WHAT IS GLUCOPHAGE?
Glucophage is a biguanide that contains metformin hydrochloride. It is a prescription medication used in addition to diet and exercise to improve glucose control in adults with type II diabetes mellitus (T2DM). Controlling hyperglycemia prevents downstream complications such as kidney damage, loss of limbs, blindness, heart attack, stroke, or nerve problems. It is important that diabetes remains controlled to lessen the chance of related complications. Glucophage is not recommended for the treatment of type I diabetes or for patients with diabetic ketoacidosis.
HOW DOES GLUCOPHAGE WORK?
Glucophage is an antidiabetic agent that works by decreasing basal and postprandial plasma glucose. Metformin lessens absorption of glucose in the intestine, lowers hepatic production of glucose, and increases insulin sensitivity by elevating peripheral glucose utilization. Metformin’s exact mechanism is not well understood, but a few methods have been postulated. These include inhibiting mitochondrial complex I activity, stimulating AMP-activated protein kinase (AMPK), inhibition of glucagon-induced increases in cyclic adenosine monophosphate (cAMP), decreasing activation of protein kinase A (PKA), and affecting gut microbiota. With Glucophage, insulin secretion does not change, however, all-day plasma insulin response and fasting insulin levels can decrease.
Common side effects include:
- Nausea and vomiting
- Vitamin B12 deficiency
- Abdominal distress
- Loss of appetite
- Bloating or gas
- Fullness or loss of appetite
WARNINGS AND PRECAUTIONS
There have been multiple reports of lactic acidosis with metformin use, with some being fatal cases. Onset was typically gradual with symptoms including muscle pain, abdominal pain, drowsiness, and respiratory distress. More severe cases of acidosis included symptoms such as hypothermia, hypotension, and bradyarrhythmias. The signs and symptoms were accompanied by increased blood lactate concentrations, anion gap acidosis, and an elevated lactate/pyruvate ratio. There are multiple risk factors that increase an individual’s chance of developing lactic acidosis while on metformin. Risk factors and subsequent risk reduction measures include:
Renal impairment – In post-marketing cases, lactic acidosis caused by metformin mostly occurred in patients that had significant renal impairment. Do not use in patients with an eGFR of less than 45 mL/min/1.73 m2. Monitor eGFR annually in patients taking Glucophage. Those at greater risk for developing renal dysfunction, such as the elderly, institute more frequent monitoring of renal function.
Drug interactions – Be cautious when using Glucophage with other drugs influencing renal function, hemodynamics, metformin uptake, and acid-base balance to prevent the development of lactic acidosis. Consider monitoring patients more frequently.
Age 65 or greater – Older patients are at a higher risk for developing renal impairment. Therefore, renal function should be assessed more often in the elderly who are on Glucophage.
Radiological studies with contrast – Iodinated contrast agents in patients on metformin have caused acute reductions in renal function and therefore lactic acidosis. Discontinue Glucophage prior to an iodinated contrast imaging procedure in patients with an eGFR of 30 to 60 mL/min/1.73 m2, in patients with hepatic impairment, alcoholism, or heart failure, or in patients receiving intra-arterial iodinated contrast. Assess eGFR 48 hours after the procedure, and reinitiate Glucophage once the renal function has stabilized.
Surgery – Restricted food and fluids during surgical procedures can elevate the risk for volume depletion, hypotension, and renal impairment. Hold Glucophage while patients have restricted food and fluid intake.
Hypoxic states – Stop Glucophage when hypoxic states occur, such as in acute congestive heart failure, cardiovascular collapse, acute myocardial infarction, and sepsis.
Alcohol – Avoid excessive alcohol intake, as alcohol increases the effects of metformin on metabolism of lactate. Warn patients of the dangers of drinking large amounts of alcohol while on Glucophage.
Hepatic impairment – Patients with hepatic impairment are at higher risk of developing lactic acidosis when taking Glucophage. Do not use Glucophage if a patient exhibits signs of hepatic disease
Vitamin B12 Deficiency
Studies have shown a decrease in vitamin B12 levels with the use of metformin. Monitor hematologic measures annually and vitamin B12 parameters every 2 to 3 years for patients taking Glucophage. If abnormalities are present, manage appropriately with Glucophage discontinuation or vitamin B12 supplementation.
Hypoglycemia with Concomitant Use of Insulin Products
Glucophage can cause hypoglycemia when used in combination with other products that lower blood glucose, such as insulin. Dose adjustments to insulin may be required to prevent the development of hypoglycemia.
The decreased macrovascular risk with Glucophage has not been proven in any clinical studies.
Carbonic Anhydrase Inhibitors (CAI)
Carbonic anhydrase inhibitors can lower serum bicarbonate and cause non-anion gap metabolic acidosis. When used concomitantly with Glucophage, this combination can elevate an individual’s risk for developing lactic acidosis. Patients that are taking these drugs in combination should be frequently monitored. Examples of CAIs include topiramate and acetazolamide.
Drugs that Decrease Clearance of Metformin
Medications that interfere with the renal elimination of metformin should be avoided. Drugs like ranolazine, dolutegravir, and cimetidine can increase a patient’s systemic exposure to metformin and elevate the risk of lactic acidosis.
Patients should avoid excessive alcohol intake. Alcohol has been shown to increase metformin’s effect on lactate metabolism, causing an increased risk for lactic acidosis.
Other Drugs Affecting Glycemic Control
When used in combination with other drugs that can cause hypoglycemia, the risk for developing hypoglycemia with Glucophage is increased. Patients should be monitored for signs of hypoglycemia when on concomitant glucose-altering agents such as steroids, diuretics, and phenytoin.
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