Anti-diabetic drug

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 or oral antihyperglycemic 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.

Overview
Diabetes mellitus type 1 is a disease caused by the lack of insulin. Insulin must be used in Type I, which must be injected or inhaled.

Diabetes mellitus type 2 is a disease of insulin resistance by cells. Treatments include (1) agents which increase the amount of insulin secreted by the pancreas, (2) agents which increase the sensitivity of target organs to insulin, and (3) agents which decrease the rate at which glucose is absorbed from the gastrointestinal tract.

Several groups of drugs, mostly given by mouth, are effective in Type II, often in combination. The therapeutic combination in Type II may include insulin, not necessarily because oral agents have failed completely, but in search of a desired combination of effects. The great advantage of injected insulin in Type II is that a well-educated patient can adjust the dose, or even take additional doses, when blood glucose levels measured by the patient, usually with a simple meter, as needed by the measured amount of sugar in the blood.

Insulin
Insulin is usually given subcutaneously, either by injections or by an insulin pump. Research is underway of other routes of administration. In acute care settings, insulin may also be given intravenously. There are several types of insulin, characterized by the rate which they are metabolized by the body.

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. All may cause weight gain.

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)
 * Second-generation agents
 * 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. Amongst common diabetic drugs, metformin, a biguanide, is the only widely used oral drug that does not cause weight gain. Metformin should be temporarily discontinued before any radiographic procedure involving intravenous iodinated contrast as patients are at an increased risk of lactic acidosis.
 * metformin (Glucophage). Metformin may be the best choice for patients who also have heart failure.
 * phenformin (DBI): used from 1960s through 1980s, withdrawn due to lactic acidosis risk.
 * buformin: also withdrawn due to lactic acidosis risk.

Metformin is usually the first-line medication used for treatment of type-2 diabetes. Initial dosing is 500 mg twice daily, but can be increased up to 1000 mg twice daily. It is also available in combination with other oral diabetic medications.

Meglitinides
Meglitinides help the pancreas produce insulin and are often called "short-acting secretagogues." Their mode of action is original, affecting potassium channels. By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, hence enhancing insulin secretion.

They are taken with meals to boost the insulin response to each meal.


 * repaglinide (Prandin) - The maximum dosage is 16 mg/day, taken 0 to 30 minutes before meals. If a meal is skipped, the medication is also skipped.
 * nateglinide (Starlix) - The maximum 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 (TZDs), also known as "glitazones," bind to PPARγ, 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.

As a result of multiple retrospective studies, there is a concern about rosiglitazone's safety, although it is established that the group, as a whole, has beneficial effects on diabetes. The greatest concern is an increase in the number of severe cardiac events in patients taking it. The ADOPT study showed that initial therapy with drugs of this type may prevent the progression of disease, as did the DREAM trial.

Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in the New England Journal of Medicine. There have been a significant number of publications since then, and a Food and Drug Administration panel voted, with some controversy, 20:3 that available studies "supported a signal of harm," but voted 22:1 to keep the drug on the market. Safety studies are continuing.

In contrast, at least one large prospective study, PROactive 05, has shown that pioglitazone may decrease the overall incidence of cardiac events in people with type II diabetes who have already had a heart attack.

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. 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.
 * miglitol (Glyset)
 * acarbose (Precose/Glucobay)

They do have the potential to cause weight loss by lowering the amount of sugar metabolized.

Incretin mimetics
Incretins are insulin secretagogues. The two main candidate molecules that fulfill criteria for being 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).

Glucagon-like peptide (GLP) analogs
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 53% homology with GLP, which increases its resistance to degradation by DPP-4 and extends its half-life.
 * Liraglutide- a once daily human analogue (97% homology) is being developed by Novo Nordisk. As of 2007, it is in phase III clinical trials.

These agents may also cause a decrease in gastric motility, responsible for the common side effect of nausea, and is probably the mechanism by which weight loss occurs.

Gastric inhibitory peptide (GIP) analogs

 * 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 analogues
Amylin agonist analogues slow gastric emptying and suppress glucagon. As of 2007, pramlintide is the only clinically available amylin analogue. Like insulin, it is administered by subcutaneous injection. The most frequent and severe adverse effect of pramlintide is nausea, which occurs mostly at the beginning of treatment and gradually reduces.

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.
 * PPARα/γ 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 the liver.

Herbal extracts
The first registered 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 kaá". 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."