Anti-diabetic drug (patient information)

# Overview
Anti-diabetic drugs treat diabetes mellitus by lowering glucose levels in the blood. With the exceptions of insulin, exenatide, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents. There are different classes of anti-diabetic drugs, and their selection depends on the nature of the diabetes, age and situation of the person, as well as other factors.
Insulin is the mainstay of treatment in Type I diabetes, in which insulin production is impaired. In Type II diabetes, Insulin is used when oral medication has become ineffective.

# Main agents

## 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. Eight types of these pills have been marketed in North America, but not all remain available. The "second-generation" drugs are now more commonly used. They are more effective 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 can not be used with type I diabetes, or diabetes of pregnancy. They can be safely used with metformin or -glitazones. The primary side effect is hypoglycemia.
- First-generation agents
tolbutamide (Orinase)
acetohexamide (Dymelor)
tolazamide (Tolinase)
chlorpropamide (Diabinese)
- tolbutamide (Orinase)
- acetohexamide (Dymelor)
- tolazamide (Tolinase)
- chlorpropamide (Diabinese)
- Second-generation agents
glipizide (Glucotrol)
glyburide (Diabeta, Micronase, Glynase)
glimepiride (Amaryl)
gliclazide (Diamicron)
- glipizide (Glucotrol)
- glyburide (Diabeta, Micronase, Glynase)
- glimepiride (Amaryl)
- gliclazide (Diamicron)

## Biguanides
Biguanides reduce hepatic glucose output and increase uptake of glucose by the periphery, including skeletal muscle. 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- phenformin (DBI): used from 1960s through 1980s, withdrawn due to lactic acidosis risk.
- buformin: also withdrawn due to lactic acidosis risk.
Metformin should be temporarily discontinued before any radiographic procedure involving intravenous iodinated contrast as patients are at an increased risk of lactic acidosis.

# Newer and adjunctive classess

## Meglitinides
Meglitinides help the pancreas produce insulin and are often called "short-acting secretagogues." Their mode of action is original (K channels ).By closing the potassium channels of the pancreas beta cells, they open the calcium channels, hence enhancing insulin exocytosis.
They are taken with meals to boost the insulin response to each meal.
- repaglinide (Prandin) - The max dosage is 16 mg/day. Take this drug 0 to 30 minutes before eating a meal. If a meal is skipped, then the medication should also be skipped.
- nateglinide (Starlix) - The max dosage is 360 mg/day, usually 120 mg three times a day (TID). It also follows the same recommendations as repaglinide.
Adverse reactions include weight gain and hypoglycemia.

## Thiazolidinediones
Thiazolidinediones (TZAs), also known as "glitazones," bind to PPAR, a type of nuclear regulatory proteins involved in transcription of genes regulating glucose and fat metabolism. These PPARs act on Peroxysome Proliferator Responsive Elements (PPRE ). The PPREs influence insulin sensitive genes, which enhance production of mRNAs of insulin dependent enzymes. The final result is better use of glucose by the cells.
- 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/Glucobay)
These medications are rarely used in the United States because of the severity of their side effects (flatulence and bloating).  They are more commonly prescribed in Europe.

## Peptide analogs

### Incretin mimetics
Incretin is an insulin secretagogue. The two main candidate molecules that fulfil criteria for an incretin are Glucagon-like peptide-1 (GLP-1) and Gastric inhibitory peptide (aka glucose-dependent Insulinotropic peptide or GIP). Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).
GLP agonists bind to a membrane GLP receptor. As a consequence of this, Insulin release from the pancreatic beta cells is increased. Endogenous GLP has a half life of only a few minutes; thus an analogue of GLP would not be practical.
- Exenatide (also Exendin-4, marketed as Byetta) is the first GLP agonist approved for the treatment of type 2 diabetes. Exenatide is NOT an analogue of GLP, but rather a GLP agonist. Exenatide has only a 53% homology with GLP and, which increases its resistance to degradation by DPP-4 and extends its  half-life.
- Liraglutide (not FDA approved)
- None are FDA approved

### DPP-4 inhibitors
Dipeptidyl peptidase-4 (DPP-4) inhibitors increase blood concentration of the incretin GLP-1 (glucagon-like peptide-1) by inhibiting its degradation by dipeptidyl peptidase-4 (DPP-4). Examples are:
- vildagliptin
- sitagliptin

### Amylin analogue
Amylin agonist analogues slow gastric emptying and suppress glucagon.
- Pramlintide.

# 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. Others are undergoing phase I/II studies.
- PPAR/ ligands (muraglitazar and tesaglitazar) - development stopped due to adverse risk profile
- SGLT (sodium-dependent glucose transporter 1) inhibitors increase urinary glucose.
- FBPase (fructose 1,6-bisphosphatase) inhibitors decrease gluconeogenesis in liver.

# Insulin by inhalation
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.  One alternative delivery method is by inhalation.  In 2006 the U.S. Food and Drug Administration approved the use of Exubera, the first inhalable insulin.
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.

# Herbal extracts
The first registred use of anti-diabetic drugs was as herbal extracts used by Indians in the Amazon Basin for the treatment of type 2 diabetes, and today promoted as vegetable insulin although  not formally an insulin analog.
The major recent development was done in Brazil around Myrcia sphaerocarpa and other Myrcia species.
"Many countries, especially in the developing world, have a long history of the use of herbal remedies in diabetes (...) STZ diabetic rats were also used to test Myrcia Uniflora extracts (...) ".
The usual treatment is with concentrated (root) Myrcia extracts, commercialized in a 4 US dollar per kilogram packed rocks (~100 times cheaper than equivalent artificial drugs), named "Pedra hume de kaa". 
Phytochemical analysis of the Myrcia extracts reported kinds of flavanone glucosides (myrciacitrins) and acetophenone glucosides (myrciaphenones), and inhibitory activities on aldose reductase and alpha-glucosidase.
A recent review article presents the profiles of plants with hypoglycaemic properties, reported in the literature from 1990 to 2000 and states that "Medical plants play an important role in the management of diabetes mellitus especially in developing countries where resources are meager."