#204 NephMadness 2020: SGLT2 Inhibitors

April 6, 2020 | By Matthew Watto, MD

SGLT2i Mechanisms, New Indications and Use in practice

Get under the hood of SGLT2 inhibitors! Listen as our guests Dr. Harish Seethapathy, Dr. Matt Sparks, and Dr. Joel Topf give us a tour through the NephMadness 2020 SGLT2i region! How do these promising drugs work, and what evidence is there for using them in non-diabetic kidney disease or kidney transplant patients

#NephMadness 2020: SGLT2i Region – AJKD Blog

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Credits

Written and Produced by: Hannah R. Abrams

Cover Art and Infographic by: Hannah R. Abrams

Hosts: Hannah R Abrams, Matthew Watto MD, FACP   

Editor: Clair Morgan of Nodderly.com (audio), Emi Okamoto MD (written)

Guests: Harish Seethapathy MD; Matthew Sparks MD; Joel Topf MD

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Time Stamps

• 00:00 Sponsor
• 00:26 Intro, disclaimer, guest bio
• 02:57 Guest one-liner and Picks of the Week*: Michael Pollan audiobook on Coffee and Caffeine Addiction
• 03:52 SGLT2i definition, background, and why we now consider CV endpoints in diabetes
• 11:16 Sponsor
• 12:00 Tubuloglomerular feedback; Balloon analogy
• 17:40 Other mechanisms for SGLT2i
• 23:05 Back to the case; Risks from SGLT2i; Counseling and Monitoring
• 34:18 SGLT2i for non-diabetic kidney disease; Possible mechanisms: Joel’s caution against early adoption
• 41:42 SGLT2 inhibitors in kidney transplant
• 45:20 Take home points and picks for the SGLT2 inhibitor region
• 49:50 Outro

SGLT2i Pearls

1. SGLT2 inhibitors have significant long-term protection of GFR. However, because they cause afferent arteriolar vasoconstriction, expect to see an acute drop in GFR after initiating.
2. SGLT2 inhibitors work with ACE inhibitors/ARBs and can still provide improvement in renal outcomes for patients with diabetic kidney disease on maximum dose ACEi/ARB.
3. Patients already on thiazide diuretics can experience significant volume loss with SGLT2i initiation. Consider reducing or stopping thiazide dose around the time of initiation!

SGLT2 Inhibitor Show Notes 

SGLT2i Mechanisms of Action

Traditionally, tubuloglomerular feedback has been considered a major mechanism of sodium-glucose cotransporter 2 inhibitor (SGLT2i) effect in diabetic kidney disease. The effectiveness of SGLT2is in other indications and beyond what is seen in other afferent arteriolar vasoconstrictors point to the potential importance of other mechanisms, such as decreasing inflammation and altering oxygen metabolism.

Tubuloglomerular Feedback

How It Works

The first step of diabetic kidney disease is that hyperglycemia causes hyperfiltration and subsequent increased reabsorption of glucose. Sodium is reabsorbed at an increased rate along with that glucose, meaning that the macula densa ‘sees’ less sodium and acts as though there is not enough blood flow to the glomerulus. The afferent arteriole vasodilates, increasing intraglomerular pressure, and over time this contributes to fibrosis and nephron loss. (Seethapathy 2020)

SGLT2 inhibition stops that increased reabsorption of glucose and sodium and therefore prevents the afferent arteriole from vasodilating. This reduces intraglomerular pressure and protects the nephron. (Seethapathy 2020)

This works with the effect of ACEi/ARB which inhibit vasoconstriction of  the efferent arteriole; SGLT2i (which decreases afferent flow) can still provide improvement in renal outcomes for diabetic kidney disease in patients on maximum doses of ACE inhibitor (which increases efferent flow). (Perkovic 2019)

Decrease in eGFR After Initiation

Because SGLT2i cause afferent arteriolar vasoconstriction, they cause an acute drop in eGFR after initiation. Over time, however, eGFR stabilizes and kidney function is actually preserved relative to placebo. (Perkovic 2019)

SGLT2i may also cause significant volume depletion upon initiation in patients already on a thiazide diuretic. Previous expert Dr. Jeff Colburn recommends considering reducing the dose or stopping thiazide diuretics while initiating SGLT2i (Curbsiders #168). Dr. Topf typically holds thiazide and thiazide-like diuretics when starting SGLT2i, and on return visits he restarts at 50% dose (expert opinion).  

Every Other Possible Mechanism

How They Work

Several proposed mechanisms may explain some of the effects of SGLT2is. SGLT2is have been shown in vitro to reduce inflammatory markers (Panchapakesan 2013) , and in animal models it has been shown to upregulate VEGF expression (Zhang 2018). These two effects may decrease nephron fibrosis and cardiac inflammation.

SGLT2 inhibitors also change the oxygen consumption of the nephron by suppressing Na-K-ATPase activity in the proximal tubule (O’Neill 2015). This may decrease interstitial fibrosis (Seethapathy 2020).

Cardiac protection from SGLT2 inhibitors also points to a mechanism other than tubuloglomerular feedback: the heart doesn’t have SGLT2 cotransporters.  SGLT2 inhibitors may block sodium-hydrogen ion exchange in the heart via NHE1 and NHE3 to decrease oxidative damage and thrombosis as well as promote natriuresis (Seethapathy 2020).

Adverse Effect: Amputation Risk, Infections, euglycemic DKA

Increased risk of amputation with SGLT2i was noted in the CANVAS trial, but this finding was not reproduced in the CREDENCE trial. Of note, though, investigators in CREDENCE were asked to examine patients’ feet at each trial visit and discontinue the medication in patients with any active condition that could lead to amputation (Gaur 2019).

Genitourinary tract infections are also a known adverse effect of SGLT2i due to their glucosuric effect (Wiviott, 2019). Genital fungal infections are common, and these are usually responsive to antifungal treatment and do not require stopping the medication unless the patient requests it. Dr. Sparks recommends counseling these patients generally that they should completely empty their bladder when urinating to avoid infection. Fournier’s gangrene is also rare though a potential risk of these medications (Bersoff-Matcha 2019). Euglycemic diabetic ketoacidosis is another rare though possible side effect as patients may have DKA with normal blood glucose levels given the induced glycosuria. 

New Indications for SGLT2 inhibitors

The CANVAS and CREDENCE trial both showed that patients with diabetes treated with canagliflozin experienced less cardiovascular events, and those in the CREDENCE trial had less kidney failure. (Neal 2017; Perkovic 2019). The impressive outcomes of SGLT2i have led to studies of them in non-diabetic kidney disease, heart failure, and kidney transplant.

SGLT2 inhibitors in Non-Diabetic Kidney Disease

Current Evidence

Beyond the mechanisms described above, SGLT2i may also limit podocyte dysfunction and act on upregulated SGLT2 expression in proteinuria (Cassis 2018). 

Given this indication that SGLT2i may have impact beyond diabetic kidney disease, two more key trials, EMPA-KIDNEY and DAPA-CKD, are currently underway to explore the potential beneficial effect of these medications in non-diabetic kidney disease (Seethapathy 2020). 

SGLT2 inhibitors in Heart Failure

Current Evidence

In the DAPA-HF trial of heart failure patients with reduced ejection fraction, even though 60% of patients did not have diabetes, SGLT2i were associated with significant decrease in risk of worsening heart failure or cardiovascular death (McMurray 2019).  Trials are ongoing regarding SGLT2i effects in heart failure with preserved ejection fraction (EMPEROR-Preserved and PRESERVED-HF).

SGLT2 inhibitors in Kidney Transplant

Current Evidence

Limited evidence currently exists for the effect of SGLT2i on outcomes in kidney transplant patients; however, they appear to be safe and a significant number of nephrologists would consider using them in this context. Key concerns include risk for infection in these immunocompromised patients, acute decrease in eGFR, and risk of dehydration. (Seethapathy 2020)

Goal

Listeners will recognize the different potential mechanisms for SGLT2i mechanisms and the different populations which may derive benefit from treatment. 

Learning objectives

After listening to this episode listeners will…  

1. Identify the theorized mechanism by which SGLT2i improve outcomes through their effect on tubuloglomerular feedback and other theorized mechanisms for SGLT2i effects
2. Develop a pathophysiological understanding of SGLT2i adverse effects, including acute decrease in GFR and genital infections
3. Recognize the potential benefit of using SGLT2i in non-diabetic patients, including for kidney disease, heart failure, and kidney transplant

References

1. Seethapahty H. #NephMadness 2020: SGLT2i Region. AJKD Blog 2020. [https://ajkdblog.org/2020/03/13/nephmadness-2020-sglt2i-region/]
2. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019. [https://pubmed.ncbi.nlm.nih.gov/30990260/]
3. Colburn J, Brigham SK, Williams PN, Watto MF. “#168 Diabetes Update with Jeff Colburn MD”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list. August 26, 2019.
4. Panchapakesan U, Pegg K, Gross S, et al. Effects of SGLT2 inhibition in human kidney proximal tubular cells–renoprotection in diabetic nephropathy?. PLoS One. 2013 [https://pubmed.ncbi.nlm.nih.gov/23390498/]
5. Zhang Y, Nakano D, Guan Y, et al. A sodium-glucose cotransporter 2 inhibitor attenuates renal capillary injury and fibrosis by a vascular endothelial growth factor-dependent pathway after renal injury in mice. Kidney Int. 2018 [https://pubmed.ncbi.nlm.nih.gov/30045814/]
6. O’Neill J, Fasching A, Pihl L, Patinha D, Franzén S, Palm F. Acute SGLT inhibition normalizes O2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats. Am J Physiol Renal Physiol. 2015 [https://pubmed.ncbi.nlm.nih.gov/26041448/]
7. Gaur L. The SGLT2i Crescendo with CREDENCE. #NephJC Chat Evidence Summary. [http://www.nephjc.com/news/credence]
8. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019 [https://pubmed.ncbi.nlm.nih.gov/30415602/]
9. Bersoff-Matcha, et al. Fournier gangrene associate with SGLT2i: a review of spontaneous postmarketing cases. Ann Internal Med. 2019 [https://www.ncbi.nlm.nih.gov/pubmed/31060053] 
10. Burgner A. #NephMadness 2017: Diabetic Nephropathy Region. AJKD Blog 2017. [https://ajkdblog.org/2017/03/07/nephmadness-2017-diabetes-region/#SGLT2]
11. Neal B et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. NEJM 2019. [https://www.ncbi.nlm.nih.gov/pubmed/28605608]
12. Cassis P, Locatelli M, Cerullo D, et al. SGLT2 inhibitor dapagliflozin limits podocyte damage in proteinuric nondiabetic nephropathy. JCI Insight. 2018 [https://pubmed.ncbi.nlm.nih.gov/30089717/]
13. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019 [https://pubmed.ncbi.nlm.nih.gov/31535829/]

Disclosures

The Curbsiders report no relevant financial disclosures. Drs. Seethapathy and Sparks report no relevant financial disclosures. Joel Topf lists the following on his blog “I have an ownership stake in a few Davita run dialysis clinics and a vascular access center. Takeda Oncology made a donation to MM4MM the program that is taking me to Mount Everest in 2018.”

Citation

Seethapathy H, Abrams HR, Okamoto E, Sparks M, Topf J, Watto MF. “#204 NephMadness 2020: SGLT2 Inhibitors”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list April 6, 2020.