Dataset Information

Epidemiology of lactic acidosis in type 2 diabetes patients with metformin in Japan.

ABSTRACT:

Purpose

To estimate the incidence of lactic acidosis (LA) and role of metformin in Japanese patients with type 2 diabetes mellitus (T2DM) treated with anti-diabetes drugs.

Methods

This retrospective propensity score matched cohort study was conducted using the Japanese Medical Data Vision claims database. T2DM patients aged 18 or above who received diabetes drugs during January 2010 through August 2014 were identified. Cases of LA were identified based on reimbursement codes and confirmed by lactic acid test and subsequent treatment by hemodialysis or intravenous sodium bicarbonate. Poisson regression and Cox proportional hazard models were used to estimate the incidence and assess if metformin use was associated with increased risk of LA.

Results

Thirty cases of LA were identified among 283?491 treated T2DM patients with 504?169 patient-years of follow-up. Crude incidence of LA was 5.95 per 100?000 patient-years. T2DM patients with chronic kidney disease (CKD) were seven-fold more likely to develop LA than those without CKD (adjusted hazard ratio (aHR), 7.33, 95%CI, 3.17-16.96). Use of metformin was not associated with risk of LA in the study population (aHR, 0.92, 95%CI, 0.33-2.55), and in the propensity score matched cohort (aHR, 0.90, 95%CI, 0.26-3.11). Similar findings were observed among diabetes patients with chronic liver disease (CLD) and CKD. The age-sex adjusted incidence rates in metformin users and non-users were 5.80 and 5.78 per 100?000 person-years, respectively (Incidence rate ratio, 1.00, p?=?0.99).

Conclusions

This study found that use of metformin was not associated with increased risk of LA in diabetic patients including those with CKD or CLD. © 2016 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.

SUBMITTER: Chang CH

PROVIDER: S-EPMC5089598 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Publications

Epidemiology of lactic acidosis in type 2 diabetes patients with metformin in Japan.

Chang Chia-Hsien CH Sakaguchi Motonobu M Dolin Paul P

Pharmacoepidemiology and drug safety 20160525 10

<h4>Purpose</h4>To estimate the incidence of lactic acidosis (LA) and role of metformin in Japanese patients with type 2 diabetes mellitus (T2DM) treated with anti-diabetes drugs.<h4>Methods</h4>This retrospective propensity score matched cohort study was conducted using the Japanese Medical Data Vision claims database. T2DM patients aged 18 or above who received diabetes drugs during January 2010 through August 2014 were identified. Cases of LA were identified based on reimbursement codes and c ...[more]

PMID: 27221971

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Project description:IntroductionPatients with type 2 diabetes (T2D) in Japan are prescribed a lower dose of metformin that their counterparts in Western countries due to concerns for the risk of lactic acidosis incidence. Here we report our study on the association between high-dose metformin administration and the incidence of lactic acidosis in Japanese patients with T2D.MethodsA Japanese claims database (April 2008-November 2018) was analyzed. Factors associated with the incidence of lactic acidosis were first identified from the database records by conducting a case-control study, and these were then used as confounding factors in subsequent analyses. The association between high-dose metformin administration (≥ 1000 mg/day) and the incidence of lactic acidosis was compared with that between low-dose metformin (< 1000 mg/day) or no metformin administration and lactic acidosis incidence by using the following approaches: a logistic regression analysis hypothesizing that metformin-associated lactic acidosis is short term; a time-dependent proportional hazard model hypothesizing that the influence of metformin is cumulative; and a case-control study in which lactic acidosis incidence was the case and metformin administration within 3 months prior to the incidence of lactic acidosis (or corresponding date for the control) was the exposure.ResultsPrescriptions for biguanide and vitamin B complex and volume depletion were identified as factors associated with the incidence of lactic acidosis. The incidence rate was higher in patients prescribed metformin than in those not receiving metformin; however, it was not higher in those prescribed high-dose metformin compared to those prescribed low-dose metformin. The estimated regression coefficient for high-dose metformin administration was 0.816 (p < 0.001); this was not higher than those for low-dose metformin (1.047), vitamin B complex (2.725) and volume depletion (3.301). The time-dependent proportional hazard analysis did not indicate any effect of metformin prescription.ConclusionThe results suggest an association between metformin administration and the incidence of lactic acidosis, but an increase in the incidence rate of lactic acidosis was not observed in those patients receiving high-dose metformin compared to those receiving low-dose metformin.

Project description:BackgroundDespite strong recommendations to use metformin as first-line therapy for type 2 diabetes (T2DM), its use has been suboptimal, likely due to concerns of lactic acidosis. This study compared the association of acidosis in patients with T2DM prescribed metformin with those prescribed other antihyperglycemic medications or no medications.MethodsThis was a retrospective cohort study of patients with newly diagnosed T2DM utilizing an administrative database, which includes medical and prescription claims. Eligible patients had a diagnosis of T2DM, had continuous health plan enrollment 3 months prior to study enrollment and during the study period, and were at least 18 years of age. Mutually exclusive exposure groups were metformin only, other antihyperglycemic medications, and no medication. Acidosis cases were stratified by exposure group and risk factors for lactic acidosis (chronic obstructive pulmonary disease, hepatic dysfunction, alcohol abuse, heart failure, renal insufficiency, age of 80 years or older, and a history of acidosis). Degree of renal insufficiency was not available. Associations between exposure and acidosis were estimated, and risk factors evaluated.ResultsA total of 132,780 patients met inclusion criteria: 24,936 (20%) metformin only group, 15,059 (11%) other antihyperglycemic medication group, and 92,785 (70%) no medication group. Acidosis was observed in 1.45 per 10,000 patient months (0.78 metformin, 1.59 other antihyperglycemic medication, 1.51 no medication). The unadjusted relative risk of acidosis was 0.5 for patients prescribed metformin only compared with the other exposure groups (95% confidence interval = 0.2-1.2). There was no significant difference in risk of acidosis between exposure groups, irrespective of risk factors for lactic acidosis.ConclusionsRisk of acidosis was similar with metformin only compared with those prescribed other antihyperglycemic medications or no medication. These results support expanded use of metformin for T2DM. Additional studies are needed to understand the impact of risk factor severity on risk of lactic acidosis.

Project description:IntroductionHepatic mitochondrial dysfunction may play a critical role in the pathogenesis of metformin-induced lactic acidosis. However, patients with severe metformin intoxication may have a 30 to 60% decrease in their global oxygen consumption, as for generalized inhibition of mitochondrial respiration. We developed a pig model of severe metformin intoxication to validate this clinical finding and assess mitochondrial function in liver and other tissues.MethodsTwenty healthy pigs were sedated and mechanically ventilated. Ten were infused with a large dose of metformin (4 to 8 g) and five were not (sham controls). Five others were infused with lactic acid to clarify whether lactic acidosis per se diminishes global oxygen use. Arterial pH, lactatemia, global oxygen consumption (VO2) (metabolic module) and delivery (DO2) (cardiac output by thermodilution) were monitored for nine hours. Oxygen extraction was computed as VO2/DO2. Activities of the main components of the mitochondrial respiratory chain (complex I, II and III, and IV) were measured with spectrophotometry (and expressed relative to citrate synthase activity) in heart, kidney, liver, skeletal muscle and platelets taken at the end of the study.ResultsPigs infused with metformin (6 ± 2 g; final serum drug level 77 ± 45 mg/L) progressively developed lactic acidosis (final arterial pH 6.93 ± 0.24 and lactate 18 ± 7 mmol/L, P < 0.001 for both). Their VO2 declined over time (from 115 ± 34 to 71 ± 30 ml/min, P < 0.001) despite grossly preserved DO2 (from 269 ± 68 to 239 ± 51 ml/min, P = 0.58). Oxygen extraction accordingly fell from 43 ± 10 to 30 ± 10% (P = 0.008). None of these changes occurred in either sham controls or pigs infused with lactic acid (final arterial pH 6.86 ± 0.16 and lactate 22 ± 3 mmol/L). Metformin intoxication was associated with inhibition of complex I in the liver (P < 0.001), heart (P < 0.001), kidney (P = 0.003), skeletal muscle (P = 0.012) and platelets (P = 0.053). The activity of complex II and III diminished in the liver (P < 0.001), heart (P < 0.001) and kidney (P < 0.005) while that of complex IV declined in the heart (P < 0.001).ConclusionsMetformin intoxication induces lactic acidosis, inhibits global oxygen consumption and causes mitochondrial dysfunction in liver and other tissues. Lactic acidosis per se does not decrease whole-body respiration.

Dataset Information

Epidemiology of lactic acidosis in type 2 diabetes patients with metformin in Japan.

Purpose

Methods

Results

Conclusions

Publications

Epidemiology of lactic acidosis in type 2 diabetes patients with metformin in Japan.

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