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Drug Design, Development and Therapy Volume 8, 2014 - Issue
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Review

Update on developments with SGLT2 inhibitors in the management of type 2 diabetes

Michael A NauckDepartment of Internal Medicine, Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, GermanyCorrespondence[email protected]
Page 1380 | Published online: 11 Sep 2014

Figures & data

Table 1 Sodium-glucose co-transporter (SGLT) family

Figure 1 Renal tubular reabsorption of glucose.

Notes: Most of the glucose in the glomerular filtrate is reabsorbed by SGLT2 in the proximal convoluted tubule and the remainder is reabsorbed by SGLT1 in the distal straight segment of the tubule, so virtually no glucose is lost in the urine. The facilitative glucose transporters (GLUTs) then enable passive diffusion of glucose from the renal tubule into the bloodstream. Pharmacological inhibition of SGLT2 reduces glucose reabsorption, causing glucose to remain in the filtrate for subsequent urinary excretion.
Abbreviations: SGLT, sodium glucose co-transporter; T2DM, type 2 diabetes mellitus.
Figure 1 Renal tubular reabsorption of glucose.

Figure 2 Renal glucose transport.

Notes: Glucose and sodium (1:1) enter the renal tubule cells with assistance from glucose transport proteins. Active transport of glucose across the luminal membrane occurs via SGLT2 (and SGLT1) and is driven by coupling glucose transport with sodium co-transport. Glucose then diffuses passively across the basolateral membrane, facilitated by GLUT2 (and GLUT1).
Abbreviations: GLUT, facilitative glucose transporter; Na+, sodium; SGLT, sodium glucose co-transporter.
Figure 2 Renal glucose transport.

Figure 3 Structure of phlorizin and candidate SGLT2 inhibitors.

Abbreviation: SGLT, sodium glucose co-transporter.
Figure 3 Structure of phlorizin and candidate SGLT2 inhibitors.

Table 2 SGLT2 inhibitors in advanced clinical development

Figure 4 Efficacy and safety data from representative Phase III studies of dapagliflozin, canagliflozin, and empagliflozin.

Notes: (A) efficacy data; (B) safety data. Phase III studies were selected in which the SGLT2 inhibitor was given as monotherapy, or with background therapy of metformin, or sulfonylurea, or insulin. *Change versus placebo; X Not reported.
Abbreviations: SGLT, sodium glucose co-transporter; FPG, fasting plasma glucose; SBP, systolic blood pressure; DPP-4i, dipeptidyl peptidase-4 inhibitor; MET, metformin; SU, sulfonylurea; Dapa, dapagliflozin; Cana, canagliflozin; Empa, empagliflozin; HbA1c, glycosylated hemoglobin.
Figure 4 Efficacy and safety data from representative Phase III studies of dapagliflozin, canagliflozin, and empagliflozin.
Figure 4 Efficacy and safety data from representative Phase III studies of dapagliflozin, canagliflozin, and empagliflozin.

Table 3 Registered cardiovascular clinical trials of SGLT2 inhibitors

Table S1 SGLT2 inhibitor clinical trials (Phase 11+)

Table S2 SGLT2 and SGLTI inhibitors currently in the development pipeline

Table S3 Efficacy data from pivotal clinical trials of SGLT2 inhibitorsTable Footnotea

Table S4 Safety data from pivotal clinical trials of SGLT2 inhibitorsTable Footnotea

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