristol.ac.uk.
¹³ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: wqingw61@163.com.
¹⁴ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: byf10784@rjh.com.cn.

Abstract

We evaluated the effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on prostate cancer by evidence triangulation. Using Mendelian randomization, we found that genetically proxied SGLT2 inhibition reduced the risk of overall (odds ratio = 0.56, 95% confidence interval [CI] = 0.38 to 0.82; 79,148 prostate cancer cases and 61,106 controls), advanced, and early-onset prostate cancer. Using electronic healthcare data (n_SGLT2i = 24,155; n_DPP4i = 24,155), we found that the use of SGLT2 inhibitors was associated with a 23% reduced risk of prostate cancer (hazard ratio = 0.77, 95% CI = 0.61 to 0.99) in men with diabetes. Using data from two prospective cohorts (n_4C = 57,779; n_{UK_Biobank} = 165,430), we found little evidence to support the association of HbA_1c with prostate cancer, implying a non-glycemic effect of SGLT2 inhibition on prostate cancer. In summary, this study provides multiple layers of evidence to support the beneficial effect of SGLT2 inhibition on reducing prostate cancer risk. Future trials are warranted to investigate whether SGLT2 inhibitors can be recommended for prostate cancer prevention.

Keywords: Mendelian randomization; SGLT2 inhibition; cohort study; electronic healthcare records; observational analysis; prostate cancer.

Publication types

Observational Study

MeSH terms

Aged
Cohort Studies
Diabetes Mellitus, Type 2 / drug therapy
Diabetes Mellitus, Type 2 / genetics
Electronic Health Records
Glycated Hemoglobin / metabolism
Humans
Male
Mendelian Randomization Analysis*
Middle Aged
Prostatic Neoplasms* / drug therapy
Prostatic Neoplasms* / genetics
Sodium-Glucose Transporter 2 / genetics
Sodium-Glucose Transporter 2 / metabolism
Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use

Substances

Sodium-Glucose Transporter 2 Inhibitors
Glycated Hemoglobin
Sodium-Glucose Transporter 2

Grants and funding

WT_/Wellcome Trust/United Kingdom