Blood lactate and pyruvate levels in diabetic patients treated with biguanides with and without sulphonylureas

Waters, A. K.; Morgan, Diane; Wales, J. K.

doi:10.1007/bf01263446

Cited by 31 publications

(9 citation statements)

References 12 publications

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“…In contrast to phenformin, which exhibits a well-defined hyperlactatemic effect, therapeutic doses of metformin used according to the current label cause little (usually less than 1-2 mmol/L) to no increase in basal and postprandial blood lactate levels [3,14,15]. The incidence of lactic acidosis with metformin is estimated to be 20 times less than with phenformin [16].…”

Section: Biguanides and Lactic Acidosismentioning

confidence: 99%

Metformin-associated lactic acidosis: Current perspectives on causes and risk

DeFronzo

Fleming²,

Chen³

et al. 2016

Metabolism

466

333

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Although metformin has become a drug of choice for the treatment of type 2 diabetes mellitus, some patients may not receive it owing to the risk of lactic acidosis. Metformin, along with other drugs in the biguanide class, increases plasma lactate levels in a plasma concentration-dependent manner by inhibiting mitochondrial respiration predominantly in the liver. Elevated plasma metformin concentrations (as occur in individuals with renal impairment) and a secondary event or condition that further disrupts lactate production or clearance (e.g., cirrhosis, sepsis, or hypoperfusion), are typically necessary to cause metformin-associated lactic acidosis (MALA). As these secondary events may be unpredictable and the mortality rate for MALA approaches 50%, metformin has been contraindicated in moderate and severe renal impairment since its FDA approval in patients with normal renal function or mild renal insufficiency to minimize the potential for toxic metformin levels and MALA. However, the reported incidence of lactic acidosis in clinical practice has proved to be very low (<10 cases per 100,000 patient-years). Several groups have suggested that current renal function cutoffs for metformin are too conservative, thus depriving a substantial number of type 2 diabetes patients from the potential benefit of metformin therapy. On the other hand, the success of metformin as the first-line diabetes therapy may be a direct consequence of conservative labeling, the absence of which could have led to excess patient risk and eventual withdrawal from the market, as happened with earlier biguanide therapies. An investigational delayed-release metformin currently under development could potentially provide a treatment option for patients with renal impairment pending the results of future studies. This literature-based review provides an update on the impact of renal function and other conditions on metformin plasma levels and the risk of MALA in patients with type 2 diabetes.

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Section: Biguanides and Lactic Acidosismentioning

confidence: 99%

Metformin-associated lactic acidosis: Current perspectives on causes and risk

DeFronzo

Fleming²,

Chen³

et al. 2016

Metabolism

466

333

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“…20 Three early investigations found a relationship between phenformin and lactate levels not demonstrable with metformin. 21-23 These data may explain reduced incidence of lactic acidosis in Swedish patients with diabetes during 1977-1991, comparing rates when phenformin was available (1.5 cases/10 000 patient-years) vs when metformin was the exclusive biguanide prescribed (0.24 cases/10 000 patient-years). 24,25 …”

Section: Resultsmentioning

confidence: 99%

Metformin in Patients With Type 2 Diabetes and Kidney Disease

Inzucchi

Lipska

Mayo

et al. 2014

JAMA

528

393

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IMPORTANCE Metformin is widely viewed as the best initial pharmacological option to lower glucose concentrations in patients with type 2 diabetes mellitus. However, the drug is contraindicated in many individuals with impaired kidney function because of concerns of lactic acidosis. OBJECTIVE To assess the risk of lactic acidosis associated with metformin use in individuals with impaired kidney function. EVIDENCE ACQUISITION In July 2014, we searched the MEDLINE and Cochrane databases for English-language articles pertaining to metformin, kidney disease, and lactic acidosis in humans between 1950 and June 2014. We excluded reviews, letters, editorials, case reports, small case series, and manuscripts that did not directly pertain to the topic area or that met other exclusion criteria. Of an original 818 articles, 65 were included in this review, including pharmacokinetic/metabolic studies, large case series, retrospective studies, meta-analyses, and a clinical trial. RESULTS Although metformin is renally cleared, drug levels generally remain within the therapeutic range and lactate concentrations are not substantially increased when used in patients with mild to moderate chronic kidney disease (estimated glomerular filtration rates, 30-60 mL/min per 1.73 m2). The overall incidence of lactic acidosis in metformin users varies across studies from approximately 3 per 100 000 person-years to 10 per 100 000 person-years and is generally indistinguishable from the background rate in the overall population with diabetes. Data suggesting an increased risk of lactic acidosis in metformin-treated patients with chronic kidney disease are limited, and no randomized controlled trials have been conducted to test the safety of metformin in patients with significantly impaired kidney function. Population-based studies demonstrate that metformin may be prescribed counter to prevailing guidelines suggesting a renal risk in up to 1 in 4 patients with type 2 diabetes mellitus—use which, in most reports, has not been associated with increased rates of lactic acidosis. Observational studies suggest a potential benefit from metformin on macrovascular outcomes, even in patients with prevalent renal contraindications for its use. CONCLUSIONS AND RELEVANCE Available evidence supports cautious expansion of metformin use in patients with mild to moderate chronic kidney disease, as defined by estimated glomerular filtration rate, with appropriate dosage reductions and careful follow-up of kidney function.

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“…Metformin usually causes only a small (17) or no (6) increase in fasting peripheral blood lactate level. However, metformin usually induces elevated plasma lactate levels after glucose loading (6).…”

Section: Results-clinical Characteristicsmentioning

confidence: 99%