SGLT-2 Inhibitors

Mechanism of Action

SGLT-2 inhibitors block the sodium-glucose co-transporter-2 protein in the proximal renal tubule of the nephron. 

• Normal function of SGLT-2: reabsorbs glucose and sodium from the glomerular filtrate.
• Effect of inhibition: increased excretion of glucose → reduced blood sugar.

Additional effects:

• Increased urinary excretion of sodium, osmotic diuresis and a reduced intravascular volume. Increased sodium delivery to the distal tubule may influence several physiological functions such as reducing fluid overload, blood pressure, and leading to a lower preload and afterload of the heart, improving cardiovascular outcomes. 
• Promote weight loss (loss of calories through increased urinary excretion of glucose)
• Reduce pressure on the kidneys (reduces intraglomerular pressure), leading to a protective effect e.g. dapagliflozin was found to prevent reaching end-stage kidney disease, CV or renal death and a decline in eGFR compared to placebo
• Improve symptoms of heart failure e.g. breathlessness 

The glucose lowering effect of SGLT-2 inhibitors is dependent on renal function

• In patients with poor renal function, the glucose lowering effect is likely to be reduced, as the amount of filtrated glucose is small and can be absorbed by SGLT1 and unblocked SGLT2 transporters. 
• For all of the described SGLT-2 inhibitors in this article, the glucose lowering efficacy is reduced in moderate renal impairment (if eGFR <45ml/min) and absent in severe renal impairment (if eGFR <30ml/min)

The systemic exposure of dapagliflozin, canagliflozin and empagliflozin also increases as renal function deteriorates.

Created in BioRender. Boucher, M. (2025) https://BioRender.com/ais3qdi

Fig 1: mechanism of action of SGLT-2 inhibitors

Pharmacokinetics

SGLT-2 inhibitors are taken orally and once daily which is possible due to their high bioavailability and long half lives, respectively. SGLT-2 inhibitors are extensively distributed and mainly metabolised by UGT enzymes to inactive metabolites. Active and inactive metabolites are excreted via urine and faeces. The following table describes the specific pharmacokinetic parameters for each SGLT-2 inhibitor:

Adverse Effects and Cautions For Use

Most commonly, SGLT-2 inhibitors lead to increased frequency of urinary tract infections and genital fungal infection (due to increase in glucose in urine). 

Serious complications such as diabetic ketoacidosis (DKA) have been reported with SGLT-2 inhibitor use. Caution should be applied with patients who have had previous diabetic ketoacidosis, and any risk factors should be addressed before commencing treatment. 

• DKA may occur atypically, with only moderately increased blood glucose levels. 
• Treatment should be held for patients undergoing surgery or in acute serious medical illness and monitoring of ketones should be undertaken 
• Symptoms of DKA include: nausea, vomiting, abdominal pain, excessive thirst, difficulty breathing, confusion and sleepiness 
• Risk factors for developing DKA with SGLT-2 inhibitor use include
  • Low beta-cell function reserve i.e. type 2 diabetes with low C-peptide or latent autoimmune diabetes or hx of pancreatitis 
  • Restricted food intake 
  • Dehydration
  • Patients with increased insulin requirements due to acute medical illness, surgery or alcohol intake

Other possible effects:

• Hypoglycaemia when used with insulin or a sulphonylurea 
• Increased urination 
• Thirst 
• Increase in serum lipids 
• Constipation 
• Increased haematocrit (dapagliflozin and empagliflozin)
• Transient and reversible (on discontinuation) increase in creatinine (dapagliflozin, empagliflozin, ertugliflozin) 
• Risk of Fournier’s gangrene (necrotizing fasciitis of genitalia and perineum) in males and females
• Hyperkalaemia and hyperphosphatemia (canagliflozin)

Cautions:

• Severe hepatic impairment and dapagliflozin (initiate at a lower dose)
• History of foot disease e.g. ulcer, peripheral arterial disease or lower limb amputation, due to increased risk of lower limb amputation
• Elderly, diuretic/antihypertensive use, renal impairment → risk of hypotension/volume depletion

Contraindications

• DKA
• Manufacturers make varying recommendations on renal function cut offs for each SGLT-2 inhibitor, although dapagliflozin and empagliflozin are licensed in the treatment of chronic kidney disease.
  • Dapagliflozin: do not initiate if  eGFR<15ml/min/1.73m2
  • Empagliflozin: do not initiate if eGFR <20ml/min/1.73m2 (reduce dose if eGFR<60ml/min/1.73m2)
  • Canagliflozin: do not initiate if eGFR <30ml/min/1.73m2 (max dose 100mg daily if eGFR<60ml/min/1.73m2)
  • Ertugliflozin: do not initiate if eGFR <45ml/min/1.73m2 (initiate at lower dose if eGFR <60ml/min/1.73m2). Discontinue if CrCl <30ml/min/1.73m2
• Avoid in severe hepatic impairment (canagliflozin, empagliflozin and ertugliflozin) due to limited clinical experience 
• Avoid >85 years old (empagliflozin) 
• Avoid in active foot disease e.g. ulceration, gangrene

Interactions

• Lithium: increased excretion → ↓ lithium levels
• Diuretics, ACE inhibitors, ARBs: ↑ risk of dehydration and hypotension
• Insulin, sulfonylureas: ↑ risk of hypoglycaemia
• UGT inducers (rifampicin, phenytoin): ↓ canagliflozin/empagliflozin exposure
• Colestyramine: ↓ canagliflozin exposure
• Canagliflozin (P-gp inhibition): ↑ digoxin and dabigatran exposure (P-gp substrates)

References

1. SGLT2 Inhibitors | Diabetes UK accessed 20/3/25
2. SGLT-2 inhibitors | Prescribing information | Diabetes – type 2 | CKS | NICE accessed 20/3/2025 
3. Forxiga 10 mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc) | 7607 accessed 20/3/2025
4. Jardiance 10 mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc) | 5441 accessed 26/3/2025
5. Invokana 100 mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc) | 8855 accessed 16/4/2025
6. Steglatro 5 mg Film-Coated Tablets – Summary of Product Characteristics (SmPC) – (emc) | 9803 accessed 23/4/2025