Oral antidiabetics

Oral antidiabetics are used to treat a relative insulin deficiency and are used in the treatment of type 2 diabetes not requiring insulin. The group of active agents consists of different representatives, which are able to lower blood sugar via different pharmacological mechanisms. The oral antidiabetic agents include:

• Biguanides(metformin)
• Sulfonylureas
• Glinides
• Glitazones
• α-Glucosidase inhibitors
• DPP-4 inhibitors
• SGLT-2 inhibitors

Biguanide

Active ingredient:

• Metformin (e.g. Diabesin®, Diabetase®, Glucobon biomo®)

The mechanism of action of the active ingredient metformin has not yet been precisely clarified. It is certain that metformin accumulates intracellularly in the mitochondria and stimulates the key enzyme of cell metabolism, the AMP-activated protein kinase (AMP kinase). This leads to an

inhibition of hepatic glucose production. Furthermore, it improves the uptake of blood glucose into muscle cells and fat cells. It also has a weak appetite suppressant effect and has a positive influence on (blood) lipids. It is administered orally and is eliminated exclusively renally with a short half-life.

Metformin is available as a mono-preparation as well as in combination with other oral antidiabetic drugs. It is taken after meals. A possible side effect is the development of lactic acidosis. Hypoglycemia, on the other hand, is not expected.

A feared side effect of metformin is lactic acidosis, which occurs particularly with continued use in the context of serious illnesses and operations, as well as with intravenous administration of iodine-containing contrast media. Metformin must therefore be discontinued in the presence of these risk factors and usually replaced by insulin therapy. On the other hand, the fact that there is no increased risk of life-threatening hypoglycaemia during therapy with metformin is favourable.

Sulfonylureas

Active ingredients:

• Glibenclamide (e.g. Euglucon®, Glibenbeta®)
• Glimepiride
• Gliclazide
• Gliquidone

Sulfonylureas are particularly suitable for normal-weight type 2 diabetics. Sulfonylureas stimulate beta cells to release more insulin, causing blood glucose to drop rapidly. The acidic sulfonamide grouping in the immediate vicinity of the aromatic ring is responsible for the action of this group of substances.

Mechanism of action: The blood sugar-lowering effect of sulfonylureas requires the presence of insulin-producing B cells. Therapy begins with a low dosage, which is then increased. are generally taken 30 minutes before meals in the morning and evening, the newer and faster-acting glimepiride (e.g. Amaryl®) once daily in the morning with breakfast.

Alpha-glucosidase inhibitors

Active ingredients:

• Acarbose (e.g. Glucobay®)
• Miglitol (e.g. Diastabol®)
• Guar flour (e.g. Glucotard®)

Alpha-glucosidase inhibitors are nitrogen-containing oligosaccharides of microbial origin. They act as competitive inhibitors of alpha-glucosidase (saccharase isomaltase) and are used in the treatment of type 2 diabetes. The alpha-glucosidase cleaves glucose-containing disaccharides of food. The enzyme is found in the brush border of the intestinal epithelium in the immediate vicinity of the Na+-dependent glucose transporter GLUT-1, which in cooperation with alpha-glucosidase ensures proper absorption of glucose. Alpha-glucosidase inhibitors thus reduce carbohydrate absorption in the intestine. This reduces the postprandial rise in blood glucose.

Prandial glucose regulators (glinides).

Active ingredients:

• Nateglinide (e.g. Starlix®)- approved only in combination with metformin
• Repaglinide (e.g. NovoNorm®)
• like the sulfonylureas, lead to insulin release by blocking the KATP channels through binding to the sulfonylurea receptor (SHR1). They are prescribed as back-up medications, for example, in renal insufficiency with creatinine clearance < 25 ml/min, in whom other oral antidiabetic agents and insulin therapy are not an option. Glinides increase insulin release in response to the level of blood glucose. They are taken at the beginning of a meal and reach their maximum effect within about 45 minutes. If the blood glucose level drops, the effect of the glinides also diminishes.

Thiazolidinediones (glitazones)

Active ingredients:

• Pioglitazone (e.g. Actos®, the only representative still approved) -
• and
• Rosiglitazone (e.g. Avandia® - no longer approved due to cardiotoxicity).

The glitazones are artificial agonists of PPARɤ. They act by activating the nuclear transcription factor PPARɤ (peroxisome proliferator-activated receptor-ɤ). Induction of genes involved in glucose and lipid metabolism occurs. They act only in the presence of insulin and increase the sensitivity of body cells to insulin. Pioglitazone also inhibits the production of glucose in the liver. Glitazones are usually only used when satisfactory blood glucose control cannot (or can no longer) be achieved with sulfonylureas or metformin. Glitazones sometimes have serious side effects.

Incretin analogues

Active ingredients:

• Exenatide
• Liraglutide
• Abliglutide
• Dulaglutide

The members of this drug class are genetically engineered peptide analogues of the endogenous incretin GLP-1. The substances bind to the GLP-1 receptor of the B-cells of the islets of Langerhans and thus promote the cAMP-mediated release of insulin. The effect is dependent on the level of blood glucose. This effect sit dependent on the level of blood glucose. Incretin analogues intensify glucose-induced insulin secretion. They also inhibit glucagon release, delay gastric emptying and decrease appetite. They are metabolically eliminated and are used in combination with metformin or sulfonylureas to treat type 2 diabetes.

Inhibitors of proteolytic incretin degradation (incretins).

Active ingredients:

• Sitagliptin = Januvia®, in combination with metformin Janumet).
• Saxagliptin
• Sitagliptin

These are novel drugs that enhance the action of the endogenous incretins GIP and GLP-1. Incretin mimetics inhibit the proteolytic enzyme dipeptidyl peptidase -4 (DPP-4). These agents reduce appetite and increase insulin production in type 2 diabetics. The drugs in these new groups of agents are currently unproven, and the therapeutic benefits are unclear.

Inhibitors of the renal sodium-glucose symporter (glioflcins).

Agents:

• Canaglifolzin
• Empagliflozin (Jardiance®)
• Dapagliflozin ( Forxida®)

Glioflzines are reversible inhibitors of the epithelial Na+- glucose symporter (SGLT-2). Glioflzines suppress renal glucose reabsorption from primary urine in the proximal tubule of the nephron (kidney). This dramatically increases glucose excretion in the urine. Agents are usually used in combination with other antihypertensive drugs in type 2 diabetics. As monotherapeutics, gliflozines are approved for patients who cannot tolerate metformin.

Antidiabetic drugs can compensate for insulin deficiency in different ways:

• Increasing inulin sensitivity (metformin, thiazolidinediones).
• Promotion of insulin secretion by blocking KATP channels (sulfonylureas, glinides)
• Promotion of insulin secretion by blocking the GLP-1 receptor of the B cells of the islets of Langerhans (incretin analogues)
• Promotion of insulin secretion and improvement of glucose tolerance by inhibition of proteolytic degradation (DPP-4) of the incretins GIP and GLP-1 Gliptins)
• Enhancement of renal glucose excretion by inhibition of the renal sodium-glucose symporter, SGLT-2 (Gliflozine)
• Reduction of glucose reabsorption (alpha-glucosidase inhibitors)

If lifestyle changes (weight reduction through dietary changes and physical exercise) in type 2 diabetics do not lead to a sufficient reduction in the HbA1c value (target HbA1c 6.5-7.5 %), then there is an indication for the initiation of drug therapy with oral antidiabetics. The drug of choice for all type 2 diabetics is the biguanide metformin.

Depending on the active ingredient, there are different interaction profiles, which can be found in the respective drug information.

Depending on the active ingredient, there are different contraindications, which can be found in the respective product information of the drug.

Due to its proven efficacy in terms of metabolic control and macrovascular risk reduction and a favourable side effect profile, metformin is now considered the drug of first choice in the medical therapy of type II diabetes mellitus.

In the case of intolerance, contraindications or insufficient efficacy of metformin, sulfonylureas (the risk of hypoglycemia must be taken into account) can be considered as monotherapeutic agents or as combination therapies. Other alternatives are: incretin analogues (GLP-1 analogues - subcutaneous use), gliptins (DPP-4 inhibitors) and gliflozins (SGLT-2 inhibitors).

In the gliptin family, evidence for a small additional benefit was shown for sitagliptin and saxagliptin (for sitagliptin in monotherapy and in combination with metformin and for the fixed combination sitagliptin/metformin for saxagliptin in combination with metformin).

Antidiabetic drugs should be used singly if possible or also as a double combination; triple or even quadruple combinations are controversial (high interaction potential, hardly any valid studies). It should be noted that most antidiabetic drugs are contraindicated in moderate to severe chronic renal insufficiency and other severe comorbidities. Therefore, antidiabetic agents should rather be combined with an appropriate form of insulin therapy when therapy escalation is required. The use of oral antidiabetics is not recommended during pregnancy and lactation.

Especially in old age, any therapy with antidiabetics should be used under close consideration of possible contraindications and interactions.