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SGLT2 inhibition — a novel strategy for diabetes treatment

Key Points

  • Side effects of current type 2 diabetes mellitus (T2DM) medications, which include hypoglycaemia, weight gain, and nausea and vomiting, can hamper glycaemic control and efforts to limit the complications of diabetes. Novel therapeutic strategies are therefore needed.

  • The kidney plays a crucial role in glucose homeostasis, mediating glucose reabsorption and, to a lesser degree, gluconeogenesis. Reabsorption of glucose in the kidney is mediated by the sodium–glucose co-transporters (SGLTs), particularly by SGLT2.

  • Although glycosuria has been historically viewed as a sign of metabolic decompensation and as an adverse clinical consequence of diabetes, inhibiting SGLT2 to increase urinary glucose excretion is emerging as a promising new strategy to treat T2DM. Importantly, it does not affect insulin action or secretion, which are common targets of existing T2DM medications.

  • Phlorizin, a compound isolated from the root bark of apple trees, was used in multiple investigations that helped to establish that hyperglycaemia contributes to the insulin resistance that characterizes T2DM. It was later identified to be a nonselective SGLT inhibitor, acting on both SGLT1 and SGLT2. However, this and other early SGLT inhibitors, such as T-1095, sergliflozin and remogliflozin, were probably not further developed because of difficulties with stability, nonselective inhibition and low bioavailability.

  • More recently, in several randomized, double-blind, placebo-controlled Phase III clinical trials, the SGLT2-selective inhibitor dapagliflozin has demonstrated statistically significant reductions in glycated haemoglobin A1c (HbA1c), as well as dose-dependent decreases in weight. Multiple agents, including canagliflozin, are also undergoing clinical trials and further data are anticipated to be reported in the near future.

  • Safety concerns associated with SGLT2 inhibition include the potential development of hypoglycaemia, urinary tract infections, renal dysfunction and genitourinary fungal infections. Together with observations of normal renal function in patients with genetic mutations in the SGLT2 gene — familial renal glycosuria — who have significant glycosuria, data from studies conducted so far have, to a degree, been reassuring.

  • Although data from further investigations are forthcoming, studies so far show that SGLT2 inhibitors may have a role in not only enhancing glycaemic control, but also potentially improving obesity and leading to blood pressure reduction through diuretic effects.

Abstract

Inhibiting sodium–glucose co-transporters (SGLTs), which have a key role in the reabsorption of glucose in the kidney, has been proposed as a novel therapeutic strategy for diabetes. Genetic mutations in the kidney-specific SGLT2 isoform that result in benign renal glycosuria, as well as preclinical and clinical studies with SGLT2 inhibitors in type 2 diabetes, support the potential of this approach. These investigations indicate that elevating renal glucose excretion by suppressing SGLT2 can reduce plasma glucose levels, as well as decrease weight. Although data from ongoing Phase III trials of these agents are needed to more fully assess safety, results suggest that the beneficial effects of SGLT2 inhibition might be achieved without exerting significant side effects — an advantage over many current diabetes medications. This article discusses the role of SGLT2 in glucose homeostasis and the evidence available so far on the therapeutic potential of blocking these transporters in the treatment of diabetes.

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Figure 1: SGLT2 mediates glucose reabsorption in the kidney.
Figure 2: Normal glucose homeostasis.
Figure 3: Renal handling of glucose in a non-diabetic individual.
Figure 4: Renal glucose handling before and following inhibition of SGLT2.
Figure 5: Available structures of SGLT inhibitors.

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Acknowledgements

This project was supported by the Veterans Administration Medical Center, San Diego and the University of California, San Diego, USA.

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Correspondence to Edward C. Chao.

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Competing interests

Robert R. Henry has consulting agreements and serves on the advisory boards of several pharmaceutical companies that are developing SGLT2 inhibitors for therapeutic uses. These include Bristol-Myers Squibb, Astra Zeneca, Johnson and Johnson, Roche Pharmaceuticals, Boehringer Ingelheim, GlaxoSmithKline Pharmaceuticals, and Isis Pharmaceuticals.

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DATABASES

OMIM

Familial renal glycosuria

FURTHER INFORMATION

ClinicalTrials.gov

Division of Endocrinology and Metabolism, UCSD Department of Medicine

The Center for Metabolic Research, VA San Diego Healthcare System

Glossary

Sodium-glucose co-transporters

(SGLTs). A family of membrane proteins that transport glucose, as well as some ions, vitamins and amino acids across the brush-border membrane of the proximal convoluted tubules in the kidney and epithelial cells in the intestine.

Familial renal glycosuria

A genetic disorder of the renal tubules characterized by persistent isolated glycosuria without hyperglycaemia. The disorder results from mutations in SLC5A2, the gene encoding sodium–glucose co-transporter 2.

Glucose excursion

This is usually defined as the change in glucose concentration from before to after a meal. In research settings this is pre- and post-oral-glucose-tolerance tests.

Antisense oligonucleotide inhibitor

When the sequence of a particular gene is known to cause a particular disease, a strand of nucleic acid can be synthesized (DNA, RNA or a chemical analogue) that will bind to the mRNA produced by that gene and inactivate that gene. Antisense is complementary to the 'sense' sequence of the target gene's mRNA.

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Chao, E., Henry, R. SGLT2 inhibition — a novel strategy for diabetes treatment. Nat Rev Drug Discov 9, 551–559 (2010). https://doi.org/10.1038/nrd3180

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