Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with glyburide and metformin; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (> 5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels > 5 mcg/mL are generally found.
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Glyburide and metformin treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, glyburide and metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, glyburide and metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking glyburide and metformin, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, glyburide and metformin hydrochloride should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS).
The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient’s physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also PRECAUTIONS). Glyburide and metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and, if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of glyburide and metformin, gastrointestinal symptoms, which are common during initiation of therapy with metformin, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking glyburide and metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling (see also PRECAUTIONS).
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking glyburide and metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery (see also CONTRAINDICATIONS and PRECAUTIONS).
Glyburide and metformin hydrochloride tablets USP contain two oral antihyperglycemic drugs used in the management of type 2 diabetes, glyburide USP and metformin hydrochloride USP.
Glyburide USP is an oral antihyperglycemic drug of the sulfonylurea class.
Glyburide and Metformin Hydrochloride Tablets USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Published Studies Related to Glyburide and Metformin (Glyburide / Metformin)
Saxagliptin, a potent, selective inhibitor of DPP-4, does not alter the pharmacokinetics of three oral antidiabetic drugs (metformin, glyburide or pioglitazone) in healthy subjects. [2011.07]
AIM: To evaluate the pharmacokinetic interactions of the potent, selective, dipeptidyl peptidase-4 inhibitor, saxagliptin, in combination with metformin, glyburide or pioglitazone... CONCLUSIONS: Saxagliptin can be co-administered with metformin, glyburide or pioglitazone without a need for dose adjustment of either saxagliptin or these OADs. (c) 2011 Blackwell Publishing Ltd.
Renal function in type 2 diabetes with rosiglitazone, metformin, and glyburide monotherapy. [2011.05]
BACKGROUND AND OBJECTIVES: In ADOPT (A Diabetes Outcomes Prevention Trial), initial monotherapy with rosiglitazone provided more durable glycemic control than metformin or glyburide in patients with recently diagnosed type 2 diabetes. Herein, we examine differences in albumin excretion, renal function (estimated GFR), and BP over 5 years between treatment groups... CONCLUSIONS: Over a 5-year period, initial monotherapy with rosiglitazone retards the rise of ACR compared with metformin, preserves eGFR compared with glyburide, and lowers BP relative to both comparators. Copyright (c) 2011 by the American Society of Nephrology
Effects of rosiglitazone, glyburide, and metformin on beta-cell function and insulin sensitivity in ADOPT. [2011.05]
CONCLUSIONS: The favorable combined changes in beta-cell function and insulin sensitivity over time with rosiglitazone appear to be responsible for its superior glycemic durability over metformin and glyburide as initial monotherapy in type 2 diabetes.
Comparison of pioglitazone vs glyburide in early heart failure: insights from a randomized controlled study of patients with type 2 diabetes and mild cardiac disease. [2010.05]
Pioglitazone may cause fluid retention, a well-known side effect of thiazolidinediones, and may exacerbate heart failure. Patients with type 2 diabetes and mild cardiac disease (New York Heart Association functional class I) received pioglitazone (n=151) or glyburide (n=149) for 1 year.Echocardiographic data suggested no significant deterioration in cardiac function with pioglitazone, although more heart failure (10 vs 7 patients), edema (21.2% vs 12.8%), and weight gain (2.56+/-4.62 kg vs 0.86+/-3.85 kg) were observed than with glyburide.
Metformin compared with glyburide in gestational diabetes: a randomized controlled trial. [2010.01]
OBJECTIVE: To compare the efficacy of metformin with glyburide for glycemic control in gestational diabetes... CONCLUSION: In this study, the failure rate of metformin was 2.1 times higher than the failure rate of glyburide when used in the management of gestational diabetes (95% confidence interval 1.2-3.9). CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00965991. LEVEL OF EVIDENCE: I.
Clinical Trials Related to Glyburide and Metformin (Glyburide / Metformin)
Efficacy and Safety of TAK-559 Combined With Glyburide in Treating Subjects With Type 2 Diabetes Mellitus. [Terminated]
The purpose of this study is to determine the safety and efficacy of TAK-559, once daily
(QD), combined with glyburide in treating Type 2 Diabetes.
A Study to Assess the Effects of Canagliflozin (JNJ-28431754) on the Pharmacokinetics, Pharmacodynamics, and Safety of Glyburide in Healthy Volunteers [Completed]
The purpose of this study is to determine how multiple doses of canagliflozin (JNJ-28431754)
affect the pharmacokinetics (ie, how the body affects the drug) and pharmacodynamics (ie,
how the drug affects the body) of a single dose of glyburide.
Glyburide (RP-1127) for Traumatic Brain Injury (TBI) [Active, not recruiting]
This is a randomized, double-blind, placebo-controlled, multi-institutional study of IV
RP-1127 (Glyburide for Injection) begun within 10 hours of complicated mild, moderate or
severe traumatic brain injury (TBI).
Glyburide and Metformin for the Treatment of Gestational Diabetes Mellitus. Systematic Review [Completed]
Since the publication in the New England Journal of Medicine (NEJM) in 2000 of the Langer's
trial comparing glyburide vs insulin in the treatment of gestational diabetes mellitus
(GDM), additional studies of oral agents for the treatment of GDM have been published
(observational, randomized controlled trials (RCT), and trials using other drugs like
Some meta-analysis to summarize the evidence have been published: Nicholson 2009 (including
4 RCT addressing different drugs), Dhulkotia 2010 (including 6 RCT addressing different
drugs, the meta-analysis combining all drugs altogether), Gui 2013 (including 5 RCT
addressing metformin vs insulin).
Oral agents are increasingly used for the treatment of GDM. Investigators aim to update the
evidence on RCTs comparing glyburide and metformin vs insulin or between them and summarize
this evidence using meta-analysis tools. Specifically, investigators aim at producing
distinct meta-analyses for each one of the three drug comparisons. This information is not
available in the literature since the most recent systematic reviews specifically dealing on
oral agents for the treatment of GDM have addressed a single drug comparison (Gui 2013) or
have combined different drug comparisons into a single meta-analysis (Dhulkotia 2010)
Glyburide Healthy Volunteer Study [Completed]
Glyburide is a medication that has been safely used for several decades to treat non-insulin
dependent diabetes. This pilot study seeks to evaluate whether glyburide, administered at
the lowest dose (1. 5 mg/dL daily) to healthy (non-diabetic) subjects is safe both physically
and cognitively. The investigators are hopeful that the results of this study will provide
the necessary foundation to evaluate this medication's use on a larger scale to determine
the feasibility of using glyburide in soldiers either prophylactically or for the treatment
of brain injury.
Page last updated: 2011-12-09