Oral antidiabetics

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

Based on mechanism of action ADO are cathegorized into 4 goups:
 * insulin sensitizers – increase cell sensitivity to insulin (biguanide, thiazolidinediones);
 * insulin secretagogues – increase the release of insulin from pancreatic β-cells (sulphonylureas, glinids);
 * intestinal glukosidase inhibitors – decrease glucose absorption in intestine − (alpha-glucosidase inhibitors);
 * inhibitors of glucose re-uptake in proximal tubule – increase glucosuria (gliflozins).

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

Biguanides
Metformin is currently a primary ADO. 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. It is a cheap drug without prescription restriction. It increases sensitivity (especially in liver and skeletal muscles) to insulin and decreases glycaemia by:
 * Mechanism of action
 * stimulating glucose utilisation in skeletal muscles and adipose tissue (glycolysis stimulation)
 * reduction of gluconeogenesis in liver
 * decreasing glucose resorption in the small intestine.

By stimulating glycolysis it also promotes lactate production. Thus, lactic acidosis can be a serious complication. Patients with renal failure, cardiopulmonal insufficiency, liver insufficiency (alcoholics) are prone to this acidosis, therefore biguanides are contraindicated.
 * Side effects

At the beginning of the treatment gastrointestinal symptoms may occur.

Intravenous administration of iodine contrast media can lead to renal failure. This may cause 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.

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
Mechanism of action

They have similar effects as biguanides. Trough 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) and are therefore not used in patients with heart failure or edema or during pregnancy.Pioglitazone is contraindicated in haematuria of unclear origin. Regular lier function testsmonitoring 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 ), it is well tolerated and suitable as an alternative to metformin.

Insulin secretagogues
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
Increased insulin release from pancreatic β-cells is achieved by blocking ATP-sensitive K + channels in the membrane. This reduces the flow of potassium from the cell, depolarizes the membrane and opens Ca 2+ channels. Influx of Ca2+ activates the insulin release. The most serious complication may be hypoglycaemia, especially with longer-acting substances. This group of drugs also increases appetite, so treatment is often associated with weight gain.
 * Mechanism of action
 * Side effects

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
Newer drugs also binding 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 (of substances) are  'repaglinide'  and  'nateglinide' .

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

Mechanism of action

By inhibiting 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 caused by the action of microbial intestinal flora on undigested compound carbohydrates.

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

Gliflozins (Sodium-glucose cotransporter 2 inhibitors)
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, uricaemia, slightly increase HDL cholesterol and, due to osmotic diuresis, slightly lower the blood pressure. Side effects

Increase in frequency of urogenital tract infections, most often mycosis in women. Due to increased diuresis, caution should be exercised in patients at risk of hypotension or volume depletion.

The risk of hypoglycaemia is minimal with gliflozins.

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

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

Exenatid is a synthetic analogue of GLP-1 (glucagon-like peptide 1), incretin analogue. It is applied s. c., so it does not belong to ADO.

Dipeptidyl peptidase-4 inhibitors (DPP-4) inhibit an enzyme, that inactivates endogenous incretins. They are less effective than incretin analogues, however cheaper and orally administrable. Substance example: sitagliptin, linagliptin.

Links

 * Diabetes Mellitus/type 2
 * Insulin therapy
 * Incretin analogs

Source

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