Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with RIOMET; 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 µg/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 RIOMET and by use of the minimum effective dose of RIOMET. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. RIOMET 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, RIOMET 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, RIOMET 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 RIOMET, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, RIOMET 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). RIOMET 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 RIOMET, 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 RIOMET 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 RIOMET, 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 Riomet (Metformin)
How Metformin Does Its Job
Source: MedPage Today Nephrology [2015.07.15]
(MedPage Today) -- New study sheds light on the drug's still-puzzling mechanism of action
Diabetes Drug Metformin May Lower Glaucoma Risk
Source: MedicineNet Glaucoma Specialty [2015.05.29]
Title: Diabetes Drug Metformin May Lower Glaucoma Risk
Category: Health News
Created: 5/28/2015 12:00:00 AM
Last Editorial Review: 5/29/2015 12:00:00 AM
Published Studies Related to Riomet (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 Riomet (Metformin)
Efficacy and Safety of Alogliptin Plus Metformin in Subjects With Type 2 Diabetes [Recruiting]
The purpose of this study is to evaluate the safety and effectiveness of alogliptin combined
with metformin, once daily (QD) or twice daily (BID), in participants with Type 2 Diabetes.
Study to Assess Safety and Pharmacokinetics (PK) of Double-Blind S-707106 Alone and in Combination With Open-Label Metformin in Patients With Type 2 Diabetes Mellitus [Recruiting]
- to evaluate the safety and PK of multiple-dose oral administration of S-707106 tablet
in fed state in patients with type 2 diabetes mellitus
- to evaluate the safety and PK of multiple-dose oral co-administration of S-707106 and
metformin in fed state in patients with type 2 diabetes mellitus
- to evaluate the effect of multiple doses of S-707106 on PK of metformin
- to evaluate the effect of multiple doses of metformin on PK of S-707106
Bioavailability of a Fixed Dose Combination Tablet With BI 10773 and Metformin Compared With the Monocomponents and Effect of Food on Bioavailability [Recruiting]
The objective of the current study is to determine the relative bioavailability of a BI
10773 / metformin fixed dose combination tablet compared to single tablets of BI 10773 and
metformin when administered together and to assess the effect of food on the bioavailability
the fixed dose combination tablet
Comparison of the Bioavailability of Metformin Between Medium Dose Linagliptin/Metformin Tablets and Medium Dose Glucophage Tablet Given With Linagliptin Tablet [Recruiting]
The data from this study will be used to compare the kinetic profile of metformin 500mg in
linagliptin/metformin fixed dose combination tablet versus Canadian metformin reference
product administered concomitantly with linagliptin 2. 5 mg tablet.
Carotid Atherosclerosis: MEtformin for Insulin ResistAnce Study [Recruiting]
Hypothesis: Treatment with metformin in overweight non-diabetic individuals with coronary
heart disease and on standard cardiovascular risk reducing agents including statins will
have a beneficial impact on carotid artery atherosclerosis compared to placebo.
Rationale: Once subjects have a heart attack, they remain at much higher than average risk
of another heart attack and stroke, despite the best current therapies to lower their
cholesterol and blood pressure and thin their blood. Many subjects with heart disease also
have problems metabolising (i. e. processing) sugar even if they do not have diabetes. There
is some evidence that metformin, a drug which improves sugar metabolism, decreases the risk
of future heart attacks in diabetic patients. However, whether metformin further reduces the
risk of heart disease beyond established treatments in people without diabetes is unknown.
Method: The investigators will test the ability metformin, a drug with proven safety, to
slow the progression of furring up (known as atherosclerosis) of blood vessels in
non-diabetic subjects with heart disease. This will be achieved by treating 2 groups of
subjects with metformin and placebo pills respectively. To measure atherosclerosis, the
investigators will carry out ultrasound scans of the big blood vessels in the neck at the
start of the study, after 1 year and after 1. 5 years of therapy. The investigators will then
be able to assess whether metformin has had a beneficial impact.