Oral antidiabetics: list, mechanism, side effects

In France, nearly 4 million people are treated for diabetes (including more than 90% for type 2 diabetes). What are oral diabetes medications? How do they act? What side effects?

Definition: what are oral antidiabetics?

Oral antidiabetics are drugs used in the management of Type 2 diabetes. They allow to reduce the concentration of glucose in the blood. They are administered orally. Unlike type 1 diabetes (linked to a deficiency in insulin), the type 2 diabetes is characterized by high blood sugar levels.

What is the mechanism of action of oral antidiabetics?

The mechanism of action varies depending on the family to which the drug belongs.
The metformin blocks the production of glucose by the liver, reduces its absorption in the intestine and promotes its use by the muscles.
►Lsodium co-transporter inhibitorsglucose type 2 reduce the absorption of glucose and sodium in the kidneys, which promotes the urinary elimination of glucose.
Gliptins block the DPP-4 enzyme, which increases the production of GLP-1 (hormone that slows down the synthesis of glucagon). Thus they promote the secretion of insulin by reducing that of glucagon (hyperglycemic hormone).
Acarbose slows the intestinal absorption of sugars by blocking the action of alpha-glucosidases (enzymes allowing the digestion of sugars from food). For this reason, the drug should be administered at the start of the meal for maximum effectiveness.
►Lglinides and sulfonylureas promote the production of insulin by the pancreas. Glinides have a shorter duration of action.

Indications: in which cases should you take oral antidiabetics?

Oral antidiabetics are prescribed in adults to treat type 2 diabetes. Only the commercial specialties Glucophage® (metformin) and Forxiga® (dapagliflozin) are indicated for adults and children over 10 years of age. More rarely, the drug Stagid® based on metformin can be used in type 1 diabetics in addition to insulin. Some oral antidiabetics have other indications in adults:

  • Processing a form ofheart failure chronic (Forxiga® and Jardiance®)
  • Treatment of a chronic kidney disease (Forxiga®)

These drugs can be used alone or combined with other oral antidiabetics or even insulin treatment.

What is the list of the main oral antidiabetics in France?

Oral antidiabetics are divided into several families:

  • Biguanide : metformin (Glucophage®, Stagid®)
  • Isodium-glucose co-transporter type 2 (SGLT2) inhibitors or gliflozins : dapagliflozin (Forxiga®), empagliflozin (Jardiance®)
  • DPP-4 inhibitors or gliptins : vildagliptin (Galvus®), sitagliptin (Januvia®, Xelevia®), saxagliptin (Onglyza®)
  • Alpha-glucosidase inhibitor : acarbose (Glucor®)
  • Glinide : repaglinide (Novonorm®)
  • Hypoglycemic sulfonamides : glibenclamide (Daonil®), gliclazide (Diamicron®), glimepiride (Amarel®), glipizide (Ozidia®)

Several specialties are composed of a combination of metformin and another antidiabetic: Janumet® (+ sitagliptin), Xigduo® (+dapagliflozin), Glucovance® (+glibenclamide), etc.

What are the side effects of oral antidiabetics?

Metformin commonly causes nausea and vomiting, diarrhea, abdominal pain, and loss of appetite. Taking it in the middle of meals and fragmented administration over the day make it possible to limit these disorders. This medicine can cause lactic acidosis (excess lactic acid) which manifests itself in particular by digestive disorders, cramps and a feeling of malaise.
Dapagliflozin and empagliflozin frequently expose to a hypoglycemiadizziness, inflammation of the vulva and vagina (in women) and glans (in men). Also, difficulty urinating, constipation and intense thirst have been reported. More rarely, these medicines can cause serious side effects such asketoacidosis diabetes and Fournier’s gangrene (necrotizing infection of the perineum). Ketoacidosis is manifested by nausea and vomiting, abdominal pain, difficulty breathing and drowsiness. Fournier’s gangrene results in intense pain, tenderness and redness of the skin, swelling of the perineum or genitals associated with fever and a feeling of malaise. The appearance of such symptoms should lead the patient to consult a doctor.
Common side effects caused by gliptins are respiratory infections (nasopharyngitis), dizziness, headaches, digestive disorders (nausea, vomiting, diarrhoea), peripheral edema (particularly of the legs and hands) and muscle pain.
Acarbose often induces flatulence, diarrhea and abdominal pain.
Repaglinide and sulfonylureas may be responsible for hypoglycaemia, abdominal pain and diarrhoea. To limit the risk of hypoglycaemia, the consumption of alcoholic beverages should be avoided and the drug should be taken before or at the start of a meal. More rarely skin conditions (itching, rash) are observed.

What are the contraindications of oral antidiabetics?

All oral antidiabetics are contraindicated in case of allergy to any component of the drug.
Metformin administration is prohibited in several cases: renal failure severe or impaired kidney function, liver failure, alcoholism, insufficient oxygen supply (heart or respiratory failure), reduced blood pH.
taking acarbose should be excluded in cases of severe renal or hepatic insufficiency, chronic inflammatory bowel diseases, intestinal obstruction and intestinal absorption disorders.
Repaglinide should not be used in the event of severe hepatic impairment, type 1 diabetes and concomitantly with gemfibrozil (hypolipidemic agent which may promote hypoglycaemia).
Sulfonylureas should not be taken in case of severe renal or hepatic insufficiency, type 1 diabetes and in combination with miconazole (treatment of mycoses).
No particular contraindications were noted with gliptins and gliflozins.

Metformin alone (monotherapy) is the first-line treatment

What are the official recommendations for oral antidiabetics?

An oral antidiabetic is prescribed in the type 2 diabetes when lifestyle and dietary rules (regular physical activity, diet) are insufficient to regulate blood sugar. According to the recommendations of the High Authority for Health (HAS), the metformin alone (monotherapy) is the first-line treatment. If the glycemic target is not reached, dual therapy (metformin + sulfonylurea) or even triple therapy (metformin + sulfonylurea + other antidiabetic) will be prescribed. Last resort, insulin treatment may be administered in addition. In case of intolerance or contraindication to metformin, it will be replaced by a sulfonylurea. If the intolerance or the contraindication concerns the sulfonamide, it will be substituted by another antidiabetic (repaglinide, acarbose, a gliptin or a gliflozin). Note that gliptin used alone (monotherapy not recommended by the HAS) does not give rise to reimbursement by health insurance. The dosage of glycated hemoglobin (marker of glycemic balance) makes it possible to evaluate the effectiveness of the treatments and to readjust the therapeutic strategy if necessary.

Sources:
– Public drug database
– Pharmacomedical.org
– Drugs for type 2 diabetes: HAS updates its evaluation of gliflozins, Haute Autorité de santé (HAS), 16/12/2020
– Drug strategy for glycemic control of type 2 diabetes, HAS and ANSM, January 2013

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