Clinical outcomes following discontinuation of metformin in patients with type 2 diabetes and advanced chronic kidney disease in Hong Kong: a territory-wide, retrospective cohort and target trial emulation studyResearch in context
Summary: Background: Current labelling advises discontinuation of metformin when estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 due to increased risk of lactic acidosis. However, in real-world practice, the risk-benefit ratios remain uncertain. We examined the risk associations...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-05-01
|
| Series: | EClinicalMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589537024001470 |
| _version_ | 1827301679707455488 |
|---|---|
| author | Aimin Yang Mai Shi Hongjiang Wu Eric SH. Lau Johnny TK. Cheung Xinge Zhang Baoqi Fan Tingting Chen Alice PS. Kong Andrea OY. Luk Ronald CW. Ma Juliana CN. Chan Elaine Chow |
| author_facet | Aimin Yang Mai Shi Hongjiang Wu Eric SH. Lau Johnny TK. Cheung Xinge Zhang Baoqi Fan Tingting Chen Alice PS. Kong Andrea OY. Luk Ronald CW. Ma Juliana CN. Chan Elaine Chow |
| author_sort | Aimin Yang |
| collection | DOAJ |
| description | Summary: Background: Current labelling advises discontinuation of metformin when estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 due to increased risk of lactic acidosis. However, in real-world practice, the risk-benefit ratios remain uncertain. We examined the risk associations of discontinued-metformin use with cardiorenal and clinical outcomes in patients with type 2 diabetes (T2D) and advanced chronic kidney disease. Methods: In this territory-wide, retrospective cohort and target trial emulation study, we included Chinese patients attending the Hong Kong Hospital Authority (HA) and enrolled in the Risk-Assessment-and-Management-Programme-for-Diabetes-Mellitus (RAMP-DM) from 2002 to 2019. Patients were stratified by discontinuation of metformin within six months after reaching eGFR < 30 ml/min/1.73 m2 from January 1, 2002 to December 31, 2018, and followed up until December 31 2019. We excluded patients who had observational time <6 months from eGFR < 30 ml/min/1.73 m2, and had their eGFR measured during a hospitalisation episode due to acute kidney injury, or missing diagnosis date of diabetes. We compared the risk associations of metformin discontinuation with clinical outcomes. The primary outcomes were major adverse cardiovascular events (MACE), end-stage kidney disease (ESKD), cancer, and all-cause mortality. A Cox-model with time-dependent exposure and covariates was used to estimate the hazard ratio (HR) of outcomes in a propensity-score overlap-weighted cohort. The risk of occurrence of lactic acidosis (serum lactate > 5.0 mmol/L with a concomitant blood pH < 7.35 or ICD-9 codes of 276.2) in discontinued-metformin versus continued-metformin users was assessed in a separate register-based cohort. Findings: A total of 33,586 metformin users with new-onset eGFR < 30 ml/min/1.73 m2 were included in the study, 7500 (22.3%) of whom discontinued metformin within 6 months whereas 26,086 (77.7%) continued use of metformin. During a median follow-up of 3.8 (IQR: 2.2–6.1) years, 16.4% (5505/33,586), 30.1% (10,113/33,586), and 7.1% (2171/30,682) had incident MACE, ESKD, and cancer respectively, and 44.4% (14,917/33,586) died. Compared to continued-metformin use, discontinuation was associated with higher risk of MACE (weighted and adjusted HR = 1.40, 95% CI: 1.29–1.52), ESKD (HR = 1.52, 1.42–1.62), and death (HR = 1.22, 1.18–1.27). No association was observed for cancer (HR = 0.93, 0.85–1.01). Discontinued-metformin users had higher change in HbA1c change at 6-month of follow-up versus continued-metformin users (weighted mean HbA1c level change: 0.5% [0.4–0.6%] versus 0.2% [0.1–0.2]). In the separate register-based cohort (n = 3235), null association was observed between metformin use and risk of lactic acidosis (weighted HR = 0.94 [0.53–1.64]). Interpretation: Our results suggest that discontinuation of metformin in patients with T2D and chronic kidney disease may be associated with increased risk of cardiovascular-renal events. Use of metformin below eGFR of 30 ml/min/1.73 m2 may be associated with cardiovascular, renal, and mortality benefits that need to be weighed against the risk of lactic acidosis, but further research is needed to validate these findings. Funding: CUHK Impact Research Fellowship Scheme. |
| first_indexed | 2024-04-24T16:30:19Z |
| format | Article |
| id | doaj.art-486a5f2183cd43c580f41a3e2ed1fff1 |
| institution | Directory Open Access Journal |
| issn | 2589-5370 |
| language | English |
| last_indexed | 2024-04-24T16:30:19Z |
| publishDate | 2024-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EClinicalMedicine |
| spelling | doaj.art-486a5f2183cd43c580f41a3e2ed1fff12024-03-30T04:39:52ZengElsevierEClinicalMedicine2589-53702024-05-0171102568Clinical outcomes following discontinuation of metformin in patients with type 2 diabetes and advanced chronic kidney disease in Hong Kong: a territory-wide, retrospective cohort and target trial emulation studyResearch in contextAimin Yang0Mai Shi1Hongjiang Wu2Eric SH. Lau3Johnny TK. Cheung4Xinge Zhang5Baoqi Fan6Tingting Chen7Alice PS. Kong8Andrea OY. Luk9Ronald CW. Ma10Juliana CN. Chan11Elaine Chow12Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, ChinaDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, ChinaDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, ChinaDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, ChinaDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, ChinaDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, ChinaDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, ChinaDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, ChinaDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, ChinaDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China; Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, ChinaDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, ChinaDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, ChinaDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China; Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China; Corresponding author. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China.Summary: Background: Current labelling advises discontinuation of metformin when estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 due to increased risk of lactic acidosis. However, in real-world practice, the risk-benefit ratios remain uncertain. We examined the risk associations of discontinued-metformin use with cardiorenal and clinical outcomes in patients with type 2 diabetes (T2D) and advanced chronic kidney disease. Methods: In this territory-wide, retrospective cohort and target trial emulation study, we included Chinese patients attending the Hong Kong Hospital Authority (HA) and enrolled in the Risk-Assessment-and-Management-Programme-for-Diabetes-Mellitus (RAMP-DM) from 2002 to 2019. Patients were stratified by discontinuation of metformin within six months after reaching eGFR < 30 ml/min/1.73 m2 from January 1, 2002 to December 31, 2018, and followed up until December 31 2019. We excluded patients who had observational time <6 months from eGFR < 30 ml/min/1.73 m2, and had their eGFR measured during a hospitalisation episode due to acute kidney injury, or missing diagnosis date of diabetes. We compared the risk associations of metformin discontinuation with clinical outcomes. The primary outcomes were major adverse cardiovascular events (MACE), end-stage kidney disease (ESKD), cancer, and all-cause mortality. A Cox-model with time-dependent exposure and covariates was used to estimate the hazard ratio (HR) of outcomes in a propensity-score overlap-weighted cohort. The risk of occurrence of lactic acidosis (serum lactate > 5.0 mmol/L with a concomitant blood pH < 7.35 or ICD-9 codes of 276.2) in discontinued-metformin versus continued-metformin users was assessed in a separate register-based cohort. Findings: A total of 33,586 metformin users with new-onset eGFR < 30 ml/min/1.73 m2 were included in the study, 7500 (22.3%) of whom discontinued metformin within 6 months whereas 26,086 (77.7%) continued use of metformin. During a median follow-up of 3.8 (IQR: 2.2–6.1) years, 16.4% (5505/33,586), 30.1% (10,113/33,586), and 7.1% (2171/30,682) had incident MACE, ESKD, and cancer respectively, and 44.4% (14,917/33,586) died. Compared to continued-metformin use, discontinuation was associated with higher risk of MACE (weighted and adjusted HR = 1.40, 95% CI: 1.29–1.52), ESKD (HR = 1.52, 1.42–1.62), and death (HR = 1.22, 1.18–1.27). No association was observed for cancer (HR = 0.93, 0.85–1.01). Discontinued-metformin users had higher change in HbA1c change at 6-month of follow-up versus continued-metformin users (weighted mean HbA1c level change: 0.5% [0.4–0.6%] versus 0.2% [0.1–0.2]). In the separate register-based cohort (n = 3235), null association was observed between metformin use and risk of lactic acidosis (weighted HR = 0.94 [0.53–1.64]). Interpretation: Our results suggest that discontinuation of metformin in patients with T2D and chronic kidney disease may be associated with increased risk of cardiovascular-renal events. Use of metformin below eGFR of 30 ml/min/1.73 m2 may be associated with cardiovascular, renal, and mortality benefits that need to be weighed against the risk of lactic acidosis, but further research is needed to validate these findings. Funding: CUHK Impact Research Fellowship Scheme.http://www.sciencedirect.com/science/article/pii/S2589537024001470MetforminCardiovascular diseaseMortalityTherapeuticsDiabetesChronic kidney disease |
| spellingShingle | Aimin Yang Mai Shi Hongjiang Wu Eric SH. Lau Johnny TK. Cheung Xinge Zhang Baoqi Fan Tingting Chen Alice PS. Kong Andrea OY. Luk Ronald CW. Ma Juliana CN. Chan Elaine Chow Clinical outcomes following discontinuation of metformin in patients with type 2 diabetes and advanced chronic kidney disease in Hong Kong: a territory-wide, retrospective cohort and target trial emulation studyResearch in context EClinicalMedicine Metformin Cardiovascular disease Mortality Therapeutics Diabetes Chronic kidney disease |
| title | Clinical outcomes following discontinuation of metformin in patients with type 2 diabetes and advanced chronic kidney disease in Hong Kong: a territory-wide, retrospective cohort and target trial emulation studyResearch in context |
| title_full | Clinical outcomes following discontinuation of metformin in patients with type 2 diabetes and advanced chronic kidney disease in Hong Kong: a territory-wide, retrospective cohort and target trial emulation studyResearch in context |
| title_fullStr | Clinical outcomes following discontinuation of metformin in patients with type 2 diabetes and advanced chronic kidney disease in Hong Kong: a territory-wide, retrospective cohort and target trial emulation studyResearch in context |
| title_full_unstemmed | Clinical outcomes following discontinuation of metformin in patients with type 2 diabetes and advanced chronic kidney disease in Hong Kong: a territory-wide, retrospective cohort and target trial emulation studyResearch in context |
| title_short | Clinical outcomes following discontinuation of metformin in patients with type 2 diabetes and advanced chronic kidney disease in Hong Kong: a territory-wide, retrospective cohort and target trial emulation studyResearch in context |
| title_sort | clinical outcomes following discontinuation of metformin in patients with type 2 diabetes and advanced chronic kidney disease in hong kong a territory wide retrospective cohort and target trial emulation studyresearch in context |
| topic | Metformin Cardiovascular disease Mortality Therapeutics Diabetes Chronic kidney disease |
| url | http://www.sciencedirect.com/science/article/pii/S2589537024001470 |
| work_keys_str_mv | AT aiminyang clinicaloutcomesfollowingdiscontinuationofmetformininpatientswithtype2diabetesandadvancedchronickidneydiseaseinhongkongaterritorywideretrospectivecohortandtargettrialemulationstudyresearchincontext AT maishi clinicaloutcomesfollowingdiscontinuationofmetformininpatientswithtype2diabetesandadvancedchronickidneydiseaseinhongkongaterritorywideretrospectivecohortandtargettrialemulationstudyresearchincontext AT hongjiangwu clinicaloutcomesfollowingdiscontinuationofmetformininpatientswithtype2diabetesandadvancedchronickidneydiseaseinhongkongaterritorywideretrospectivecohortandtargettrialemulationstudyresearchincontext AT ericshlau clinicaloutcomesfollowingdiscontinuationofmetformininpatientswithtype2diabetesandadvancedchronickidneydiseaseinhongkongaterritorywideretrospectivecohortandtargettrialemulationstudyresearchincontext AT johnnytkcheung clinicaloutcomesfollowingdiscontinuationofmetformininpatientswithtype2diabetesandadvancedchronickidneydiseaseinhongkongaterritorywideretrospectivecohortandtargettrialemulationstudyresearchincontext AT xingezhang clinicaloutcomesfollowingdiscontinuationofmetformininpatientswithtype2diabetesandadvancedchronickidneydiseaseinhongkongaterritorywideretrospectivecohortandtargettrialemulationstudyresearchincontext AT baoqifan clinicaloutcomesfollowingdiscontinuationofmetformininpatientswithtype2diabetesandadvancedchronickidneydiseaseinhongkongaterritorywideretrospectivecohortandtargettrialemulationstudyresearchincontext AT tingtingchen clinicaloutcomesfollowingdiscontinuationofmetformininpatientswithtype2diabetesandadvancedchronickidneydiseaseinhongkongaterritorywideretrospectivecohortandtargettrialemulationstudyresearchincontext AT alicepskong clinicaloutcomesfollowingdiscontinuationofmetformininpatientswithtype2diabetesandadvancedchronickidneydiseaseinhongkongaterritorywideretrospectivecohortandtargettrialemulationstudyresearchincontext AT andreaoyluk clinicaloutcomesfollowingdiscontinuationofmetformininpatientswithtype2diabetesandadvancedchronickidneydiseaseinhongkongaterritorywideretrospectivecohortandtargettrialemulationstudyresearchincontext AT ronaldcwma clinicaloutcomesfollowingdiscontinuationofmetformininpatientswithtype2diabetesandadvancedchronickidneydiseaseinhongkongaterritorywideretrospectivecohortandtargettrialemulationstudyresearchincontext AT julianacnchan clinicaloutcomesfollowingdiscontinuationofmetformininpatientswithtype2diabetesandadvancedchronickidneydiseaseinhongkongaterritorywideretrospectivecohortandtargettrialemulationstudyresearchincontext AT elainechow clinicaloutcomesfollowingdiscontinuationofmetformininpatientswithtype2diabetesandadvancedchronickidneydiseaseinhongkongaterritorywideretrospectivecohortandtargettrialemulationstudyresearchincontext |