Phenformin-Associated Lactic Acidosis: Pathogenesis and Treatment

Misbin, Robert I.

doi:10.7326/0003-4819-87-5-591

Cited by 115 publications

(46 citation statements)

References 34 publications

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“…The risk of lactic acidosis is high when tissue underperfusion and hypoxia coincide (e.g., in renal, cardiac, or hepatic failure; coronary disease; hemorrhage; respiratory distress; or septic shock) (3,4). Biguanide oral antidiabetic agents have been associated with an increased risk of lactic acidosis (5)(6)(7)(8). Phenformin was withdrawn from use in the U.S. in 1977 for this reason, with an associated incidence of lactic acidosis subsequently estimated at 40 -64/100,000 patientyears (7,8).…”

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confidence: 99%

Comparative Outcomes Study of Metformin Intervention Versus Conventional Approach The COSMIC Approach Study

et al. 2005

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OBJECTIVE—Metformin was approved by the Food and Drug Administration in 1995 subject to the conduct of a randomized trial to evaluate the risk of lactic acidosis or other serious adverse events (SAEs) with this agent, under usual care conditions. RESEARCH DESIGN AND METHODS—The Comparative Outcomes Study of Metformin Intervention versus Conventional (COSMIC) Approach Study was a randomized, open-label, active-comparator, parallel-group, 1-year trial in type 2 diabetic patients suboptimally controlled on diet or sulfonylurea. Patients received metformin (n = 7,227) or other usual care treatments (n = 1,505). The primary end point was the incidence of SAEs, death, and hospitalization. RESULTS—SAEs occurred in 10.3% (95% CI 9.6–11.1%) of the metformin group and in 11.0% (9.5–12.7%) of the usual care group (P = 0.431). Lactic acidosis did not occur. All-cause mortality (1.1% [0.9–1.4%] vs. 1.3% [0.8–2.0%], P = 0.596) and hospitalization (9.4% [8.8–10.1%] vs. 10.4% [8.9–12.1%], P = 0.229) were similar between groups. CONCLUSIONS—The incidence of SAEs was similar between groups. Lactic acidosis was not observed. Metformin may be safely prescribed for type 2 diabetes if contraindications and warnings are respected. This study demonstrates the utility of large, simple trials for risk evaluation of treatments for common diseases.

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Comparative Outcomes Study of Metformin Intervention Versus Conventional Approach The COSMIC Approach Study

et al. 2005

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“…This was followed in the 1950s and 1960s by the approval of other first-generation sulfonylureaschlorpropamide, acetohexamide, and tolazamide. A biguanide, phenformin, was approved in 1959 for use in the management of type 2 diabetes, but its association with fatal lactic acidosis resulted in its recall as an "imminent hazard" in 1977 (1,2).…”

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Rapid Increase in the Use of Oral Antidiabetic Drugs in the United States, 1990–2001

2003

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OBJECTIVE—To describe the use of oral antidiabetic drugs for management of type 2 diabetes in the U.S. from 1990 through 2001. RESEARCH DESIGN AND METHODS—Data on oral antidiabetic drugs were derived from two pharmaceutical marketing databases from IMS Health, the National Prescription Audit Plus and the National Disease and Therapeutic Index. RESULTS—In 1990, 23.4 million outpatient prescriptions of oral antidiabetic agents were dispensed. By 2001, this number had increased 3.9-fold, to 91.8 million prescriptions. Glipizide and glyburide, two sulfonylurea medications, accounted for ∼77% of prescriptions of oral antidiabetic drugs in 1990 and 35.5% of prescriptions in 2001. By 2001, the biguanide metformin (approved in 1995) had captured ∼33% of prescriptions, and the thiazolidinedione insulin sensitizers (rosiglitazone and pioglitazone marketed beginning in 1999) accounted for ∼17% of market share. Compared with patients treated in 1990, those in 2001 were proportionately younger and they more often used oral antidiabetic drugs and insulin in combination. Internists and general and family practitioners were the primary prescribers of this class of drugs. CONCLUSIONS—Consistent with the reported increase in the prevalence of type 2 diabetes, the number of dispensed outpatient prescriptions of oral antidiabetic drugs increased rapidly between 1990 and 2001. This period was marked by an increase in the treatment of younger people and the use of oral antidiabetic drugs in combination. With the approval in the last decade of several new types of oral antidiabetic medications with different mechanisms of action, options for management of type 2 diabetes have expanded.

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“…In type A lactic acidosis, there is clear evidence of conditions causing tissue hypoxia, such as shock or hypovolemia; in type B, there is no obvious cause for tissue hypoxia. The mortality in patients with lactic acidosis is >85% in type A and 50% in type B (1,4,5). The therapy of lactic acidosis has consisted primarily of intravenous bicarbonate, frequently in excess of 1,000 meq/d (1)(2)(3)(4).…”

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Treatment of Lactic Acidosis with Dichloroacetate in Dogs

Park¹,

Arieff²,

Leach³

et al. 1982

J. Clin. Invest.

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A B S T R A C T Lactic acidosis is a clinical condition due to accumulation of H+ ions from lactic acid, characterized by blood lactate levels >5 mM and arterial pH <7.25. In addition to supportive care, treatment usually consists of intravenous NaHCO3, with a resultant mortality >60%. Dichloroacetate (DCA) is a compound that lowers blood lactate levels under various conditions in both man and laboratory animals. It acts to increase pyruvate oxidation by activation of pyruvate dehydrogenIse. We evaluated the effects of DCA in the treatment of two different models of type B experimental lactic acidosis in diabetic dogs: hepatectomy-lactic acidosis and phenformin-lactic acidosis. The metabolic and systemic effects examined included arterial blood pH and levels of bicarbonate and lactate; the intracellular pH (pHi) in liver and skeletal muscle; cardiac index, arterial blood pressure and liver blood flow; liver lactate uptake and extrahepatic splanchnic (gut) lactate production; and mortality. Effects of DCA were compared with those of either NaCl or NaHCO3. The infusion of DCA and NaHCO3, delivered equal amounts of volume and sodium, although the quantity of NaHCO3 infused (2.5 meq/kg per h) was insufficient to normalize arterial pH.In phenformin-lactic acidosis, DCA-treated animals had a mortality of 22%, vs. 89% in those treated with NaHCO3. DCA therapy increased arterial pH and bicarbonate, liver pHi and cardiac index, with increased This work was presented in part at

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Phenformin-Associated Lactic Acidosis: Pathogenesis and Treatment

Cited by 115 publications

References 34 publications

Comparative Outcomes Study of Metformin Intervention Versus Conventional Approach The COSMIC Approach Study

Comparative Outcomes Study of Metformin Intervention Versus Conventional Approach The COSMIC Approach Study

Rapid Increase in the Use of Oral Antidiabetic Drugs in the United States, 1990–2001

Treatment of Lactic Acidosis with Dichloroacetate in Dogs

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