Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Glipizide/Metformin HCl 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 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 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. Glipizide/Metformin HCl tablets 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, Glipizide/Metformin HCl 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, glipizide and metformin hydrochloride 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 Glipizide/Metformin HCl tablets, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, Glipizide/Metformin HCl 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). Glipizide/Metformin HCl 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 Glipizide/Metformin HCl tablets, 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 Glipizide/Metformin HCl 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 Glipizide/Metformin HCl 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.)
Published Studies Related to Glipizide and Metformin (Glipizide / Metformin)
Effects of Metformin Versus Glipizide on Cardiovascular Outcomes in Patients With
Type 2 Diabetes and Coronary Artery Disease. 
OBJECTIVEThe two major classes of antidiabetic drugs, sulfonylureas and
metformin, may differentially affect macrovascular complications and mortality in
diabetic patients. We compared the long-term effects of glipizide and metformin
on the major cardiovascular events in type 2 diabetic patients who had a history
of coronary artery disease (CAD).RESEARCH DESIGN AND METHODSThis study is a
multicenter, randomized, double-blind, placebo-controlled clinical trial...
Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. [2011.09]
CONCLUSIONS: Despite similar 52-week glycemic efficacy, dapagliflozin reduced weight and produced less hypoglycemia than glipizide in type 2 diabetes inadequately controlled with metformin. Long-term studies are required to further evaluate genital and urinary tract infections with SGLT2 inhibitors.
Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. [2007.03]
AIM: To compare the efficacy and safety of sitagliptin vs. glipizide in patients with type 2 diabetes and inadequate glycaemic control [haemoglobin A(1c) (HbA(1c)) > or = 6.5 and < or = 10%] on metformin monotherapy... CONCLUSIONS: In this study, the addition of sitagliptin compared with glipizide provided similar HbA(1c)-lowering efficacy over 52 weeks in patients on ongoing metformin therapy. Sitagliptin was generally well tolerated, with a lower risk of hypoglycaemia relative to glipizide and with weight loss compared with weight gain with glipizide.
Lack of pharmacokinetic interaction for ISIS 113715, a 2'-0-methoxyethyl modified antisense oligonucleotide targeting protein tyrosine phosphatase 1B messenger RNA, with oral antidiabetic compounds metformin, glipizide or rosiglitazone. 
BACKGROUND: ISIS 113715 is a 20-mer phosphorothioate antisense oligonucleotide (ASO) that is complementary to the protein tyrosine phosphatase 1B (PTP-1B) messenger RNA and subsequently reduces translation of the PTP-1B protein, a negative regulator of insulin receptor. ISIS 113715 is currently being studied in early phase II clinical studies to determine its ability to improve or restore insulin receptor sensitivity in patients with type 2 diabetes mellitus. Future work will investigate the combination of ISIS 113715 with antidiabetic compounds... CONCLUSION: These data provide evidence that ISIS 113715 exhibits no clinically relevant pharmacokinetic interactions on the disposition and clearance of the oral antidiabetic drugs. The results of these studies support further study of ISIS 113715 in combination with antidiabetic compounds.
Effect on glycemic control of the addition of 2.5 mg glipizide GITS to metformin in patients with T2DM. [2005.05]
AIMS: This study evaluated the effects on glycemic control of the addition of 2.5 mg glipizide GITS to metformin in patients with mild-to-moderate, but suboptimally controlled type 2 diabetes... CONCLUSIONS: This study showed that the addition of 2.5 mg glipizide GITS to metformin significantly improved glucose control in patients with type 2 diabetes inadequately controlled by metformin monotherapy.
Clinical Trials Related to Glipizide and Metformin (Glipizide / Metformin)
Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans [Recruiting]
The SUGARMGH investigators are studying the influence of inherited gene variants on the
response to two commonly prescribed type 2 diabetes medications, metformin and glipizide.
They hypothesize that variants in genes that are associated with type 2 diabetes or related
traits may impact the effect of anti-diabetic medications. In addition, physiological
responses to an insulin secretagogue or an insulin sensitizer may shed light on the
mechanism of action of reported genetic associations.
A Study of MK-3102 in Participants With Type 2 Diabetes Mellitus With Chronic Kidney Disease or Kidney Failure on Dialysis (MK-3102-019 AM2) [Recruiting]
The purpose of this study is to evaluate the efficacy and safety of MK-3102 in participants
with type 2 diabetes mellitus and moderate or severe chronic renal insufficiency or end
stage renal disease on dialysis with inadequate glycemic control.
Outpatient Discharge Therapy With Saxagliptin+MetforminXR vs GlipizideXL for Type 2 Diabetes With Severe Hyperglycemia [Recruiting]
Saxagliptin + Metformin XR (S+M) will be effective in stabilizing blood glucose (BG) levels
in patients with newly diagnosed type 2 diabetes (T2DM) with severe hyperglycemia (BG levels
300 to 450 mg/dl) and glucose toxicity and with no criteria for inpatient admission or
occurrence of severe hypoglycemia compared to glipizide XL.
The study may provide preliminary evidence to support the role of S+M as a bridging,
stabilizing and safe therapy in patients with severe hyperglycemia
Efficacy and Safety Study of Alogliptin Compared to Glipizide in Elderly Diabetics [Recruiting]
The purpose of this study is to evaluate the efficacy and safety of alogliptin compared to
glipizide in elderly diabetic patients who have not received treatment or are on a single
Food Study of Glipizide and Metformin HCl Tablets 5 mg/500 mg to Metaglip® Tablets 5 mg/500 mg [Completed]
The objective of this study was to investigate the bioequivalence of Mylan's glipizide and
metformin HCl 5 mg/500 mg tablets to Bristol-Myers Squibb's Metaglip® 5 mg/500 mg tablets
following a single, oral 5 mg/500 mg (1 x 5 mg/500 mg) dose administration under fed