Antidiabetic drugs

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.

Overview of antidiabetic drugs

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!

Antihyperglycemic therapy algorithm for type 2 diabetes

References:^[1][2]

• 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
      • Sulfonylurea, meglitinides
    • 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
  • Mechanism
    • These agents do not depend on residual insulin production.
    • Effective in patients with nonfunctional endocrine pancreatic β-cells
  • Biguanides (metformin), SGLT-2 inhibitor, thiazolidinediones, alpha-glucosidase inhibitors

Active agent

• Metformin

Clinical profile

• Mechanism of action: enhances the effect of insulin
  • Reduction in insulin resistance via modification of glucose metabolic pathways
    • Inhibits mitochondrial glycerophosphate dehydrogenase (mGPD)
      • Decreases hepatic gluconeogenesis and intestinal glucose absorption
    • Increases peripheral insulin sensitivity
  • Lowers postprandial and fasting blood glucose levels
  • Reduces LDL, increases HDL
• Indications: drug of choice in all patients with type 2 diabetes
• Clinical characteristics
  • Glycemic efficacy: lowers HbA1c by 1.2–2% over 3 months
  • Weight loss or weight stabilization
  • No risk of hypoglycemia
  • Beneficial effect on dyslipidemia
  • Studies show metformin reduces the risk of macroangiopathic complications in diabetic patients.
  • Cost-effective
• Important side effects
  • Metformin-associated lactic acidosis
    • Incidence: ∼ 8 cases/100,000 patient years
    • Clinical features: frequently nonspecific
      • Gastrointestinal prodromal symptoms: nausea, vomiting, diarrhea, abdominal pain
      • Severe symptoms: muscle cramps, hyperventilation, apathy, disorientation, coma
      • High-risk groups
        • Elderly individuals
        • Patients with cardiac or renal insufficiency
    • Diagnostics
      • Arterial blood gas (ABG): metabolic acidosis and anion gap
      • ↑ Serum lactate
    • Treatment: discontinue metformin and treat acidosis
  • Gastrointestinal complaints are common: nausea, diarrhea, flatulence
  • Vitamin B12 deficiency
  • Metallic taste in the mouth (dysgeusia)
• Contraindications
  • Renal failure (if creatinine clearance < 30 mL/min)
  • Severe liver failure
  • Intravenous iodinated contrast medium
  • Pause metformin prior to surgery
  • Chronic pancreatitis, starvation ketosis, ketoacidosis, sepsis
  • Heart failure (NYHA III and IV), respiratory failure, shock, sepsis
  • Alcoholism
• Important interactions: sulfonylureas

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]

Active agents

• Pioglitazone
• Rosiglitazone

Clinical profile

• Mechanism of action: activation of the transcription factor PPARγ (peroxisome proliferator-activated receptor of gamma type in the nucleus) → ↑ transcription of genes involved in glucose and lipid metabolism → ↑ levels of adipokines such as adiponectin and insulin sensitivity → ↑ storage of triglycerides and subsequent reduction of products of lipid metabolism (e.g., free fatty acids) that enhance insulin sensitivity → ↑ glucose utilization and ↓ hepatic glucose production
• Indications: may be considered as monotherapy in patients with severe renal failure and/or contraindications for insulin therapy
• Clinical characteristics
  • Glycemic efficacy: lowers HbA1c by 1% in 3 months
  • Favorable effect on lipid metabolism: ↓ triglyceride, ↓ LDL, ↑ HDL
  • No risk of hypoglycemia
  • Onset of action is delayed by several weeks.
• Important side effects ^[5]
  • Fluid retention and edema
  • Weight gain
  • Increased risk of heart failure
  • Increased risk of bone fractures (osteoporosis)
  • Rosiglitazone: increased risk of cardiovascular complications like cardiac infarction or death
• Contraindications
  • Congestive heart failure (NYHA III or IV)
  • Liver failure
  • Pioglitazone: history of bladder cancer or active bladder cancer; macrohematuria of unknown origin

References:^[6][7][8]

Active agents

• Glyburide: the standard substance of this class with a relatively long half-life
• Glipizide: a short-acting agent

Clinical profile

• Mechanism of action
  • Sulfonylureas block ATP-sensitive potassium channels of the pancreatic β-cells → depolarization of the cell membrane → calcium influx → insulin secretion
  • Extrapancreatic effect: decreases hepatic gluconeogenesis and increases peripheral insulin sensitivity
• 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
    • Increased risk in patients with renal failure
  • Weight gain
  • Hematological changes: granulocytopenia, hemolytic anemia
  • Allergic skin reactions
  • Alcohol intolerance
  • Compared to metformin, sulfonylureas are associated with more cardiovascular (macrovascular) complications.
• Contraindications
  • Severe cardiovascular comorbidity
  • Obesity
  • Sulfonamide allergy (particularly long-acting substances)
  • Severe liver failure
  • Severe kidney failure

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:^[9]

Active agents

• Repaglinide: the leading agent in the class of meglitinides, which is well tolerated by patients with chronic kidney disease
• Nateglinide

Clinical profile

• Mechanism of action
  • Enhances insulin secretion (similar mechanism of action to that of the sulfonylureas)
  • Meglitinides should be taken shortly before meals.
• 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
  • Life-threatening hypoglycemia (less risky than sulfonylureas)
    • Increased risk in patients with renal failure
  • Weight gain
  • Hepatotoxicity (rare)
• Contraindications
  • Severe liver failure
  • Severe renal failure
• Interactions: sulfonylureas

Active agents

• Exenatide
• Liraglutide: rapid-release formula that is administered daily
• Albiglutide: extended-release formula that is administered once weekly
• Dulaglutide

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 :
• Contraindications
  • Preexisting symptomatic gastrointestinal motility disorders
  • Chronic pancreatitis or a family history of pancreatic tumors

References:^{[10][11][12][13][14][15]}

Active agents

• Sitagliptin
• Saxagliptin
• Linagliptin

Clinical profile

• Mechanism of action: Gliptins indirectly increase the endogenous incretin effect by inhibiting the DPP-4 that breaks down GLP-1 → increased 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; because insulin release is glucose-dependent
  • Usually no weight changes
• Important side effects
  • Gastrointestinal symptoms: diarrhea, constipation (milder than in GLP-1 agonist exposure)
  • Arthralgia
  • Headaches, dizziness
  • Increased feeling of satiety (often favorable) due to delayed gastric emptying
  • Nasopharyngitis and upper respiratory tract infection
  • Urinary infections (mild)
  • Increased risk of pancreatitis
  • Worsening renal function, acute renal failure
• Contraindications
  • Hypersensitivity
  • Liver failure
  • Renal failure

References:^{[1][10][11][16][17]}

Active agents

• Dapagliflozin
• Empagliflozin
• Canagliflozin

Clinical profile

• Mechanism of action: reversible inhibition of the sodium-dependent glucose co-transporter (SGLT-2) in the proximal tubule of the kidney → reduced glucose reabsorption in the kidney → glycosuria and polyuria
• Indications: : a treatment option used especially in young patients with treatment-compliant type 2 DM without significant renal failure
• Clinical characteristics
  • Glycemic efficacy: lowers HbA1c by 0.6% over 3 months
  • Promotes weight loss
  • Reduces blood pressure
• Important side effects
  • Urinary tract infections, genital infections (vulvovaginitis, balanitis)
  • Dehydration; as a result of polyuria
  • Severe diabetic ketoacidosis
• Contraindications
  • Chronic kidney disease
  • Recurrent urinary tract infections (e.g., in patients with anatomical or functional anomalies of the urinary tract)

Active agents

• Acarbose
• Miglitol

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
  • Glycemic efficacy: lowers HbA1c by 0.8% over 3 months
  • No risk of hypoglycemia
• Important side effects: gastrointestinal complaints (flatulence, abdominal discomfort, diarrhea)
• Contraindications
  • Inflammatory bowel disease
  • Conditions associated with malabsorption
  • Severe renal failure

• One-Minute Telegram 10-2020-2/3: Positive effects of SGLT2 inhibitors in patients with heart failure regardless of diabetes status

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