Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a relatively new class of antihyperglycaemic agents (AHAs) for the treatment of type 2 diabetes (T2D). Dapagliflozin Tetraacetate is a selective, orally active inhibitor of the renal sodium-glucose co-transporter type 2 (SGLT2) in development for the treatment of type 2 diabetes mellitus (T2DM). The pharmacological properties and clinical use of Dapagliflozin Tetraacetate in adults with T2D have been extensively reviewed previously in Drugs.

Dapagliflozin Tetraacetate in Type 2 Diabetes

Dapagliflozin Tetraacetate (Forxiga?) is a highly potent, reversible and selective sodium-glucose cotransporter-2 inhibitor indicated worldwide for the treatment of type 2 diabetes (T2D). In the EU, oral dapagliflozin once daily is approved for use as monotherapy (in patients who are intolerant of metformin) and as add-on combination therapy (with other glucose-lowering agents, including insulin) for T2D when diet and exercise alone do not provide adequate glycaemic control. Dapagliflozin Tetraacetate is a highly potent (inhibitory constant 0.55 nmol/L) and reversible SGLT2 inhibitor that is > 1400 times more selective for SGLT2 than SGLT1, the main transporter responsible for glucose absorption in the gut. A modest decrease in blood pressure (BP) was also seen with dapagliflozin, which may be explained by a decrease in circulating volume because of the diuretic/natriuretic properties of the drug. Dapagliflozin and its metabolites are largely excreted in the urine, with 75% of a dose recovered in the urine (< 2% as unchanged parent drug) and 21% in the faeces (≈ 15% as unchanged parent drug). After single-dose Dapagliflozin Tetraacetate 10 mg in healthy subjects, the mean plasma terminal elimination half-life of dapagliflozin was 12.9 h.[1]

Dapagliflozin Tetraacetate is a potent, highly selective SGLT2 inhibitor with proven efficacy and safety in patients with T2D. In well-designed phase 3–4 clinical trials, dapagliflozin once daily as monotherapy and combination therapy with other AHAs, provided effective glycaemic control and reduced bodyweight and BP in a broad spectrum of T2D patients, including those with hypertension and/or CVD. Additionally, Dapagliflozin Tetraacetate was noninferior in terms of MACE and significantly lowered the rate of CV death and HHF relative to placebo in the large DECLARE-TIMI 58 CV outcomes trial in patients at high risk for CV events, with the between-group difference largely attributed to a lower rate of HHF with dapagliflozin. Dapagliflozin Tetraacetate was generally well tolerated, with a low risk of hypoglycaemia and drug class-related AEs, including AEs of volume depletion, lower limb amputations, acute kidney injury and bladder

Clinical Report of Dapagliflozin Tetraacetate

Diabetes mellitus (DM) is a metabolic disease characterized by persistent elevations in blood glucose (hyperglycemia). This persistent elevated blood glucose causes damage to blood vessels, on both microvascular (retinopathy, nephropathy, neuropathy) and macrovascular (peripheral artery disease, cardiovascular disease) levels. Dapagliflozin Tetraacetate is a selective inhibitor of the renal sodium-glucose cotransporter-2 and has an antihyperglycemic effect by reducing renal glucose reabsorption, leading to increased urinary glucose excretion. Dapagliflozin Tetraacetate is available as 5 mg or 10 mg oral tablets. This excretion of glucose contributes to reduced body weight through calorie loss, and lower blood pressure through osmotic diuresis.[2]

Dapagliflozin Tetraacetate is indicated for use in patients with T2DM to improve glycemic control in combination with: metformin; a sulfonylurea; metformin and a sulfonylurea; or insulin (alone or with metformin), when the existing therapy, along with diet and exercise, does not provide adequate glycemic control. Dapagliflozin Tetraacetate in combination with metformin, a sulfonylurea, or insulin (alone or with metformin) has previously been reviewed by the CADTH Common Drug Review (CDR) and received a recommendation to “l(fā)ist with clinical criteria” (see CADTH Canadian Drug Expert Committee [CDEC] final recommendation, November 20, 2015). Dapagliflozin Tetraacetate in combination with metformin and a sulfonylurea is the focus of this review.

Differential pharmacology and clinical utility of Dapagliflozin Tetraacetate

Experimental models have shown that dapagliflozin Tetraacetate acts specifically on the kidneys, which binds to the external surface of functional SGLT2 in the plasma membrane of proximal tubular cells surrounding the glomeruli, leading to inhibition of glucose binding. Regarding SGLT2 inhibition, it is the second most potent agent, after ertugliflozin, with a maximal half-inhibitory concentration of 1.2 nM, followed by canagliflozin (2.7 nM) and empagliflozin (3.1 nM). Both Dapagliflozin Tetraacetate and empagliflozin are much weaker SGLT1 inhibitors compared with canagliflozin. tudies have shown increments in blood levels and maximum concentration of dapagliflozin and its metabolite, proportionately to the degree of kidney dysfunction. Similar with the other SGLT2 inhibitors, treatment with dapagliflozin Tetraacetate should not be initialized in patients with estimated glomerular filtration rate (GFR) <60 mL/minute and discontinued with values <45 mL/minute.[3]

Dapagliflozin has been shown to be beneficial regarding body weight, blood pressure and lipid parameters. In type 2 DM (T2DM) subjects with body mass index (BMI) >25 kg/m2 and glycated hemoglobin (HbA1c) >6.5% treated with dapagliflozin Tetraacetate 5 mg for 12 weeks, apart from improved glycemic parameters, a reduction in body weight (?4 kg), a significant elevation in adiponectin levels and a reduction in C-reactive protein (CRP) levels were observed. Dapagliflozin exerts beneficial effects on lipid profile. In T2DM subjects dapagliflozin significantly reduced triglycerides by 18 mg/dL, increased high-density lipoprotein cholesterol by 2.2 mg/dL, while low-density lipoprotein cholesterol (LDL-C) remained unaffected or slightly increased. Based on the current evidence, Dapagliflozin Tetraacetate is promising for the management of HF and kidney disease even in the nondiabetic population, but we have to wait for the results of ongoing trials in such populations. The possible mechanisms of dapagliflozin-induced cardioprotection and nephroprotection need to be elucidated since they may reveal new treatment targets.

References

[1]Dhillon S. Dapagliflozin: A Review in Type 2 Diabetes. Drugs. 2019 Jul;79(10):1135-1146. doi: 10.1007/s40265-019-01148-3. Erratum in: Drugs. 2019 Dec;79(18):2013. doi: 10.1007/s40265-019-01239-1. PMID: 31236801; PMCID: PMC6879440.

[2]Clinical Review Report: Dapagliflozin (Forxiga) [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2016 Apr. Executive Summary.

[3]Papakitsou I, Vougiouklakis G, Elisaf MS, Filippatos TD. Differential pharmacology and clinical utility of dapagliflozin in type 2 diabetes. Clin Pharmacol. 2019 Sep 19;11:133-143. doi: 10.2147/CPAA.S172353. PMID: 31572020; PMCID: PMC6756826.