Anti-diabetic medications treat diabetes mellitus by lowering glucose levels in the blood. With the exceptions of insulin, exenatide, liraglutide 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 that increase the amount of insulin secreted by the pancreas, (2) agents that increase the sensitivity of target organs to insulin, and (3) agents that 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.
|This section does not cite any references or sources. (April 2013)|
Insulin is usually given subcutaneously, either by injections or by an insulin pump. Research of other routes of administration is underway. In acute-care settings, insulin may also be given intravenously. In general, there are three types of insulin, characterized by the rate which they are metabolized by the body. They are rapid acting insulins, intermediate acting insulins and long acting insulins. Examples of rapid acting insulins include
- Regular insulin (Humulin R, Novolin R)
- Insulin lispro (Humalog)
- Insulin aspart (Novolog)
- Insulin glulisine (Apidra)
- Prompt insulin zinc (Semilente, Slightly slower acting)
Examples of intermediate acting insulins include
- Isophane insulin, neutral protamine Hagedorn (NPH) (Humulin N, Novolin N)
- Insulin zinc (Lente)
Examples of long acting insulins include
- Extended insulin zinc insulin (Ultralente)
- Insulin glargine (Lantus)
- Insulin detemir (Levemir)
The following table compares some common anti-diabetic agents, generalizing classes, although there may be substantial variation in individual drugs of each class. When the table makes a comparison such as "lower risk" or "more convenient" the comparison is with the other drugs on the table.
|Comparison of anti-diabetic medication|
|Sulfonylurea (glyburide, glimepiride, glipizide)||Stimulating insulin release by pancreatic beta cells by inhibiting the KATP channel|
|Metformin||Acts on liver to cause decrease in insulin resistance|
|Alpha-glucosidase inhibitor (acarbose, miglitol, voglibose)||Reduces glucose absorbance by acting on small intestine to cause decrease in production of enzymes needed to digest carbohydrates||
|Thiazolidinediones (Pioglitazone, Rosiglitazone)||Reduce insulin resistance by activating PPAR-γ in fat and muscle||
Most anti-diabetic agents are contraindicated in pregnancy, in which insulin is preferred.
Insulin sensitizers address the core problem in Type II diabetes—insulin resistance.
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. Among common diabetic drugs, metformin is the only widely used oral drug that does not cause weight gain.
Typical reduction in glycated hemoglobin (A1C) values for metformin is 1.5–2.0%
- Metformin (Glucophage) may be the best choice for patients who also have heart failure, 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.
- Buformin also was withdrawn due to lactic acidosis risk.
Metformin is usually the first-line medication used for treatment of type 2 diabetes. In general, it is 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. There is an immediate release as well as an extended-release formulation, typically reserved for patients experiencing GI side-effects. It is also available in combination with other oral diabetic medications.
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). 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 glycated hemoglobin (A1C) values are 1.5–2.0%. Some examples are:
- rosiglitazone (Avandia): the European Medicines Agency recommended in September 2010 that it be suspended from the EU market due to elevated cardiovascular risks.
- pioglitazone (Actos)
- troglitazone (Rezulin): used in 1990s, withdrawn due to hepatitis and liver damage risk
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 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. 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. 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.
Sulfonylureas were the first widely used oral anti-hyperglycaemic medications. They are insulin secretagogues, triggering insulin release by inhibiting 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. A 2012 study found sulfonylureas raise the risk of death compared with metformin.
Sulfonylureas bind strongly to plasma proteins. Sulfonylureas are useful only 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 cannot 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 glycated hemoglobin (A1C) values for second-generation sulfonylureas are 1.0–2.0%.
- First-generation agents
- Second-generation agents
Nonsulfonylurea secretagogues 
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. By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, thereby enhancing insulin secretion.
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 glycated hemoglobin (A1C) values are 0.5–1.0%.
Adverse reactions include weight gain and hypoglycemia.
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 glycated hemoglobin (A1C) values are 0.5–1.0%.
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 that the culinary mushroom maitake (Grifola frondosa) has a hypoglycemic effect, possibly due to the mushroom acting as a natural alpha glucosidase inhibitor.
Peptide analogs 
Injectable 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).
Injectable Glucagon-like peptide analogs and agonists 
Glucagon-like peptide (GLP) agonists bind to a membrane GLP receptor. As a consequence, 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. Exenatide has only 53% homology with GLP, which increases its resistance to degradation by DPP-4 and extends its half-life. Typical reductions in A1C values are 0.5–1.0%.
- Liraglutide, a once-daily human analogue (97% homology), has been 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.
- 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
Dipeptidyl Peptidase-4 Inhibitors 
GLP-1 analogs resulted in weight loss and had more gastrointestinal side-effects, while in general DPP-4 inhibitors were 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.
- vildagliptin (Galvus) EU Approved 2008
- sitagliptin (Januvia) FDA approved Oct 2006
- saxagliptin (Onglyza) FDA Approved July 2009
- linagliptin (Tradjenta) FDA Approved May 2, 2011
A result in one RCT comprising 206 patients aged 65 or older (mean baseline HgbA1c of 7.8%) receiving either 50 or 100 mg/d of Sitagliptin was shown to reduce HbA1c by 0.7% (combined result of both doses). A combined result of 5 RCTs enlisting a total of 279 patients aged 65 or older (mean baseline HbA1c of 8%) receiving 5 mg/d of Saxagliptin was shown to reduce HbA1c by 0.73%. A combined result of 5 RCTs enlisting a total of 238 patients aged 65 or older (mean baseline HbA1c of 8.6%) receiving 100 mg/d of Vildagliptin was shown to reduce HbA1c by 1.2%. Another set of 6 combined RCTs involving Alogliptin (not yet approved, might be released in 2012) was shown to reduce HbA1c by 0.73% in 455 patients aged 65 or older who received 12.5 or 25 mg/d of the medication.
Injectable 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. Typical reductions in A1C values are 0.5–1.0%.
Natural substances 
A number of medicinal plants have been studied for the treatment of diabetes, however there is insufficient evidence to determine their effectiveness. Cinnamon has blood sugar-lowering properties, however whether or not it is useful for treating diabetes is unknown. Researchers from Australia's Swinburne University have found extracts from Australian Sandalwood and Indian Kino tree slows down two key enzymes in carbohydrate metabolism.  Bioassay-directed fractionation techniques led to isolation of isoorientin as the main hypoglycemic component in Gentiana olivieri.
While chromium supplements have no beneficial effect on healthy people, there might be an improvement in glucose metabolism in individuals with diabetes, although the evidence for this effect remains weak. Vanadyl sulfate, a salt of vanadium, is still in preliminary studies. There is tentative research that thiamine may prevent some diabetic complications however more research is needed.
- Cambon-Thomsen, A.; Rial-Sebbag, E.; Knoppers, B. M. (2007). "Trends in ethical and legal frameworks for the use of human biobanks". European Respiratory Journal 30 (2): 373–382. doi:10.1183/09031936.00165006. PMID 17666560. adapted from table 2, which includes a list of issues
- Consumer Reports Health Best Buy Drugs. "The Oral Diabetes Drugs: Treating Type 2 Diabetes". Best Buy Drugs (Consumer Reports): 20. Retrieved September 18 2012, which is citing
- Agency for Healthcare Research and Quality (March 2011). "Oral Diabetes Medications for Adults With Type 2 Diabetes. An Update". Comparative Effectiveness Review. number 27 (AHRQ Pub. No. 11–EHC038–1). Retrieved 28 November 2012.
- Bennett, W. L.; Maruthur, N. M.; Singh, S.; Segal, J. B.; Wilson, L. M.; Chatterjee, R.; Marinopoulos, S. S.; Puhan, M. A. et al. (2011). "Comparative effectiveness and safety of medications for type 2 diabetes: An update including new drugs and 2-drug combinations". Annals of internal medicine 154 (9): 602–613. doi:10.1059/0003-4819-154-9-201105030-00336. PMID 21403054.
- Table entries taken from page 185 in: Elizabeth D Agabegi; Agabegi, Steven S. (2008). Step-Up to Medicine (Step-Up Series). Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-7153-6.
- 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". BMJ (Clinical research ed.) 335 (7618): 497. doi:10.1136/bmj.39314.620174.80. PMC 1971204. PMID 17761999.
- Fimognari; Pastorelli, R; Incalzi, RA (2006). "Phenformin-induced lactic acidosis in an older diabetic patient: a recurrent drama (phenformin and lactic acidosis)". Diabetes Care 29 (4): 950–1. doi:10.2337/diacare.29.04.06.dc06-0012. PMID 16567854.
- Verdonck; Sangster, B; Van Heijst, AN; De Groot, G; Maes, RA (1981). "Buformin concentrations in a case of fatal lactic acidosis". Diabetologia 20 (1): 45–6. doi:10.1007/BF01789112. PMID 7202882.
- European Medicines Agency, "European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim", EMA, 23 September 2009
- Hinterthuer, Adam (October 1, 2008). "Retired Drugs: Failed Blockbusters, Homicidal Tampering, Fatal Oversights". Wired News. Retrieved 2009-06-21.
- Haffner, Steven M. (2007). "Expert Column – A Diabetes Outcome Progression Trial (ADOPT)". Medscape. Retrieved 2007-09-21.
- Gagnon, Louise (2007). "DREAM: Rosiglitazone Effective in Preventing Diabetes". Medscape. Retrieved 2007-09-21.
- Nissen; Wolski, K (2007). "Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes". The New England Journal of Medicine 356 (24): 2457–71. doi:10.1056/NEJMoa072761. PMID 17517853. Lay summary – Associated Press (May 21, 2007).
- Wood, Shelley (2007-07-31). "FDA Advisory Panels Acknowledge Signal of Risk With Rosiglitazone, but Stop Short of Recommending Its Withdrawal". Heartwire. Retrieved 2007-09-21.
- Ajjan; Grant, PJ (2008). "The cardiovascular safety of rosiglitazone". Expert opinion on drug safety 7 (4): 367–76. doi:10.1517/147403220.127.116.117. PMID 18613801.
- Erdmann; Dormandy, JA; Charbonnel, B; Massi-Benedetti, M; Moules, IK; Skene, AM; Proactive, Investigators (2007). "The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study". Journal of the American College of Cardiology 49 (17): 1772–80. doi:10.1016/j.jacc.2006.12.048. PMID 17466227.
- Rendell (2004). "Advances in diabetes for the millennium: drug therapy of type 2 diabetes". MedGenMed : Medscape general medicine 6 (3 Suppl): 9. PMC 1474831. PMID 15647714.
- "Helping the pancreas produce insulin". HealthValue. Archived from the original on September 27 2007. Retrieved 2007-09-21.
- Konno; Tortorelis, DG; Fullerton, SA; Samadi, AA; Hettiarachchi, J; Tazaki, H (2001). "A possible hypoglycaemic effect of maitake mushroom on type 2 diabetic patients". Diabetic Medicine 18 (12): 1010. doi:10.1046/j.1464-5491.2001.00532-5.x. PMID 11903406.
- Hong; Xun, M; Wutong, W (2007). "Anti-diabetic effect of an alpha-glucan from fruit body of maitake (Grifola frondosa) on KK-Ay mice". The Journal of pharmacy and pharmacology 59 (4): 575–82. doi:10.1211/jpp.59.4.0013. PMID 17430642.
- Kubo; Aoki, H; Nanba, H (1994). "Anti-diabetic activity present in the fruit body of Grifola frondosa (Maitake). I". Biological & Pharmaceutical Bulletin 17 (8): 1106–10. doi:10.1248/bpb.17.1106. PMID 7820117.
- Lo, HC; Hsu, TH; Chen, CY (2008). "Submerged culture mycelium and broth of Grifola frondosa improve glycemic responses in diabetic rats". The American journal of Chinese medicine 36 (2): 265–85. doi:10.1142/S0192415X0800576X. PMID 18457360.
- Manohar; Talpur, NA; Echard, BW; Lieberman, S; Preuss, HG (2002). "Effects of a water-soluble extract of maitake mushroom on circulating glucose/insulin concentrations in KK mice". Diabetes, obesity & metabolism 4 (1): 43–8. doi:10.1046/j.1463-1326.2002.00180.x. PMID 11874441.
- Horio; Ohtsuru, M (2001). "Maitake (Grifola frondosa) improve glucose tolerance of experimental diabetic rats". Journal of nutritional science and vitaminology 47 (1): 57–63. doi:10.3177/jnsv.47.57. PMID 11349892.
- Matsuur; Asakawa, C; Kurimoto, M; Mizutani, J (2002). "Alpha-glucosidase inhibitor from the seeds of balsam pear (Momordica charantia) and the fruit bodies of Grifola frondosa". Bioscience, Biotechnology, and Biochemistry 66 (7): 1576–8. doi:10.1271/bbb.66.1576. PMID 12224646.
- Briones; Bajaj, M (2006). "Exenatide: a GLP-1 receptor agonist as novel therapy for type 2 diabetes mellitus". Expert opinion on pharmacotherapy 7 (8): 1055–64. doi:10.1517/14656518.104.22.1685. PMID 16722815.
- Gallwitz (2006). "Exenatide in type 2 diabetes: treatment effects in clinical studies and animal study data". International journal of clinical practice 60 (12): 1654–61. doi:10.1111/j.1742-1241.2006.01196.x. PMID 17109672.
- Cvetković; 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.
- http://www.drugs.com/nda/liraglutide_080530.html May 2008
- http://www.medicalnewstoday.com/articles/74913.php "Liraglutide Provides Significantly Better Glucose Control Than Insulin Glargine In Phase 3 Study" June 2007
- http://www.medicalnewstoday.com/articles/110349.php "Clinical Study Shows Liraglutide Reduced Blood Sugar, Weight, And Blood Pressure In Patients With Type 2 Diabetes" June 2008
- http://www.novonordisk.com/science/about_rd/quarterly_rd_update.asp Oct 2008 Inc results of LEAD 6 extension
- http://money.cnn.com/news/newsfeeds/articles/marketwire/0580389.htm January 2009
- National Prescribing Service (August 1, 2010). "Dipeptidyl peptidase-4 inhibitors ('gliptins') for type 2 diabetes mellitus". RADAR.
- Amori RE, Lau J, Pittas AG (2007). "Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis". JAMA 298 (2): 194–206. doi:10.1001/jama.298.2.194. PMID 17622601.
- Barzilei, N; Mahoney EM, Guo H (2009). "Sitagliptin is well tolerated and leads to rapid improvement in blood glucose in the first days of monotherapy in patients aged 65 years and older with T2DM". Diabetes 58: 587.
- Doucet, J; Chacra, A, Maheux, P, Lu, J, Harris, S, Rosenstock, J (2011 Apr). "Efficacy and safety of saxagliptin in older patients with type 2 diabetes mellitus". Current medical research and opinion 27 (4): 863–9. doi:10.1185/03007995.2011.554532. PMID 21323504.
- Pratley, RE; Rosenstock, J, Pi-Sunyer, FX, Banerji, MA, Schweizer, A, Couturier, A, Dejager, S (2007 Dec). "Management of type 2 diabetes in treatment-naive elderly patients: benefits and risks of vildagliptin monotherapy". Diabetes Care 30 (12): 3017–22. doi:10.2337/dc07-1188. PMID 17878242.
- Pratley, RE; McCall, T, Fleck, PR, Wilson, CA, Mekki, Q (2009 Nov). "Alogliptin use in elderly people: a pooled analysis from phase 2 and 3 studies". Journal of the American Geriatrics Society 57 (11): 2011–9. doi:10.1111/j.1532-5415.2009.02484.x. PMID 19793357.
- Yeh, GY; Eisenberg, DM, Kaptchuk, TJ, Phillips, RS (2003 Apr). "Systematic review of herbs and dietary supplements for glycemic control in diabetes". Diabetes Care 26 (4): 1277–94. doi:10.2337/diacare.26.4.1277. PMID 12663610.
- Kirkham, S; Akilen, R, Sharma, S, Tsiami, A (2009 Dec). "The potential of cinnamon to reduce blood glucose levels in patients with type 2 diabetes and insulin resistance". Diabetes, obesity & metabolism 11 (12): 1100–13. doi:10.1111/j.1463-1326.2009.01094.x. PMID 19930003.
- "Indian plant extracts may help treat diabetes". The Times Of India. 4 July 2012.
- Hypoglycaemic activity of Gentiana olivieri and isolation of the active constituent through bioassay- directed fractionation techniques. Ekrem Sezik, Mustafa Aslan, Erdem Yesilada, Shigeru Ito, Life Sciences, 28 January 2005, Volume 76, Issue 11, Pages 1223–1238, doi:10.1016/j.lfs.2004.07.024
- Balk, EM; Tatsioni, A; Lichtenstein, AH; Lau, J; Pittas, AG (2007). "Effect of chromium supplementation on glucose metabolism and lipids: a systematic review of randomized controlled trials". Diabetes Care 30 (8): 2154–63. doi:10.2337/dc06-0996. PMID 17519436.
- Thompson, KH; Lichter, J, LeBel, C, Scaife, MC, McNeill, JH, Orvig, C (2009 Apr). "Vanadium treatment of type 2 diabetes: a view to the future". Journal of Inorganic Biochemistry 103 (4): 554–8. doi:10.1016/j.jinorgbio.2008.12.003. PMID 19162329.
- Thornalley, PJ (2005 Aug). "The potential role of thiamine (vitamin B1) in diabetic complications". Current diabetes reviews 1 (3): 287–98. doi:10.2174/157339905774574383. PMID 18220605.
Further reading