Anti-diabetic medication 1

Anti-diabetic medication
Anti-diabetic medications 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.
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.

Secretagogues

Sulfonylureas
Sulfonylureas were the first widely used oral anti-hyperglycaemic 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
• tolbutamide (Orinase)
• acetohexamide (Dymelor)
• tolazamide (Tolinase)
• chlorpropamide (Diabinese)
• Second-generation agents
• glipizide (Glucotrol)
• glyburide (Diabeta, Micronase, Glynase)
• glimepiride (Amaryl)
Anti-diabetic medication 2

• gliclazide (Diamicron)

Nonsulfonylurea secretagogues

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.

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, 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) may be the best choice for patients who also have heart failure,[3] but it should be
temporarily discontinued before any radiographic procedure involving intravenous iodinated contrast, as patients
are at an increased risk of lactic acidosis.
• Phenformin (DBI) was used from 1960s through 1980s, but was withdrawn due to lactic acidosis risk.[4]
• Buformin also was withdrawn due to lactic acidosis risk.[5]
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 it 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
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 [6]). 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%. Some examples are:
• rosiglitazone (Avandia)
• pioglitazone (Actos)
• troglitazone (Rezulin): used in 1990s, withdrawn due to hepatitis and liver damage risk[7]
Anti-diabetic medication 3

Multiple retrospective studies have resulted in 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 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 2 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 mushroom acting as a natural alpha glucosidase inhibitor.[20]
Anti-diabetic medication 4

Peptide analogs

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 (glucose-dependent insulinotropic
peptide, GIP). Both GLP-1 and GIP are
rapidly inactivated by the enzyme dipeptidyl
peptidase-4 (DPP-4).

Glucagon-like peptide analogs and

agonists

Glucagon-like peptide (GLP) agonists bind

to a membrane GLP receptor.[2] As a
consequence, insulin release from the
pancreatic beta cells is increased. Overview of insulin secretion
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 analogs

• None are FDA approved

Injectable peptide analogs

DPP-4 inhibitors (also known as glyptins) lowered hemoglobin A1C values by 0.74%, comparable to other
antidiabetic drugs.[30] GLP-1 analogs resulted in weight loss and had more gastrointestinal side effects, while DPP-4
inhibitors were generally weight neutral and increased risk for infection and headache, but both classes appear to
present an alternative to other antidiabetic drugs. However, weight gain and/or hypoglycaemia have been observed
when DPP-4 inhibitors were used with sulfonylureas; effect on long-term health and morbidity rates are still
unknown.[31]
Dipeptidyl peptidase-4 (DPP-4) inhibitors increase blood concentration of the incretin GLP-1 by inhibiting its
degradation by dipeptidyl peptidase-4.
Typical reductions in A1C values are 0.5-1.0%.
Examples are:
Anti-diabetic medication 5

• 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.
• Imeglimin will be the first of a new class if approved.

Alternative medicine
A recent review article presents the profiles of plants with hypoglycaemic properties, reported in the literature from
1990 to 2000 and states "Medical plants play an important role in the management of diabetes mellitus, especially in
developing countries where resources are meager."[32]
The first registered use of antidiabetic 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.[33]
The major recent development was done in Brazil around Myrcia sphaerocarpa and other Myrcia species.[34] The
usual treatment is with concentrated Myrcia root 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.[35]
Garlic also significantly reduces fasting blood glucose levels in rats with alloxan-induced diabetes.[36]
At least two studies have shown cinnamon can act significantly to reduce some effects of diabetes. One study on
humans 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 "the inclusion of cinnamon in the diet of
people with type 2 diabetes will reduce risk factors associated with diabetes and cardiovascular diseases."[37] 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 "the
MHCP is fully capable of mimicking insulin" and recommended further studies.[38] [39] 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 it lowers blood sugar is the mushroom acts as a
Anti-diabetic medication 6

natural alpha glucosidase inhibitor.[40] Other mushrooms like Reishi,[41] [42] Agaricus blazei,[43] [44] [45] [46]
Agrocybe cylindracea[47] and Cordyceps[48] [49] [50] [51] [52] have been noted to lower blood sugar levels to a certain
extent, although the mechanism is currently unknown.

Cassia
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.[53]
The study on laboratory rats at Department of Biochemistry, Biophysics and Molecular Biology, Iowa State
University, published in 2001, used purified hydroxychalcone (MCHP) from cinnamon. Part of the study's
conclusion stated "the MHCP is fully capable of mimicking insulin" and recommended further studies.[54] [55]
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.[56]

Chromium and vanadium supplementation

Cholesterol and triglycerides are risk factors in heart disease and diabetes, and studies show chromium lowers levels
of total cholesterol, LDL cholesterol, and triglycerides.[57] [58] [59] [60] Chromium supplements, such as chromium
picolinate, have been shown to improve glucose tolerance in people with type 2 diabetes,[61] [62] [63] although other
studies have not replicated this result.[64] A meta analysis of these trials concluded chromium supplements had no
beneficial effect on healthy people, but there might be an improvement in glucose metabolism in diabetics, although
the authors stated the evidence for this effect remains weak.[65]
Vanadyl sulfate, a salt of vanadium, seems to improve glucose control in people with type 2 diabetes.[66] [67] [68] [69]
[70]

Benfotiamine, a provitamin 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.[71] Studies have shown taking oral benfotiamine
can prevent diabetic retinopathy,[72] neuropathy,[73] and nephropathy[74] 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-based treatments

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
Anti-diabetic medication 7

(Juniperus communis); bulbs of garlic (Allium sativum) and roots of liquorice (Glycyrhizza glabra). The study
concluded: "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".[75]

Medicinal fungi
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.[76] Other mushrooms like Reishi,[41] [42] Agaricus
blazei,[43] [44] [45] [77] Agrocybe cylindracea[78] and Cordyceps[48] [49] [50] [51] [52] have been noted to lower blood
sugar levels to a certain extent, although the mechanism is currently unknown.

Notes
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[2] "Helping the pancreas produce insulin" (http:/ / www. healthvalue. net/ diabetespancreasbeta. html). HealthValue. . Retrieved 2007-09-21.
[3] Eurich; McAlister, FA; Blackburn, DF; Majumdar, SR; Tsuyuki, RT; Varney, J; Johnson, JA (2007). "Benefits and harms of antidiabetic
agents in patients with diabetes and heart failure: systematic review." (http:/ / www. pubmedcentral. nih. gov/ articlerender.
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[4] Fimognari; Pastorelli, R; Incalzi, RA (2006). "Phenformin-induced lactic acidosis in an older diabetic patient: a recurrent drama (phenformin
and lactic acidosis)." (http:/ / care. diabetesjournals. org/ cgi/ pmidlookup?view=long& pmid=16567854). Diabetes care 29 (4): 950–1.
doi:10.2337/diacare.29.04.06.dc06-0012. PMID 16567854. .
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[8] Haffner, Steven M. (2007). "Expert Column - A Diabetes Outcome Progression Trial (ADOPT)" (http:/ / www. medscape. com/ viewarticle/
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[9] Gagnon, Louise (2007). "DREAM: Rosiglitazone Effective in Preventing Diabetes" (http:/ / www. medscape. com/ viewarticle/ 546503).
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PMID 17466227.
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[17] Lo, HC; Hsu, TH; Chen, CY (2008). "Submerged culture mycelium and broth of Grifola frondosa improve glycemic responses in diabetic
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Anti-diabetic medication 8

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References
• Lebovitz, Harold E. (2004). Therapy For Diabetes Mellitus and Related Disorders (4th ed.). Alexandria, VA:
American Diabetes Association. ISBN 1-58040-187-2.
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Prentice Hall. ISBN 0-13-089329-3.
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