Anti-diabetic drug

Anti-diabetic drug

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.
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.
Contents
• 1 Insulin
• 2 Secretagogues
o 2.1 Sulfonylureas
o 2.2 Meglitinides
• 3 Sensitizers
o 3.1 Biguanides
o 3.2 Thiazolidinediones
• 4 Alpha-glucosidase inhibitors
• 5 Peptide analogs
o 5.1 Incretin mimetics
 5.1.1 Glucagon-like peptide (GLP) analogs and agonists
 5.1.2 Gastric inhibitory peptide (GIP) analogs
o 5.2 DPP-4 inhibitors
o 5.3 Amylin analogues
• 6 Experimental agents
• 7 Alternative medicine
• 8 Notes
• 9 References

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.
Secretagogues
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.
Typical reductions in A1C values for second generation sulfonylureas are 1.0-2.0%.
• First-generation agents
o tolbutamide (Orinase)
o acetohexamide (Dymelor)
o tolazamide (Tolinase)
o chlorpropamide (Diabinese)
• Second-generation agents
o glipizide (Glucotrol)
o glyburide (Diabeta, Micronase, Glynase)
o glimepiride (Amaryl)
o gliclazide (Diamicron)
Meglitinides
Meglitinides help the pancreas produce insulin and are often called "short-acting secretagogues." They act on the same potassium channels as sulfonylureas, but at a different binding site.[1] By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, hence enhancing insulin secretion.[2]
They are taken with or shortly before meals to boost the insulin response to each meal. If a meal is skipped, the medication is also skipped.
Typical reductions in A1C values are 0.5-1.0%.
• repaglinide (Prandin)
• nateglinide (Starlix)
Adverse reactions include weight gain and hypoglycemia.
Sensitizers
Insulin sensitizers address the core problem in Type II diabetes—insulin resistance. Among oral hypoglycemic agents, insulin sensitizers are the largest category.[3]
Biguanides
Main article: Biguanide
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, a biguanide, has become the most commonly used agent for type 2 diabetes in children and teenagers. Amongst common diabetic drugs, metformin is the only widely used oral drug that does not cause weight gain.
Typical reductions in A1C values for metformin is 1.5-2.0%.
• metformin (Glucophage). Metformin may be the best choice for patients who also have heart failure.[4] Should be temporarily discontinued before any radiographic procedure involving intravenous iodinated contrast as patients are at an increased risk of lactic acidosis.
• phenformin (DBI): used from 1960s through 1980s, withdrawn due to lactic acidosis risk.[5]
• buformin: also withdrawn due to lactic acidosis risk.[6]
Metformin is usually the first-line medication used for treatment of type-2 diabetes. It is generally prescribed at initial diagnosis in conjunction with exercise and weight loss as opposed to in the past, where Metformin was prescribed after diet and exercise had failed. Initial dosing is 500 mg once daily, then if need be increased to 500 mg twice daily up to 1000 mg twice daily. It is also available in combination with other oral diabetic medications.
There is an extended release formulation available, but it is typically reserved for patients experiencing GI side effects.
Thiazolidinediones
Main article: Thiazolidinedione
Thiazolidinediones (TZDs), also known as "glitazones," bind to PPARγ, a type of nuclear regulatory protein involved in transcription of genes regulating glucose and fat metabolism. These PPARs act on Peroxysome Proliferator Responsive Elements (PPRE [1]). 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.
Typical reductions in A1C values are 1.5-2.0%.
• rosiglitazone (Avandia)
• pioglitazone (Actos)
• troglitazone (Rezulin): used in 1990s, withdrawn due to hepatitis and liver damage risk.[7]
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,[8] as did the DREAM trial.[9]
Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in the New England Journal of Medicine.[10] There have been a significant number of publications since then, and a Food and Drug Administration panel[11] 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. The meta-analysis was not supported by an interim analysis of the trial designed to evaluate the issue, and several other reports have failed to conclude the controversy. This weak evidence for adverse effects has reduced the use of rosiglitazone, despite its important and sustained effects on glycemic control.[12] 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.[13]
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.
Typical reductions in A1C values are 0.5-1.0%.
• 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. They do have the potential to cause weight loss by lowering the amount of sugar metabolized.
Research has shown the culinary mushroom Maitake (Grifola frondosa) has a hypoglycemic effect,[14][15][16][17][18][19] possibly due to the fact the mushroom naturally acts as an alpha-glucosidase inhibitor.[20]
Peptide analogs


Overview of insulin secretion
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 and agonists
GLP agonists bind to a membrane GLP receptor.[2] 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-1 agonist approved for the treatment of type 2 diabetes. Exenatide is not an analogue of GLP, but rather a GLP agonist.[21][22] Exenatide has only 53% homology with GLP, which increases its resistance to degradation by DPP-4 and extends its half-life.[23] Typical reductions in A1C values are 0.5-1.0%.
• Liraglutide, a once daily human analogue (97% homology), is being developed by Novo Nordisk under the brand name Victoza. The product was approved by the European Medicines Agency (EMEA) on July 3, 2009, and by the U.S. Food and Drug Administration (FDA) on January 25, 2010.[24][25][26][27][28][29]
• Taspoglutide is presently in Phase III Clinical Trials with Hoffman-La Roche.
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).
Typical reductions in A1C values are 0.5-1.0%.
Examples are:
• vildagliptin (Galvus) EU Approved 2008.
• sitagliptin (Januvia) FDA approved Oct 2006.
• saxagliptin (Onglyza) FDA Approved July 2009.
Amylin analogues
Amylin agonist analogues slow gastric emptying and suppress glucagon. They have all the incretins actions except stimulation of insulin secretion. 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. Typical reductions in A1C values are 0.5-1.0%.
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, aleglitazar - under clinical development)
• SGLT2 (sodium-dependent glucose transporter 2) inhibitors increase urinary glucose.
• FBPase (fructose 1,6-bisphosphatase) inhibitors decrease gluconeogenesis in the liver.
Alternative medicine
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."[30]
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.[31] The major recent development was done in Brazil around Myrcia sphaerocarpa and other Myrcia species.[32] The usual treatment is with concentrated (root) Myrcia extracts, commercialized as "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.[33]
Walnut leaf can significantly reduce fasting blood glucose levels in rats with alloxan-induced diabetes, and rats thus treates show some evidence of regeneration of the beta cells.[34] Garlic also significantly reduces fasting blood glucose levels in rats with alloxan-induced diabetes.[35]
At least two studies have shown that cinnamon can act significantly reducing some effects of diabetes. One study on people used fine ground cassia (Cinnamomum aromaticum) for oral consumption. Another study used an extract (MHCP) on laboratory rats. The study on people published in 2003 conducted in the Department of Human Nutrition, NWFP Agricultural University, Peshawar, Pakistan concluded "that the inclusion of cinnamon in the diet of people with type 2 diabetes will reduce risk factors associated with diabetes and cardiovascular diseases."[36] The study on laboratory rats at Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University published in 2001 used purified hydroxychalcone (MHCP) from cinnamon. Part of the study's conclusion stated that "the MHCP is fully capable of mimicking insulin" and recommended further studies.[37][38] The Food and Drug Administration has not yet evaluated the use of cinnamon for the management of diabetes. It should be noted that the spice sold as cinnamon is often obtained from C. verum (true cinnamon), not C. aromaticum (cassia).
Research has shown the Maitake mushroom (Grifola frondosa) has a hypoglycemic effect, and may be beneficial for the management of diabetes.[14][15][16][17][18][19] The reason Maitake lowers blood sugar is due to the fact the mushroom naturally acts as an alpha glucosidase inhibitor.[2] Other mushrooms like Reishi,[39][40] Agaricus blazei,[41][42][43][44] Agrocybe cylindracea[45] and Cordyceps[46][47][48][49][50] have been noted to lower blood sugar levels to a certain extent, although the mechanism is currently unknown.
Cinnamon
Though not yet evaluated by the Food and Drug Administration, at least two studies have shown that cinnamon can act significantly reducing some effects of diabetes. One study on people used fine ground cinnamon (Cinnamomum cassia) for oral consumption. Another study used an extract (MHCP) on laboratory rats.
The study on people published in 2003 conducted in the Department of Human Nutrition, NWFP Agricultural University, Peshawar, Pakistan concluded:
The results of this study demonstrate that intake of 1, 3, or 6 g of cinnamon per day reduces serum glucose, triglyceride, LDL cholesterol, and total cholesterol in people with type 2 diabetes and suggest that the inclusion of cinnamon in the diet of people with type 2 diabetes will reduce risk factors associated with diabetes and cardiovascular diseases.[51]
The study on laboratory rats at Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University published in 2001 used purified hydroxychalcone from cinnamon. The extract was named "MHCP". Part of the study's conclusion stated that "the MHCP is fully capable of mimicking insulin" and recommended further studies.[52][53]
Other studies have failed to reproduce these results, and, because large doses of cinnamon are not innocuous, some experts advise against treatment of diabetes with cinnamon.[54]
Chromium and vanadium
Chromium - Cholesterol and triglycerides are risk factors in heart disease and diabetes, and studies show that chromium lowers levels of total cholesterol, LDL cholesterol, and triglycerides.[55][56][57][58] Chromium supplements such as chromium picolinate have been shown to improve glucose tolerance in people with type 2 diabetes,[59][60][61] although other studies have not replicated this result.[62] A meta analysis of these trials concluded that chromium supplements had no beneficial effect on healthy people, but that there might be an improvement in glucose metabolism in diabetics, although the authors stated that the evidence for this effect remains weak.[63]
Vanadium - A form of vanadium, vanadyl sulfate, seems to improve glucose control in people with type 2 diabetes.[64][65][66][67][68]
A pilot study has also found evidence that Tai Chi and Qigong reduce the severity of type 2 diabetes.[69]
Benfotiamine, a pro-vitamin of vitamin B1 which has been in use in Europe as an over-the-counter medicine for alcoholic neuropathy for the past half century with no significant side-effects or toxicity, has recently been found to block the major metabolic pathways by which excess blood glucose in the body is transformed into the advanced glycation endproducts (AGEs) which cause diabetic complications.[70] Studies have shown that taking oral benfotiamine can prevent diabetic retinopathy,[71] diabetic neuropathy,[72] and diabetic nephropathy[73] independently of any affect on the blood sugar levels of the patient. In theory, taking benfotiamine might allow patients to be less scrupulous in trying to normalize blood sugar levels and thus free them from the danger of hypoglycemia and the stress of stringent blood sugar monitoring, while still protecting them against the negative effects of hyperglycemia. Research is ongoing to establish the full significance of benfotiamine in the treatment of diabetes.
Traditional plant treatments for diabetes
A study was made of the effects on glucose homeostasis in normal and streptozotocin (induced) diabetic mice of eleven plants that have been used as traditional treatments for diabetes. The mice were given diets containing dried leaves from the following plants: agrimony (Agrimonia eupatoria), alfalfa (Medicago sativa), blackberry (Rubus fructicosus), celandine (Chelidonium majus), eucalyptus (Eucalyptus globulus), lady's mantle (Alchemilla vulgaris), and lily of the valley (Convallaria majalis); seeds of coriander (Coriandrum sativum); dried berries of juniper (Juniperus communis); bulbs of garlic (Allium sativum) and roots of liquorice (Glycyrhizza glabra). The study concluded that "The results suggest that certain traditional plant treatments for diabetes, namely agrimony, alfalfa, coriander, eucalyptus and juniper, can retard the development of streptozotocin diabetes in mice".[74]
Mushrooms
Research has shown the Maitake mushroom (Grifola frondosa) has a hypoglycemic effect, and may be beneficial for the management of diabetes.[14][15][16][17][18][19] The reason Maitake lowers blood sugar is due to the fact the mushroom naturally acts as an alpha glucosidase inhibitor.[75] Other mushrooms like Reishi,[39][40] Agaricus blazei,[41][42][43][76] Agrocybe cylindracea[77] and Cordyceps[46][47][48][49][50] have been noted to lower blood sugar levels to a certain extent, although the mechanism is currently unknown.
Aloe vera Oral administration of aloe vera might be a useful adjunct for lowering blood glucose in diabetic patients as well as for reducing blood lipid levels in patients with hyperlipidaemia[citation needed]. Ten controlled clinical trials were found to reach that conclusion in four independent literature searches. However, caveats reported in each study led the researchers to conclude that aloe vera's clinical effectiveness was not yet sufficiently defined in 1999.[78]