Overview
Canagliflozin (brand names Invokana, Invokamet) is a sodium-glucose co-transporter-2 (SGLT2) inhibitor approved by the FDA in 2013 for type 2 diabetes mellitus. By blocking glucose reabsorption in the proximal renal tubule, canagliflozin causes urinary excretion of approximately 60–80 g of glucose per day, producing insulin-independent lowering of blood glucose along with modest weight loss and blood-pressure reduction.
The CANVAS Program and CREDENCE trials established canagliflozin as the first SGLT2 inhibitor to demonstrate significant reductions in major adverse cardiovascular events (MACE) and the first to show robust renal protection—including reduced progression to end-stage kidney disease—in patients with type 2 diabetes and diabetic nephropathy. CREDENCE was stopped early in 2018 because of overwhelming renal benefit, leading to an expanded FDA indication for diabetic kidney disease.
More recently, canagliflozin has attracted attention beyond diabetes. The NIA Interventions Testing Program reported that canagliflozin extended median lifespan in male mice by approximately 14%, one of the largest survival effects observed in that program, prompting active interest in SGLT2 inhibitors as candidate gerotherapeutics. The mechanisms proposed include caloric restriction–mimetic effects, AMPK activation, ketone-body elevation, and reduced systemic inflammation.
Despite its benefits, canagliflozin carries notable risks including a black-box warning for lower-limb amputations based on the CANVAS data, increased risk of diabetic ketoacidosis (sometimes euglycemic), and genital mycotic infections. Careful patient selection and ongoing monitoring are essential.
Quick facts
- Mechanism
- SGLT2 inhibitor blocking renal glucose reabsorption with cardiorenal and putative longevity effects
- Primary use
- Type 2 diabetes; diabetic kidney disease; cardiovascular risk reduction
- Evidence
- strong
- FDA
- Approved
- Route
- Oral tablet, once daily before the first meal
- Typical results
- HbA1c reductions of 0.7–1.0%; ~2–3 kg weight loss; ~3–5 mmHg systolic BP reduction; major renal and cardiovascular outcome benefits
Chemical information
Canagliflozin (C₂₄H₂₅FO₅S) is a longevity compound with a molecular weight of 444.52 g/mol. Its structural characteristics underpin its biological activity in longevity and anti-aging research.
How Canagliflozin works
Canagliflozin selectively inhibits SGLT2, the sodium-glucose co-transporter responsible for approximately 90% of renal glucose reabsorption in the proximal convoluted tubule. Blockade increases urinary glucose excretion (glucosuria) and produces sodium-coupled natriuresis, lowering plasma glucose, body weight, and blood pressure independently of insulin secretion. Secondary metabolic effects include increased ketogenesis, modest GLP-1-like appetite reduction, and shifts in renal hemodynamics that lower glomerular hyperfiltration.
Cardiovascular and renal benefits appear to derive from multiple mechanisms beyond glucose lowering: reduction in plasma volume and preload, modest blood-pressure reduction, attenuation of glomerular hyperfiltration via restoration of tubuloglomerular feedback, and improvements in cardiac energetics through enhanced fatty acid and ketone oxidation in the failing myocardium.
Proposed longevity mechanisms include AMPK activation, reductions in mTOR signaling, suppression of inflammatory pathways, and a sustained mild caloric deficit from glucosuria. The NIA ITP mouse data suggest these effects can translate to lifespan extension in mammals, though no controlled human longevity data exist.
Canagliflozin also weakly inhibits SGLT1 in the intestine at peak plasma concentrations, blunting post-prandial glucose excursions—an effect more prominent than with other SGLT2 inhibitors and that may contribute to its glycemic and metabolic profile.
- SGLT2 inhibition: Blocks ~90% of renal glucose reabsorption, producing glucosuria
- Insulin-independent glucose lowering: Works regardless of beta-cell function
- Cardiorenal protection: Reduces MACE, heart failure hospitalization, and progression of kidney disease
- SGLT1 inhibition: Weak intestinal SGLT1 blockade contributes to post-prandial control
- Longevity signal: ~14% median lifespan extension in male mice (NIA ITP)
Pharmacokinetics
| Parameter | Value | Significance |
|---|---|---|
| Molecular Mass | 444.52 g/mol | Small molecule with good oral bioavailability |
| Oral bioavailability | ~65% | Once-daily oral dosing |
| Tmax | 1–2 hours | Take before first meal of day for best post-prandial effect |
| Half-life | ~10.6 hours (100 mg); ~13.1 hours (300 mg) | Supports once-daily dosing |
| Metabolism | Primarily UGT1A9 and UGT2B4 glucuronidation | Minimal CYP450 involvement |
| Elimination | Feces (~42%) and urine (~33%) | Dose-adjust in renal impairment (eGFR <60) |
Dosing & administration
Canagliflozin dosing varies by indication and individual factors. Refer to the official prescribing information for approved indications.
Any use should be conducted under qualified medical supervision with appropriate monitoring of safety markers.
Side effects & safety
Safety data for Canagliflozin is established for approved indications via clinical trials. Long-term effects in humans remain incompletely characterized.
Common
- • Genital mycotic infections (more common in women)
- • Urinary tract infections
- • Increased urination (polyuria)
- • Thirst and mild dehydration
- • Constipation and nausea
Serious / potential risks
- • Lower-limb amputations (black box warning from CANVAS data)
- • Diabetic ketoacidosis, including euglycemic DKA
- • Acute kidney injury, particularly with volume depletion
- • Fournier's gangrene (necrotizing perineal infection)
- • Bone fractures (CANVAS data; not consistently replicated)
- • Severe hypersensitivity and angioedema
Drug interactions
| Medication | Interaction | Recommendation |
|---|---|---|
| Loop and thiazide diuretics | Additive volume depletion and hypotension | Reduce diuretic dose or monitor closely at initiation |
| Insulin and sulfonylureas | Increased hypoglycemia risk | Lower insulin or sulfonylurea dose when starting canagliflozin |
| UGT inducers (rifampin, phenytoin, ritonavir) | Reduced canagliflozin exposure | Consider dose increase if AUC drops significantly |
| Digoxin | Increased digoxin AUC by ~20% | Monitor digoxin levels and clinical response |
| ACE inhibitors/ARBs | Additive renoprotective and BP-lowering effects (favorable) | Standard pairing in diabetic kidney disease |
Storage & handling
Lyophilized (powder)
- • Store at -20°C to 4°C (freezer or refrigerator)
- • Protect from light and moisture
- • Stable for 12–24 months when stored properly
- • Keep in original sealed container until reconstitution
Reconstituted solution
- • Refrigerate at 2–8°C after reconstitution
- • Use bacteriostatic water for multi-dose reconstitution
- • Typical stability: 14–28 days refrigerated
- • Do not freeze reconstituted solution
Cost & availability
| Source | Cost | Notes |
|---|---|---|
| Research suppliers | Varies widely | Quality and purity vary significantly between sources |
| Compounding pharmacies | Prescription required | Higher quality assurance and purity testing |
The bottom line
Canagliflozin is a longevity compound with research interest in diabetes, longevity, cardioprotection. While preclinical evidence is encouraging, it has received FDA approval for specific indications. Any use should be under qualified medical supervision.
Best for
- • Researchers studying longevity and anti-aging research
- • Individuals interested in diabetes under medical guidance
Not for
- • Self-administration without medical supervision
- • Pregnant or breastfeeding individuals
- • Individuals with contraindicated conditions
Related compounds
Frequently asked questions
References
- [1] Neal B, Perkovic V, Mahaffey KW, et al.. Canagliflozin and cardiovascular and renal events in type 2 diabetes (CANVAS Program). N Engl J Med (2017). doi: 10.1056/NEJMoa1611925 PMID: 28605608
- [2] Perkovic V, Jardine MJ, Neal B, et al.. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy (CREDENCE). N Engl J Med (2019). doi: 10.1056/NEJMoa1811744 PMID: 30990260
- [3] Miller RA, Harrison DE, Allison DB, et al.. Canagliflozin extends life span in genetically heterogeneous male but not female mice. JCI Insight (2020). doi: 10.1172/jci.insight.140019 PMID: 32990681
- [4] U.S. Food and Drug Administration. Invokana (canagliflozin) prescribing information. FDA Label (2023).