Antidiabetic Drugs

Posts Tagged ‘Glucovance’

The biguanide, metformin (Glucophage®, Novo-metformin, Nu-metformin and Gen-metformin) is an oral antihyperglycemic agent used in the management of non-insulin-dependent diabetes mellitus (NIDDM). Phenformin, another biguanide, was withdrawn from the market in many countries because of the high risk of inducing lactic acidosis; however, metformin is associated with a very low incidence of lactic acidosis because it has different pharmacokinetic properties. For example, metformin is not metabolized by the liver, therefore, there are no high- risk groups demonstrating an impaired metabolism. One benefit of metformin, in contrast to the sulphonylureas, is that hypoglycemia does not occur during monotherapy. Also, obese patients with NIDDM may favour metformin because it does not appear to cause an increase in body weight.

Metformin has been available in Canada since 1972. Since marketing, the Canadian Adverse Drug Reaction Monitoring Program (CADRMP) has received 11 reports (7 women, 4 men) of lactic acidosis associated with the use of metformin.

Summary of cases:
• The mean age was 68 years (range 39 to 91 years).
• Patients, for whom a daily dose was reported, were prescribed 1.5 grams.
• The actual lactate level was provided in only three cases.
• The outcomes were: four people died; four recovered; two patients had not yet recovered at the time of reporting; and one recovered with residual effects.
• In all cases, one or more risk factors for developing lactic acidosis were present: Five cases (3 fatal), had pre-existing renal insufficiency; in four cases, there was implicit evidence of congestive heart failure from the concomitant medications being taken (e.g., digoxin, furosemide); and in one report, the patient consumed an excessive amount of alcohol while on metformin. Finally, one report involved a 91-year-old man who developed lactic acidosis and acute renal failure 2 days after metformin was initiated. The complicating factor, following the onset of the reaction, was that metformin treatment was continued and the patient underwent a diagnostic examination using radiocontrast media.

The Canadian Adverse Drug Reaction Advisory Committee was asked to review the above 11 cases of lactic acidosis. The committee concluded that none of the cases provided evidence that metformin was definitely the cause of the acidosis, but for most patients, it may have been a contributing factor.

The above cases, reported to CADRMP, occurred primarily in patients with explicit or implicit evidence of renal insufficiency or congestive heart failure. The diabetic patient is susceptible to complications that cause morbidity and premature mortality, including cardiovascular and renal impairment. While some evidence suggests that the risk of lactic acidosis with metformin is unrelated to age, elderly diabetic patients will have developed complications that possibly increase this risk. Thus, careful selection of patients and continuous monitoring for any changes in condition that may lead to contraindication of the drug is important.

The contraindications associated with the use of metformin include patients:

a) with hypersensitivity to metformin or related agents
b) with medical conditions, including

• i) renal impairment or unknown renal function
• ii) liver disease
• iii) alcoholism
• iv) intercurrent infection, or
• v) cardiopulmonary insufficiency

c) undergoing medical or diagnostic examinations, e.g., angiography or i.v. pyelography

d) with a history of ketoacidosis or lactic acidosis

Although the development of lactic acidosis is rare, the reported case fatality rate is 30% to 50%. Nevertheless, lactic acidosis is largely preventable by strict observance of such risk factors; therefore, it is important to heed the contraindications, precautions and warnings detailed in the product monograph.

Brand Name: Glucovance
Active Ingredient: metformin / glyburide
Indication: Treatment of type 2 diabetes
Company Name: Bristol-Myers Squibb Company
Availability: Approved by FDA on July 31, 2000

Introduction

The drugs metformin and glyburide are commonly used by people with type 2 diabetes to control blood glucose levels. Individually the agents may or may not be effective. But together they pack a synergistic punch. A new combination of metformin and glyburide in a single tablet (250 mg metformin and 1.25 mg glyburide), manufactured by Bristol-Myers Squibb under the trade name Glucovance, helped people with type 2 diabetes achieve greater blood glucose control than either pill alone, reported investigators at the 60th annual meeting of the American Diabetes Association in June 2000. Glucovance is currently under review by the FDA.

How It Works

Metformin increases insulin action in peripheral tissues and reduces hepatic glucose output by inhibiting gluconeogenesis. Metformin may also reduce plasma glucose by decreasing the absorption of glucose from the small intestine.

Glyburide is a sulfonylurea that causes hypoglycemia by stimulating insulin release from pancreatic beta cells. Sulfonylureas may also further increase insulin levels by reducing hepatic clearance of the hormone.

Clinical Study Results

A total of 806 people with type 2 diabetes age 60 and older were randomized into multicenter, double-blind, placebo-controlled trials. Patients received either placebo, 2.5 mg glyburide, 500 mg metformin, 250 mg/1.25 mg metformin/glyburide, or 500 mg/2.5 mg metformin/glyburide, and were followed for 20 weeks. At the end of the study period, 66% of the 250 mg/1.25 mg metformin/glyburide group and 72% of the 500 mg/2.5 mg metformin/glyburide group achieved HbA1C levels of less than or equal to 7%, compared to 20% of patients taking placebo, 60% of those on glyburide alone, and 50% of those taking metformin alone.

Subjects in both metformin/glyburide groups also demonstrated significantly larger mean decreases in absolute postprandial glucose (-60.7 mg/dL for the 250mg/1.25 mg group and -58.8 mg/dL for the 500 mg/2.5 mg group) compared to patients taking placebo (+4.5 mg/dL), glyburide (-42.4 mg/dL), or metformin (-40.3 mg/dL) alone. Subjects taking metformin/glyburide also experienced larger mean increases in absolute 2-hour postprandial insulin (29.7 mU/ml for the 250mg/1.25 mg group and 25.0 mU/ml for the 500 mg/2.5 mg group) compared to patients taking placebo (0.9 mU/ml), glyburide (15.1 mU/ml), or metformin (4.0 mU/ml) alone. Finally, subjects in both metformin/glyburide groups also demonstrated significantly larger mean decreases in fasting plasma glucose (-41.5 mg/dL for the 250 mg/1.25 mg group and -40.1 mg/dL for the 500 mg/2.5 mg group) compared to patients taking placebo (+4.6 mg/dL), glyburide (-35.7 mg/dL), or metformin (-21.2 mg/dL) alone.

Adverse Events

Glucovance-related adverse events were minor and included diarrhea, nausea, upset stomach, and hypoglycemia. Patients taking the 250 mg/1.25 mg metformin/glyburide combination had fewer gastrointestinal side effects than patients taking metformin and fewer symptoms of hypoglycemia than those taking glyburide. Patients taking the 500 mg/2.5 mg metformin/glyburide combination reported more symptoms of hypoglycemia than patients taking glyburide, establishing the 250 mg/1.25 mg dosage as the optimal dosage of Glucovance.

The drugs metformin and glyburide are commonly used by people with type 2 diabetes to control blood glucose levels. Individually the agents may or may not be effective, but together they pack a one-two punch. A new combination of metformin and glyburide in a single tablet (250 mg metformin and 1.25 mg glyburide), manufactured by Bristol-Myers Squibb under the trade name Glucovance, helped people with type 2 diabetes achieve greater blood sugar control than either pill alone, reported investigators at the 60th annual meeting of the American Diabetes Association in June 2000. Glucovance is currently under review by the FDA.

A total of 806 people with type 2 diabetes age 60 and older took part in the clinical trials. Patients received either placebo, 2.5 mg glyburide, 500 mg metformin, 250 mg/1.25 mg metformin/glyburide or 500 mg/2.5 mg metformin/glyburide, and were followed for 20 weeks. At the end of the study period, 66 percent of the 250 mg/1.25 mg metformin/glyburide group and 72 percent of the 500 mg/2.5 mg metformin/glyburide group achieved HbA1C levels of less than or equal to seven percent — a measure of adequate blood sugar control — compared to 20 percent of patients taking placebo, 60 percent of those on glyburide alone and 50 percent of those taking metformin alone. Patients taking a metformin/glyburide combination also experienced better control of blood glucose and insulin levels both before and after eating.

“It is quite possible that the results of this study may lead to a new treatment paradigm for patients with type 2 diabetes,” said Dr. Daniel Donovan, assistant clinical professor of medicine, College of Physicians & Surgeons, Columbia University, and one of the study investigators. “None of the currently available oral antidiabetic drugs can, by themselves, address both of the major causes of type 2 diabetes: insulin resistance and insulin deficiency. The results of this study are encouraging because they demonstrate that by prescribing this novel oral antidiabetic, which attacks both major defects of type 2 diabetes, we can help our patients to aggressively control their blood sugar and, most importantly, avoid potentially serious complications.”

Side effects related to Glucovance were minor and included diarrhea, nausea, upset stomach and hypoglycemia.