Oral antidiabetics

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Oral antidiabetics (OAD) are drugs used in the treatment of diabetes mellitus. Their mechanism of action depends on endogenous insulin production and therefore cannot be used in patients with type 1 diabetes.

Based on the mechanism of action, OAD are categorized into 4 groups:

  • insulin sensitizers – increase cell sensitivity to insulin (biguanide, thiazolidinediones)
  • insulin secretagogues – increase the release of insulin from pancreatic β-cells (sulphonylureas, glinids)
  • intestinal glucosidase inhibitors – decrease glucose absorption in intestine − (alpha-glucosidase inhibitors)
  • inhibitors of glucose reuptake in proximal tubule – increase glucosuria (gliflozins)

Insulin sensitizers[edit | edit source]

Insulin sensitizers increase cell sensitivity to insulin. They do not cause hypoglycemia, and thus are referred to as "euglycemizing drugs".

Biguanides[edit | edit source]

Metformin is currently the primary OAD. It is well tolerated and can be beneficial to combine with other antidiabetics. It reduces cardiovascular mortality by 50% and metformin treatment has positive long term effects (it is advised to start the treatment as early as the stage of prediabetes). It does not cause weight gain (as opposed to secretagogues and thiazolidinediones), which makes it advantageous even for obese patients.[1] It is a cheap drug.

Mechanism of action

It increases sensitivity (especially in liver and skeletal muscles) to insulin and decreases glycemia by:

  • stimulating glucose utilization in skeletal muscles and adipose tissue (glycolysis stimulation)
  • reduction of gluconeogenesis in liver
  • decreasing glucose resorption in the small intestine.
Side effects

By stimulating glycolysis it also promotes lactate production. Thus, lactic acidosis can be a serious complication. Patients with renal failure, cardiopulmonary insufficiency, and liver insufficiency (alcoholics) are prone to this acidosis; therefore, biguanides are contraindicated in such cases.

At the beginning of the treatment, gastrointestinal symptoms may occur.

Intravenous administration of iodine contrast media can lead to renal failure. This may cause lactate accumulation and increase the risk of lactic acidosis. Therefore, biguanide use must be discontinued 48 hours before such examination. They are also discontinued before surgery.[2]

They are not recommended for the treatment of diabetes during pregnancy. Insulin should be used to maintain blood sugar levels in order to minimize the risk of fetal malformations.

Thiazolidinediones[edit | edit source]

Mechanism of action

They have similar effects to biguanides. Through the PPAR-γ nuclear receptor, they activate the transcription of genes responsible for carbohydrate and fat metabolism.

Side effects

They cause mild fluid retention (which is why diuretics are sometimes added to the treatment regime) and are therefore not used in patients with heart failure or edema or during pregnancy. Pioglitazone is contraindicated in hematuria of unclear origin. Regular liver function tests monitoring is required. Weight gain often occurs (fluid retention, increase in adipose tissue). An eye examination is also appropriate before use due to the risk of worsening diabetic macular edema.

Currently only one drug is used: pioglitazone (rosiglitazone has no beneficial effect on cardiovascular mortality and has been withdrawn from the market[3]). It is well tolerated and suitable as an alternative to metformin.

Insulin secretagogues[edit | edit source]

They increase the release of insulin from pancreatic β-cells.

They are associated with the risk of possible induced hypoglycemia and they cause weight gain.

Sulphonylureas[edit | edit source]

Mechanism of action

Increased insulin release from pancreatic β-cells is achieved by blocking ATP-sensitive K+ channels in the cell membrane. This reduces the efflux of potassium from the cell, depolarizes the membrane and opens Ca 2+ channels. Influx of Ca2+ activates insulin release.

Side effects

The most serious complication may be hypoglycemia, especially with longer-acting substances. This group of drugs also increases appetite, so treatment is often associated with weight gain.

In practice, drugs of the second generation (glipizid) and third generation (glimepiride) are used. Most often in combination therapy with metformin (especially with insufficient compensation of type 2 DM with metformin monotherapy).

Glinides[edit | edit source]

These are newer drugs that also bind to ATP-sensitive K+ channels' in the membrane of β-cells. Their onset of action is quick, which makes them ideal for use with food to compensate for postprandial hyperglycemia. Examples include 'repaglinide' and 'nateglinide.

Alpha-glucosidase inhibitors[edit | edit source]

They are used to control postprandial hyperglycemia. The basic substance used in this group is acarbose.

Mechanism of action

By inhibiting digestive enzymes, they limit and slow down the absorption of carbohydrates in the small intestine. The inhibited enzyme does not break down the carbohydrates and therefore they cannot be absorbed (absorption of monosaccharides remains unchanged).

Side effects

Flatulence, diarrhea, and abdominal pain as a result of the action of microbial intestinal flora, which metabolize undigested compound carbohydrates.

If a patient develops hypoglycemia due to other medications, they cannot be treated orally with sucrose but only glucose.

Gliflozins (Sodium-glucose cotransporter 2 inhibitors)[edit | edit source]

Mechanism of action

They inhibit the SGLT-2 transporter in the proximal tubule of the nephron, thereby blocking glucose reuptake and increasing glycosuria. Thus, the renal threshold for glucose is shifted and blood glucose is lowered. Increased glucose losses lead to energy loss and weight loss. At the same time, they reduce glycated hemoglobin, uricemia, slightly increase HDL cholesterol and, due to osmotic diuresis, slightly lower the blood pressure.

Side effects

  • Increased risk of urogenital tract infections: most often, mycosis in women.
  • Due to increased diuresis, their use must be cautioned in patients at risk of hypotension or volume depletion.

The risk of hypoglycemia is minimal with gliflozins.

Dapagliflozin, canagliflozin, and empagliflozin are available in the Czech Republic.

Empangliflozin for oral use

Incretins[edit | edit source]

Substances that modulate the effects of incretins can now be used in the treatment of type 2 diabetes.[4] They are very effective, safe, but expensive. They increase insulin secretion, inhibit glucagon and act only in hyperglycemia.

Exenatide is a synthetic analogue of GLP-1 (glucagon-like peptide 1): an incretin analogue. It is administered subcutaneously, so it is not a OAD.

Dipeptidyl peptidase-4 inhibitors (DPP-4) inhibit an enzyme, that inactivates endogenous incretins. They are less effective than incretin analogues; however, they are cheaper and administered orally. Examples include sitagliptin and linagliptin.

References[edit | edit source]

Source[edit | edit source]

  • BULTAS, Jan. Kurz Farmakoterapie kardiovaskulárních chorob. 3. LF UK, 2010.

Bibliography[edit | edit source]

  • LINCOVÁ, Dagmar – FARGHALI, Hassan, et al. Základní a aplikovaná farmakologie. 2.. edition. Praha : Galén, 2007. 672 pp. pp. 392–396. ISBN 978-80-7262-373-0.
  • KVAPIL, Milan. Antidiabetika, která mě zaujala. Interní medicína pro praxi. 2016, y. 18, vol. 3, p. 125-129, ISSN 1214-8687. 

  • SLÍVA, Jiří and Martin VOTAVA. Pharmacology. 1st edition. Prague: Triton, 2011. 394 pp.  ISBN 9788073875008 .

Citations[edit | edit source]

  1. TREVOR, Anthony J. Katzung & Trevor's pharmacology: examination & board review. 10th ed. New York: McGraw-Hill Medical, c2013. a LANGE medical book. ISBN 978-0-07-178923-3.
  2. SUCHOPÁR, Josef, VALENTOVÁ, Štěpánka, ed. Remedia compendium. 4. vyd. Praha: Panax, 2009. ISBN 978-80-902806-4-9.
  3. SCHEEN, A J. [Suspension of the commercialization of sibutramine and rosiglitazone in Europe]. Rev Med Liege [online]2010, vol. 65, no. 10, p. 574-9, Available from <https://www.ncbi.nlm.nih.gov/pubmed/21128363>. ISSN 0370-629X. 
  4. SANUSI, Himawan. The role of incretin on diabetes mellitus. Acta Med Indones [online] . 2009, vol 41, no. 4, pp. 205-12, also available from < https://www.ncbi.nlm.nih.gov/pubmed/20737753 >. ISSN 0125-9326.