The Phantom of Lactic Acidosis due to Metformin in Patients With Diabetes

Misbin, Robert I.

doi:10.2337/diacare.27.7.1791

Cited by 184 publications

(124 citation statements)

References 30 publications

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“…Indeed, the nearabsence of any cases of lactic acidosis in large observational studies and the fact that metformin levels do not correlate with lactate levels in individuals who do develop lactic acidosis supports the viewpoint that metformin may be "an innocent bystander" in sick patients rather than a causal agent (19,20). As noted by Misbin (17), "the increased risk of lactic acidosis (attributable to metformin) is either zero or so close to zero that it cannot be factored into ordinary clinical decision making." By corollary, 2 decades ago, ␤-blockers were considered contraindicated in heart failure, and commonly accepted "quality indicators" for the use of ␤-blockers explicitly stated that people with left ventricular dysfunction or heart failure were "ineligible" for receipt of ␤-blockers (21).…”

mentioning

confidence: 86%

“…Although the contraindication to metformin arose over concerns about the potential for lactic acidosis and its relation to phenformin (another biguanide that was removed from the market after 306 cases of lactic acidosis were reported in the 1970s), there is a paucity of evidence that actually links metformin with lactic acidosis (17,18). Indeed, the nearabsence of any cases of lactic acidosis in large observational studies and the fact that metformin levels do not correlate with lactate levels in individuals who do develop lactic acidosis supports the viewpoint that metformin may be "an innocent bystander" in sick patients rather than a causal agent (19,20).…”

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confidence: 99%

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Improved Clinical Outcomes Associated With Metformin in Patients With Diabetes and Heart Failure

et al. 2005

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OBJECTIVE -Metformin is considered contraindicated in patients with heart failure because of concerns over lactic acidosis, despite increasing evidence of potential benefit. The aim of this study was to evaluate the association between metformin and clinical outcomes in patients with heart failure and type 2 diabetes.RESEARCH DESIGN AND METHODS -Using the Saskatchewan Health databases, 12,272 new users of oral antidiabetic agents were identified between the years 1991 and 1996. Subjects with incident heart failure (n ϭ 1,833) were identified through administrative records based on ICD-9 code 428 and grouped according to antidiabetic therapy: metformin monotherapy (n ϭ 208), sulfonylurea monotherapy (n ϭ 773), or combination therapy (n ϭ 852). Multivariate Cox proportional hazards models were used to assess differences in all-cause mortality, all-cause hospitalization, and the combination (i.e., all-cause hospitalization or mortality).RESULTS -Average age of subjects was 72 years, 57% were male, and average follow-up was 2.5 Ϯ 2.0 (SD) years. Compared with sulfonylurea therapy, fewer deaths occurred in subjects receiving metformin: 404 (52%) for sulfonylurea monotherapy versus 69 (33%) for metformin monotherapy (hazard ratio CONCLUSIONS -Metformin, alone or in combination, in subjects with heart failure and type 2 diabetes was associated with lower morbidity and mortality compared with sulfonylurea monotherapy.[

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confidence: 86%

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confidence: 99%

Improved Clinical Outcomes Associated With Metformin in Patients With Diabetes and Heart Failure

et al. 2005

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“…Moreover, metformin might be stopped because it is contraindicated in patients with advanced liver diseases with associated cirrhosis, ascites, or encephalopathy [25]. Although the real risk is minimal [26], the potential of metformin to cause lactic acidosis might lead physicians to withhold metformin in patients with advanced liver disease [25].…”

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confidence: 99%

Impact of cancer on adherence to glucose-lowering drug treatment in individuals with diabetes

et al. 2015

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Aims/hypothesis Adherence to glucose-lowering drug (GLD) treatment regimens is crucial for metabolic control and improving prognosis. Because a diagnosis of cancer might have an impact on adherence to medication, this study explored changes in adherence to GLDs following a cancer diagnosis.Methods All new users of GLDs between 1998 and 2011 who lived in the Eindhoven Cancer Registry-PHARMO Database Network catchment area were selected. Those with a primary cancer diagnosis during follow-up were considered cases and matched with eligible controls without cancer during followup. Medication possession ratio (MPR) was used as indicator for medication adherence. Segmented linear auto-regression analysis with interrupted time series was used to assess changes in MPR for cases compared with controls (i.e. overall trend) due to (any) cancer diagnosis and specific cancer types. Results From the 52,228 GLD users selected, 3,281 cases with cancer and 12,891 controls without cancer during follow-up were included in the study. In our analyses, before cancer diagnosis the MPR increased by 0.10% per month (95% CI 0.10, 0.10). Besides a significant drop in MPR at the time of cancer diagnosis of −6.3% (95% CI −6.5, −6.0), there was an ongoing, yet lower, monthly decline in MPR (−0.20%; 95% CI −0.21, −0.20) after cancer diagnosis. The largest drops in MPR at the time of cancer diagnosis, in the range of 11-15%, were seen among patients with stage IV disease and gastrointestinal or pulmonary cancers. Conclusions/interpretation Our findings indicate a clear decline in adherence to GLD treatment regimens following a cancer diagnosis. The reason for the decline in MPR needs to be further elucidated.

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“…Although, no case of LA was recorded in the clinical trials of metformin, which included .70,000 patient-years of exposure to metformin treatment (7,9,10), a secondary analysis of .41,000 person-years in type 2 diabetes showed that the incidence of LA in diabetic patients not exposed to metformin was between 9.7 and 16.7 per 100,000 person-years (11). Previous studies of metformin tolerability demonstrated safe therapeutic use of metformin in patients with no renal risk factors (12), but no real-life evidence has supported its safe use in patients with various levels of renal impairment. The objective of this study was to determine whether the use of metformin is associated with an increased risk of LA in patients with normal and mildly, moderately, or even severely reduced kidney function in a real-world setting.…”

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Incidence of Lactic Acidosis in Patients With Type 2 Diabetes With and Without Renal Impairment Treated With Metformin: A Retrospective Cohort Study

et al. 2014

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OBJECTIVE To determine whether the use of metformin in type 2 diabetic patients with various kidney functions is associated with an increased risk of lactic acidosis (LA). RESEARCH DESIGN AND METHODS This study was a retrospective analysis of U.K. patient records from the Clinical Practice Research Datalink database from 1 January 2007 to 31 December 2012. Inclusion criteria were 1) diagnosis of type 2 diabetes before 1 January 2007, 2) treatment with metformin, and 3) at least one assessment of renal function between 2007 and 2012. Renal function was assessed by glomerular filtration rate and categorized as normal (N), mildly reduced (Mi), moderately reduced (Mo), or severely reduced (Se) function. The outcome of the study was LA. RESULTS A total of 77,601 patients treated with metformin for type 2 diabetes were identified. There were 35 LA events (10.37 [95% CI 7.22–14.42] per 100,000 patient-years) of which none were fatal and 23 were linked to a comorbidity. No significant difference in the incidence of LA was observed across N, Mi, Mo and Se renal function groups (7.6 [0.9–27.5], 4.6 [2.00–9.15], 17 [10.89–25.79], and 39 [4.72–140.89] cases per 100,000 patient-years, respectively). CONCLUSIONS The overall LA incidence rate for patients on metformin in this study was within the range of rates reported in the literature for patients with type 2 diabetes, and no significant difference was observed among patients with N, Mi, Mo, and Se function.

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The Phantom of Lactic Acidosis due to Metformin in Patients With Diabetes

Cited by 184 publications

References 30 publications

Improved Clinical Outcomes Associated With Metformin in Patients With Diabetes and Heart Failure

Improved Clinical Outcomes Associated With Metformin in Patients With Diabetes and Heart Failure

Impact of cancer on adherence to glucose-lowering drug treatment in individuals with diabetes

Incidence of Lactic Acidosis in Patients With Type 2 Diabetes With and Without Renal Impairment Treated With Metformin: A Retrospective Cohort Study

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