Indications
Dapagliflozin is approved as an adjunct therapy to improve glycemic control in individuals aged 10 years and older with type 2 diabetes mellitus, when combined with diet and exercise. Additionally, it serves a role in reducing the risk of progressive chronic kidney disease, end-stage kidney disease, cardiovascular mortality, and hospitalization due to heart failure. It is indicated for reducing cardiovascular death and heart failure complications in adults with heart failure and for minimizing heart failure-related hospitalizations in adults with type 2 diabetes and established cardiovascular conditions or multiple risk factors. Combination formulations involving dapagliflozin, such as those paired with saxagliptin or metformin hydrochloride, are similarly approved for enhancing glycemic control in adult patients with type 2 diabetes.
Pharmacodynamics
Dapagliflozin functions by reducing sodium reabsorption and elevating sodium delivery to the distal tubules, potentially impacting physiological functions such as reducing cardiac pre- and afterload, modulating sympathetic activity, and decreasing intraglomerular pressure through enhanced tubuloglomerular feedback. In clinical observations, administration of dapagliflozin in patients with type 2 diabetes mellitus leads to increased urinary glucose excretion, peaking at approximately 70 grams per day after 12 weeks at doses of 5 or 10 mg daily, with near-maximal excretion at a 20 mg dosage. This mechanism also results in an increased urinary volume. Dapagliflozin does not significantly prolong the QTc interval, even at doses up to 150 mg, nor with single doses as high as 500 mg in healthy individuals.
Absorption
Oral administration of dapagliflozin achieves peak plasma concentration within 1 to 2 hours under fasting conditions. The Cmax and AUC values rise proportionally with the dose within the therapeutic range, and the drug exhibits an absolute oral bioavailability of 78% following a 10 mg dose. Although a high-fat meal can decrease the Cmax by up to 50% and delay Tmax by approximately 1 hour, these changes do not significantly affect the AUC, allowing dapagliflozin to be administered irrespective of food intake.
Metabolism
Dapagliflozin undergoes primary glucuronidation to form an inactive 3-O-glucuronide metabolite, accounting for 60.7% of its metabolism. Additional minor metabolites include another glucuronidated metabolite, a de-ethylated metabolite, and a hydroxylated metabolite. Metabolic pathways involve enzymes such as CYP1A1, CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP3A4, as well as UGT1A9, UGT2B4, and UGT2B7, with glucuronidation primarily mediated by UGT1A9.
Mechanism of Action
Dapagliflozin functions by inhibiting the activity of the sodium-glucose cotransporter 2 (SGLT2), which is predominantly found in the proximal tubule of the nephron. SGLT2 is responsible for approximately 90% of glucose reabsorption in the kidneys. By blocking this transporter, dapagliflozin promotes the excretion of glucose in the urine. This mechanism aids in achieving improved glycemic control and may also contribute to weight loss in individuals with type 2 diabetes mellitus.
