Monograph of Dapagliflozin

Introduction/Overview

Dapagliflozin is a selective sodium‑glucose co‑transporter 2 (SGLT2) inhibitor that has revolutionized the management of type 2 diabetes mellitus (T2DM) and heart failure with reduced ejection fraction (HFrEF). Its unique mechanism of action, favorable safety profile, and emerging evidence for cardiovascular and renal protection have positioned it as a cornerstone in contemporary therapeutic algorithms. The scope of this chapter is to provide a comprehensive pharmacological perspective tailored to medical and pharmacy students, emphasizing the drug’s pharmacodynamics, pharmacokinetics, therapeutic applications, safety considerations, and practical clinical aspects.

Students will acquire an integrated understanding of dapagliflozin that enables informed clinical decision‑making and patient education. The learning objectives are:

• Describe the pharmacodynamic profile and molecular mechanism of dapagliflozin.
• Summarize the absorption, distribution, metabolism, and excretion characteristics of the drug.
• Identify approved indications and evaluate off‑label uses.
• Recognize common and serious adverse events, including box warnings.
• Discuss drug interactions, contraindications, and special patient populations.

Classification

Drug Classes and Categories

Dapagliflozin belongs to the class of sodium‑glucose co‑transporter 2 (SGLT2) inhibitors, a subgroup of antidiabetic agents that function by blocking renal glucose reabsorption. It is marketed under the brand name Farxiga® and is available as an oral tablet in 5 mg and 10 mg strengths. Within the broader pharmacological taxonomy, dapagliflozin is classified as an antidiabetic medication, a cardiovascular protective agent, and a renal protective agent.

Chemical Classification

The chemical structure of dapagliflozin consists of a bicyclic scaffold featuring a 1,3,4‑triazole ring fused to an imidazolidinone moiety. The molecule is a low‑molecular‑weight compound (MW ≈ 380 g mol⁻¹) and is moderately lipophilic (log P ≈ 1.5). Its physicochemical properties facilitate high oral bioavailability and effective renal tubular penetration.

Mechanism of Action

Pharmacodynamics

Dapagliflozin selectively inhibits the SGLT2 protein located on the luminal membrane of proximal tubular epithelial cells. By blocking glucose reabsorption, it induces glucosuria, thereby lowering plasma glucose concentrations. The inhibition is dose‑dependent, with a maximal effect observed at 10 mg once daily. The drug’s selectivity for SGLT2 over SGLT1 is > 1,000‑fold, minimizing gastrointestinal side effects associated with SGLT1 blockade.

Receptor Interactions

The target receptor, SGLT2, is a transmembrane protein that co‑transports sodium and glucose in a 1:1 ratio. Dapagliflozin binds to an allosteric site distinct from the substrate binding pocket, leading to a conformational change that reduces transporter affinity for glucose. This mechanism results in a sustained decrease in renal tubular reabsorption without significant systemic receptor activation.

Molecular/Cellular Mechanisms

By reducing glucose reabsorption, dapagliflozin lowers the effective glomerular filtration rate (GFR) transiently through osmotic diuresis and natriuresis. This mild reduction in intraglomerular pressure contributes to renal protection. Additionally, the drug may improve cardiac preload and afterload via volume depletion, thereby exerting beneficial effects in heart failure. At the cellular level, dapagliflozin’s action is confined to proximal tubular cells, with negligible interaction with myocardial or hepatic receptors.

Pharmacokinetics

Absorption

After oral administration, dapagliflozin is rapidly absorbed, reaching peak plasma concentrations (C_max) within 1–4 h. Bioavailability is approximately 70 % and is not significantly affected by food intake, although a high‑fat meal may delay absorption slightly. The drug’s solubility is adequate for standard tablet formulations, and no active metabolites contribute to pharmacodynamic effects.

Distribution

Dapagliflozin exhibits a volume of distribution of about 100 L. Plasma protein binding is moderate (~ 30 %), primarily to albumin. The drug penetrates renal tubular cells efficiently due to its lipophilic nature. Distribution to other tissues, including the heart and liver, is limited, which reduces off‑target effects.

Metabolism

Metabolic clearance occurs mainly via hepatic oxidation mediated by cytochrome P450 enzymes CYP2C8 and CYP3A4. Minor pathways involve glucuronidation. The primary metabolite, a glucuronide conjugate, is pharmacologically inactive. Because of extensive first‑pass metabolism, the parent compound remains the principal circulating species responsible for therapeutic action.

Excretion

Renal excretion accounts for the majority of dapagliflozin elimination. Approximately 67 % of the administered dose is recovered unchanged in the urine within 24 h, whereas 15 % is excreted as the inactive glucuronide metabolite. Hepatic excretion is minimal. The drug’s clearance (CL) is roughly 0.6 L h⁻¹ kg⁻¹, and the terminal half‑life (t_1/2) is 12–13 h, supporting once‑daily dosing.

Half‑Life and Dosing Considerations

The pharmacokinetic profile permits stable plasma concentrations with once‑daily administration. Dose‑adjustment is recommended for patients with reduced renal function: a 10 mg dose is acceptable for eGFR ≥45 mL min⁻¹ 1.73 m²; 5 mg is advised for eGFR 30–44 mL min⁻¹ 1.73 m²; and the drug should be discontinued when eGFR falls below 30 mL min⁻¹ 1.73 m². Hepatic impairment does not necessitate dose modification, but caution is warranted in severe cases.

Therapeutic Uses/Clinical Applications

Approved Indications

• Type 2 diabetes mellitus (T2DM): Used as monotherapy or in combination with metformin, sulfonylureas, insulin, or other glucose‑lowering agents to improve glycemic control.
• Heart failure with reduced ejection fraction (HFrEF): Added to standard heart‑failure therapy to reduce hospitalization and cardiovascular mortality.
• Chronic kidney disease (CKD) with albuminuria: Employed to slow the progression of CKD and reduce albuminuria independent of glucose lowering.

Off‑Label Uses

While not formally approved, dapagliflozin demonstrates potential benefits in several areas. Emerging evidence suggests a role in heart failure with preserved ejection fraction (HFpEF), and in reducing hepatic fat accumulation in non‑alcoholic steatohepatitis (NASH). However, these applications remain investigational and are not recommended outside clinical trials.

Adverse Effects

Common Side Effects

• Genital mycotic infections (candidiasis) – 3–5 % incidence.
• Urinary tract infections – 2–4 % incidence.
• Volume depletion symptoms (polyuria, dizziness) – 2–3 % incidence.
• Lower‑extremity neuropathy – rare (≤ 1 %).

Serious/Rare Adverse Reactions

• Diabetic ketoacidosis (DKA) – rare but potentially fatal; more prevalent in type 1 diabetes or insulin‑dependent patients.
• Hypotension and syncope – particularly in elderly or volume‑depleted individuals.
• Bone fractures – increased risk noted in post‑marketing surveillance.
• Acute kidney injury (AKI) – uncommon; often reversible upon discontinuation.

Black Box Warnings

The drug carries a black box warning for the risk of ketoacidosis, genital infections, and volume depletion. Patients should be counseled regarding early recognition of symptoms and the importance of maintaining adequate hydration.

Drug Interactions

Major Drug–Drug Interactions

• Diuretics (loop or thiazide): Combined use may enhance volume depletion and hypotension.
• ACE inhibitors/ARBs: May increase the risk of AKI due to synergistic renal hemodynamic effects.
• NSAIDs: Potential for reduced diuretic efficacy and increased renal risk.
• Glucocorticoids: May blunted glucose‑lowering effect.
• Other SGLT2 inhibitors: Not indicated; additive effects may increase adverse events.

Contraindications

Dapagliflozin is contraindicated in:

• Type 1 diabetes mellitus.
• Patients with DKA or a history of recurrent ketoacidosis.
• Severe renal impairment (eGFR <30 mL min⁻¹ 1.73 m²).
• Pregnancy and lactation due to insufficient safety data.

Special Considerations

Use in Pregnancy/Lactation

Animal studies have not demonstrated teratogenicity, yet human data are limited. The drug is classified as pregnancy category B; however, it is generally avoided unless benefits outweigh risks. Lactation exclusion is advised due to potential excretion in breast milk.

Pediatric/Geriatric Considerations

Clinical trials in pediatric populations are ongoing; thus, dapagliflozin is not approved for use in children. In geriatric patients, caution is warranted due to age‑related decline in renal function and increased susceptibility to hypotension. Dose adjustments based on eGFR are essential.

Renal/Hepatic Impairment

Renal impairment: Dose adjustment is required for eGFR 30–44 mL min⁻¹ 1.73 m² (5 mg daily). Discontinuation is advised when eGFR <30 mL min⁻¹ 1.73 m². Hepatic impairment: No dose adjustment is necessary for mild to moderate hepatic dysfunction; data for severe hepatic impairment are lacking, so use is discouraged.

Summary/Key Points

• Dapagliflozin selectively inhibits renal SGLT2, inducing glucosuria and osmotic diuresis.
• Optimal once‑daily dosing (5–10 mg) is supported by a half‑life of 12–13 h and limited protein binding.
• Approved for T2DM, HFrEF, and CKD with albuminuria; off‑label use in HFpEF and NASH is investigational.
• Common adverse events include genital mycotic infections and volume depletion; serious risks involve DKA and AKI.
• Drug interactions with diuretics, ACE inhibitors, ARBs, NSAIDs, and glucocorticoids necessitate careful monitoring.
• Contraindicated in type 1 diabetes, severe renal disease, pregnancy, and lactation.
• Special populations: geriatric patients require dose adjustments; pediatric use remains unapproved.
• Clinicians should educate patients on symptom recognition for ketoacidosis and maintain adequate hydration.

By integrating pharmacodynamic and pharmacokinetic knowledge with clinical safety considerations, students will be equipped to apply dapagliflozin judiciously in diverse therapeutic contexts, ensuring optimal patient outcomes.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
3. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
4. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
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7. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.