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Sodium glucose cotransporter 2 (SGLT2) inhibitors--Their role in the kidneys.

LEARNING OBJECTIVES

1. Describe the mechanism of action of sodium-glucose cotransporter 2 inhibitors--canagliflozin, dapagliflozin and empagliflozin.

2. Discuss the possible renoprotective benefits of SGLT2 inhibitors in patients with type 2 diabetes mellitus.

BACKGROUND

Diabetes is one of the most common chronic diseases worldwide and is among the leading causes of kidney failure (World Health Organization [WHO], 2016). Diabetic nephropathy will affect up to half of diabetics in their lifetime (McFarlane, Gilbert, MacCallum, & Senior, 2013). It is estimated that 3.4 million Canadians are currently living with diabetes with the majority classified as type 2 (Diabetes Canada, 2017a, 2017b). Type 2 diabetes mellitus is characterized by resistance to the action of insulin, impaired insulin secretion, or both (Diabetes Canada, 2017b). Pharmacological management is continuing to evolve, with more than 30 different antihyperglycemic agents available for use in type 2 diabetes mellitus. Metformin is generally the first pharmacological agent of choice, and additional agents are added based on patient characteristics such as cardiovascular disease, risk of hypoglycemia, weight concerns, and other comorbidities (Arnason & Mansell, 2017). It becomes challenging to choose antihyperglycemic medications when patients also have renal insufficiency since many are renally excreted and, thus, the risk of adverse of events increases. The sodium-glucose cotransporter 2 (SGLT2) inhibitors--canagliflozin, dapgliflozin and empagliflozin--are new agents approved for treatment of type 2 diabetes mellitus in Canada, and are considered in addition to metformin (Arnason & Mansell, 2017). This article will discuss emerging evidence on the use of SGLT2 inhibitors in patients with renal impairment.

MECHANISM OF ACTION

The SGLT2 transporter is the main site for glucose reabsorption in the proximal renal tubules (DeFronzo, Davidson & Del Prato (2012). The expression and activity of SGLT2 are increased in individuals with diabetes, leading to additional glucose reabsorption and consistently elevated blood sugars (Wanner, 2017). Inhibition of SGLT2 decreases reabsorption of filtered glucose from the tubular lumen and lowers the threshold for glucose by approximately 30 to 50% (DeFronzo et al., 2012; Wanner, 2017). This results in increased urinary excretion of glucose, thereby lowering plasma glucose concentrations (DeFronzo et al., 2012). SGLT2 inhibitors improve glycemic control and decrease hemoglobin A1C by 0.7-1% (Canadian Diabetes Association, 2016). Given that SGLT2 inhibitors work in the kidneys, their efficacy is dependent on renal function and, therefore, the glucose-lowering effects may be reduced or absent in patients who have moderate or severe renal impairment, respectively (Wanner, 2017). The mechanism of action of SGLT2 inhibitors is independent of insulin, which negates any potential risks for hypoglycemia (Wanner, 2017). SGLT2 inhibitors also cause natriuresis (urinary excretion of sodium) and weight loss, and are associated with an antihypertensive effect through sodium cotransport (Wanner, 2017).

RENOPROTECTIVE EFFECTS

As seen in Table 1, SGLT2 inhibitor use is generally restricted in patients with stages 3 to 5 of chronic kidney disease (CKD). This is reflective of decreases in the blood glucose lowering effects in patients with increasing renal impairment (i.e., as estimated glomerular filtration rate [eGFR] declines) (Wanner, 2017). Contrary to current dosing guidelines, emerging evidence suggests potential renoprotective effects in patients with eGFR [greater than or equal to] 30 ml/min (Wanner et al., 2016; Neal et al., 2017).

Empagliflozin (Jaridance[R])

Empagliflozin was the first SGLT2 inhibitor to demonstrate reduction in both macrovascular (e.g., cardiovascular death, myocardial infarction, and stroke) and microvascular (e.g., retinopathy and nephropathy) outcomes in patients with type 2 diabetes mellitus at high risk for cardiovascular events (Fitchett et al., 2016). An analysis of renally-impaired patients (creatinine clearance [CrCl] < 60ml/min) from this major trial showed a lower risk of progression of diabetic kidney disease and lower rates of renal events such as macroalbumaria, doubling serum creatinine, and initiation of renal-replacement therapy (Wanner et al., 2016). The adverse events reported in patients with impaired renal function were comparable to that in the general study population (Wanner et al., 2016). A discussion around adverse events with SGLT2 inhibitors is outlined in the succeeding section.

Canagliflozin (Invokana[R])

Recently published studies now suggest a potential class effect with regards to the cardiovascular and renal outcomes with SGLT2 inhibitors. In a renal endpoints trial of patients at high cardiovascular risk, progression of albuminuria and the renal composite outcome (composed of sustained reduction in eGFR, the need for renal replacement therapy, or death from any cause) occurred less frequently in patients taking canagliflozin (Neal et al., 2017). The renal effects data with canagliflozin are comparable to what was seen with empagliflozin (Tucker, 2017). One notable difference is the increased risk of lower limb amputation in patients taking canagliflozin (Neal et al., 2017; Tucker, 2017).

Dapagliflozin (Forxiga[R])

The dapagliflozin renal function data are less robust than with the other SGLT2 inhibitors described previously, likely limited by a small sample size. In patients with type 2 diabetes mellitus, CKD stage 3, and increased albuminaria, dapagliflozin was associated with reductions in albuminuria and delay of worsening renal function (Fioretto, Stefansson, Johnsson, Cain, & Sjostrom, 2016). The analysis did not show an increase in serious renal adverse events with dapagliflozin (Fioretto et al, 2016).

It is important to note that renal events in the studies mentioned above were categorized as secondary and/or exploratory outcomes. The analyses were not sufficiently powered to detect statistically significant difference in the pre-specified renal outcomes.

POSSIBLE RENOPROTECTIVE MECHANISMS

The potential mechanisms for renal effects are likely to be multifactorial (Wanner, 2017). SGLT2 inhibitors are thought to exert pleiotropic effects--that is, they may produce renoprotective benefits through several possible mechanisms, with renal hemodynamic effects playing a key role. Because glucose and sodium are co-transported in the proximal tubules, inhibition of SGLT2 also decreases sodium reabsorption (Wanner, 2017). The macula densa cells sense the increase in sodium in the nephron, which reduces renal blood flow and glomerular hyperfiltration (Wanner, 2017). This manifests as reductions in albuminuria and stabilization of eGFR (Wanner, 2017). Other effects such as improved glycemic control; increase in glucagon levels; decrease in serum uric acid levels; activation of hypoxia-inducible factor 1 and subsequent erythropoiesis; reductions in vascular stiffness, vascular resistance, blood pressure and body weight; natriuresis; and the effect on systemic and renal neurohormonal systems may also contribute to improvements in progression of renal disease (Neal et al., 2017; Wanner, 2017; Wanner et al., 2016).

ADVERSE EVENTS

The most common adverse effects of SGLT2 inhibitors are increased risk of genitourinary tract infections, hyperkalemia, and reduced intravascular volume resulting in hypotension (Arnason & Mansell, 2017). The risk of these adverse reactions increases with worsening renal function (Wanner, 2017). In studies involving patients with renal impairment, adverse events were more commonly reported in SGLT2 inhibitors compared to standard treatment (Wanner et al., 2016; Neal et al., 2017). Therefore, careful monitoring for renal function and volume status should be undertaken to minimize potential risks (Arnason & Mansell, 2017). There have also been reports of acute kidney injury, euglycemic diabetic ketoacidosis, increased risk of lower extremity amputations, and bone fractures with SGLT2 inhibitors (DeSantis, 2017).

SUMMARY

SGLT2 inhibitors are a new class of antihyperglycemic agents indicated for the treatment of type 2 diabetes mellitus. They decrease blood glucose concentrations by increasing urinary excretion of glucose. Empagliflozin and canagliflozin have been shown to have beneficial effects on preservation of renal function in patients with diabetic kidney disease who are at risk for cardiovascular events. Future findings from ongoing renal outcome trials will confirm if the renoprotective benefits are a class effect. Possible mechanisms for improvement in renal function include direct renovascular and hemodynamic effects. Monitoring of renal function may improve glucose-lowering efficacy and reduce the risk of adverse events in patients with increasing renal impairment.

REFERENCES

Arnason, T., & Mansell, K. (2017). Diabetes mellitus. In RxTx. Retrieved from https://www.e-therapeutics.ca/

Canadian Diabetes Association. (2016). Antihyperglycemic agents for use in type 2 diabetes. Retrieved from http://guidelines.diabetes.ca/cdacpg_resources/Chl3_Tablel_Antihyperglycemic_agents_type_2_nov-2016.pdf

DeFronzo, R.A., Davidson, J.A., & Del Prato, S. (2012). The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes, Obesity and Metabolism, 14(1), 5-14.

DeSantis, A. (2017). Sodium-glucose co-transporter 2 inhibitors for the treatment of type 2 diabetes mellitus. Retrieved from https://www.uptodate.com/contents/sodium-glucose-co-transporter-2-inhibitors-for-the-treatment-of-type-2-diabetes-mellitus?source=search_result&search=sodium%20glucose%20co%20transporter%202%20inhibitors&selectedTitle=l~44

Diabetes Canada. (2017a). Diabetes statistics in Canada. Retrieved from http://www.diabetes.ca/how-you-can-help/advocate/why-federal-leadership-is-essential/diabetes-statistics-in-canada

Diabetes Canada. (2017b). Types of diabetes. Retrieved from http://www.diabetes.ca/about-diabetes/types-of-diabetes

Fioretto, R, Stefansson, B.V., Johnsson, E., Cain, VA., & Sjostrom, CD. (2016). Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment. Diabetologia, 59, 2036-2039.

Fitchett, D., Zinman, B., Wanner, C, Lachin, J.M., Hantel, S., Salsali, A.,... & Inzucchi, S.E., the EMPA-REG OUTCOME[R] trial investigators. (2016). Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: Results of the EMPA-REG OUTCOME[R] trial. European Heart Journal, 37(19), 1526-34.

Forxiga. (2014). In RxTx. Retrieved from https://www.e-therapeutics.ca/

Invokana. (2014). In RxTx. Retrieved from https://www.e-therapeutics.ca/

Jardiance. (2015). In RxTx. Retrieved from https://www.e-therapeutics.ca/

McFarlane, P., Gilbert, R.E., MacCallum, L., & Senior, P. (2013). Chronic kidney disease in diabetes. Canadian Journal of Diabetes, 37, S129-S136.

Neal, B., Perkovic, V., Mahaffey, K.W., de Zeeuw, D., Fulcher, G., Erondu, N.,... Matthews, D.R. for the CANVAS Program Collaborative Group. (2017). Canagliflozin and cardiovascular and renal events in type 2 diabetes. New England Journal of Medicine, published June 12, 2017. Retrieved from http://www.nejm.org/doi/pdf/10.1056/NEJMoal611925

Tucker, M E. (2017). CANVAS: Experts spar on canagliflozin risk/benefit in diabetes. Retrieved from http://www.medscape.com/viewarticle/881719

Wanner, C. (2017). EMPA-REG OUTCOME: The nephrologist's point of view. The American Journal of Medicine, 130(65), S63-S72.

Wanner, C, Inzucchi, S. E., Lachin, J. M., Fitchett, D., von Eynatten, M., Mattheus, M., ... & Zinman, B. for the EMPA-REG OUTCOME investigators. (2016). Empagliflozin and progression of kidney disease in type 2 diabetes. New England Journal of Medicine, 375(4), 323-334.

World Health Organization. (2016). Diabetes fact sheet. Retrieved from http://www.who.int/mediacentre/factsheets/fs312/en/

By Brittani Prete, BSP, and Marisa Battistella, PharmD, ACPR

ABOUT THE AUTHORS

Brittani Prete, BSP, Primary Care Pharmacy Resident, University Health Network, Toronto, ON;

Marisa Battistella, PharmD, ACPR, Clinician Scientist, Assistant Professor, Leslie Dan Faculty of Pharmacy, University of Toronto, Pharmacy Clinician Scientist, Clinical Pharmacist--Nephrology, University Health Network, Toronto, ON

Address for correspondence: Marisa Battistella, University Health Network, 200 Elizabeth Street, EB 214, Toronto, ON M5G 2C4

Email: marisa.battistella@uhn.ca
Table 1: Dosing of SGLT2 Inhibitors

                                 Canagliflozin (Invokana[R])

Usual dose                       100-300 mg once daily
eGFR [greater than or equal to]  No dose adjustment
60 ml/min (stage 2 CKD)          necessary
eGFR 45 - 60 ml/min (stage       Should not be initiated.
3A CKD)                          Adjust to or maintain at 100
                                 mg once daily if taking and
                                 eGFR declines.
eGFR 30 - 44 ml/min (stage       Discontinue - use is
3B CKD)                          contraindicated
eGFR 15 - 30 ml/min (stage       Use is contraindicated
4 CKD)
eGFR <15 (end-stage renal        Use is contraindicated
disease, dialysis)

                                    Dapagliflozin (Forxiga[R])

Usual dose                          5 -10 mg once daily
eGFR [greater than or equal to]     No dose adjustment
60 ml/min (stage 2 CKD)             necessary
eGFR 45 - 60 ml/min (stage          Discontinue - use is
3A CKD)                             contraindicated
eGFR 30 - 44 ml/min (stage          Use is contraindicated
3B CKD)
eGFR 15 - 30 ml/min (stage          Use is contraindicated
4 CKD)
eGFR <15 (end-stage renal           Use is contraindicated
disease, dialysis)

                                    Emp agliflozin (Jardiance[R])

Usual dose                          10- 25 mg once daily
eGFR [greater than or equal to]     No  dose adjustment
60 ml/min (stage 2 CKD)             necessary
eGFR 45 - 60 ml/min (stage          Sho uld not be initiated. Close
3A CKD)                             mon itoring of renal function is
                                    rec ommended.

eGFR 30 - 44 ml/min (stage          Dis continue - use is
3B CKD)                             con traindicated
eGFR 15 - 30 ml/min (stage          Use  is contraindicated
4 CKD)
eGFR <15 (end-stage renal           Use is contraindicated
disease, dialysis)

Adapted from the product monographs of Invokana[R], Forxiga[R],
Jardiance[R]
COPYRIGHT 2017 Canadian Association of Nephrology Nurses & Technologists
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2017 Gale, Cengage Learning. All rights reserved.

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Title Annotation:CONTINUING EDUCATION SERIES
Author:Prete, Brittani; Battistella, Marisa
Publication:CANNT Journal
Date:Jul 1, 2017
Words:2007
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