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

Michael A Nauck, Michael A Nauck

Abstract

The importance of the kidney's role in glucose homeostasis has gained wider understanding in recent years. Consequently, the development of a new pharmacological class of anti-diabetes agents targeting the kidney has provided new treatment options for the management of type 2 diabetes mellitus (T2DM). Sodium glucose co-transporter type 2 (SGLT2) inhibitors, such as dapagliflozin, canagliflozin, and empagliflozin, decrease renal glucose reabsorption, which results in enhanced urinary glucose excretion and subsequent reductions in plasma glucose and glycosylated hemoglobin concentrations. Modest reductions in body weight and blood pressure have also been observed following treatment with SGLT2 inhibitors. SGLT2 inhibitors appear to be generally well tolerated, and have been used safely when given as monotherapy or in combination with other oral anti-diabetes agents and insulin. The risk of hypoglycemia is low with SGLT2 inhibitors. Typical adverse events appear to be related to the presence of glucose in the urine, namely genital mycotic infection and lower urinary tract infection, and are more often observed in women than in men. Data from long-term safety studies with SGLT2 inhibitors and from head-to-head SGLT2 inhibitor comparator studies are needed to fully determine their benefit-risk profile, and to identify any differences between individual agents. However, given current safety and efficacy data, SGLT2 inhibitors may present an attractive option for T2DM patients who are failing with metformin monotherapy, especially if weight is part of the underlying treatment consideration.

Keywords: anti-diabetes agents; efficacy; hyperglycemia; safety; sodium glucose co-transporter type 2 inhibitors; type 2 diabetes mellitus.

Figures

Figure 1
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 2
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 3
Figure 3
Structure of phlorizin and candidate SGLT2 inhibitors. Abbreviation: SGLT, sodium glucose co-transporter.
Figure 4
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
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.

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Source: PubMed

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