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Abkürzungen
CKD
Chronic kidney disease
ICU
Intensive care unit
eGFR
Estimated glomerular filtration rate
AKI
Acute kidney injury
KDIGO
Kidney Disease Improving Global Outcomes
SMD
Standardized mean difference
Main text
Metformin is the most widely used oral antihyperglycemic agent. Because it is eliminated unmodified in urine, patients with renal insufficiency can accumulate metformin and may develop lactic acidosis [1]. Recent guidelines only restrict the use of metformin in patients with severe chronic kidney disease (CKD) because the benefit is considered larger than the risk for lactic acidosis [2]. Lactate measurement has a central role in identifying and monitoring critical illness [3]. A better understanding of the impact of metformin on lactate levels could improve clinical assessment of the critically ill.
Data were collected by combining data from Danish nationwide medical databases with laboratory data [4]. This multicenter cohort included all adults (≥ 18 years) hospitalized and surviving 24 h of intensive care unit (ICU) treatment in northern Denmark between January 2010 and August 2017. We required ≥ 3 lactate measurements between 6 h before until 24 h after ICU admission, with ≥ 12 h between first and last measurement. Patients receiving dialysis before ICU admission were excluded.
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Metformin use was defined as a filled prescription for metformin within 90 days before ICU admission [4]. CKD stage was assessed by the mean estimated glomerular filtration rate (eGFR) 365 days until 7 days before ICU admission [5]. Acute kidney injury (AKI) within 24 h after ICU admission was defined and staged according to the KDIGO creatinine criteria. Lactate trajectories over time for metformin users and nonusers were fitted by a mixed-effects model assuming unstructured covariance and including individual-level random intercept and slope. Time was modeled as a natural cubic spline with knot locations at − 1 h, + 4 h, and + 12 h relative to ICU admission. Time-by-group interaction was entered as a covariate, and analyses were subsequently stratified by eGFR level or AKI stage. Differences in maximum lactate level with 95% confidence intervals between metformin users and nonusers were model-based.
We studied 20,741 patients with a total of 209,394 lactate measurements, of whom 1905 (9%) patients used metformin (Table 1). Compared with nonusers, metformin users had a similar preadmission eGFR but had more often AKI stage 2 or 3. Metformin users had 0.61 (0.45–0.77) mmol/L higher maximum lactate levels than nonusers (Fig. 1a). This difference was highest for patients with eGFR ≤ 45 ml/min/1.73 m2 (1.06 [0.72–1.39] mmol/L; Fig. 1b). Differences in maximum lactate levels between metformin users and nonusers were more pronounced in patients with AKI stage 2 or 3 (Fig. 1c), with a difference of 0.30 (0.15–0.45) mmol/L for patients without AKI, and 0.12 (− 0.24 to 0.48), 1.00 (0.35–1.65), and 1.75 (1.03–2.47) mmol/L among patients with AKI stage 1, 2, or 3, respectively. The difference between metformin users and nonusers disappeared within 24 h of ICU admission. However, the time until this difference disappeared was longer for patients with moderate to severe CKD or AKI (Fig. 1).
Table 1
Characteristics of metformin users and nonusers
Characteristic
Total (N = 20,741)
Metformin users (N = 1905)
Metformin nonusers (N = 18,836)
SMD*
Age, median [IQR], years
69 [58–77]
70 [63–76]
69 [58–77]
0.24
Male sex
11,697 (56)
1193 (63)
10,504 (56)
0.14
Charlson Comorbidity Index
0.52
0
6894 (33)
305 (16)
6589 (35)
1 or 2
8147 (39)
737 (39)
7410 (39)
3 or higher
5700 (27)
863 (45)
4837 (26)
Diabetes mellitus
4594 (22)
1903 (100)
2691 (14)
3.45
Sulfonylureas
476 (2)
250 (13)
226 (1)
0.48
Insulin
1473 (7)
443 (23)
1030 (5)
0.52
Other antihyperglycemic agents
445 (2)
259 (14)
186 (1)
0.50
Preadmission eGFR, median [IQR], ml/min/1.73 m2
80 [58–95]
77 [58–92]
80 [58–95]
0.07
≥ 60 ml/min/1.73 m2
12,892 (62)
1345 (71)
11,547 (61)
0.48
45–60 ml/min/1.73 m2
2189 (11)
278 (15)
1911 (10)
≤ 45 ml/min/1.73 m2
2442 (12)
221 (12)
2221 (12)
Missing
3218 (16)
61 (3)
3157 (17)
ICU admission type
0.20
Medical
9942 (48)
1019 (53)
8923 (47)
Emergency surgical
6344 (31)
456 (24)
5888 (31)
Elective surgical
3149 (15)
345 (18)
2804 (15)
Missing
1306 (6)
85 (4)
1221 (6)
Time from hospital admission to ICU admission, median [IQR], h†
5.1 [0.0–30.5]
5.3 [0.0–29.4]
5.1 [0.0–30.7]
0.06
SAPS-II score, median [IQR]
40 [30–52]
42 [31–53]
40 [30–52]
0.09
Missing
11,456 (55)
1024 (54)
10,432 (55)
Mechanical ventilation
9305 (45)
815 (43)
8490 (45)
0.05
Inotropes or vasopressors
8943 (43)
854 (45)
8089 (43)
0.04
Renal replacement therapy
1257 (6)
152 (8)
1105 (6)
0.09
AKI stage within 24 h
0.47
No AKI
10,597 (51)
982 (52)
9615 (51)
1
3584 (17)
388 (20)
3196 (17)
2
1436 (7)
198 (10)
1238 (7)
3
1877 (9)
261 (14)
1616 (9)
Missing
3247 (16)
76 (4)
3171 (17)
30-day mortality
4367 (21)
346 (18)
4021 (21)
0.08
Data are expressed as no. (%) or median [IQR]
*As general guidance, it is suggested that effect sizes are likely to be “small” when an SMD approximates 0.2, likely to be “medium” when an SMD is 0.5, and “large” when an SMD is higher than 0.8
†In total, data are missing for 19 (0.1%) patients
SMD standardized mean difference, eGFR estimated glomerular filtration rate, ICU intensive care unit, SAPS-II Simple Acute Physiology Score II, AKI acute kidney injury
×
In this large cohort of critically ill patients, metformin users had higher lactate levels than nonusers in the early phase of critical illness, which disappeared within 24 h of ICU admission. Importantly, the difference in lactate levels between metformin users and nonusers was higher in patients with more severe AKI, while the difference was almost similar across preadmission eGFR subgroups. This may be explained by reduced clearance of metformin or lactate, or both. A limitation is that blood metformin concentrations were unavailable to confirm this because such correlation was found in patients receiving renal replacement therapy for metformin-associated lactic acidosis [6].
The monitoring of lactate trajectories is recommended during critical illness [3]. Awareness of factors affecting this biomarker will improve its interpretation. We report that the association of metformin use with increased lactate levels is more pronounced in patients who develop AKI stage 2 or 3 than in patients without AKI or who develop AKI stage 1.
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Acknowledgements
We want to thank Trine Frøslev, MSc (Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark), for the acquisition of data and Daan J. Touw, PharmD, PhD (Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, The Netherlands), for interpretation of data and critically revising the manuscript for important intellectual content. Both received no additional compensation for the work provided.
Ethics approval and consent to participate
The Danish Data Protection Agency approved the study (record number 2015-57-0002, Aarhus University record number 2016-051-000001/432). According to Danish law, no ethical approval or informed consent was required for this registry-based study.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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