1.GLUCOPHAGE HISTORY
How was Glucophage discovered?

Glucophage is a product of Bristol-Myers Squibb.

Bristol-Myers Squibb is a pharmaceutical and related health care products company whose mission is to extend and enhance human life by providing the highest-quality pharmaceuticals and health care products. Bristol-Myers Squibb' medicines are making a difference in the lives of millions of customers across the globe.

Bristol-Myers Squibb is one of 20 U.S. companies listed in the new Global 100 Most Sustainable Corporations in the World. The new global business ranking identifies the top 100 companies that are most open to leading the way to a more sustainable world. 

Note: World-drugs.net sells generic version of Glucophage

2.GLUCOPHAGE FACTS

Glucophage is a type of antidiabetic medicine known as a biguanide. 

Glucophage works in a number of ways to decrease the amount of sugar in the blood of people with type 2 diabetes.

Firstly, Glucophage reduces the amount of sugar produced by cells in the liver. Secondly, it increases the sensitivity of muscle cells to insulin. This enables the cells to remove sugar from the blood more effectively. Finally, it also delays absorption of sugar from the intestines into the bloodstream after eating. Overall, Glucophage reduces blood sugar levels both between and directly after meals. 

3.ABOUT GLUCOPHAGE MEDICATION

What is Diabetes and what are its causes

Diabetes (diabetes mellitus): a condition characterized by hyperglycemia resulting from the body's inability to use blood glucose for energy. In type 1 diabetes, the pancreas no longer makes insulin and therefore blood glucose cannot enter the cells to be used for energy. In Type 2 diabetes, either the pancreas does not make enough insulin or the body is unable to use insulin correctly.

Pre-diabetes: a condition in which blood glucose levels are higher than normal but are not high enough for a diagnosis of Diabetes. People with pre-diabetes are at increased risk for developing Type 2 diabetes and for heart disease and stroke. Other names for pre-Diabetes are impaired glucose tolerance and impaired fasting glucose.

Type 1 diabetes: a condition characterized by high blood glucose levels caused by a total lack of insulin. Occurs when the body's immune system attacks the insulin-producing beta cells in the pancreas and destroys them. The pancreas then produces little or no insulin. Type 1 diabetes develops most often in young people but can appear in adults.

Type 2 diabetes: a condition characterized by high blood glucose levels caused by either a lack of insulin or the body's inability to use insulin efficiently. Type 2 diabetes develops most often in middle-aged and older adults but can appear in young people.

Other causes of diabetes

There are some other causes of Diabetes, including certain diseases of the pancreas, but they are all very rare. Sometimes an accident or an illness may reveal Diabetes if it is already there, but they do not cause it.

What are the symptoms of Diabetes?

The main symptoms of Diabetes are:

• increased thirst
• going to the loo all the time – especially at night
• extreme tiredness
• weight loss
• genital itching or regular episodes of thrush
• blurred vision.

Type 2 diabetes develops slowly and the symptoms are usually less severe. Some people may not notice any symptoms at all and their Diabetes is only picked up in a routine medical check up. Some people may put the symptoms down to 'getting older' or 'overwork'.

Type 1 Diabetes develops much more quickly, usually over a few weeks, and symptoms are normally very obvious.

In both types of Diabetes, the symptoms are quickly relieved once the Diabetes is treated. Early treatment will also reduce the chances of developing serious health problems.

What are the risk factors for Diabetes?

Age
All people are vulnerable to the disease throughout their lives. However, the risk is higheras you grow older. There is a gradual increase in susceptibility, with slight peaks at puberty and during pregnancy, until we reach the age of 40. Then there is a rapid jump.

Heredity
If you have a family history of Diabetes, especially parents or siblings with Diabetes, then you're near the top of the list in terms of risk. Heredity is the most important predisposing factor for Diabetes, especially for type-I Diabetes.

Type II diabetes also tends to run in families, but since 80 to 85 percent of all cases occur among people who are over 40 and overweight, obesity is considered more important in the development of this form of the disease.

Obesity
80 to 85 percent of people with type-II diabetes are overweight. It is true that not all overweight people have Diabetes. But if you are obese, you may be setting yourself up for this disease 10 or 20 years from now. (You are considered obese, if you are more than 20 percent over ideal body weight.)

Race
In the United States the disease is more common among African-Americans, Hispanics and American Indians. More than 40% of Pima Indians in the United States have type 2 diabetes. However, that race alone does not predict Diabetes; it must be combined with another factor, such as obesity.

Poverty
Researchers have uncovered a link between poverty and Diabetes. In a survey in the USA, households with the lowest income-under $15,000- was found to have the highest incidence of Diabetes.

Having impaired glucose tolerance
Having high blood pressure or high cholesterol levels (240 mg/dl or more)

In women, having a history of gestational Diabetes or delivery of babies weighing more than 9 pounds

Complications of Diabetes

When you are not properly managing your Type 2 diabetes, you greatly increase your risk of Diabetes-related complications. Every one percent increase in your A1C level above 6 percent elevates the risk of Diabetes-related complications, including stroke, heart attack, blindness and loss of limbs. Here are some of the more common risks associated with Type 2 diabetes:

Heart Disease and Stroke

• Diabetes carries an increased risk for heart attack and stroke related to poor circulation.
• People with Diabetes are two to four times more likely to suffer strokes.
• Two-thirds of the people with Diabetes die of heart disease or stroke.

Kidney Disease

•   The kidneys filter the waste products from the body.
•   Diabetes can damage the kidneys, leading to failure.

Eye Complications

•   Diabetes can cause eye problems and may lead to blindness.
•   Every year up to 24,000 people lose their sight to Diabetes

Nerve Damage 

• Diabetes can cause nerve damage (neuropathy), which can affect feelings in arms, hands, legs or feet, and cause you to lose sensitivity to pain.
• Severe nerve damage can lead to limb amputation.

Foot Complications

• Diabetes can cause foot ulcers, nerve damage to the feet, infections and loss of blood flow resulting in possible amputation.

Skin Complications

• Diabetes can cause a range of skin disorders, such as itching, diabetic blisters, bacterial and fungus infections.
• Although these conditions are serious, you can lower your risk of Diabetes-related complications by managing your Diabetes every day.

Treatment of Diabetes

An anti-diabetic drug or oral hypoglycemic agent is used to treat diabetes mellitus. They usually work by lowering the glucose levels in the blood. There are different types of anti-diabetic drugs, and their use depends on the nature of the Diabetes, age and situation of the person, as well as other factors.

Insulin is the only non-oral antidiabetic drug. It is the mainstay of treatment in type I Diabetes, in which insulin production is impaired. In Type II diabetes , it is used when oral medication has become ineffective.

Antidiabetics

Sulfonylureas
Sulfonylureas were the first widely used oral hypoglycemic medications. They are insulin secretagogues, triggering insulin release by direct action on the KATP channel of the pancreatic beta cells. Seven types of these pills have been marketed in North America. Four, known as "first-generation" drugs, have been in use for some time, but not all remain available. Three "second-generation" drugs, are now more commonly used. They are stronger than first-generation drugs and have fewer side effects.

Sulfonylureas bind strongly to plasma proteins. Sulfonylureas are only useful in Type II diabetes , as they work by stimulating endogenous release of insulin. They work best with patients over 40 years old, who have had diabetes mellitus for under ten years. They cannot be used with type I diabetes, or Diabetes of pregnancy. They can be safely used with biguanides and glitazones. The toxicity of these drugs on the whole is relatively low.

First-generation agents

• Tolbutamide (Orinase)
• Acetohexamide (Dymelor)
• Tolazamide (Tolinase)
• Chlorpropamide (Diabinese)

Second-generation agents

• Glipizide (Glucotrol)
• Glyburide (Diabeta, Micronase, Glynase)
• Glimepiride (Amaryl)

Meglitinides

Meglitinides are related to sulfonylureas. The amplification of insulin release is shorter and more intense, and they are taken with meals to boost the insulin response to each meal.

• Repaglinide (Prandin)
• Nateglinide (Starlix)

Biguanides

Biguanides reduce hepatic glucose output. Although it must be used with caution in patients with impaired liver or kidney function, metformin has become the most commonly used agent for Type 2 diabetes in children and teenagers.

• Metformin (Glucophage)
• Phenformin (DBI): used in 1960-1980s, withdrawn due to lactic acidosis risk.  

Thiazolidinediones

Thiazolidinediones, also known as "glitazones," bind to PPAR?, a type of nuclear regulatory protein involved in transcription of numerous genes regulating glucose and fat metabolism. They act as "insulin sensitizers" without increasing insulin secretion.

• Pioglitazone (Actos)
• Troglitazone (Rezulin): used in 1990s, withdrawn due to hepatitis and liver damage risk.

Alpha glucosidase inhibitors

Alpha glucosidase inhibitors are "diabetes pills" but not technically hypoglycemic agents because they do not have a direct effect on insulin secretion or sensitivity. These agents slow the digestion of starch in the small intestine, so that glucose from the starch of a meal enters the bloodstream more slowly, and can be matched more effectively by an impaired insulin response or sensitivity. These agents are effective by themselves only in the earliest stages of impaired glucose tolerance, but can be helpful in combination with other agents in type 2 diabetes.

• Miglitol (Glyset)
• Acarbose (Precose)

Experimental agents

Many other potential drugs are currently in investigation by pharmaceutical companies. Some of these are simply newer members of one of the above classes, but some work by novel mechanisms. For example, at least one compound that enhances the sensitivity of glucokinase to rising glucose is in the stage of animal research.

Insulin by mouth

The basic appeal of oral hypoglycemic agents is that most people would prefer a pill to an injection. Unlike all the oral drugs described in this article, insulin is a protein. Protein hormones, like meat proteins, are digested in the stomach and gut.

However, the potential market for an oral form of insulin is enormous and many laboratories have attempted to devise ways of moving enough intact insulin from the gut to the portal vein to have a measurable effect on blood sugar. One can find several research reports over the years describing promising approaches or limited success in animals, and limited human testing, but as of 2004, no products appear to be successful enough to bring to market. 

4.GLUCOPHAGE EFFECTIVENESS
When is Glucophage best taken?

Absorption

The absolute bioavailability of a Glucophage 500 mg tablet given under fasting conditions is approximately 50-60%. Studies using single oral doses of Glucophage 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of Glucophage doses, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve, and a 35 minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg dose of Glucophage with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown. 

Following a single oral dose of Glucophage XR , Cmax is achieved with a median value of 7 hours and a range of 4 hours to 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of Glucophage, however, the extent of absorption (as measured by AUC) is similar to Glucophage. 

Although the extent of Glucophage absorption (as measured by AUC) from the Glucophage XR tablet increased by approximately 50% when given with food, there was no effect of food on Cmax and Tmax of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of Glucophage XR. 

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of Glucophage 850 mg averaged 654 ± 358 L. Glucophage is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Glucophage partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of Glucophage, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 m g/mL. During controlled clinical trials of Glucophage, maximum metformin plasma levels did not exceed 5 m g/mL, even at maximum doses.

Metabolism and Elimination

Intravenous single-dose studies in normal subjects demonstrate that Glucophage is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. 

5.GLUCOPHAGE EFFECTS ON SPECIAL POPULATION
How do different people react to Glucophage?

Nursing Mothers

Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If Glucophage or Glucophage XR is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered. 

Geriatrics

Limited data from controlled pharmacokinetic studies of Glucophage in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function. Glucophage and Glucophage XR treatment should not be initiated in patients 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced. 

Pediatrics

No pharmacokinetic data from studies of pediatric patients are currently available. After administration of a single oral Glucophage 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function. 

Gender

Glucophage pharmacokinetic parameters did not differ significantly between normal subjects and patients with Type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with Type 2 diabetes, the antihyperglycemic effect of Glucophage was comparable in males and females. 

Race

No studies of Glucophage pharmacokinetic parameters according to race have been performed. In controlled clinical studies of Glucophage in patients with Type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

6.GLUCOPHAGE EFFECTS ON MEDICAL CONDITIONS
How does Glucophage affect your existing condition/ailment?

In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of Glucophage between patients with Type 2 diabetes and normal subjects, nor is there any accumulation of Glucophage in either group at usual clinical doses.

The pharmacokinetics of Glucophage XR in patients with Type 2 diabetes is comparable to those in healthy normal adults.

Renal Insufficiency

In patients with decreased renal function, the plasma and blood half-life of Glucophage is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance.

Hepatic Insufficiency

No pharmacokinetic studies of Glucophage have been conducted in patients with hepatic insufficiency.

7.OTHER/ALTERNATE USES OF GLUCOPHAGE
What else does Glucophage treat?

Glucophage has also been used to prevent the development of Diabetes in people at risk for Diabetes and to treat polycystic ovaries. 

8.ADVERSE/SIDE EFFECTS of GLUCOPHAGE
What are the side effects of Glucophage?

In a US double-blind clinical study of Glucophage in patients with Type 2 diabetes, a total of 141 patients received Glucophage therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the Glucophage patients, and those were more common in Glucophage- than placebo-treated patients, are listed in the Table 1 below.

Diarrhea led to discontinuation of study medication in 6% of patients treated with Glucophage. Additionally, the following adverse reactions were reported in ³1.0 - £5.0% of Glucophage patients and were more commonly reported with Glucophage than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. In worldwide clinical trials over 900 patients with Type 2 diabetes have been treated with Glucophage XR in placebo- and active-controlled studies. In placebo-controlled trials, 781 patients were administered Glucophage XR and 195 patients received placebo. Adverse reactions reported in greater than 5% of the Glucophage XR patients, and those were more common in Glucophage XR- than placebo-treated patients, are listed in Table 2.

Diarrhea led to discontinuation of study medication in 0.6% of patients treated with Glucophage XR. Additionally, the following adverse reactions were more commonly reported with Glucophage XR than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.