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Renal, metabolic and cardiovascular considerations of SGLT2 inhibition

Nature Reviews Nephrology volume 13, pages 11–26 (2017)Cite this article

Subjects

Key Points

  • The kidneys contribute to the maintenance of normal glucose homeostasis by using glucose as a metabolic fuel, by producing glucose via gluconeogenesis, and by reabsorbing all filtered glucose

  • Under physiological conditions SGLT2 reabsorbs the majority (80–90%) of filtered glucose, while SGLT1 reabsorbs the remaining 10–20% of glucose

  • Kidneys contribute to the development of hyperglycaemia in diabetes by producing excess amounts of glucose and by increasing glucose reabsorption in response to an elevated threshold for glucosuria and an increase in the maximum glucose reabsorptive capacity (TmG)

  • SGLT2 inhibitors improve glucose tolerance by reducing both the threshold for glucosuria and the TmG and by ameliorating glucotoxicity leading to enhanced β-cell function and improved insulin sensitivity in muscle

  • The efficacy of SGLT2 inhibitors is partially offset by an increase in endogenous glucose production and enhanced glucose reabsorption by SGLT1

  • Findings from the EMPA-REG OUTCOME study suggest that the SGLT2 inhibitors might be beneficial in reducing cardiovascular events and preventing the progression of renal disease in patients with type 2 diabetes mellitus at high cardiovascular risk

Abstract

The kidney has a pivotal role in maintaining glucose homeostasis by using glucose as a metabolic fuel, by producing glucose through gluconeogenesis, and by reabsorbing all filtered glucose through the sodium–glucose cotransporters SGLT1 and SGLT2 located in the proximal tubule. In patients with diabetes, the maximum glucose reabsorptive capacity (TmG) of the kidney, as well as the threshold for glucose spillage into the urine, are elevated, contributing to the pathogenesis of hyperglycaemia. By reducing the TmG and, more importantly, the threshold of glucosuria, SGLT2 inhibitors enhance glucose excretion, leading to a reduction in fasting and postprandial plasma glucose levels and improvements in both insulin secretion and insulin sensitivity. The beneficial effects of SGLT2 inhibition extend beyond glycaemic control, however, with new studies demonstrating that inhibition of renal glucose reabsorption reduces blood pressure, ameliorates glucotoxicity and induces haemodynamic effects that lead to improved cardiovascular and renal outcomes in patients with type 2 diabetes mellitus. In this Review we examine the role of SGLT2 and SGLT1 in the regulation of renal glucose reabsorption in health and disease and the effect of SGLT2 inhibition on renal function, glucose homeostasis, and cardiovascular disease.

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Figure 1: Role of the kidney in glucose homeostasis.
Figure 2: Glucose handling by the kidney.
Figure 3: Effect of dapagliflozin on maximum renal glucose reabsorption (TmG) and glucose threshold.
Figure 4: Effect of dapagliflozin on HbA1c and body weight.
Figure 5: Effect of dapagliflozin on tissue sensitivity to insulin and β-cell function.
Figure 6: Effect of diabetes and SGLT2 inhibition on afferent and efferent arteriolar tone, glomerular filtration rate (GFR), and sodium (Na+) excretion.
Figure 7: Effect of empagliflozin on cardiovascular events.
Figure 8: Potential mechanisms for the beneficial effect of empagliflozin on cardiovascular outcomes.
Figure 9: Beneficial effects of SGLT2 inhibition on glucose homeostasis and the cardiovascular and renal systems.

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Acknowledgements

R.A.D. is supported by NIH grants RO1DK24093-33 and R01DK103841-01A1. M.A.-G. is supported by NIH grant RO1-DK-097554-3. We are thankful to Ernest Wright and Chiara Ghezzi, University of California Los Angeles, who were helpful in reviewing and commenting on the manuscript before submission.

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  1. Diabetes Division, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, 78229, Texas, USA

    Ralph A. DeFronzo, Luke Norton & Muhammad Abdul-Ghani

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All authors contributed equally to researching data for the article, discussion of the content, and revising or editing the manuscript before submission.

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Correspondence to Ralph A. DeFronzo.

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R.A.D. has consulted for AstraZeneca, Janssen, and Boehringer Ingelheim, is a member of the Speaker's Bureau for AstraZeneca and Novo Nordisk, and has received grant support from AstraZeneca, Janssen, and Boehringer Ingelheim. His salary is supported in part by the South Texas Veterans Health Care System. The other authors declare no competing interests.

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Glossary

Maximum renal glucose reabsorptive capacity

(TmG). The TmG represents the maximum capacity of the renal tubule to reabsorb glucose that is filtered by the glomerulus, and is expressed in mg per minute.

Threshold for glucosuria

Represents the plasma glucose concentration at which glucose spillage into the urine is first observed.

Stepped hyperglycaemic clamp

A technique in which the plasma glucose concentration is raised by a fixed amount (for example, ∼2.2 mmol/l) over a fixed time (for example, 30 minutes) to sequentially raise the plasma glucose concentration to 28–33 mmol/l (500–600 mg/dl). This technique enables the TmG and threshold for glucosuria to be calculated.

First phase insulin secretion

The early response of insulin (within 0–10 minutes) to an acute intravenous injection of glucose.

Second phase insulin secretion

The late response of insulin (within 10–120 minutes) to a sustained rise in plasma glucose concentration brought about by a continuous intravenous infusion of glucose.

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DeFronzo, R., Norton, L. & Abdul-Ghani, M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol 13, 11–26 (2017). https://doi.org/10.1038/nrneph.2016.170

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