Binding and blocking SGLT2 (Sodium-Glucose Co-Transporter 2) protein in proximal tubule of kidney. Results in:
- Reduced Renal glucose reabsorption
- Increased glucose excretion in urine

- Liberates insulin from pancreatic beta-cells
(prolong depolarization in membrane → ↓ permeability to K+ → open Ca++ channel → Ca++ influx → Insulin release)

Metabolic:
- Reduced glucose levels and may improve insulin sensitivity in peripheral tissues
- Weight loss, lower TG, inc HDLc

CVS:
- Lower blood pressure due to fluid loss and potential improvements in vascular function
- Cardio protective (mainly Dapa and Empa): reduction in heart failure, major CV events, arrhythmia

Renal:
- mild diuresis (osmotic)
- renoprotective (red albuminuria and progression of diabetic kidney disease

Metabolic/Other:
- ↓ plasma TG, cholesterol, FFA

Gliclazide ↓ microthrombosis:
- partially inhibit platelet aggregation and adhesion
- fibrinolytic - ↑ tPA activity

Glimepiride extra-pancreatic:
- ↑ active glucose transport molecules
- lipogenesis and glycogenesis in fat and muscle
- inhibits hepatic gluconeogenesis (by ↑ Fructose-2,6-bisphosphate)

Rapid
PO BA: 60-60%

Well absorbed
PO BA: 100%

90-99% PB

95-99% Albumin bound

50-100L
Dapa: 118L Empa: 74L

gliclazide 0.42 l/kg
glibenclamide 0.15 l/kg
glimepiride 0.12 l/kg

Liver (phase 1 and 2 enzymes)
Dapa, Empa (CYP3A4)
Active and inactive metabolites

extensive hepatic metabolism via
CYP2C9 to inactive metabolites

mostly urine
small fraction feces

30-50% excreted in urine
Remainder in feces

6-12 L/hr

Gliclazide 12-20 hrs
Gliblencamide 1-2hrs
Glimepiride 5-8hrs

13-16hrs

Elimination impaired in severe renal impairment

- Polyuria, UTIs, Dehydration
- Potential risk of AKI
- Ketoacidosis
- Toxicity (rare): excessive fluid loss and electrolyte imbalances

- Hypoglycaemia
- GI disturbances
- Cholestatic jaundice
- LFT derangement
- Leucopenia, thrombocytopenia
- some Potentially teratogenic

synthetic glycoside analogs that are chemically designed to resemble the naturally occurring glucose molecules but with modifications to inhibit glucose reabsorption

An s-phenylsulfonylurea structure with substitutions on the
phenyl ring and urea terminus

SGLT2 Inhibitors

Sulfonylurea

1. treatment of non-insulin-dependent
(type II) diabetes mellitus
2. risk reduction in cardiovascular events, heart failure and kidney disease progression, even without diabetes

treatment of non-insulin-dependent
(type II) diabetes mellitus

Dapagliflozin
Empagliflozin
Ertugliflozin

1. first-generation: tolbutamide
2. second-generation: gliclazide, glibenclamide
3. third-generation: glimepiride.

Level 3

Level 3

reduction of blood glucose levels

Hypoglycaemia

Onset variable
Peak 1-2hrs
Duration 24 hrs

single medications or in combination with metformin or with gliptins

tablet form
MR also available.

PO

PO

- Renal dose adjustment in eGFR<30
- Risk of dehydeation and electrolyte imbalances

Hypoglycaemia with NsAIDs, salicylates, sulfonamides, oral anticoagulants, MAoIs, and beta-adrenergic antagonists

Long acting sulfonylureas should be stopped prior to major surgery