What is the role of Gliflozin (Sodium-glucose cotransporter 2 inhibitor) in treating type 2 diabetes?

Role of SGLT2 Inhibitors in Type 2 Diabetes Management

SGLT2 inhibitors (gliflozins) should be considered a cornerstone therapy for type 2 diabetes patients, particularly those with cardiovascular disease, heart failure, or chronic kidney disease, due to their proven benefits in reducing cardiovascular mortality, heart failure hospitalizations, and progression of kidney disease beyond glycemic control. 1

Mechanism of Action

SGLT2 inhibitors work by:

• Inhibiting sodium-glucose cotransporter-2 in the proximal renal tubule 2
• Reducing reabsorption of filtered glucose and lowering the renal threshold for glucose
• Increasing urinary glucose excretion
• Increasing sodium delivery to the distal tubule, which increases tubuloglomerular feedback and reduces intraglomerular pressure 2

Glycemic Control Benefits

• Provide effective glucose lowering independent of insulin action 2
• Can be used regardless of diabetes duration, provided renal function is acceptable 1
• Demonstrate greater HbA1c reduction compared to other oral antihyperglycemic agents, with benefits maintained up to 1 year 1
• Show additional improvement in glucose control when added to other antihyperglycemic medications 1

Cardiovascular Benefits

SGLT2 inhibitors offer substantial cardiovascular protection:

• Reduce major adverse cardiovascular events (MACE) by 14% in patients with established cardiovascular disease 3
• Significantly reduce hospitalization for heart failure:
  • Empagliflozin: 35% reduction 1
  • Canagliflozin: 33% reduction 1
  • Dapagliflozin: 27% reduction 1, 3
• Empagliflozin reduces cardiovascular death by 38% and all-cause mortality by 32% 3
• Benefits in heart failure are consistent regardless of presence or absence of diabetes history 1
• Effective in both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) 3

Renal Benefits

• Reduce risk of progression of kidney disease 3
• Canagliflozin reduces risk of end-stage kidney disease by 32% 3
• Dapagliflozin significantly lowers the risk of sustained decline in eGFR, end-stage kidney disease, or death from renal causes 1
• Beneficial effects on multiple renal endpoints are observed regardless of the presence or absence of diabetes 1, 4

Available SGLT2 Inhibitors

Currently approved SGLT2 inhibitors include:

• Canagliflozin (Invokana)
• Dapagliflozin (Farxiga)
• Empagliflozin (Jardiance)
• Ertugliflozin
• Sotagliflozin (dual SGLT1/2 inhibitor) 1, 5

Dosing and Renal Function Considerations

• Standard doses:

  • Empagliflozin: 10 mg daily
  • Dapagliflozin: 10 mg daily
  • Canagliflozin: 100 mg daily 3

• Renal function adjustments:

  • No dose adjustment required for eGFR ≥60 mL/min/1.73 m² 3
  • For eGFR 45-59 mL/min/1.73 m², maximum dose of canagliflozin is 100 mg daily 3
  • For eGFR 30-44 mL/min/1.73 m², empagliflozin and dapagliflozin may be continued if tolerated 3
  • Generally not recommended for initiation if eGFR <30 mL/min/1.73 m² 3

Positioning in Treatment Algorithm

SGLT2 inhibitors should be prioritized for:

1. Patients with type 2 diabetes and established cardiovascular disease or high cardiovascular risk 1
2. Patients with type 2 diabetes and heart failure (with either reduced or preserved ejection fraction) 1, 3
3. Patients with type 2 diabetes and chronic kidney disease (eGFR 20-60 mL/min/1.73 m² and/or albuminuria) 3
4. Patients with type 2 diabetes who would benefit from weight loss or blood pressure reduction 1

Adverse Effects and Precautions

• Common side effects include genital mycotic infections and increased urination 3
• Low risk of hypoglycemia unless used with insulin or insulin secretagogues 3
• Use with caution in patients with volume depletion or hypotension 3
• Discontinue at least 3 days before planned surgery to prevent postoperative ketoacidosis 3
• Consider reducing total daily insulin dose by approximately 20% when starting therapy if HbA1c is well-controlled 3
• May require adjustment of diuretic doses due to potential intravascular volume contraction 3

Clinical Pearls

• Benefits extend beyond glycemic control to include cardiovascular and renal protection 1, 3
• Can be used in monotherapy or as add-on to other antihyperglycemic agents 1
• Consider continuing therapy even if eGFR declines below initiation threshold, as cardiovascular benefits persist 3
• May be combined with DPP-4 inhibitors (gliptins) for complementary modes of action without significant pharmacokinetic interactions 6
• Benefits in heart failure and renal protection are increasingly recognized as class effects, independent of glycemic control 4

SGLT2 inhibitors represent a paradigm shift in diabetes management, moving beyond glucose control to address the cardiovascular and renal complications that drive morbidity and mortality in type 2 diabetes.