Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with metformin hydrochloride extended-release tablets; 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 hydrochloride extended-release tablets and by use of the minimum effective dose of metformin hydrochloride extended-release tablets. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin hydrochloride extended-release tablet 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, metformin hydrochloride extended-release tablets 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, metformin hydrochloride extended-release tablets 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 metformin hydrochloride extended-release tablets, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin hydrochloride extended-release tablets 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). Metformin hydrochloride extended-release tablets 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 metformin hydrochloride extended-release tablets, gastrointestinal symptoms, which are common during initiation of therapy, 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 metformin hydrochloride extended-release tablets 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 metformin hydrochloride extended-release tablets, 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).
Media Articles Related to Metformin Extended-Release (Metformin)
Diabetes Drug Metformin Safe for Patients With Kidney Disease: Review
Source: MedicineNet metformin Specialty [2014.12.24]
Title: Diabetes Drug Metformin Safe for Patients With Kidney Disease: Review
Category: Health News
Created: 12/23/2014 12:00:00 AM
Last Editorial Review: 12/24/2014 12:00:00 AM
Published Studies Related to Metformin Extended-Release (Metformin)
Effect of combination therapy with repaglinide and metformin hydrochloride on
glycemic control in Japanese patients with type 2 diabetes mellitus. 
exercise... CONCLUSIONS: Combination therapy with repaglinide and metformin resulted in an
The effect of metformin on apoptosis in a breast cancer presurgical trial. 
presurgical trial... CONCLUSION: Overall, we found no significant modulation of apoptosis by
Efficacy and safety of canagliflozin versus glimepiride in patients with type 2
diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results
from a randomised, double-blind, phase 3 non-inferiority trial. 
metformin... INTERPRETATION: Canagliflozin provides greater HbA1c reduction than does
Study design and rationale of a dose-ranging trial of LX4211, a dual inhibitor of
SGLT1 and SGLT2, in type 2 diabetes inadequately controlled on metformin
Sodium-glucose cotransporters 1 (SGLT1) and 2 (SGLT2) are the major cellular
transporters responsible for gastrointestinal (GI) glucose absorption and renal
glucose reabsorption, respectively... Safety is evaluated with particular focus on hypoglycemia, GI symptoms,
and incidence of genitourinary tract infections.
Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do
not have adequate glycemic control with metformin plus sulfonylurea: a 52-week
randomized trial. 
CONCLUSIONS: Findings suggest that canagliflozin may be a new therapeutic tool
Clinical Trials Related to Metformin Extended-Release (Metformin)
Metabolic Effect of Metformin in Obese Insulin Resistant Adolescents With Normal Glucose Tolerance [Active, not recruiting]
The primary objective of this randomized, parallel group, double-blind, placebo-controlled
study is to determine whether treatment with metformin enhances insulin sensitivity in a
group of ethnically diverse obese insulin-resistant adolescents with normal glucose
Drug Interaction With Metformin [Completed]
The purpose of the study is to determine the effect of metformin on dapagliflozin exposure
and the effect of dapagliflozin on metformin exposure in healthy volunteers. Additionally,
the safety and tolerability of dapagliflozin will be assessed in the presence and absence of
metformin in healthy volunteers
Rosiglitazone-Metformin Combination Versus Metformin-Sulfonylurea Combination On Beta-Cell Function In Type 2 Diabetes [Active, not recruiting]
It has been shown in previous study that progressive glycemic deterioration was associated
with progressive loss of b-cell function, measured by the decrease in plasma insulin levels,
irrespective of the therapy used (diet, sulfonylureas or metformin).There is growing evidence
that thiazolidinediones could have a positive action on the b-cell function. But it has not
yet been demonstrated that they could protect from a deterioration in insulin secretion in
the long term. So, it appears interesting to study the long term evolution of the b-cell
function and the possible protection with rosiglitazone in patients with type 2 diabetes
showing evidence of loss of b-cell function with metformin alone.
Efficacy and Safety of Prandial Inhalation of Technosphere/Insulin in Combination With Metformin or Technosphere/Insulin Alone Versus 2 Oral Anti-Diabetic Agents in Subjects With Type 2 Diabetes [Active, not recruiting]
to demonstrate the efficacy of inhaled Technosphere/Insulin in combination with metformin
versus combination metformin and a secretagogue
To Compare the Effect of Liraglutide When Given Together With Metformin With the Effect of Metformin Given Alone and With the Effect of Glimepiride and Metformin Given Together [Active, not recruiting]
This trial is conducted in Europe, Oceania, Africa, Asia and South America.
This trial is designed to show the effect of treatment with liraglutide when adding to
existing metformin therapy and to compare it with the effects of metformin monotherapy and
combination therapy of metformin and glimepiride.
The 26 weeks double-blind period will be followed by an 18 months open label extension.