Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study.
OBJECTIVE
The objective of this study was to determine whether treatment with metformin in patients with renal impairment is associated with a higher risk of lactic acidosis or elevated lactate concentrations compared with users of a noninsulin antidiabetic drug (NIAD) who had never used metformin.


METHODS
A cohort of 223,968 metformin users and 34,571 diabetic patients who had never used metformin were identified from the Clinical Practice Research Datalink (CPRD).The primary outcome was defined as either a CPRD READ code lactic acidosis or a record of a plasma lactate concentration >5 mmol/L. The associations between renal impairment, dose of metformin, and the risk of lactic acidosis or elevated lactate concentrations were determined with time-dependent Cox models and expressed as hazard ratios (HRs).


RESULTS
The crude incidence of lactic acidosis or elevated lactate concentrations in current metformin users was 7.4 per 100,000 person-years (vs. 2.2 per 100,000 person-years in nonusers). Compared with nonusers, risk of lactic acidosis or elevated lactate concentrations in current metformin users was significantly associated with a renal function <60 mL/min/1.73 m(2) (adjusted HR 6.37 [95% CI 1.48-27.5]). The increased risk among patients with impaired renal function was further increased in users of ≥730 g of metformin in the preceding year (adjusted HR 11.8 [95% CI 2.27-61.5]) and in users of a recent high daily dose (>2 g) of metformin (adjusted HR 13.0 [95% CI 2.36-72.0]).


CONCLUSIONS
Our study is consistent with current recommendations that the renal function of metformin users should be adequately monitored and that the dose of metformin should be adjusted, if necessary, if renal function falls below 60 mL/min/1.73 m(2).
Scientific Institute for Quality of Healthcare, Radboud University Nijmegen Medical Center, Nijmegen, the NetherlandsHospital Pharmacy 'ZANOB', 's-Hertogenbosch, the Netherlands.
Willemijn L
WL
Eppenga
Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the NetherlandsDepartment of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, the Netherlands.
Arief
A
Lalmohamed
Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the Netherlands.
Arjen F
AF
Geerts
Hospital Pharmacy 'ZANOB', 's-Hertogenbosch, the NetherlandsDivision of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the Netherlands.
Hieronymus J
HJ
Derijks
Scientific Institute for Quality of Healthcare, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
Michel
M
Wensing
Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the NetherlandsDepartment of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, the Netherlands.
Antoine
A
Egberts
Scientific Institute for Quality of Healthcare, Radboud University Nijmegen Medical Center, Nijmegen, the NetherlandsDepartment of Clinical Pharmacy, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
Peter A G M
PA
De Smet
Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the NetherlandsDepartment of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, the NetherlandsCare and Public Health Research Institute (CAPHRI), Maastricht, the Netherlands f.devries@uu.nl.
Frank
F
de Vries
D000140:Acidosis, Lactic / Q000097:blood* / Q000139:chemically induced / Q000175:diagnosis / Q000453:epidemiology*; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D015897:Comorbidity; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000453:epidemiology*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D015994:Incidence; D019344:Lactic Acid / Q000097:blood; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000009:adverse effects*; D008875:Middle Aged; D051437:Renal Insufficiency / Q000188:drug therapy / Q000453:epidemiology*; D012107:Research Design; D018570:Risk Assessment; D012307:Risk Factors
D007004:Hypoglycemic Agents; D019344:Lactic Acid; D008687:Metformin