Two Truths and a Lie: Flozinator Edition

The 2022 NSMC Internship is broken down into four rotations. One rotation is Podcasting. There are two deliverables for that rotation:

1. Why Nephrology, a solo essay recorded as a podcast

2. Two Truths and a Lie, a group project that requires mixing multiple speakers, from multiple continents into a cohesive podcast.

Pod Four divided into two teams to complete the second deliverable, here is one of those teams.

Cast:

• Susan Thanabalasingam

• Dana Larsen

• Mythri Shankar

• Sandy Suresh

References

1. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. New England Journal of Medicine. 2017 Aug 17;377(7):644–57.

2. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. New England Journal of Medicine. 2019 Jun 13;380(24):2295–306.

3. Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in Patients with Chronic Kidney Disease. New England Journal of Medicine. 2020 Oct 8;383(15):1436–46.

4. Joshi SS, Singh T, Newby DE, Singh J. Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure. Heart. 2021 Jul 1;107(13):1032–8.

5. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. New England Journal of Medicine. 2015 Nov 26;373(22):2117–28.

Script

Contributors: Susan Thalabalasingam, Mythri Shankar, Dana Larsen, Sandhya Suresh

Host (Susan):

Hey everyone! Welcome to our episode of 2 truths and a lie, an NSMC podcast.

Let’s go over the ground rules.

One at a time each member of our elite education panel will state two truths and one lie about Nephrology.

This episode will focus specifically on SGLT2 inhibitors. 

The other panelist will then discuss which statement they think is The Lie.

Our presenter will then educate us all on which statement is incorrect and why.

So let’s warm up our lie detectors.

Let’s meet our four players for today.

I’m your host Susan Thanabalasingam and I’m a first year internal medicine resident at Queen’s University in Kingston, Ontario, Canada. I’m really excited to be your host today and to have an amazing discussion with these wonderful women today! 

Our second panelist is Dr. Mythri Shankar from India. Hi Dr. Mythri, can you please introduce yourself?

Mythri: Hello everyone. I am Dr. Mythri Shankar, Assistant Professor in Nephrology from  Institute of Nephro-urology, Bengaluru, India.I am also the Associate Program Director of the NSMC. Glad to be here and I have no conflicts of interest to declare.

Our third Panelist Dr. Dana Larsen from the United States of America! Hi Dr. Larsen, can you please introduce yourself? 

Dana: Hi all! I am Dana Larsen, a second year nephrology fellow at University of California, San Francisco and so grateful to get to be on this podcast with this great group today. I have no conflicts of interest in today’s topics. 

Our fourth Panelist is Dr. Sandhya Suresh from India. Hi Dr. Suresh, can you please introduce yourself?

Sandhya: Hi to all my fellow members of the 4th Pod, the Distal convoluted Pod and also… Hi to everyone listening to this podcast. I am Dr. Sandhya Suresh and I’m an early career nephrologist working in a medical college in Southern India. My only declaration here is that I am a flozinator who is continually amazed by everything that the SGLT inhibitors can do. 

Susan: Great, so let me start, I’ll give you 3 statements. My statements all focus on the use of SGLT2i in the non-diabetic CKD setting, which is a cohort that merits special attention when discussing the benefits of SGLT2i use (Susan)

1. SGLT-2 inhibitors are nephroprotective in diabetic and non-diabetic CKD (TRUE)

2. SGLT2 inhibitors decrease proteinuria in non-diabetic CKD (TRUE)

3. SGLT2 inhibitors are indicated for all etiologies of non-diabetic CKD (FALSE) 

Explanation for 1 → Statement 1 is TRUE. SGLT-2 inhibitors are in fact nephroprotective in BOTH diabetic and non-diabetic CKD. The CREDENCE trial was the first to specifically examine kidney outcomes in patients with diabetic, proteinuric CKD, and it demonstrated significant decrease in risk for kidney failure and cardiovascular events in patients treated with canagliflozin (Perkovic et al, 2019). As the effects were independent of glucose lowering effects, further studies have been conducted in the non-diabetic CKD setting. DAPA-CKD included patients with both diabetic and non-diabetic CKD and found that the use of dapagliflozin was associated with decreased risk of >= 50% decline in eGFR, ESKD or death from renal or cardiovascular causes (Heerspink et al, 2020). 

Explanation for 2 → Statement 2 is ALSO TRUE. We do in fact have compelling data that proteinuria is reduced with the use of SGLT2i in non-diabetic kidney disease. Pre-specified analyses from the DAPA-CKD trial demonstrated that dapagliflozin significantly reduced proteinuria in both diabetic and non-diabetic CKD, although the effect was larger in the diabetic subset. Because clinical outcomes were similar with dapagliflozin initiation between diabetic and non-diabetic patients, despite this difference in effect size on proteinuria, it has been postulated that the observed nephroprotection may not actually be related to reduction in proteinuria. 

Explanation for 3 → Statement 3 was the FALSE statement. In DAPA-CKD, included etiologies of non diabetic CKD were FSGS, minimal change disease, chronic pyelonephritis, chronic interstitial nephritis and hypertensive, IgA, membranous, and obstructive nephropathies. However, patients with lupus nephritis, polycystic kidney disease and vasculitis were excluded. The results of EMPA-Kidney are highly anticipated, in part as it includes a larger number of participants without diabetes, in particular those with glomerular disease, which will hopefully give us more answers about whether these patients will also benefit from SGLT2i initiation. EMPA-Kidney does however also exclude patients with PKD (The EMPA-KIDNEY Collaborative Group, 2022).

That was fun, I can’t wait to hear more from the rest of our panelists. Moving on to Dr. Mythri now, can you please give us your 2 truths and a lie?

Mythri:

1. SGLT2i are the initial therapy for T2DM (FALSE)

2. SGLT2i are beneficial in heart failure with reduced ejection fraction as it reduces both preload and afterload (TRUE)

3. SGLT2i are analogs of Phlorizin (TRUE)

Explanation for 1. SGLT2i are not the initial therapy. Initial therapy consists of lifestyle modifications, diet and exercise (American diabetes association guidelines 2021).

Explanation for 2.  SGLT2 inhibitors promote osmotic diuresis and natriuresis in patients with and without diabetes, and thus may reduce preload. SGLT2 inhibitors may also have vascular effects (including improving endothelial function) that promote vasodilation and thus may also reduce afterload. It has also been postulated that SGLT2 inhibitors may improve myocardial metabolism and thus improve cardiac efficiency. SGLT2 inhibitors promote osmotic diuresis and natriuresis in patients with and without diabetes, and thus may reduce preload (Joshi et al, 2021).

Explanation for 3:A natural compound, phlorizin, was isolated from apple trees in the early 1800s and for decades played an important role in diabetes and renal physiology research. The compound is poorly absorbed from the gastrointestinal tract and inhibits both SGLT1 (primarily found in the gastrointestinal tract) and SGLT2. Analogs of phlorizin have been developed that circumvent these two problems. These are the current SGLT2i (Atanasov et al, 2016).

Susan: That was great Dr. Mythri, thank you, I feel like I learned so much! Moving on to Dr. Dana, can you give us your 2 truths and a lie?

Dana:

Awesome, thank you Susan! Alright, please identify the lie from among these statements all concerning potential SGLT2 side effects:

1. SGLT2 inhibitors definitively increase the risk of vulvovaginal candidiasis and may increase the risk of urinary tract infections. (TRUE)

2. SGLT2 inhibitors do not definitively increase risk of bladder cancers. (TRUE)

3. SGLT2 inhibitors definitively increase risk for limb amputations. (FALSE)

Do you think you have the answer!?! Let’s take a closer look…

My first statement, SGLT2 inhibitors definitely increase the risk of urinary tract infections and vulvovaginal candidiasis is TRUE. Multiple studies on SGLT2 inhibitors including a 2018 canagliflozin RCT and a 2013 dapagliflozin RCT have shown 2-4 fold increase in vulvovaginal candidiasis in 10-15% of patients on SGLT2 inhibitors compared with placebo (Neal et al, 2017). A 2019 meta-analysis of over 100 RCTs with SGLT2s compared with other anti-diabetic agents or placebo did NOT show an increase in risk of UTIs for SGLT2s as a group, though there was a signal for increased risk of UTIs specifically for dapagliflozin, mechanistically it is unclear why this would be the case (Donnan et al, 2019). At this time, where there is definitive increased risk of vulvovaginal candidiasis, increased risk of UTI is likely not something you need to counsel your patients on.

Alright, moving on, our second statement, SGLT2 inhibitors do not definitely increase risk of bladder cancers is also TRUE. While few cases of bladder cancers have been diagnosed in patients taking dapagliflozin, half of these occurred within the first 6 months, which is thought to be too soon for tumorigenesis promotion by dapagliflozin itself. EMPA-REG trial did not find increased incidence of bladder cancer once event rates that occured within the first 6mo of drug therapy were removed (Kohler et al, 2017). Currently, the FDA recommends ongoing postmarketing surveillance 

And finally, moving on to our final statement which must be FALSE given the name of the game, the statement says SGLT2 inhibitors definitively increase risk for limb amputations. While the CANVAS program found that in the over 10,000 combined patients from their two major trials there was an increased risk of amputations 6.3 vs 3.4 per 1000 participants with hazard ratio 1.97, these amputations were primarily at the level of the toe or metatarsal, not the limb (Neal et al, 2017). Furthermore, there is ongoing discussion over true risk of amputation attributed to SGLT2 inhibitors as post hoc analysis of empa-reg and CREDENCE, the renal outcomes trial for canagliflozin, no association for increased risk of lower extremity amputation was found (Perkovic et al, 2019). While further investigation into the topic is warranted, we can rest assured that this is our FALSE statement on side effects of SGLT2-inhibitors.

Susan: Wow Dana, thanks so much for those very important lessons on SGLT2i side effects, I certainly have a lot of take home points from your discussion! 

Perfect, now we’ll move on to Dr. Sandhya. Please join me in welcoming her to give us our final set of 2 truths and a lie today.

Sandhya:

Thank you Susan. So here, I will be focussing my 2 truths and a lie on the cardioprotective effects of SGLT2 inhibitors. Without further ado, here are my 3 statements:

Statement 1: Increased ketone body production is postulated as one of the mechanisms for the cardioprotective effects of SGLT2 inhibitors (TRUE)

Statement 2: Glucose lowering effect and cardiovascular benefits both decline at lower GFRs (FALSE)

Statement 3: Sotagliflozin in a combined SGLT2 and SGLT1 inhibitor which has demonstrated cardioprotective benefits (TRUE)

Explanations for the above statements: 

Let me go through the explanation for each statement one by one.

Statement 1 is true. The cardioprotective effects of SGLT2 inhibitors may be multifactorial. While they target the traditional cardiovascular risk factors through their glycosuric and natriuretic effects, it is also postulated that SGLT2 inhibitors improve the cardiac metabolism and bioenergetics. 90-95% of cardiac energy is derived from mitochondrial oxidative metabolism for which the predominant fuel is free fatty acids. In a diabetic heart, the metabolic flexibility in terms of substrate utilization is impaired and the myocardium becomes more dependent on free fatty acids as fuel leading to build up of free fatty acid intermediates which lead to lipotoxicity and myocardial dysfunction. SGLT2 inhibitors produce a starvation simulation with reduced insulin and higher glucagon levels which promotes lipolysis and ketogenesis. They also reduce the excretion of ketone bodies by reducing the GFR. These ketone bodies like beta hydroxybutyrate serve as an alternate super fuel for myocardial cells producing ATP more efficiently and help to preserve the mitochondrial integrity and these factors lead to improved cardiac efficiency (Joshi et al, 2021).

Now coming to statement 2. The glucose lowering effect of SGLT2 inhibitors does decrease with declining GFRs because the magnitude of glucose excretion and consequently the HbA1c reduction is dependent on the filtered glucose load. This filtered glucose load is high in diabetic patients with normal GFR and reduced in patients with renal impairment thereby leading to reduction in the glucose lowering effect of SGLT2 inhibitors (Kelly et al, 2018). Conversely, the cardioprotective effects of this class of drugs seems to be remarkably preserved at lower GFRs as has been demonstrated in several trials. For example, in the EMPAREG OUTCOME trial, analysis of a subgroup of patients with prevalent kidney disease was done which included type 2 diabetic patients with established cardiovascular disease and an estimated GFR between 30-60 . There was significant reduction in the cardiovascular and all-cause mortality as well as hospitalization for heart failure in this subgroup and this effect was consistent across different categories of GFR (Wanner et al, 2017). So statement 2 is false.

So by that logic statement 3 has to be a truth. We often talk about the 4 traditional flozins so I just wanted to throw in a statement about this new subclass within this class of agents. Sotagliflozin is an SGLT2 inhibitor which also inhibits the intestinal SGLT1 transporters. It was originally targeted for use in patients with type 1 diabetes mellitus with the hope that SGLT1 inhibition in the intestine could reduce postprandial hyperglycemia and improve overall glycemic control in these patients. Studies have also shown excellent efficacy for this purpose. However they also showed a higher incidence of Diabetic ketoacidosis episodes. 2 cardiovascular trials were conducted, both of which unfortunately, ended early as they lost funding sometime during the COVID pandemic. The SCORED trial included CKD patients and the SOLOIST-WHF trial included patients who had recently recovered from an episode of decompensated heart failure. I won't go into the strengths and limitations of these trials but they did show benefit in terms of cardiovascular endpoints in the sotagliflozin group compared to placebo (Bhatt et al, 2021; Bhat et al, 2021). The drug isn’t commercially available as of now and is not FDA approved yet but it remains as a novel agent within the SGLT2i landscape.

Susan (Conclusion by host):

Amazing, thank you so much Dr. Sandhya! That was an enlightening discussion on cardioprotection with SGLT2i use. 

And this has been so much fun! I hope you’ve all found our conversation really helpful and informative - I certainly know that I have learned a lot from my colleagues today. I can’t thank them enough for sharing their time and expertise with us. Be sure to tune in next time for more FOAMed nephrology education.