• Clinical science

Antidiabetic drugs

Abstract

Antidiabetic drugs (with the exception of insulin) are all pharmacological agents that have been approved for hypoglycemic 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.

Overview

Overview of antidiabetic drugs

Class Mechanism of action Side effects Contraindications
Biguanide (metformin)
  • Lactic acidosis
  • Weight loss
  • Gastrointestinal complaints are common (e.g. diarrhea, abdominal cramps)
  • Reduced vitamin B12 absorption
Sulfonylureas (e.g., glyburide, glimepiride)
Meglitinides (nateglinide, repaglinide)
  • 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
  • Preexisting, symptomatic gastrointestinal motility disorders
SGLT-2 inhibitors (canagliflozin, dapagliflozin, empagliflozin)
  • Increased glucosuria through the inhibition of SGLT-2 in the kidney
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)
Amylin analogs (pramlintide)
  • Reduce glucagon release
  • Reduce gastric emptying
  • Increase satiety
  • Gastroparesis

Common contraindications of antidiabetic agents

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!

Antihyperglycemic therapy algorithm for type 2 diabetes

References:[1][2]

Effects

  • Insulinotropic agents
    • Mechanism: stimulate the secretion of insulin from pancreatic β-cells
      • Glucose-independent: Insulin is secreted regardless of the blood glucose level, even if blood glucose levels are low → risk of hypoglycemia
      • Glucose-dependent: Insulin secretion is stimulated by elevated blood glucose levels (postprandially). These antidiabetic agents depend on residual β-cell function.
        • GLP-1 agonists, DPP-4 inhibitors
  • Non-insulinotropic agents

Biguanides (metformin)

Active agent

  • Metformin
    • Prescription
      • Gradual dose titration to minimize gastrointestinal side effects ; the maximum dosage is 2000 mg/day, after which point side effects outweigh the beneficial effect
      • In renal failure: use with caution; dosage limitation! Regular monitoring of renal function is important.

Clinical profile

Metformin treatment must be paused prior to the administration of a contrast medium or scheduled surgery to reduce the risk of lactic acidosis!

Because of its favorable risk-benefit ratio, metformin is the drug of choice for monotherapy and combination therapy in all stages of type 2 DM!
References:[1][3][4]

Thiazolidinediones (glitazones, insulin sensitizers)

Active agents

Clinical profile

References:[5][6]

Sulfonylureas

Active agents

Clinical profile

  • Mechanism of action
  • Indications: particularly suitable for patients who are not overweight, do not consume alcohol, and adhere to a consistent dietary routine
  • Clinical characteristics
    • Glycemic efficacy: lowers HbA1c by 1.2% over 3 months
    • Long-term experience
    • Low-cost
  • Important side effects
    • Life-threatening hypoglycemia
    • Weight gain
    • Hematological changes: granulocytopenia, hemolytic anemia
    • Allergic skin reactions
    • Alcohol intolerance
    • Compared to metformin, sulfonylureas are associated with more cardiovascular (macrovascular) complications.
  • Contraindications

Beta-blockers may mask the warning signs of hypoglycemia (e.g., tachycardia) and decrease serum glucose levels even further (→ see hypoglycemia). Since sulfonylureas also increase the risk of hypoglycemia, the combination of these two substances should be avoided!
References:[7]

Meglitinides (sulfonylurea analogue)

Active agents

Clinical profile

  • Mechanism of action
  • Indications: : particularly suitable for patients with postprandial peaks in blood glucose levels
  • Clinical characteristics
    • Glycemic efficacy: lowers HbA1c by 0.75% over 3 months
    • More expensive than sulfonylureas
  • Important side effects
  • Contraindications
    • Severe liver failure
    • Severe renal failure
  • Interactions: sulfonylureas

Incretin mimetics (GLP-1 receptor agonists)

Active agents

Clinical profile

  • Mechanism of action
    • Incretin effect: food intake → activation of enteroendocrine cells in the gastrointestinal tract → release of GLP-1 GLP-1 degradation via the enzyme DPP-4 → end of the GLP-1 effect
    • Incretin mimetic drugs bind to the GLP-1 receptors and are resistant to degradation by DPP-4 enzyme → increase insulin secretion, decrease glucagon secretion, slow gastric emptying (↑ feeling of satiety, ↓ weight)
  • Clinical characteristics
    • Glycemic efficacy: lowers HbA1c by 0.5–1.5% over 3 months
    • Subcutaneous injection
    • Weight loss
    • No risk of hypoglycemia
  • Side effects
    • Gastrointestinal complaints (particularly impaired gastric emptying!)
    • Increased risk of pancreatitis and potentially pancreatic cancer :
    • Potential risk of medullary thyroid cancer (MTC): further investigation required
  • Contraindications

References:[8][9][10][11][12][13]

Dipeptidyl peptidase-4 inhibitors (gliptins)

Active agents

Clinical profile

  • Mechanism of action: Gliptins indirectly increase the endogenous incretin effect by inhibiting the dipeptidyl peptidase-4 enzyme; that breaks down glucagon-like peptide 1increased insulin secretion, decreased glucagon secretion, delayed gastric emptying
  • Indications: See the antihyperglycemic therapy algorithm for type 2 diabetes.
  • Clinical characteristics
    • Glycemic efficacy: lowers HbA1c by 0.5–0.75% over 3 months
    • No risk of hypoglycemia unless insulin and/or insulinotropic drugs are used simultaneously
  • Important side effects
    • Gastrointestinal complaints: diarrhea, constipation (milder than in GLP-1 agonist exposure)
    • Arthralgia
    • Headaches, dizziness
    • Increased risk of pancreatitis
  • Contraindications
    • Hypersensitivity
    • Liver failure
    • Moderate to severe renal failure

References:[1][8][9]

SGLT-2 inhibitors (gliflozins)

Active agents

Clinical profile

Alpha-glucosidase inhibitors

Active agents

Clinical profile

  • Mechanism of action
    • Inhibits alpha-glucosidase; decreased intestinal glucose absorption; The drug is particularly effective in controlling postprandial blood glucose levels.
    • The undigested carbohydrates reach the colon, where they are degraded by intestinal bacteria, resulting in the production of intestinal gas.
  • Clinical characteristics
  • Important side effects: gastrointestinal complaints (flatulence, abdominal discomfort, diarrhea)
  • Contraindications
    • Inflammatory bowel disease
    • Conditions associated with malabsorption
    • Severe renal failure