Targeting the kidney and glucose excretion with dapagliflozin: preclinical and clinical evidence for SGLT2 inhibition as a new option for treatment of type 2 diabetes mellitus

Figures & data

Figure 1 (A) In the normal range of blood glucose levels, the majority of glucose is reabsorbed in the kidney predominantly via the action of SGLT2 and GLUT2 in the S1 segment of the proximal tubule. (B) SGLT2 inhibitors block the reabsorption of glucose in the S1 proximal tubule under normal or hyperglycemic conditions, resulting in urinary glucose excretion.

Abbreviations: SGLT, sodium-glucose cotransporter; GLUT, glucose transporter.

Figure 2 SGLT2 expression was determined in an array of 72 human tissues. Shown are representative tissues quantified using TaqMan quantitative PCR analysis with primer/probe sets designed to amplify and detect regions of (A) exon 6–7 and (B) exon 13 of SGLT2 and normalized to GAPDH.

Note: Copyright © 2010. Reprinted with permission from Springer Science+Business Media B.V. Chen J, William S, Ho S, et al. Quantitative PCR tissue expression profiling of the human SGLT2 gene and related family members. Diabetes Ther. 2010;1(2):57–92.¹⁷
Abbreviations: SGLT, sodium-glucose cotransporter; PCR, polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.

Figure 3 Single oral doses of dapagliflozin were demonstrated to stimulate an increase in urinary glucose excretion in Zucker diabetic fatty rats (A) over 6 hours, and (B) 24 hours post dose.

Notes: *P < 0.0001; ^†P < 0.05, each versus vehicle. Copyright © 2008. Reprinted with permission from American Diabetes Association. Han S, Hagan DL, Taylor JR, et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes. 2008;57(6):1723–1729.³³
Abbreviation: BW, body weight.

Figure 4 Once-daily oral administration of dapagliflozin resulted in significant, dose-dependent reductions in the plasma glucose of fed and fasting Zucker diabetic fatty rats over 15 days.

Notes: *P < 0.0001; ^†P < 0.05, each versus vehicle. Copyright © 2008. Reprinted with permission from American Diabetes Association. Han S, Hagan DL, Taylor JR, et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes. 2008;57(6):1723–1729.³³
Abbreviation: Ad lib, Ad libitum.

Table 1 Glycemic efficacy of 10 mg dapagliflozin for initial Phase III trials

Therapy	Duration	n	Baseline HbA1c, %a		Mean change from baseline in HbA1c, %a		Baseline FPG, mg/dLa		Mean change from baseline in FPG, mg/dLa
			DAPA	COMP	DAPA	COMP	DAPA	COMP	DAPA	COMP
Monotherapy versus placebo (primary cohort)^Citation43	24 weeks	274	8.01 ± 0.96	7.84 ± 0.87	−0.89 (0.11)e	−0.23 (0.10)	166.6 ± 41.5	159.9 ± 42.1	−28.8 (4.0)e	−4.1 (3.9)
Add-on to metformin versus placebo^Citation45	24 weeks	546	7.92 ± 0.82	8.11 ± 0.96	−0.84 [−0.98 to −0.70]e	−0.30 [−0.44 to −0.16]	156.0 ± 38.7	165.6 ± 46.3	−23.4 [−28.8 to −18.0]e	−6.0 [−11.2 to −0.72]
Initial therapy with metformin versus metformin or DAPA^Citation44	24 weeks	638	NR	NR	−1.98 (0.08)f	met: −1.44 (0.08) dapa alone: −1.45 (0.07)	NR	NR	−60.4 (2.5)f	met: −34.8 (2.5) dapa alone: −46.4 (2.5)
Add-on to metformin versus glipizide^Citation58,b	52 weeks	814	7.7 ± 0.9	7.7 ± 0.9	−0.52 [−0.60 to −0.44]	−0.52 [−0.60 to −0.44]	162.2 ± 37.8	164.0 ± 41.4	−22.3 [−25.6 to −19.3]	−18.7 [−22.0 to −17.7]
Add-on to insulin versus placebo^Citation48,Citation78	24 weeks	807	8.57 ± 0.82	8.47 ± 0.77	−0.90 (0.05)e	−0.30 (0.05)	173.1 ± 54.9	170.6 ± 57.2	−21.7(3.3)e	3.3 (3.4)
Add-on to pioglitazone versus placebo^Citation46	24 weeks	420	8.37	8.34	−0.97 (0.08)g	−0.42 (0.08)	165c		−29.6 (2.9)d	−5.5 (2.9)
Add-on to glimepiride versus placebo^Citation47,Citation79	24 weeks	592	8.07 ± 0.79	8.15 ± 0.74	−0.82 (0.06)e	−0.13 (0.06)	172.1 ± 36.8	172.6 ± 37.3	−28.5e	−2.0

Notes:

a Mean ± standard deviation, adjusted mean (standard error), or [95% confidence interval];

b dapagliflozin was started at 2.5 mg/d and titrated up to 10 mg/d;

c baseline demographics provided for total patients enrolled and randomized;

d P ≤ 0.001 versus placebo;

e P ≤ 0.0001 versus placebo;

f P ≤ 0.0001 versus metformin;

g described as significant but P value not explicit.

Abbreviations: FPG, fasting plasma glucose; DAPA, dapagliflozin; COMP, comparator; NR, not reported; met, metformin.

Table 2 Body weight changes associated with 10 mg dapagliflozin for initial Phase III trials

Therapy	Duration	n	Baseline weight, kga		Mean change from baseline in weight, kga
			DAPA	COMP	DAPA	COMP
Monotherapy versus placebo (primary cohort)^Citation43	24 weeks	274	94.2 ± 18.7	88.8 ± 19.0	−3.2 (0.5)	−2.2 (0.4)
Add-on to metformin versus placebo^Citation45	24 weeks	546	86.3 ± 17.5	87.7 ± 19.2	−2.9 [−3.3 to −2.4]e	−0.9 [−1.4 to −0.4]
Initial therapy with metformin versus metformin or DAPA^Citation44	24 weeks	638	NR	NR	−3.33 (0.24)f	met: −1.36 (0.24) dapa: −2.73 (0.23)
Add-on to metformin versus glipizide^Citation58,b	52 weeks	814	88.4	87.6	−3.2 [−3.6 to −2.9]g	1.4 [1.1 to 1.8]
Add-on to insulin versus placebo^Citation48,Citation78	24 weeks	807	94.5 ± 16.8	94.5 ± 19.8	−1.67 (0.18)e	0.02 (0.18)
Add-on to pioglitazone versus placebo^Citation46	24 weeks	420	86 kgc		−0.14 (0.28)d	1.64 (0.28)
Add-on to glimepiride versus placebo^Citation47,Citation79	24 weeks	592	80.6 ± 17.9	80.9 ± 15.8	−2.26 (0.22)e	−0.72 (0.23)

Notes:

a Mean ± standard deviation, adjusted mean (standard error), or [95% confidence interval];

b dapagliflozin was started at 2.5 mg/d and titrated up to 10 mg/d;

c baseline demographics provided for total patients enrolled and randomized;

d P ≤ 0.001 versus placebo;

e P ≤ 0.0001 versus placebo;

f P ≤ 0.01 versus metformin;

g P ≤ 0.0001 versus glipizide.

Abbreviations: DAPA, dapagliflozin; COMP, comparator; NR, not reported; met, metformin.

Figure 5 Dapagliflozin treatment of Zucker diabetic fatty rats at the initiation of a high-fat diet (A) did not have a significant effect on β-cell mass and (B) improved islet morphology. Box plots of the same data presented as insets. Representative 10× images of immunofluorescently stained β-cells (anti-insulin, green) and Hoescht-stained nuclei showed (C) poor islet morphology and scattered β-cells in obese, vehicle-treated Zucker diabetic fatty rats compared with (D) improved islet morphology and insulin-staining intensity in dapagliflozin-treated animals. Islet size was increased in these obese, dapagliflozin-treated rats compared with (E) lean Zucker diabetic fatty rats.

Note:^†P < 0.05 versus obese fat-fed group. Copyright © 2010. Reprinted with permission from John Wiley and Sons. Macdonald FR, Peel JE, Jones HB, et al. The novel SGLT2 inhibitor dapagliflozin sustains pancreatic function and preserves islet morphology in obese, diabetic rats. Diabetes Obes Metab. 2010;12(11): 1004–1012.⁶⁰
Abbreviation: Dapa, dapagliflozin.

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