The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes 19 (Suppl. 2):747-830, 1970).
UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and benefits of glipizide and of alternative modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.
Lactic Acidosis —There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (> 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increases lactate:pyruvate ratio; metformin plasma levels were generally > 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of glipizide and metformin hydrochloride. In glipizide and metformin hydrochloride treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.
Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue glipizide and metformin hydrochloride and report these symptoms to their healthcare provider.
For each of the known and possible risk factors for metformin-associated lactic acidosis,recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:
- Renal Impairment —The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney Clinical recommendations based upon the patients renal function include (see Dosage and Administration, Clinical Pharmacology):
- Before initiating glipizide and metformin hydrochloride, obtain an estimated glomerular filtration rate (eGFR)
- Glipizide and metformin hydrochloride is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2. Initiation of glipizide and metformin hydrochloride is not recommended in patients with eGFR between 30-45 mL/min/1.73 m2 (see Contraindications)
- Obtain an eGFR at least annually in all patients taking glipizide and metformin hydrochloride. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
- In patients taking glipizide and metformin hydrochloride whose eGFR falls below 45 mL/min/1.73 m2 , assess the benefit and risk of continuing therapy.
- Drug interactions —The concomitant use of glipizide and metformin hydrochloride with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation. Consider more frequent monitoring of patients.
- Age 65 or Greater —The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.
- Radiologic studies with contrast —Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop glipizide and metformin hydrochloride at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mlL/min/1.73 m2 ; in patients with a history of hepatic impairment, alcoholism or heart failure, or in patients who will be administered intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after the imaging procedure, and restart glipizide and metformin hydrochloride if renal function is stable.
- Hypoxic states —Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. When such an event occurs, discontinue glipizide and metformin hydrochloride.
- Excessive Alcohol intake —Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving glipizide and metformin hydrochloride.
- Hepatic impairment —Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of glipizide and metformin hydrochloride in patients with clinical or laboratory evidence of hepatic disease.
Glipizide-metformin hydrochloride tablets are capable of producing hypoglycemia; therefore, proper patient selection, dosing, and instructions are important to avoid potential hypoglycemic episodes. The risk of hypoglycemia is increased when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents or ethanol. Renal insufficiency may cause elevated drug levels of both glipizide and metformin hydrochloride. Hepatic insufficiency may increase drug levels of glipizide and may also diminish gluconeogenic capacity, both of which increase the risk of hypoglycemic reactions. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.
Renal and Hepatic Disease:
The metabolism and excretion of glipizide may be slowed in patients with impaired renal and/or hepatic function. If hypoglycemia should occur in such patients, it may be prolonged and appropriate management should be instituted.
Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because glipizide and metformin hydrochloride tablets belong to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered.In postmarketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.
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