Canagliflozin

canagliflozin

Canagliflozin is an SGLT2 inhibitor approved for type 2 diabetes — and one of only a handful of drugs to extend lifespan in NIH-funded mouse longevity testing. The CANVAS trial reduced cardiovascular events; the ITP added a 14% male-mouse lifespan extension that surprised everyone.

SGLT2 inhibitorPrescription requiredEvidence B
⚠ Not medical advice.Not medical advice. This page is educational. Discuss with your physician before starting, changing, or stopping any medication.

Why it matters

Canagliflozin is increasingly interesting to longevity-focused clinicians for two reasons. First, the large CANVAS and CREDENCE trials in type 2 diabetics showed substantial reductions in major adverse cardiovascular events, heart failure hospitalization, and renal disease progression — effects that appeared larger than glycemic improvement alone could explain. Second, the NIH Interventions Testing Program (Miller 2020) reported that canagliflozin extended median lifespan in genetically heterogeneous male UM-HET3 mice by 14% — placing it among the most robust longevity signals ever observed in the program. The female-mouse effect was absent, which is unusual. The mechanism is debated: caloric loss via urinary glucose, glycemic excursion reduction, modest ketogenesis, renal preservation, or some combination. Translation to healthy humans is unproven. No randomized trial of SGLT2 inhibition in metabolically healthy adults for longevity endpoints has been completed. The off-label longevity use is becoming common in longevity clinics, particularly Peter Attia's practice and others. The drug is generally well-tolerated but has real safety considerations — most importantly euglycemic DKA in fasting or low-carb users, and genital fungal infections (which is essentially a guaranteed nuisance, not a safety crisis). Cost-benefit is real to evaluate: ~$650/month brand, much less generic.

Uses

Label uses (approved)
  • Type 2 diabetes mellitus
  • Cardiovascular risk reduction in T2D with established CVD
  • Diabetic kidney disease
  • Heart failure with reduced ejection fraction (HFrEF)
Off-label (educational only)
  • Longevity / healthspan in metabolically healthy adultsweak (animal data only)
  • Cardiac protection in pre-diabetesmoderate
  • Uric acid lowering / goutmoderate
  • Weight lossmoderate

Dosing

Label dose
100 mg once daily before the first meal. May increase to 300 mg daily if needed and tolerated.
Off-label / biohacker dose
Off-label longevity dosing in non-diabetic adults: typically 100 mg daily. The ITP mouse data used a dose equivalent to roughly 100 mg in humans. No human longevity trial has been conducted.
Titration: Start 100 mg; assess hydration and blood pressure at 2 weeks. Reduce or hold during illness, dehydration, or before surgery. Adequate hydration is essential because the drug intentionally causes osmotic diuresis. Caution in elderly and patients on diuretics or ACE inhibitors.
When to take: Morning, before the first meal.

Side effects & warnings

Common
  • Increased urinary frequency
  • Genital mycotic infection (yeast, especially in uncircumcised men)
  • Urinary tract infection
  • Thirst
  • Mild weight loss
Uncommon but serious
  • Hypotension
  • Volume depletion
  • Acute kidney injury
  • Hyperkalemia
  • Constipation
Serious warnings
Diabetic ketoacidosis (including normoglycemic DKA) is a serious documented risk — especially in low-carb dieters, fasting, illness, surgery, and alcohol use. Lower limb amputation signal in the CANVAS trial (later largely attributed to peripheral vascular disease, but remains in labeling). Fournier's gangrene (necrotizing genital infection) is rare but life-threatening. Increased fracture risk in some trials. Patients on insulin or sulfonylureas have hypoglycemia risk requiring dose adjustment.

Biomarkers affected

blood pressure
decrease
Typical 4-6 mmHg systolic and 1-2 mmHg diastolic reduction via osmotic diuresis and natriuresis; sustained over 6-12 months.
Evidence: strong
fasting glucose
decrease
Robust reduction in fasting glucose via urinary glucose excretion of 60-100 g/day; effect is dose-dependent and largely independent of insulin sensitivity.
Evidence: strong
hba1c
decrease
Typical HbA1c reduction of 0.7-1.1% at 100-300 mg/day in T2D patients; smaller effect in metabolically healthy users.
Evidence: strong
hdl c
increase
Small HDL-C increase (2-5%) observed in CANVAS and other trials; clinical significance modest.
Evidence: moderate
triglycerides
decrease
Mild triglyceride reduction (5-10%) in most trials; mechanism related to improved glycemic control and weight loss.
Evidence: moderate
uric acid
decrease
10-20% reduction in serum uric acid via URAT1 inhibition and uricosuric effect; one of the strongest non-allopurinol options.
Evidence: strong

Monitoring

eGFR and electrolytes at baseline, 1 month, then every 6-12 months. Blood pressure, urinalysis. Educate patient on DKA symptoms (nausea, abdominal pain, fatigue) and to seek care promptly. Avoid during illness, prolonged fasting, or perioperatively.

The honest risk picture

## Serious Risks **Euglycemic diabetic ketoacidosis (DKA).** This is the most important safety concern for off-label longevity use. SGLT2 inhibitors can trigger DKA with normal or only mildly elevated blood glucose — especially in fasting, low-carb dieting, illness, alcohol use, or perioperative states. Recognition is delayed because glucose is not alarming. Hold the drug during illness, prolonged fasting (>24 hours), and 3 days before any surgery. Educate patients on DKA symptoms: nausea, vomiting, abdominal pain, deep breathing, fatigue, fruity breath. **Genital mycotic infection** is common (3-12% incidence) — typically yeast infection in women and balanitis in men, especially uncircumcised. Hygiene reduces but does not eliminate risk. **Volume depletion and acute kidney injury.** Particularly in elderly, patients on diuretics or ACE inhibitors, or during illness. Hydration is essential. **Fournier's gangrene** (necrotizing genital infection) is rare but life-threatening. Any genital pain, swelling, or fever requires urgent evaluation. **Amputation signal** in CANVAS (HR 1.97 for lower limb amputation, primarily toes) — later analyses attribute most to underlying peripheral vascular disease. Remains in labeling. Caution in patients with PAD. **Fracture risk** elevated in some trials (mechanism unclear, possibly volume-related). ## Practical Cautions - **Hydration is non-negotiable.** Aim for at least 2.5 liters of water daily during use. - **Hold for illness, fasting, surgery.** DKA risk multiplies. - **Genital hygiene** — daily washing reduces but does not prevent mycotic infection. - **Drug interactions:** Diuretics (additive volume loss), insulin and sulfonylureas (hypoglycemia), digoxin (level monitoring). - **Off-label longevity use is speculative.** Discuss informed consent honestly — there is no human longevity trial.

Practical context

Cost (US, retail)
$650/mo
Legality
Prescription-only globally. FDA-approved for T2D, cardiorenal indications. Off-label longevity use is legal but unstudied in humans.
Interactions
true

FAQ

Why is canagliflozin in a longevity guide?+
The NIH Interventions Testing Program found canagliflozin extended median lifespan in male UM-HET3 mice by 14% — one of the strongest longevity signals in the program's history. The female-mouse effect was absent. The mechanism is unclear; it may involve glycemic flattening, caloric restriction mimicry, or renal protection.
Should I take canagliflozin if I'm not diabetic?+
There is no human trial of canagliflozin in metabolically healthy adults for longevity. The off-label use is legitimate but speculative. The drug's risks (DKA in low-carb dieters, genital infection, dehydration) are real and require informed consent.
What about euglycemic DKA?+
This is the most important safety issue. Patients on SGLT2 inhibitors can develop ketoacidosis with normal or only mildly elevated blood glucose — especially when fasting, on a low-carb diet, sick, or post-surgery. Recognition is delayed because glucose isn't alarming. Hold the drug during illness, fasting, and 3 days before surgery.
Will it lower my uric acid?+
Yes — typically 10-20% reduction. This is one of the few drugs that lowers both blood glucose and uric acid simultaneously.
References (5)+
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