1. GLIPIZIDE XL HISTORY
(How was Glipizide XL discovered?)

Glipizide XL is an oral medium-to-long acting anti-diabetic drug from the sulfonylurea class.

Glipizide XL has been available since in 1984.

2.GLIPIZIDE XL FACTS

Glipizide XL is an antidiabetic medication, which is used in those patients with adult maturity onset or non-insulin dependent diabetes (NIDDM). Glipizide XL works by lowering blood sugar levels by stimulating the production and release of insulin from the pancreas. Glipizide XL also promotes the movement of sugar from the blood into the cells in the body, which need it. 

3.ABOUT GLIPIZIDE XL 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 anti-diabetic 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
• 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.

• Rosiglitazone (Avandia)
• 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.GLIPIZIDE XL EFFECTIVENESS
(When is Glipizide XL best taken?)

Gastrointestinal absorption of Glipizide or Glipizide XL in man is uniform, rapid, and essentially complete. Peak plasma concentrations occur 1-3 hours after a single oral dose of Glipizide XL. The half-life of elimination ranges from 2-4 hours in normal subjects, whether given intravenously or orally. The metabolic and excretory patterns are similar with the two routes of administration, indicating that first-pass metabolism is not significant. Glipizide does not accumulate in plasma on repeated oral administration. It has been reported that total absorption and disposition of an oral dose was unaffected by food in normal volunteers, but absorption was delayed by about 40 minutes. Thus Glipizide was more effective when administered about 30 minutes before, rather than with, a test meal in diabetic patients. Protein binding was studied in serum from volunteers who received oral Glipizide and found to be 98-99% one hour after either route of administration. The apparent volume of distribution of glipizide after intravenous administration was 11 liters, indicative of localization within the extracellular fluid compartment. In mice no Glipizide or metabolites were detectable autoradiographically in the brain or spinal cord of males or females, nor in the fetuses of pregnant females. In another study, however, very small amounts of radioactivity were detected in the fetuses of rats given labelled drug.

The metabolism of Glipizide is extensive and occurs mainly in the liver. The primary metabolites are inactive hydroxylation products and polar conjugates and are excreted mainly in the urine. Less than 10% unchanged Glipizide is found in the urine. 

5.GLIPIZIDE XL EFFECTS ON SPECIAL POPULATION
(How do different people react to Glipizide XL?)

Pregnancy

Glipizide XL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Nursing Mothers

Although it is not known whether Glipizide XL is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. 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 the drug is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use:

Safety and effectiveness in pediatric patients have not been established

Geriatric Use:

Of the total number of patients in clinical studies of Glipizide XL 33 percent were 65 and over. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some individuals cannot be ruled out. Approximately 1-2 days longer were required to reach steady state in the elderly.

6.GLIPIZIDE XL EFFECTS ON MEDICAL CONDITIONS
(How does Glipizide XL affect your existing condition/ailment?)

Glipizide XL should not be used if you suffer from life long inherited blood diseases, which can cause a variety of symptoms, including mental health problems (porphyrias). 

7.OTHER/ALTERNATE USES OF GLIPIZIDE XL
(What else does Glipizide XL treat?)

Glipizide XL is used, along with diet and exercise, in the treatment of type 2 diabetes.

8.ADVERSE/SIDE EFFECTS of GLIPIZIDE XL
(What are the side effects of Glipizide XL?)

Gastrointestinal: Gastrointestinal disturbances are the most common reactions. Gastrointestinal complaints were reported with the following approximate incidence: nausea and diarrhea, one in seventy; constipation and gastralgia, one in one hundred. They appear to be dose-related and may disappear on division or reduction of dosage. Cholestatic jaundice may occur rarely with sulfonylureas; Glipizide should be discontinued if this occurs.

Dermatologic : Allergic skin reactions including erythema, morbilliform or maculopapular eruptions, urticaria, pruritus, and eczema have been reported in about one in seventy patients. These may be transient and may disappear despite continued use of Glipizide; if skin reactions persist, the drug should be discontinued. Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.

Miscellaneous : Dizziness, drowsiness, and headache have each been reported in about one in fifty patients treated with Glipizide. They are usually transient and seldom require discontinuance of therapy.

Extended Release Tablets

In U.S. controlled studies the frequency of serious adverse experiences reported was very low and causal relationship has not been established. The 580 patients from 31 to 87 years of age who received Glipizide extended-release tablets in doses from 5 mg to 60 mg in both controlled and open trials were included in the evaluation of adverse experiences. All adverse experiences reported were tabulated independently of their possible causal relation to medication.

Hypoglycemia: Only 3.4% of patients receiving Glipizide extended-release tablets had hypoglycemia-documented by/ a blood glucose measurement <60 mg/dl and or symptoms believed to be associated with hypoglycemia. In a comparative efficacy study of Glipizide XL and Glipizide, hypoglycemia occurred rarely with an incidence of less than 1% with both drugs.

In double-blind, placebo-controlled studies the adverse experiences reported with an incidence of 3% or more in Glipizide XL treated patients include:

Adverse Effect	Glipizide XL (%)	Placebo (%)
(N=278)	(N=69)
Asthenia	10.1	13.0
Headache	8.6	8.7
Dizziness	6.8	5.8
Nervousness	3.6	2.9
Tremor	3.6	0.0
Diarrhea	5.4	0.0
Flatulence	3.2	1.4

The following adverse experiences occurred with an incidence of less than 3% in Glipizide XL treated patients:

Body as a Whole: Pain. 

Nervous System : Insomnia, paresthesia, anxiety, depression and hypesthesia. 

Gastrointestinal : Nausea, dyspepsia, constipation and vomiting.

Metabolic : Hypoglycemia. 

Musculoskeletal : Arthralgia, leg cramps and myalgia. 

Cardiovascular : Syncope. 

Skin : Sweating and pruritus. 

Respiratory : Rhinitis. 

Special Senses : Blurred vision. 

Urogenital : Polyuria.

Other adverse experiences occurred with an incidence of less than 1% in Glipizide XL treated patients:

Body as a Whole : Chills.

Nervous System : Hypertonia, confusion, vertigo, somnolence, gait abnormality and decreases libido. 

Gastrointestinal : Anorexia and trace blood in stool.

Metabolic : Thirst and edema. 

Cardiovascular : Arrhythmia, migraine, flushing and hypertension.

Skin : Rash and urticaria.

Respiratory : Pharyngitis and dyspnea.

Special Senses : Pain in the eye, conjunctivitis and retinal hemorrhage.

Urogenital : Dysuria.

Although these adverse experiences occurred in patients treated with Glipizide XL, a causal relationship to the medication has not been established in all cases.

There have been rare reports of gastrointestinal irritation and gastrointestinal bleeding with use of another drug in this non-deformable sustained release formulation, although causal relationship to the drug is uncertain.