IMPORTANCE Additional treatments are needed for heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be an effective treatment for patients with HFrEF, even those without diabetes. OBJECTIVE To evaluate the effects of dapagliflozin in patients with HFrEF with and without diabetes. DESIGN, SETTING, AND PARTICIPANTS Exploratory analysis of a phase 3 randomized trial conducted at 410 sites in 20 countries. Patients with New York Heart Association classification II to IV with an ejection fraction less than or equal to 40% and elevated plasma N-terminal pro B-type natriuretic peptide were enrolled between

Dapagliflozin selectively inhibits renal glucose reabsorption by inhibiting sodium-glucose cotransporter-2 (SGLT2). It was developed as an insulin-independent treatment approach for type 2 diabetes mellitus (T2DM). The safety, tolerability, pharmacokinetics, and pharmacodynamics of the drug were evaluated in single-ascending-dose (SAD; 2.5-500 mg) and multiple-ascending-dose (MAD; 2.5-100 mg daily for 14 days) studies in healthy subjects. Dapagliflozin exhibited dose-proportional plasma concentrations with a half-life of approximately 17 h. The amount of glucosuria was also dose-dependent. Cumulative amounts of glucose excreted on day 1, relating to doses from 2.5-100 mg (MAD), ranged from 18 to 62 g; day 14 values were comparable to day 1 values, with no apparent changes in glycemic parameters. Doses of approximately 20-50 mg provided close-to-maximal SGLT2 inhibition for at least 24 h. Dapagliflozin demonstrates pharmacokinetic (PK) characteristics and dose-dependent glucosuria that are sustained over 24 h, which indicates that it is suitable for administration in once-daily doses and suggests that further investigation of its efficacy in T2DM patients is warranted.

The effect of a sodium glucose cotransporter 2 inhibitor (SGLT2i) in reducing heart failure hospitalization in the EMPA-REG OUTCOMES trial has raised the possibility of using these agents to treat established heart failure. We hypothesize that osmotic diuresis induced by SGLT2 inhibition, a distinctly different diuretic mechanism than that of other diuretic classes, results in greater electrolyte-free water clearance and, ultimately, in greater fluid clearance from the interstitial fluid (IF) space than from the circulation, potentially resulting in congestion relief with minimal impact on blood volume, arterial filling and organ perfusion. We utilize a mathematical model to illustrate that electrolyte-free water clearance results in a greater reduction in IF volume compared to blood volume, and that this difference may be mediated by peripheral sequestration of osmotically inactive sodium. By coupling the model with data on plasma and urinary sodium and water in healthy subjects who received either the SGLT2i dapagliflozin or loop diuretic bumetanide, we predict that dapagliflozin produces a 2-fold greater reduction in IF volume compared to blood volume, while the reduction in IF volume with bumetanide is only 78% of the reduction in blood volume. Heart failure is characterized by excess fluid accumulation, in both the vascular compartment and interstitial space, yet many heart failure patients have arterial underfilling because of low cardiac output, which may be aggravated by conventional diuretic treatment. Thus, we hypothesize that, by reducing IF volume to a greater extent than blood volume, SGLT2 inhibitors might provide better control of congestion without reducing arterial filling and perfusion.

OBJECTIVETo examine the effect of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on the major components of renal glucose reabsorption (decreased maximum renal glucose reabsorptive capacity [TmG], increased splay, and reduced threshold), using the pancreatic/stepped hyperglycemic clamp (SHC) technique.RESEARCH DESIGN AND METHODSSubjects with type 2 diabetes (n = 12) and matched healthy subjects (n = 12) underwent pancreatic/SHC (plasma glucose range 5.5–30.5 mmol/L) at baseline and after 7 days of dapagliflozin treatment. A pharmacodynamic model was developed to describe the major components of renal glucose reabsorption for both groups and then used to estimate these parameters from individual glucose titration curves.RESULTSAt baseline, type 2 diabetic subjects had elevated TmG, splay, and threshold compared with controls. Dapagliflozin treatment reduced the TmG and splay in both groups. However, the most significant effect of dapagliflozin was a reduction of the renal threshold for glucose excretion in type 2 diabetic and control subjects.CONCLUSIONSThe SGLT2 inhibitor dapagliflozin improves glycemic control in diabetic patients by reducing the TmG and threshold at which glucose is excreted in the urine.

Sodium-glucose co-transporter 2 (SGLT2) is predominantly expressed in the S1 segment of the proximal tubule of the kidney and is the major transporter responsible for mediating renal glucose reabsorption. Dapagliflozin is an orally active, highly selective SGLT2 inhibitor that improves glycemic control in patients with type 2 diabetes mellitus (T2DM) by reducing renal glucose reabsorption leading to urinary glucose excretion (glucuresis). Orally administered dapagliflozin is rapidly absorbed generally achieving peak plasma concentrations within 2 h. Dose-proportional systemic exposure to dapagliflozin has been observed over a wide dose range (0.1-500 mg) with an oral bioavailability of 78 %. Dapagliflozin has extensive extravascular distribution (mean volume of distribution of 118 L). Dapagliflozin metabolism occurs predominantly in the liver and kidneys by uridine diphosphate-glucuronosyltransferase-1A9 to the major metabolite dapagliflozin 3-O-glucuronide (this metabolite is not an SGLT2 inhibitor at clinically relevant exposures). Dapagliflozin is not appreciably cleared by renal excretion (<2 % of dose is recovered in urine as parent). Dapagliflozin 3-O-glucuronide elimination occurs mainly via renal excretion, with 61 % of a dapagliflozin dose being recovered as this metabolite in urine. The half-life for orally administered dapagliflozin 10 mg was 12.9 h. Maximal increases in urinary glucose excretion were seen at doses ≥20 mg/day in patients with T2DM. No clinically relevant differences were observed in dapagliflozin exposure with respect to age, race, sex, body weight, food, or presence of T2DM. Pharmacodynamic changes are dependent on plasma glucose and renal function, and decreases in urinary glucose excretion were observed due to the lower filtered load (plasma glucose × glomerular filtration rate) in healthy volunteers compared to subjects with T2DM. After multiple doses of dapagliflozin, urinary glucose excretion was associated with dose-related decreases in plasma glucose parameters in subjects with T2DM. Patients with severe renal or hepatic impairment show higher systemic exposure to dapagliflozin. No clinically relevant drug interactions were observed that would necessitate dose adjustment of dapagliflozin when administered with other antidiabetic or cardiovascular medications, as well as drugs that could potentially influence dapagliflozin metabolism.

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Although the bioflavonoids, a large group of polyphenolic natural products, exert chemopreventive effects in cardiovascular disease and cancer, there is little information about the disposition of these dietary components in man. The objective of this study was to investigate the plasma-protein binding of the most abundant bioflavonoid, quercetin, using 14C-labelled quercetin. An ultracentrifugation assay (170,000 g for 16 h at 20 degrees C) was shown to sediment plasma proteins. Binding of quercetin to normal plasma was extensive (99.1+/-0.5%, mean +/- s.d., n = 5). The unbound fraction varied as much as 6-fold, 0.3-1.8%, between subjects. This high binding was independent of quercetin concentration over the range 1.5-15 microM (0.5-5 microg mL(-1)). Human serum albumin was the primary protein responsible for the binding of quercetin in plasma (99.4+/-0.1%). Binding by alpha1-acid glycoprotein (39.2+/-0.5%) and very-low-density lipoproteins (<0.5% of total quercetin) did not make substantial contributions to overall plasma binding. The equilibrium association constant for the binding of quercetin to serum albumin was 267+/-33 x 10(3) M(-1) (n = 15). Thermodynamic data for the binding of quercetin to serum albumin indicated spontaneous, endothermic association. Displacement studies suggested that in man the 'IIA' subdomain binding site of human serum albumin was the primary binding site for quercetin. Association of quercetin with erythrocytes was significantly (P < 0.001) reduced by plasma protein binding. These data indicate poor cellular availability of quercetin because of its extensive binding to plasma proteins.

Dapagliflozin was well tolerated and showed predictable dose-proportional PK and PD parameters in both healthy and T2DM Japanese subjects.