Articles
Metformin use and mortality in patients with advanced chronic kidney disease: national, retrospective, observational, cohort study Szu-Chun Hung, Yu-Kang Chang, Jia-Sin Liu, Ko-Lin Kuo, Yu-Hsin Chen, Chih-Cheng Hsu, Der-Cherng Tarng
Summary Background Metformin is recommended as a first-line treatment for patients with type 2 diabetes. However, use of this drug has been contraindicated in individuals with impaired kidney function because of the perceived risk of lactic acidosis. Evidence now supports cautious use of metformin in people with mild-to-moderate chronic kidney disease. However, studies examining the use of metformin in patients with advanced chronic kidney disease are lacking. We aimed to assess the safety of metformin in patients with type 2 diabetes and advanced (approximately stage 5) chronic kidney disease. Methods We did a retrospective, observational, cohort study of patients with type 2 diabetes who were enrolled prospectively in Taiwan’s national health insurance research database between Jan 1, 2000, and June 30, 2009, and had follow-up data until Dec 31, 2009. We included individuals with a serum creatinine concentration greater than 530 μmol/L, which is approximately equivalent to stage 5 chronic kidney disease. From a consecutive sample of 12 350 patients with type 2 diabetes and chronic kidney disease, 1005 used metformin and 11 345 were non-users. We matched users and non-users of metformin by propensity score in a 1:3 ratio. Our primary outcome was all-cause mortality. Findings 813 metformin users were matched by propensity score to 2439 non-users. The two groups of patients did not differ significantly by 30 baseline clinical and socioeconomic variables. Median follow-up in the matched cohort was 2·1 years (range 0·3–9·8). All-cause mortality was reported in 434 (53%) of 813 metformin users and in 1012 (41%) of 2439 non-users. After multivariate adjustment, metformin use was an independent risk factor for mortality (adjusted hazard ratio 1·35, 95% CI 1·20–1·51; p6
346 (43%)
1047 (43%)
··
Antihypertensive drugs ACE inhibitors
..
..
··
242 (30%)
725 (30%)
0·98
ARBs
371 (46%)
1136 (47%)
0·64
β blockers
400 (49%)
1192 (49%)
0·87
Calcium-channel blockers
620 (76%)
1857 (76%)
0·94
Diuretics
638 (78%)
1927 (79%)
0·75
Antidiabetic drugs Sulfonylurea
543 (67%)
1656 (68%)
0·56
Meglitinide
211 (26%)
669 (27%)
0·41
α-glucosidase inhibitor
114 (14%)
350 (14%)
0·82
Thiazolidinedione
117 (14%)
339 (14%)
0·73
Sitagliptin
5 (1%)
9 (40 DDD) and the prescribed daily dose (≤500 mg, 501–1000 mg, >1000 mg), relative to no metformin use. DDD is a technical unit of measurement defined as the assumed average maintenance dose per day for a drug used for its main indication in adults, which is 2000 mg for metformin. To assess effect modification, we did subgroup analyses in prespecified strata of clinical interest, including age (40 DDD
164/292
28·7
1·52 (1·21–1·75)
1·58 (1·25–1·80)
16/292
1·5
1·26 (0·80–2·20)
1·28 (0·81–2·24)
p for trend
··
0·044
0·051
··
0·667
0·503
Users Defined daily dose
··
··
Prescribed daily dose ≤500 mg/day
93/193
15·1
1·10 (0·81–1·40)
1·14 (0·85–1·44)
4/193
1·8
1·33 (0·98–2·98)
1·35 (0·97–2·88)
501–1000 mg/day
129/255
17·2
1·23 (0·87–1·37)
1·30 (0·93–1·45)
8/255
1·4
1·22 (0·95–2·45)
1·27 (0·96–2·32)
>1000 mg/day
212/365
28·2
1·52 (1·24–1·72)
1·57 (1·29–1·83)
24/365
0·064
0·048
p for trend
··
··
··
1·5
1·27 (0·98–2·44)
1·29 (0·96–2·38)
··
0·633
0·488
Data before propensity score matching are presented in the appendix (p 5). DDD=defined daily dose. *Adjusted for all covariates in table 1.
Table 2: Risk of death and metabolic acidosis in patients with type 2 diabetes and advanced (approximately stage 5) chronic kidney disease after propensity score matching (n=3252)
Cumulative incidence (%)
A
See Online for appendix
All-cause mortality
80
Metformin non-user Metformin user p
Metformin use and mortality in patients with advanced chronic kidney disease: national, retrospective, observational, cohort study Szu-Chun Hung, Yu-Kang Chang, Jia-Sin Liu, Ko-Lin Kuo, Yu-Hsin Chen, Chih-Cheng Hsu, Der-Cherng Tarng
Summary Background Metformin is recommended as a first-line treatment for patients with type 2 diabetes. However, use of this drug has been contraindicated in individuals with impaired kidney function because of the perceived risk of lactic acidosis. Evidence now supports cautious use of metformin in people with mild-to-moderate chronic kidney disease. However, studies examining the use of metformin in patients with advanced chronic kidney disease are lacking. We aimed to assess the safety of metformin in patients with type 2 diabetes and advanced (approximately stage 5) chronic kidney disease. Methods We did a retrospective, observational, cohort study of patients with type 2 diabetes who were enrolled prospectively in Taiwan’s national health insurance research database between Jan 1, 2000, and June 30, 2009, and had follow-up data until Dec 31, 2009. We included individuals with a serum creatinine concentration greater than 530 μmol/L, which is approximately equivalent to stage 5 chronic kidney disease. From a consecutive sample of 12 350 patients with type 2 diabetes and chronic kidney disease, 1005 used metformin and 11 345 were non-users. We matched users and non-users of metformin by propensity score in a 1:3 ratio. Our primary outcome was all-cause mortality. Findings 813 metformin users were matched by propensity score to 2439 non-users. The two groups of patients did not differ significantly by 30 baseline clinical and socioeconomic variables. Median follow-up in the matched cohort was 2·1 years (range 0·3–9·8). All-cause mortality was reported in 434 (53%) of 813 metformin users and in 1012 (41%) of 2439 non-users. After multivariate adjustment, metformin use was an independent risk factor for mortality (adjusted hazard ratio 1·35, 95% CI 1·20–1·51; p6
346 (43%)
1047 (43%)
··
Antihypertensive drugs ACE inhibitors
..
..
··
242 (30%)
725 (30%)
0·98
ARBs
371 (46%)
1136 (47%)
0·64
β blockers
400 (49%)
1192 (49%)
0·87
Calcium-channel blockers
620 (76%)
1857 (76%)
0·94
Diuretics
638 (78%)
1927 (79%)
0·75
Antidiabetic drugs Sulfonylurea
543 (67%)
1656 (68%)
0·56
Meglitinide
211 (26%)
669 (27%)
0·41
α-glucosidase inhibitor
114 (14%)
350 (14%)
0·82
Thiazolidinedione
117 (14%)
339 (14%)
0·73
Sitagliptin
5 (1%)
9 (40 DDD) and the prescribed daily dose (≤500 mg, 501–1000 mg, >1000 mg), relative to no metformin use. DDD is a technical unit of measurement defined as the assumed average maintenance dose per day for a drug used for its main indication in adults, which is 2000 mg for metformin. To assess effect modification, we did subgroup analyses in prespecified strata of clinical interest, including age (40 DDD
164/292
28·7
1·52 (1·21–1·75)
1·58 (1·25–1·80)
16/292
1·5
1·26 (0·80–2·20)
1·28 (0·81–2·24)
p for trend
··
0·044
0·051
··
0·667
0·503
Users Defined daily dose
··
··
Prescribed daily dose ≤500 mg/day
93/193
15·1
1·10 (0·81–1·40)
1·14 (0·85–1·44)
4/193
1·8
1·33 (0·98–2·98)
1·35 (0·97–2·88)
501–1000 mg/day
129/255
17·2
1·23 (0·87–1·37)
1·30 (0·93–1·45)
8/255
1·4
1·22 (0·95–2·45)
1·27 (0·96–2·32)
>1000 mg/day
212/365
28·2
1·52 (1·24–1·72)
1·57 (1·29–1·83)
24/365
0·064
0·048
p for trend
··
··
··
1·5
1·27 (0·98–2·44)
1·29 (0·96–2·38)
··
0·633
0·488
Data before propensity score matching are presented in the appendix (p 5). DDD=defined daily dose. *Adjusted for all covariates in table 1.
Table 2: Risk of death and metabolic acidosis in patients with type 2 diabetes and advanced (approximately stage 5) chronic kidney disease after propensity score matching (n=3252)
Cumulative incidence (%)
A
See Online for appendix
All-cause mortality
80
Metformin non-user Metformin user p
