Antidiabetic drugs (with the exception of insulin) are all pharmacological agents that have been approved for hyperglycemic treatment in type 2 diabetes mellitus (DM). If lifestyle modifications (weight loss, dietary modification, and exercise) do not sufficiently reduce A1C levels (target level: ∼ 7%), pharmacological treatment with antidiabetic drugs should be initiated. These drugs may be classified according to their mechanism of action as insulinotropic or non-insulinotropic. They are available as monotherapy or combination therapies, with the latter involving two (or, less commonly, three) antidiabetic drugs and/or insulin. The exact treatment algorithms are reviewed in the treatment section of diabetes mellitus. The drug of choice for all type 2 diabetic patients is metformin. This drug has beneficial effects on glucose metabolism and promotes weight loss or at least weight stabilization. In addition, numerous studies have demonstrated that metformin can reduce mortality and the risk of complications. If metformin is contraindicated, not tolerated, or does not sufficiently control blood glucose levels, another class of antidiabetic drug may be administered. Most antidiabetic drugs are not recommended or should be used with caution in patients with moderate or severe renal failure or other significant comorbidities. Oral antidiabetic drugs are not recommended during pregnancy or breastfeeding.
|Class||Mechanism of action||Side Effects||Contraindications|
|Biguanide (metformin)||Enhances the effect of insulin||Lactic acidosis, Weight loss Gastrointestinal complaints are common (e.g. diarrhea, abdominal cramps) Reduced vitamin B12 absorption||Chronic kidney disease ,Liver failure ,Metformin must be paused before administration of iodinated contrast medium and major surgery.|
|Sulfonylureas (e.g., glyburide, glimepiride)||Increase insulin secretion from pancreaticβ-cells||Risk of hypoglycemia ,Weight gain , Hematological changes: agranulocytosis, hemolysis||Severe cardiovascular comorbidity Obesity Sulfonamide allergy (particularly long-actingsubstances)|
|Meglitinides (nateglinide, repaglinide)||• Increase insulin secretion from pancreaticβ-cells||• Risk of hypoglycemia • Weight gain||Severe renal or liver failure|
|DPP-4 inhibitors (saxagliptin, sitagliptin)||• Inhibit GLP-1 degradation → promotes glucose-dependent insulin secretion||• Gastrointestinal complaints • Pancreatitis • Headache, dizziness • Arthralgia||• Liver failure • Moderate to severe renal failure|
|GLP-1 agonists (incretin mimetic drugs: exenatide, liraglutide, albiglutide)||• Direct stimulation of the GLP-1 receptor||• Nausea • Increased risk of pancreatitisand possibly pancreatic cancer||• Preexisting, symptomatic gastrointestinal motility disorders|
|SGLT-2 inhibitors (canagliflozin, dapagliflozin, empagliflozin)||• Increased glucosuria through the inhibition of SGLT-2 in the kidney||• Genital yeast infections and urinary tract infections • Polyuria and dehydration • Diabetic ketoacidosis||• Chronic kidney disease • Recurrent urinary tract infections|
|Alpha-glucosidase inhibitors(acarbose)||• Reduce intestinal glucose absorption||• Gastrointestinal complaints (flatulence, diarrhea, feeling of satiety)||• Any preexisting intestinal conditions (e.g., inflammatory bowel disease) • Severe renal failure|
|Thiazolidinediones (pioglitazone)||• Reduce insulin resistance through the stimulation of PPARs (peroxisomeproliferator-activated receptors) • Increase transcription of adipokines||• Weight gain • Edema • Cardiac failure • Increased risk of bone fractures(osteoporosis)||• Congestive heart failure • Liver failure|
|Amylin analogs (pramlintide)||• Reduce glucagon release • Reduce gastric emptying • Increase satiety||• Risk of hypoglycemia • Nausea||• Gastroparesis|
Common contraindications of antidiabetic agents:
• Type 1 diabetes mellitus: Patients require insulin therapy (see principles of insulin therapy).
• Pregnancy and breastfeeding (also see gestational diabetes): All antidiabetic agents are contraindicated. Antidiabetic drugs should be substituted with human insulin as early as possible (ideally prior to the pregnancy).
• Renal failure : Antidiabetic drugs that may be administered if GFR < 30 mL/min include DPP-4 inhibitors, incretin mimetic drugs, meglitinides, and thiazolidinediones.
• Morbidity and surgery
• Pause antidiabetic treatment in the following cases:
• Major surgery performed under general anesthesia
• Acute conditions requiring hospitalization (infections, organ failure)
• Elective procedures associated with an increased risk of hypoglycemia (periods of fasting, irregular food intake)
Sulfonylureas are associated with the highest risk of hypoglycemia. All other substances do not carry a significant risk of hypoglycemia when used as a monotherapy. Combination therapy, particularly with sulfonylurea, significantly increases the risk of hypoglycemia!