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 substances consists of different representatives that are able to lower blood sugar via different pharmacological mechanisms. The different agents are used according to the diabetes stage therapy. Depending on how advanced the type 2 diabetes is, different therapy stages may be necessary.

Sulfonylureas: Sulfonylureas, like the , are able to stimulate the production of insulin by the pancreas, largely independent of blood glucose levels. A possible side effect is that lnsulin production may overshoot the target, with the risk of hypoglycemia. A regular intake of carbohydrates is therefore necessary with sulfonylureas, which have a longer duration of action. Sulfonylureas, like glinides, can be used in combination with other oral antidiabetic agents.

• Glibenclamide
• Glimeripiride
• Gliclacid
• Gliquidone

Glinides (prandial glucose regulators): like the sulfonylureas, cause insulin release by blocking 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 decreases.

• Nateglinide (e.g. Starlix®)- approved only in combination with metformin
• Repaglinide (e.g. NovoNorm®)

Incretin analog ues: Incretin analogues are genetically engineered peptide analogues of GLP-1. The four substances bind to the GLP-1 receptor of the B cells in the islets of Langernhans and promote cAMP-mediated insulin release. This effect is dependent on the level of blood glucose. It increases with rising blood glucose and is completely absent at blood glucose levels >70mg/dl.

• Exenatide
• Liraglutide
• Albiglutide
• Dulaglutide

Inhibition of incretin proteolysis (gliptins): Gliptins significantly enhance the action of a hormone secreted by the small intestine after food intake. This hormone (GLP-1) significantly stimulates the release of insulin from the pancreas, when blood sugar rises or is already too high, it slows down gastric emptying and thus ensures a faster feeling of satiety. Furthermore, the intestinal hormone suppresses glucose production in the liver. In this way, the body's own natural GLP-1 hormones are preserved for longer. The blood sugar is lowered as needed. As a result, gliptins involve only a low risk of hypoglycaemia and are weight-neutral, i.e. do not lead to weight gain. Gliptins can be given, for example, in combination with metformin, sulfonylurea, insulin or glitazones. In general, DPP-4 inhibitors are well tolerated.

• Linagliptin
• Saxagliptin
• Sitagliptin
• Vildagliptin

Inhibition of renal sodium-glucose symporter (Gliflozine ): SGLT-2 inhibitors: are modern agents that have a beneficial effect on the heart and kidney in addition to effectively lowering blood glucose. In a healthy state, it is important that the sugars and salts filtered out in the kidney are returned to the body. This return transport of glucose from the primary urine of the kidney occurs up to the blood sugar level of about 180 mg/dl or 10 mmol/l. Two types of transport proteins are primarily responsible for this return transport: SGLT-1 and SGLT-2, where SGLT stands for sodium-glucose co-transporter. SGLT-2 is responsible for the greater part of the sugar return (approx. 90 %). If this transporter is inhibited by medication, the excess sugar is excreted in the urine. This can lower blood sugar levels and, as an additional effect, lead to weight loss and a reduction in blood pressure. SGLT-2 inhibitors also have a positive effect on the heart and kidneys, which are particularly affected by diabetes. This can reduce the risk of secondary diseases such as heart failure and kidney failure. In principle, an SGLT-2 inhibitor can also be combined well with other antidiabetic drugs, as the mechanisms of action complement each other.

• Canagliflozin
• Dapagliflozin
• Empagliflozin

Biguanide : 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, 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.

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

Thiazolidinediones (Glitazones): Thiazolidinediones exert their effects via activation of the peroxisome proliferator-activated receptor gamma (PPAR-γ). This receptor belongs to the subfamily of 48 known nuclear receptors that regulate gene expression after ligand binding. The PPAR subfamily consists of three subtypes, the alpha, beta/delta, and gamma PPA receptors. Natural ligands of the PPA receptors are for example fatty acids, bile acids or oxysterols. There is only one approved representative of this group of active substances.

• Pioglitazone (e.g. Actos®, the only representative still approved) -

• Rosiglitazone (e.g. Avandia®- no longer approved due to cardiotoxicity)

Alpha-glucosidase inhibitors: 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 the diet. 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.

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

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.

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 2 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.