Dapagliflozin — The SGLT2 Inhibitor
Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor originally developed for type 2 diabetes. Beyond glycemic control, it has garnered significant interest in longevity medicine for its profound cardioprotective and renoprotective effects, as well as its ability to mimic aspects of fasting by shifting systemic metabolism toward fatty acid oxidation.
Mechanism of Action
Dapagliflozin selectively inhibits SGLT2 in the proximal tubule of the kidney, preventing the reabsorption of filtered glucose and sodium. This induces glycosuria and natriuresis, lowering blood glucose independently of insulin. Systemically, this shift in fuel utilization mimics fasting, increasing circulating ketone bodies such as beta-hydroxybutyrate. This metabolic state activates nutrient-deprivation pathways including AMPK and SIRT1, while downregulating mTOR. These downstream effects reduce oxidative stress, lower systemic inflammation, and improve mitochondrial function, driving its broad organ-protective benefits.
Human Trial Evidence
Extensive human trials, notably DAPA-HF and DAPA-CKD, have demonstrated that dapagliflozin significantly reduces the risk of cardiovascular death, hospitalization for heart failure, and chronic kidney disease progression, even in patients without diabetes. While there are no published human trials explicitly measuring lifespan extension as a primary endpoint, its robust efficacy in reducing all-cause mortality in high-risk populations makes it a compelling candidate for healthspan extension.
Dosing Protocol
The standard clinical dose is 10 mg once daily, taken orally with or without food. As a prescription-only medication, its use for healthspan extension is off-label and strictly requires medical supervision.
Safety & Contraindications
Common adverse effects include genital mycotic infections and urinary tract infections due to glycosuria. It carries a rare but serious risk of euglycemic diabetic ketoacidosis (DKA), particularly in patients on severe carbohydrate-restricted diets or during acute illness. It may also cause volume depletion and hypotension. Contraindicated in patients with severe renal impairment or on dialysis. This is a prescription-only medication.