Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

Meng, Wei; Ellsworth, Bruce A.; Nirschl, Alexandra A.; McCann, Peggy J.; Patel, Manorama; Girotra, Ravindar N.; Wu, Gang; Sher, Philip M.; Morrison, Eamonn P.; Biller, Scott A.; Zahler, Robert; Deshpande, Prashant P.; Pullockaran, Annie; Hagan, Deborah; Morgan, Nathan; Taylor, Joseph R.; Obermeier, Mary; Humphreys, W. Griffith; Khanna, Ashish K.; Discenza, Lorell; Robertson, James G.; Wang, Aiying; Han, Song‐Ping; Wetterau, John R.; Janovitz, Evan B.; Flint, Oliver; Whaley, Jean M.; Washburn, William N.

doi:10.1021/jm701272q

Cited by 535 publications

(398 citation statements)

References 40 publications

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“…It is approved for the treatment of type 2 diabetes mellitus (T2DM), where it promotes glycosuria 1, 5. T2DM increases the incidence of congestive heart failure (CHF) 6, 7.…”

mentioning

confidence: 99%

Interaction Between the Sodium‐Glucose–Linked Transporter 2 Inhibitor Dapagliflozin and the Loop Diuretic Bumetanide in Normal Human Subjects

Wilcox

Shen

Boulton

et al. 2018

JAHA

107

105

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BackgroundDapagliflozin inhibits the sodium‐glucose–linked transporter 2 in the renal proximal tubule, thereby promoting glycosuria to reduce hyperglycemia in type 2 diabetes mellitus. Because these patients may require loop diuretics, and sodium‐glucose–linked transporter 2 inhibition causes an osmotic diuresis, we evaluated the diuretic interaction between dapagliflozin and bumetanide.Methods and ResultsHealthy subjects (n=42) receiving a fixed diet with ≈110 mmol·d−1 of Na+ were randomized to bumetanide (1 mg·d−1), dapagliflozin (10 mg·d−1), or both for 7 days, followed by 7 days of both. There were no meaningful pharmacokinetic interactions. Na+ excretion increased modestly with the first dose of dapagliflozin (22±6 mmol·d−1; P<0.005) but by more (P<0.005) with the first dose of bumetanide (74±7 mmol·d−1; P<0.005), which was not significantly different from both diuretics together (80±5 mmol·d−1; P<0.005). However, Na+ excretion with dapagliflozin was 190% greater (P<0.005) when added after 1 week of bumetanide (64±6 mmol·d−1), and Na+ excretion with bumetanide was 36% greater (P<0.005) when added after 1 week of dapagliflozin (101±8 mmol·d−1). Serum urate was increased 4% by bumetanide but reduced 40% by dapagliflozin or 20% by combined therapy (P<0.05).ConclusionsFirst‐dose Na+ excretion with bumetanide and dapagliflozin is not additive, but the weekly administration of one diuretic enhances the initial Na+ excretion with the other, thereby demonstrating mutual adaptive natriuretic synergy. Combined therapy reverses bumetanide‐induced hyperuricemia. This requires further study in diabetic patients with hyperglycemia who have enhanced glycosuria and natriuresis with dapagliflozin.Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00930865.

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“…It is approved for the treatment of type 2 diabetes mellitus (T2DM), where it promotes glycosuria 1, 5. T2DM increases the incidence of congestive heart failure (CHF) 6, 7.…”

mentioning

confidence: 99%

Interaction Between the Sodium‐Glucose–Linked Transporter 2 Inhibitor Dapagliflozin and the Loop Diuretic Bumetanide in Normal Human Subjects

Wilcox

Shen

Boulton

et al. 2018

JAHA

107

105

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“…Studies have shown that oral administration of sergiflozin, a SGLT-2 inhibitor in normal and streptozotocin induced diabetic rats, increased urinary excretion in a dose dependent manner and attenuated the increase in blood glucose level following an OGTT without stimulating insulin release [86]. Similarly, dapagliflozin, a potent SGLT-2 inhibitor caused a dose dependent reduction in blood glucose level by as much as 60% in STZ-induced diabetic rats over a 5-hr period following oral administration [87]. These findings are consistent with the findings of this study.…”

Section: Discussionmentioning

confidence: 99%

Antihyperglycemic Studies on the Leaf Extract and Active Fractions of <i>Newbouldia laevis</i> (Bignoniaceae)

Osigwe¹,

Akah²,

Nworu³

et al. 2015

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Optimal control of chronic hyperglycemia prevents both micro and macro vascular complications-a leading cause of morbidity and mortality in diabetic subjects. This study was undertaken to give credence to the traditional use of Newbouldia laevis leaves in the treatment of diabetes mellitus (DM). Dichloromethane-methanol (1:1) extract (DME) of N. laevis leaves was prepared by cold maceration. Separation of DME into column chromatographic fractions yielded the n-hexane fraction (HF), ethylacetate fraction (EF) and methanol fraction (MF). The extract and fractions were evaluated for antihyperglycemic activity in alloxanized diabetic rats. The results showed that the oral administration of extract and fractions (250, 500, 1000 mg/kg) caused a significant (P < 0.5) and dose-dependent reduction in blood glucose level in diabetic rats. The hypoglycemic potency after 24 h was in the order MF (methanol fraction; 56.31%) > DME (dichloromethane/methanol extract; 36.19%) > EF (ethylacetate fraction; 20.70%) > HF (n-hexane fraction; 10.09. The methanol fraction, which showed the highest potency in oral glucose tolerance test (OGTT), was further separated into column chromatographic sub-fractions-F₁, F₂, F₃ and F₄ fractions. These sub-fractions were evaluated for antihyperglycemic activity. Sub-fractions F₁, F₂ and F₃ (1000 mg/kg) did produce significant (P > 0.05) reduction in blood glucose level after 24 h. Sub-fraction F4 (50, 100, 200 mg/kg), however caused a significant (P < 0.05) and dose-dependent reduction in blood glucose level. The reduction at 200 mg/kg dose of F 4 (74.57%) was significantly (P < 0.05) higher than that of glibenclamide (58.04%). These findings suggest that leaf extract and fractions of Newbouldia laevis possess antihyperglycemic activities and can be the basis for the folk use N. laevis in management of diabetes mellitus.

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“…In vitro studies have indicated a comparable inhibitory potency against rat SGLT2 or human SGLT2. Dapagliflozin administration to diabetic rats resulted in a 55% reduction in blood glucose 5 h after a single dose (58).…”

Section: Sglts As Therapeutic Targetsmentioning

confidence: 97%

“…One example is dapagliflozin (BMS-512148), a compound containing C-glycosylation, which confers on it a longer half-life than that of phlorizin (57). In addition, compared to SGLT1, it is 1220-fold more selective for SGLT2, whereas phlorizin is only 10-fold more selective (58). In vitro studies have indicated a comparable inhibitory potency against rat SGLT2 or human SGLT2.…”

Section: Sglts As Therapeutic Targetsmentioning

confidence: 99%

The Na+/glucose cotransporters: from genes to therapy

Sabino-Silva

Mori

David-Silva

et al. 2010

Braz J Med Biol Res

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Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

Cited by 535 publications

References 40 publications

Interaction Between the Sodium‐Glucose–Linked Transporter 2 Inhibitor Dapagliflozin and the Loop Diuretic Bumetanide in Normal Human Subjects

Interaction Between the Sodium‐Glucose–Linked Transporter 2 Inhibitor Dapagliflozin and the Loop Diuretic Bumetanide in Normal Human Subjects

Antihyperglycemic Studies on the Leaf Extract and Active Fractions of <i>Newbouldia laevis</i> (Bignoniaceae)

The Na+/glucose cotransporters: from genes to therapy

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Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

Cited by 535 publications

References 40 publications

Interaction Between the Sodium‐Glucose–Linked Transporter 2 Inhibitor Dapagliflozin and the Loop Diuretic Bumetanide in Normal Human Subjects

Interaction Between the Sodium‐Glucose–Linked Transporter 2 Inhibitor Dapagliflozin and the Loop Diuretic Bumetanide in Normal Human Subjects

Antihyperglycemic Studies on the Leaf Extract and Active Fractions of &lt;i&gt;Newbouldia laevis&lt;/i&gt; (Bignoniaceae)

The Na+/glucose cotransporters: from genes to therapy

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Antihyperglycemic Studies on the Leaf Extract and Active Fractions of <i>Newbouldia laevis</i> (Bignoniaceae)