Sulfonylurea

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General formula of a sulfonylurea, showing the sulfonylurea backbone itself in red and the side chains that distinguish each compound in blue.

Sulfonylurea (UK: sulphonylurea) derivatives are a class of antidiabetic drugs that are used in the management of diabetes mellitus type 2. They act by increasing insulin release from the beta cells in the pancreas.

Drugs in this class[edit]

First generation[edit]

Second generation[edit]

Some classify glimepiride as second-generation,[1] while others classify it as third-generation.[2]

Chemistry[edit]

All sulfonylureas contain a central S-phenylsulfonylurea structure (red) with a p- substituent on the phenyl ring (R) and various groups terminating the urea N′ end group (R2).

Sulfonylurea group

Pharmacology[edit]

Mechanism of action[edit]

Glucose Insulin Release Pancreas

Sulfonylureas bind to an ATP-dependent K+(KATP) channel on the cell membrane of pancreatic beta cells. This inhibits a tonic, hyperpolarizing efflux of potassium, thus causing the electric potential over the membrane to become more positive. This depolarization opens voltage-gated Ca2+ channels. The rise in intracellular calcium leads to increased fusion of insulin granulae with the cell membrane, and therefore increased secretion of (pro)insulin.

There is some evidence that sulfonylureas also sensitize β-cells to glucose, that they limit glucose production in the liver, that they decrease lipolysis (breakdown and release of fatty acids by adipose tissue) and decrease clearance of insulin by the liver.

The KATP channel is an octameric complex of the inward-rectifier potassium ion channel Kir6.2 and sulfonylurea receptor SUR1 which associate with a stoichiometry of Kir6.24/SUR14.

Pharmacokinetics[edit]

Various sulfonylureas have different pharmacokinetics. The choice depends on the propensity of the patient to develop hypoglycemia – long-acting sulfonylureas with active metabolites can induce hypoglycemia. They can, however, help achieve glycemic control when tolerated by the patient. The shorter-acting agents may not control blood sugar levels adequately.

Due to varying half-life, some drugs have to be taken two (e.g. tolbutamide) or three times a day rather than once (e.g. glimepiride). The short-acting agents may have to be taken about 30 minutes before the meal, to ascertain maximum efficacy when the food leads to increased blood glucose levels.

Some sulfonylureas are metabolised by liver metabolic enzymes (cytochrome P450) and inducers of this enzyme system (such as the antibiotic rifampicin) can therefore increase the clearance of sulfonylureas. In addition, because some sulfonylureas are bound to plasma proteins, use of drugs that also bind to plasma proteins can release the sulfonylureas from their binding places, leading to increased clearance.

Uses[edit]

Sulfonylureas are used primarily for the treatment of diabetes mellitus type 2, specifically when metformin is contraindicated or not efficient. Sulfonylureas are ineffective where there is absolute deficiency of insulin production such as in type 1 diabetes or post-pancreatectomy.

Efficacy[edit]

Although for many years sulfonylureas were the first drugs to be used in new cases of diabetes, in the 1990s it was discovered that obese patients might benefit more from metformin. In the UKPDS study it was found that treatment with insulin or sulphonylurea drugs had no significant effect on microvascular or macrovascular outcomes in overweight patients, the group most commonly encountered in clinical practice and that tight glucose control does not change overall mortality or diabetes related mortality. Review articles on the treatment of type 2 diabetes have not accurately transmitted the valid POEM results (patient oriented evidence that matters) of the UKPDS to clinicians.[3]

In an analysis of 72 randomised controlled trials (RCTs) with 22,589 participants a cochrane review on monotherapy with sulfonylureas concluded there is insufficient evidence from RCTs to support the decision as to whether to initiate sulphonylurea monotherapy. Data on patient-important outcomes are lacking. Therefore, large-scale and long-term randomised clinical trials with low risk of bias, focusing on patient-important outcomes as mortality, diabetic complications, adverse events and health-related quality of life are required.[4]

Intensive glycaemic control compared with conventional glycaemic control was analysed in a 2013 systematic review including 28 trials. It did not show significant differences for all-cause mortality and cardiovascular mortality. Intensive glycaemic control seemed to reduce the risk of microvascular complications, if we disregard the risks of bias, but increased the risk of hypoglycaemia and serious adverse events.[5]

Side effects and cautions[edit]

Hypoglycemia[edit]

Sulfonylureas, as opposed to metformin, the thiazolidinediones, exenatide, symlin and other newer treatment agents may induce hypoglycemia as a result of excesses in insulin production and release. This typically occurs if the dose is too high, and the patient is fasting.

Second generation sulfonylureas have 5,64 higher risk for severe hypoglycaemia than metformin and a 6,11 higher risk than thiazolidinediones in 4 and 6 trials.[4]

Intensive glycaemic control with combined therapy increases the relative risk of severe hypoglycaemia by 30%.[6]

Weight gain[edit]

Like insulin, sulfonylureas can induce weight gain, mainly as a result of their effect to increase insulin levels. Compared with sulfonylureas, thiazolidinediones and repaglinide produced similar gains in body weight (1 to 5 kg). Metformin produced no weight gain compared with most other oral agents or placebo.[7]

Other side-effects[edit]

Abdominal upset, headache and hypersensitivity reactions.

Death[edit]

Data on patient-important outcomes as mortality, diabetic complications, adverse events and health-related quality of life are lacking. First generation sulfonylurea showed statistical significance for cardiovascular mortality in favour of placebo (RR 2.63, 95% CI 1.32 to 5.22; P = 0.006; 2 trials; 553 participants; HRB). Mortality data for the second generation sulfonylurea versus placebo were sparse.[4] All sulfonylureas carry an FDA-required warning about possible increased risk of cardiovascular death. In a meta analysis of 115 trials in type 2 diabetes, the use of sulfonylureas is associated with increased mortality and a higher risk of stroke, whereas the overall incidence of MACE (Major cardiovascular events) appears to be unaffected. The results of this meta-analysis need to be interpreted with caution, mainly because of limitations in trial quality and under-reporting of information on cardiovascular events and mortality.[8]

Thigh glucose control with combined therapy including sulfonylurea.

A meta analysis of 14 trials found intensive glycaemic control did not seem to reduce all cause mortality in patients with type 2 diabetes. The data remained insufficient to prove or refute a relative risk reduction for cardiovascular mortality, non-fatal myocardial infarction, composite microvascular complications, or retinopathy at a magnitude of 10%. There was no effect on the risk of nephropathy, and the relative risk of severe hypoglycaemia was increased by 30%.[6]

Loss of beta cells[edit]

Some diabetes experts feel that sulfonylureas as tolbutamide and glibenclamide accelerate the loss of beta cells from the pancreas, and should be avoided.[9][10] Relative to metformin, a greater rate of decline in beta cell function over time and therapy failure rate has been observed with sulfonylurea treatment.[11]

Contraindications[edit]

Sulfonylureas are contraindicated in pregnancy and lactation, type 1 diabetes, renal insufficiency for long acting products, severe liver problems and allergy to sulfonamides. Impairment of liver or kidney function increase the risk of hypoglycemia.

Interactions[edit]

Drugs that potentiate or prolong the effects of sulfonylureas and therefore increase the risk of hypoglycemia include acetylsalicylic acid and derivatives, allopurinol, sulfonamides, and fibrates.

Drugs that worsen glucose tolerance, contravening the effects of antidiabetics, include corticosteroids, isoniazide, oral contraceptives and other estrogens, sympathomimetics, and thyroid hormones. Sulfonylureas tend to interact with a wide variety of other drugs, but these interactions, as well as their clinical significance, vary from substance to substance.[12][13]

Research[edit]

Sulfonylureas can be used to treat some types of neonatal diabetes. While historically patients with hyperglycemia and low blood insulin levels were diagnosed with Type I Diabetes by default, it has been found that patients who receive this diagnosis before 6 months of age are often, in fact, candidates for receiving sulfonylureas rather than insulin throughout life.[14]

History[edit]

Sulfonylureas were discovered by the chemist Marcel Janbon and co-workers,[15] who were studying sulfonamide antibiotics and discovered that the compound sulfonylurea induced hypoglycemia in animals.[16]

References[edit]

  1. ^ Triplitt CL, Reasner CA (2011). "Chapter 83: diabetes mellitus". In DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM. Pharmacotherapy: a pathophysiologic approach (8th ed.). New York, NY: McGraw-Hill. p. 1274. ISBN 0-07-170354-3. 
  2. ^ Davidson J (2000). Clinical diabetes mellitus: a problem-oriented approach. Stuttgart: Thieme. p. 422. ISBN 0-86577-840-X. 
  3. ^ Shaughnessy AF, Slawson DC (2003). "What happened to the valid POEMs? A survey of review articles on the treatment of type 2 diabetes". BMJ 327 (7409): 266. doi:10.1136/bmj.327.7409.266. PMC 167157. PMID 12896940. 
  4. ^ a b c Hemmingsen B, Schroll JB, Lund SS, Wetterslev J, Gluud C, Vaag A, Sonne DP, Lundstrøm LH, Almdal T (2013). "Sulphonylurea monotherapy for patients with type 2 diabetes mellitus". Cochrane Database Syst Rev 4: CD009008. doi:10.1002/14651858.CD009008.pub2. PMID 23633364. 
  5. ^ Hemmingsen, B; Lund, SS; Gluud, C; Vaag, A; Almdal, TP; Hemmingsen, C; Wetterslev, J (Nov 11, 2013). "Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus.". The Cochrane database of systematic reviews 11: CD008143. PMID 24214280. 
  6. ^ a b Hemmingsen, B.; Lund, S. S.; Gluud, C.; Vaag, A.; Almdal, T.; Hemmingsen, C.; Wetterslev, J. (24 November 2011). "Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials". BMJ 343 (nov24 1): d6898–d6898. doi:10.1136/bmj.d6898. 
  7. ^ Bolen, Shari (18 September 2007). "Systematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes Mellitus". Annals of Internal Medicine 147 (6): 386. doi:10.7326/0003-4819-147-6-200709180-00178. 
  8. ^ Monami, M.; Genovese, S.; Mannucci, E. (October 2013). "Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials". Diabetes, Obesity and Metabolism 15 (10): 938–953. doi:10.1111/dom.12116. 
  9. ^ Maedler, K; Carr, RD; Bosco, D; Zuellig, RA; Berney, T; Donath, MY (Jan 2005). "Sulfonylurea induced beta-cell apoptosis in cultured human islets.". The Journal of clinical endocrinology and metabolism 90 (1): 501–6. PMID 15483097. 
  10. ^ Takahashi, A; Nagashima, K; Hamasaki, A; Kuwamura, N; Kawasaki, Y; Ikeda, H; Yamada, Y; Inagaki, N; Seino, Y (Sep 2007). "Sulfonylurea and glinide reduce insulin content, functional expression of K(ATP) channels, and accelerate apoptotic beta-cell death in the chronic phase.". Diabetes research and clinical practice 77 (3): 343–50. PMID 17316868. 
  11. ^ Eurich, DT; Simpson, SH; Majumdar, SR; Johnson, JA (Jun 2005). "Secondary failure rates associated with metformin and sulfonylurea therapy for type 2 diabetes mellitus.". Pharmacotherapy 25 (6): 810–6. PMID 15927899. 
  12. ^ Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X. 
  13. ^ Dinnendahl, V.; Fricke, U., eds. (2010). Arzneistoff-Profile (in German) 4 (23 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3. 
  14. ^ Greeley SA, Tucker SE, Naylor RN, Bell GI, Philipson LH (2010). "Neonatal diabetes mellitus: a model for personalized medicine". Trends Endocrinol. Metab. 21 (8): 464–72. doi:10.1016/j.tem.2010.03.004. PMC 2914172. PMID 20434356. 
  15. ^ Janbon M, Chaptal J, Vedel A, Schaap J (1942). "Accidents hypoglycémiques graves par un sulfamidothiodiazol (le VK 57 ou 2254 RP)". Montpellier Med. 441: 21–22. 
  16. ^ Patlak M (2002). "New weapons to combat an ancient disease: treating diabetes". FASEB J. 16 (14): 1853. doi:10.1096/fj.02-0974bkt. PMID 12468446.