Anti-diabetic medication

Drugs used in diabetes 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. Type 2 diabetes mellitus is the most common type of diabetes. 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.

Insulin

Main article: insulin (medication)

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.[1]

Examples of rapid acting insulins include

Examples of intermediate acting insulins include

Examples of long acting insulins include

Most anti-diabetic agents are contraindicated in pregnancy, in which insulin is preferred.[2]

Sensitizers

Insulin sensitizers address the core problem in Type II diabetes—insulin resistance.

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. 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 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

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).[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 glycated hemoglobin (A1C) values are 1.5–2.0%. Some examples are:

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,[9] as did the DREAM trial.[10]

Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in the New England Journal of Medicine.[11] There have been a significant number of publications since then, and a Food and Drug Administration panel[12] 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.[13] 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.[14]

Secretagogues

Secretagogues are drugs that increase insulin output from the pancreas.

Sulfonylureas

Main article: Sulfonylurea

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.

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%.

Nonsulfonylurea secretagogues

Meglitinides

Main article: Meglitinide

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.[15] By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, thereby enhancing insulin secretion.[16]

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.

Peptide analogs

Overview of insulin secretion

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.[16] 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.

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

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.[26]

Dipeptidyl peptidase-4 (DPP-4) inhibitors increase blood concentration of the incretin GLP-1 by inhibiting its degradation by dipeptidyl peptidase-4.

Examples are:

DPP-4 inhibitors lowered hemoglobin A1C values by 0.74%, comparable to other antidiabetic drugs.[27]

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).[28] 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%.[29] 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%.[30] 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.[31]

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, 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%.

Glycosurics

SGLT-2 inhibitors block the re-uptake of glucose in the renal tubules, promoting loss of glucose in the urine. This causes both mild weight loss, and a mild reduction in blood sugar levels with little risk of hypoglycaemia.[32]

Comparison

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[33][34]
agent[34] mechanism[2] advantages[34] disadvantages[34]
Sulfonylurea (glyburide, glimepiride, glipizide) Stimulating insulin release by pancreatic beta cells by inhibiting the KATP channel
  • Causes an average of 5–10 pounds weight gain
  • Increased risk of hypoglycemia
  • Glyburide has increases risk of hypoglycemia slightly more as compared with glimepiride and glipizide
Metformin Acts on the liver to reduce gluconeogenesis and causes a decrease in insulin resistance via increasing AMPK signalling.
  • Not associated with weight gain
  • Low risk of hypoglycemia as compared to alternatives
  • Good effect on LDL cholesterol
  • Decreases triglycerides
  • No effect on blood pressure
  • Inexpensive
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
  • Slightly decreased risk of hypoglycemia as compared to sulfonylurea
  • Not associated with weight gain
  • Decreases triglycerides
  • No effect on cholesterol
  • Less effective than most other diabetes pills in decreasing glycated hemoglobin
  • Increased risk of GI problems than other diabetes pills except metformin
  • Inconvenient dosing
  • Expensive
Thiazolidinediones (Pioglitazone, Rosiglitazone) Reduce insulin resistance by activating PPAR-γ in fat and muscle
  • Lower risk of hypoglycemia
  • Slight increase in high-density lipoprotein
  • Actos linked to decreased triglycerides
  • Convenient dosing
  • Increased risk of heart failure
  • Causes an average of 5–10 pounds weight gain
  • Associated with higher risk of edema
  • Associated with higher risk of anemia
  • Increases low-density lipoprotein
  • Avandia linked to increased triglycerides and risk of heart attack
  • Actos linked to increased risk of bladder cancer
  • Slower onset of action
  • Requires monitoring for hepatoxicity
  • Associated with increased risk of limb fractures
  • Expensive

Generic

Many anti-diabetes drugs are available as generics. These include:[35]

No generics are available for dipeptidyl peptidase-4 inhibitors (Januvia, Onglyza) and other combinations.

References

  1. ↑ Diabetes Mellitus, Alvin C. Powers in Harrison's Principles of Internal Medicine, 18th edition, Chapter 345, ISBN 978-0071748896
  2. 1 2 3 4 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.
  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". BMJ (Clinical research ed.) 335 (7618): 497. doi:10.1136/bmj.39314.620174.80. PMC 1971204. PMID 17761999.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ http://www.healthvalue.net/diabetesinsulinPPAR.html
  7. ↑ European Medicines Agency, "European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim", EMA, 23 September 2009
  8. ↑ Hinterthuer, Adam (October 1, 2008). "Retired Drugs: Failed Blockbusters, Homicidal Tampering, Fatal Oversights". Wired News. Retrieved 2009-06-21.
  9. ↑ Haffner, Steven M. (2007). "Expert Column – A Diabetes Outcome Progression Trial (ADOPT)". Medscape. Retrieved 2007-09-21.
  10. ↑ Gagnon, Louise (2007). "DREAM: Rosiglitazone Effective in Preventing Diabetes". Medscape. Retrieved 2007-09-21.
  11. ↑ 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).
  12. ↑ 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.
  13. ↑ Ajjan; Grant, PJ (2008). "The cardiovascular safety of rosiglitazone". Expert opinion on drug safety 7 (4): 367–76. doi:10.1517/14740338.7.4.367. PMID 18613801.
  14. ↑ 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.
  15. ↑ 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.
  16. 1 2 "Helping the pancreas produce insulin". HealthValue. Archived from the original on September 27, 2007. Retrieved 2007-09-21.
  17. ↑ 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:10.1517/14656566.7.8.1055. PMID 16722815.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ http://www.drugs.com/nda/liraglutide_080530.html May 2008
  21. ↑ http://www.medicalnewstoday.com/articles/74913.php "Liraglutide Provides Significantly Better Glucose Control Than Insulin Glargine In Phase 3 Study" June 2007
  22. ↑ 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
  23. ↑ http://www.drugdevelopment-technology.com/projects/liraglutide/
  24. ↑ http://www.novonordisk.com/science/about_rd/quarterly_rd_update.asp Oct 2008 Inc results of LEAD 6 extension
  25. ↑ http://money.cnn.com/news/newsfeeds/articles/marketwire/0580389.htm January 2009
  26. ↑ National Prescribing Service (August 1, 2010). "Dipeptidyl peptidase-4 inhibitors ('gliptins') for type 2 diabetes mellitus". RADAR.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ Doucet, J; Chacra, A; Maheux, P; Lu, J; Harris, S; Rosenstock, J (April 2011). "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.
  30. ↑ Pratley, RE; Rosenstock, J; Pi-Sunyer, FX; Banerji, MA; Schweizer, A; Couturier, A; Dejager, S (December 2007). "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.
  31. ↑ Pratley, RE; McCall, T; Fleck, PR; Wilson, CA; Mekki, Q (November 2009). "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.
  32. ↑ Dietrich, E; Powell, J; Taylor, JR (November 2013). "Canagliflozin: a novel treatment option for type 2 diabetes.". Drug Design, Development and Therapy 22 (7): 1399–1408. doi:10.2147/DDDT.S48937. PMID 24285921.
  33. ↑ 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
  34. 1 2 3 4 Consumer Reports Health Best Buy Drugs. "The Oral Diabetes Drugs: Treating Type 2 Diabetes" (PDF). Best Buy Drugs (Consumer Reports): 20. Retrieved September 18, 2012., which is citing
  35. ↑ "The Oral Diabetes Drugs Treating Type 2 Diabetes Comparing Effectiveness, Safety, and Price" (PDF). Retrieved July 17, 2013.

Further reading

This article is issued from Wikipedia - version of the Tuesday, May 03, 2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.