Risk of lactic acidosis in type 2 diabetes patients using metformin: A case control study

Aharaz, Abdellatif; Pottegård, Anton; Henriksen, Daniel Pilsgaard; Hallas, Jesper; Beck‐Nielsen, Henning; Lassen, Annmarie Touborg

doi:10.1371/journal.pone.0196122

Cited by 44 publications

(37 citation statements)

References 30 publications

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“…These ndings are partly in line with the results described in a UK population cohort study on the same group of patients (adjusted HR: 6.06, 95% CI: 1.37-27.10) [7]. Conversely, metformin use has not been associated with an increased risk of LA in other studies [5] [12] [13]. It should be noted that recommendations on the use of metformin in patients with CKD are based on observational studies, which could represent a limitation for its endorsement [3,4].…”

Section: Discussionsupporting

confidence: 85%

Lactic acidosis associated with metformin in diabetic patients with chronic kidney disease: a multicentre case-control study using electronic health records

Ávila

Videla

Gómez-Lumbreras

et al. 2020

Preprint

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Background Several studies have assessed the risk of lactic acidosis with metformin use. However, data of this association in patients with renal impairment are still scarce and controversial. Our aim was therefore to assess the association between metformin and lactic acidosis in Spanish type 2 diabetic patients with chronic kidney disease. Methods A case-control study (ALIMAR-C2) was performed using the electronic health records from hospitals linked to their corresponding primary healthcare regions. The cases were adult (≥ 18 years) diabetic patients with chronic kidney disease, admitted to seven Spanish hospitals from 2010 to 2016. Ten controls (≥ 18 years, diabetic patients with chronic kidney disease) per case were selected from the population within the same primary healthcare region of the hospital cases. The patients’ hospital health records were linked to their corresponding primary healthcare information. Analyses included multivariable logistic regression and adjustment for potential confounders. Results Our study included 126 cases and 1,260 matched controls. The current use of metformin and administration at high doses (> 2 g) were associated with lactic acidosis (adjusted OR: 1.92, 95% CI: 1.21–3.03; OR: 3.13, 95% CI: 1.63–6.01, respectively). The estimated case fatality rate was 46.8% (95% CI: 38.3–55.5%). An increased risk of lactic acidosis was observed in patients with mild to moderate renal impairment (OR: 3.41, 95% CI: 1.48–7.85). As an unexpected finding, diuretic drugs use was also associated with lactic acidosis (OR: 2.73, 95% CI: 1.67–4.46). Conclusions Metformin was associated with an increased risk of lactic acidosis in patients with type 2 diabetes mellitus and chronic kidney disease. New data is needed to confirm the association between diuretic drugs and lactic acidosis in this group of patients.

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Section: Discussionsupporting

confidence: 85%

Lactic acidosis associated with metformin in diabetic patients with chronic kidney disease: a multicentre case-control study using electronic health records

Ávila

Videla

Gómez-Lumbreras

et al. 2020

Preprint

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“…Patients with low eGFR may suffer from a range of systemic complications simultaneously, and metformin accumulation is probably not the cause of lactic acidosis in these subjects in most cases . This is also supported by the work by Aharaz et al who found no relation between metformin and neither the incidence rate of or risk of acute hospitalization with acute lactic acidosis. Notable is, however, that the most extreme subjects with moderate to severe (45‐59 mL/min/1.73 m 2 ) and mild to moderate (60‐89 mL/min/1.73 m 2 ) kidney impairment were according to the simulations at risk of overexposure.…”

Section: Discussionmentioning

confidence: 73%

“…3,4 The main safety concern for metformin is an elevated risk of lactic acidosis, which has been shown to be loosely or unrelated to metformin plasma concentrations above 5 mg/L. [5][6][7] Finding predictive markers of variability would aid tailoring metformin therapy and potentially improve metformin efficacy and safety. At physiological pH, metformin is protonated and relies on transporters to cross membranes.…”

Section: Introductionmentioning

confidence: 99%

Using a semi‐mechanistic model to identify the main sources of variability of metformin pharmacokinetics

Stage

Wellhagen

Christensen

et al. 2018

Basic Clin Pharma Tox

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Metformin pharmacokinetics (PK) is highly variable, and researchers have for years tried to shed light on determinants of inter‐individual (IIV) and inter‐occasion variability (IOV) of metformin PK. We set out to identify the main sources of PK variability using a semi‐mechanistic model. We assessed the influence of subject characteristics, including seven genetic variants. Data from three studies of healthy individuals with PK measurements of plasma and urine after single dose or at steady‐state were used in this study. In total, 87 subjects were included (16 crossover subjects). Single nucleotide polymorphisms in ATM, OCT1, OCT2, MATE1 and MATE2‐K were investigated as dominant, recessive or additive. A three‐compartment model with transit absorption and renal elimination with a proportional error was fitted to the data using NONMEM 7.3. Oral parameters were separated from disposition parameters as dose‐dependent absolute bioavailability was determined with support from urine data. Clearance was expressed as net renal secretion and filtration, assuming full fraction unbound and fraction excreted. Mean transit time and peripheral volume of distribution were identified as the main sources of variability according to estimates, with 94% IOV and 95% IIV, respectively. Clearance contributed only with 16% IIV. Glomerular filtration rate and body‐weight were the only covariates found to affect metformin net secretion, reducing IIV to 14%. None of the genetic variants were found to affect metformin PK. Based on our analysis, finding covariates explaining absorption of metformin is much more valuable in understanding variability and avoiding toxicity than elimination.

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“…However, the strength of the relationship between metformin and lactic acidosis has been dramatically overstated [4]. Several clinical studies have shown that there is no significant correlation between metformin concentration and lactic acidosis [1,4,[30][31][32]. Furthermore, the current study and meta-analyses show that the morbidity of lactic acidosis using metformin is not significantly different from other hypoglycemic treatments, such as sulfonylureas, insulin, and other oral hypoglycemic agents [33][34][35][36][37][38][39].…”

Section: Discussionmentioning

confidence: 74%

“…As the first-line therapy of type 2 diabetes mellitus (T2DM), metformin is applying to nearly one-third of diabetes patients worldwide [1]. Therefore, in urgent situations, such as acute myocardial infarction, many of them cannot withhold the metformin prior to percutaneous coronary intervention (PCI)-related contrast medium administration [2].…”

Section: Introductionmentioning

confidence: 99%

Effect of continuous use of metformin on kidney function in diabetes patients with acute myocardial infarction undergoing primary percutaneous coronary intervention

Zhu

Liu

2020

BMC Cardiovasc Disord

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Background: Diabetes patients presenting with ST-segment elevation myocardial infarction (STEMI) scheduled for primary percutaneous coronary intervention (PCI) have an increased risk of contrast induced-acute kidney injury (CI-AKI). The effects of continuous use of metformin on kidney function are still controversial in patients submitted to primary PCI. This study aimed to assess continuous metformin therapy on kidney function in diabetic patients undergoing coronary intervention. Methods: Two hundred eighty-four patients with metformin-treated diabetes, who underwent coronary intervention within 24 h for STEMI, were enrolled in the retrospective study. All the patients had estimated glomerular filtration rate (eGFR) of > 30 mL/min/1.73 m 2 . According to the physicians' decisions after admission, 119 patients continued metformin treatment after primary PCI, while 165 patients discontinued it > 48 h after the procedure. Serum creatinine was collected at admission and within 48 h post primary PCI to evaluate the incidence of CI-AKI. We performed a multiple logistic regression analysis to examine the determinants of CI-AKI. Results: No statistical difference in CI-AKI incidence between the continuous and the discontinuous metformin group (12.6%vs10.3%, p = 0.545). Multivariable logistic regression analysis indicated eGFR ≤60 ml/min/1.73 m 2 [p = 0.025, OR: 3.131; 95% CI (1.156-8.482)] and contrast volume [p = 0.002, OR: 1.010; 95% CI (1.004-1.016)] were predictive factors of CI-AKI. Metformin therapy was irrelevant to CI-AKI [p = 0.365, OR: 0.698; 95% CI (0.320-1.521)]. No case of lactic acidosis was found in this study. Besides, the study supported discontinuation of metformin was not beneficial for patients' blood glucose control after admission. Conclusions: The study indicated that the metformin continuation after primary PCI for STEMI in diabetic patients with eGFR > 30 ml/min / 1.73 m 2 did not increase the risk of CI-AKI.

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Risk of lactic acidosis in type 2 diabetes patients using metformin: A case control study

Cited by 44 publications

References 30 publications

Lactic acidosis associated with metformin in diabetic patients with chronic kidney disease: a multicentre case-control study using electronic health records

Lactic acidosis associated with metformin in diabetic patients with chronic kidney disease: a multicentre case-control study using electronic health records

Using a semi‐mechanistic model to identify the main sources of variability of metformin pharmacokinetics

Effect of continuous use of metformin on kidney function in diabetes patients with acute myocardial infarction undergoing primary percutaneous coronary intervention

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