What is the mechanism of action of Synjardy (empagliflozin and metformin)?

Mechanism of Action of Synjardy (Empagliflozin and Metformin)

Synjardy combines two antihyperglycemic medications with complementary mechanisms of action: empagliflozin inhibits SGLT2 in the kidneys to increase urinary glucose excretion, while metformin decreases hepatic glucose production and improves peripheral insulin sensitivity.

Empagliflozin Component

Empagliflozin works through the following mechanisms:

• Primary mechanism: Inhibits sodium-glucose co-transporter 2 (SGLT2) in the proximal tubule of the kidney 1
• This inhibition reduces renal glucose reabsorption from the glomerular filtrate back into circulation
• Lowers the renal threshold for glucose, thereby increasing urinary glucose excretion
• Results in approximately 64-78 grams of glucose excretion per day depending on dosage 1
• Produces a mild diuretic effect with increased urinary volume (341 mL increase on day 1) 1
• Works independently of insulin secretion or action, making it effective regardless of β-cell function

Metformin Component

Metformin exerts its effects through multiple pathways:

• Primary mechanism: Decreases hepatic glucose production 2
• Additionally:
  • Decreases intestinal absorption of glucose
  • Improves insulin sensitivity by increasing peripheral glucose uptake and utilization
  • Does not increase insulin secretion (insulin levels may actually decrease with therapy) 2

Complementary Effects

The combination provides several advantages:

1. Dual attack on hyperglycemia:

   • Empagliflozin removes glucose through the kidneys
   • Metformin reduces glucose production and improves utilization

2. Metabolic benefits:

   • Weight reduction (primarily from empagliflozin)
   • Blood pressure reduction (primarily from empagliflozin)
   • Low risk of hypoglycemia when used without insulin secretagogues 3

3. Cardiovascular and renal benefits:

   • Empagliflozin has demonstrated cardiovascular and renal protective effects 4
   • Metformin is considered safe in patients with cardiovascular disease

Clinical Considerations

• Renal function: Empagliflozin's glucose-lowering efficacy decreases with declining renal function 1

  • Not recommended when eGFR <45 mL/min/1.73m² due to reduced efficacy
  • Metformin should be dose-reduced when eGFR <45 mL/min/1.73m² and stopped when <30 mL/min/1.73m² 4

• Common side effects:

  • Empagliflozin: genital mycotic infections, urinary tract infections
  • Metformin: gastrointestinal effects (nausea, diarrhea)
  • Both have low risk of hypoglycemia when used without insulin secretagogues

• Pharmacokinetics:

  • No significant drug-drug interactions between the components 3
  • Fixed-dose combination tablets are bioequivalent to individual tablets 5

Pitfalls and Caveats

• Risk of euglycemic diabetic ketoacidosis with empagliflozin component, especially in insulin-deficient patients 4
• Risk of lactic acidosis with metformin component in patients with severe renal impairment, alcoholism, or acute illness 4
• Volume depletion can occur due to the diuretic effect of empagliflozin
• Efficacy of empagliflozin component is reduced in patients with renal impairment

By combining these complementary mechanisms, Synjardy provides effective glycemic control through multiple pathways while offering additional cardiovascular and metabolic benefits beyond glucose reduction.