Anti-diabetic drug
From Wikipedia, the free encyclopedia
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.
Diabetes mellitus
Types of Diabetes
Diabetes mellitus type 1
Diabetes mellitus type 2
Gestational diabetes
Pre-diabetes:
Impaired fasting glycaemia
Impaired glucose tolerance
Disease Management
Diabetes management:
•Diabetic diet
•Anti-diabetic drugs
•Conventional insulinotherapy
•Intensive insulinotherapy
Other Concerns
Cardiovascular disease
Diabetic comas:
•Diabetic hypoglycemia
•Diabetic ketoacidosis
•Nonketotic hyperosmolar
Diabetic myonecrosis
Diabetic nephropathy
Diabetic neuropathy
Diabetic retinopathy
Diabetes and pregnancy
Blood tests
Blood sugar
Fructosamine
Glucose tolerance test
Glycosylated hemoglobin
Contents
[hide]
* 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 Herbal extracts
* 8 Notes
* 9 References
Insulin
Main article: 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
Main article: Sulfonylurea
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
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
Main article: Meglitinide
Meglitinides help the pancreas produce insulin and are often called
"short-acting secretagogues." Their mode of action is original, affecting
potassium channels.[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 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.
Sensitizers
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 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 (Glucophage). Metformin may be the best choice for patients who also
have heart failure.[3]
* 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.
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.
Thiazolidinediones
Main article: Thiazolidinedione
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 [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.
* 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,[4] as did the DREAM trial.[5]
Concerns about the safety of rosiglitazone arose when a retrospective
meta-analysis was published in the New England Journal of Medicine.[6] There
have been a significant number of publications since then, and a Food and Drug
Administration panel[7] 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.[8] 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.[9]
Alpha-glucosidase inhibitors
Main article: Alpha-glucosidase inhibitor
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.
They do have the potential to cause weight loss by lowering the amount of sugar
metabolized.
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.[10][11] Exenatide has only 53% homology with GLP,
which increases its resistance to degradation by DPP-4 and extends its
half-life.[12]
* Liraglutide, a once daily human analogue (97% homology), is being developed by
Novo Nordisk. As of 2007[update], it is in phase III clinical trials.[13]
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
Main article: Dipeptidyl peptidase-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. They have
all the incretins actions except stimulation of insulin secretion. As of
2007[update], 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, aleglitazar - under clinical development)
* SGLT (sodium-dependent glucose transporter 1) inhibitors increase urinary
glucose.
* FBPase (fructose 1,6-bisphosphatase) inhibitors decrease gluconeogenesis in
the liver.
Herbal extracts
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."[14] Animal
studies have found that walnut leaf[15] and garlic can significantly reduce
fasting blood glucose levels in rats with alloxan-induced diabetes.[16]
Myrcia
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.[17] 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 (...) ".[18]
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.[19]
Cinnamon
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 "that the
inclusion of cinnamon in the diet of people with type 2 diabetes will reduce
risk factors associated with diabetes and cardiovascular diseases."[20] 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.[21] [22] The Food
and Drug Administration has not yet evaluated the use of cinnamon for the
management of diabetes.
Notes
1. ^ Rendell M (2004). "Advances in diabetes for the millennium: drug therapy of
type 2 diabetes". MedGenMed 6 (3 Suppl): 9. PMID 15647714. Free full text with
registration at Medscape. Full text at PMC: 1474831
2. ^ a b "Helping the pancreas produce insulin". HealthValue. Retrieved on
2007-09-21.
3. ^ Eurich DT, McAlister FA, Blackburn DF, et al (2007). "Benefits and harms of
antidiabetic agents in patients with diabetes and heart failure: systematic
review". BMJ 335 (7618): 497. doi:10.1136/bmj.39314.620174.80. PMID 17761999.
4. ^ Haffner, Steven M. (2007). "Expert Column - A Diabetes Outcome Progression
Trial (ADOPT)". Medscape. Retrieved on 2007-09-21.
5. ^ Gagnon, Louise (2007). "DREAM: Rosiglitazone Effective in Preventing
Diabetes". Medscape. Retrieved on 2007-09-21.
6. ^ Nissen SE, Wolski K (2007). "Effect of rosiglitazone on the risk of
myocardial infarction and death from cardiovascular causes". N Engl J Med 356
(24): 2457–71. doi:10.1056/NEJMoa072761. PMID 17517853. http://content.nejm.org/cgi/content/full/356/24/2457.
Lay summary – Associated Press (2007-05-21).
7. ^ Wood, Shelley (2007-07-31). "FDA Advisory Panels Acknowledge Signal of Risk
With Rosiglitazone, but Stop Short of Recommending Its Withdrawal". Heartwire.
Retrieved on 2007-09-21.
8. ^ Ajjan RA, Grant PJ (2008). "The cardiovascular safety of rosiglitazone".
Expert Opin Drug Saf 7 (4): 367–76. doi:10.1517/14740338.7.4.367. PMID 18613801.
9. ^ Erdman, Erland; Dormandy, JA; Charbonnel, B; Massi-Benedetti, M;Moules,
IK;Skene,AM (2007). "The Effect of Pioglitazone on Recurrent Myocardial
Infarction in 2,445 Patients With Type 2 Diabetes and Previous Myocardial
Infarction. Results From PROactive (PROactive 05)". J Am Coll Cardiol 49 (17):
1772–1780. doi:10.1016/j.jacc.2006.12.048. PMID 17466227. http://www.medscape.com/viewarticle/554997.
Retrieved on 21 May 2007.
10. ^ Briones M, Bajaj M (June 2006). "Exenatide: a GLP-1 receptor agonist as
novel therapy for Type 2 diabetes mellitus". Expert Opin Pharmacother 7 (8):
1055–64. doi:10.1517/14656566.7.8.1055. PMID 16722815.
11. ^ Gallwitz B (December 2006). "Exenatide in type 2 diabetes: treatment
effects in clinical studies and animal study data". Int J Clin Pract 60 (12):
1654–61. doi:10.1111/j.1742-1241.2006.01196.x. PMID 17109672.
12. ^ Cvetković RS, Plosker GL (2007). "Exenatide: a review of its use in
patients with type 2 diabetes mellitus (as an adjunct to metformin and/or a
sulfonylurea)". Drugs 67 (6): 935–54. doi:10.2165/00003495-200767060-00008. PMID
17428109.
13. ^ "Novo Nordisk A/S - R&D Pipeline: Liraglutide (NN2211)". Novo Nordisk
(2007). Retrieved on 2007-09-30.
14. ^ Bnouham M et al (2006). "Medicinal plants with potential antidiabetic
activity - A review of ten years of herbal medicine research (1990-2000)" (PDF).
Int J Diabetes & Metabolism 14: 1–25. http://ijod.uaeu.ac.ae/iss_1401/a.pdf.
15. ^ Jelodar G, Mohsen M, Shahram S (2007). "Effect of Walnut leaf, coriander
and pomegranate on blood glucose and histopathology of pancreas of alloxan
induced diabetic rats". African Journal of Traditional, Complimentary and
Alternative Medicines 4 (3): 299–305. http://www.bioline.org.br/request?tc07044.
Retrieved on 10 May 2008.
16. ^ Jelodar GA, Maleki M, Motadayen MH, Sirus S (February 2005). "Effect of
fenugreek, onion and garlic on blood glucose and histopathology of pancreas of
alloxan-induced diabetic rats". Indian J Med Sci 59 (2): 64–9. PMID 15738612.
http://www.indianjmedsci.org/article.asp?issn=0019-5359;year=2005;volume=59;issue=2;spage=64;epage=69;aulast=Jelodar.
17. ^ Soumyanath, Amala(ed.) (2005-11-01). Traditional Medicines for Modern
Times (1st Edition ed.). Taylor & Francis. ISBN 0-415-33464-0.
18. ^ McNeill, John H. (1999-02-01). Experimental Models of Diabetes (1st
Edition ed.). CRC Press. pp. 208. ISBN 0-8493-1667-7.
19. ^ Matsuda, H; Nishida N, Yoshikawa M. (March 2002). "Antidiabetic principles
of natural medicines. V. Aldose reductase inhibitors from Myrcia multiflora DC.
(2): Structures of myrciacitrins III, IV, and V". Chem Pharm Bull (Tokyo) 50(3):
429–31. doi:10.1248/cpb.50.429.
20. ^ Alam Khan, MS, PHD, Mahpara Safdar, MS, Mohammad Muzaffar Ali Khan, MS,
PHD, Khan Nawaz Khattak, MS and Richard A. Anderson, PHD, Cinnamon Improves
Glucose and Lipids of People With Type 2 Diabetes, DIABETES CARE, Vol. 26, Numbr
12, December 2003, retrieved August 4, 2008
21. ^ Karalee J. Jarvill-Taylor, PhD, Richard A. Anderson, PhD and Donald J.
Graves, PhD A Hydroxychalcone Derived from Cinnamon Functions as a Mimetic for
Insulin in 3T3-L1 Adipocytes Journal of the American College of Nutrition Vol.
20, No. 4, 327-336 (2001), retrieved August 4, 2008
22. ^ Richard A. Anderson, Ph.D., CNS, Cinnamon, Glucose Tolerance and Diabetes,
www.ars.usda.gov, August 23, 2005, retrieved August 4, 2008
References
* Lebovitz, Harold E. (2004). Therapy For Diabetes Mellitus and Related
Disorders (4th ed. ed.). Alexandria, VA: American Diabetes Association. ISBN
1-58040-187-2.
* Adams, Michael Ian; Holland, Norman Norwood (2003). Core Concepts in
Pharmacology. Englewood Cliffs, NJ: Prentice Hall. ISBN 0-13-089329-3.
[show]
v • d • e
Oral antidiabetic drugs and Insulin analogs (A10)
Insulin
Sensitizers
Biguanides
Metformin · Buformin‡ · Phenformin‡
TZDs (PPAR)
Pioglitazone · Rivoglitazone† · Rosiglitazone · Troglitazone‡
Dual PPAR agonists
Aleglitazar† · Muraglitazar§ · Tesaglitazar§
Secretagogues
Sulfonylureas
1st generation: Carbutamide · Chlorpropamide · Gliclazide · Tolbutamide ·
Tolazamide
2nd generation: Glipizide · Glibenclamide (Glyburide) · Gliquidone ·
Glyclopyramide
3rd generation: Glimepiride
Meglitinides
Nateglinide · Repaglinide · Mitiglinide
GLP-1 analog
Exenatide · Liraglutide† · Albiglutide†
DPP-4 inhibitors
Alogliptin† · Linagliptin† · Saxagliptin† · Sitagliptin · Vildagliptin
Analogs
fast acting (Insulin lispro · Insulin aspart · Insulin glulisine) · long acting
(Insulin glargine · Insulin detemir) · Inhalable insulin (Exubera)
Other
Alpha-glucosidase inhibitors
Acarbose · Miglitol · Voglibose
Amylin analog
Pramlintide
SGLT2 inhibitor
Dapagliflozin† · Remogliflozin† · Sergliflozin†
†Undergoing clinical trials. ‡ Withdrawn from market. §Development halted.
[show]
v • d • e
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