Hey, #MedTwitter! We've been thinking a lot about SGLT2i (more coming up on your Friday email) in heart failure, and wanted to give space for overview of the evidence and potential mechanisms.
So without further ado, here's a #tweetorial on #SGLT2i and #HeartFailure!
So without further ado, here's a #tweetorial on #SGLT2i and #HeartFailure!
1/ SGLT2 inhibitors show clear benefits in heart failure, in patients with and without Diabetes. So what are the underlying mechanisms, we wondered?
2/ A Background:
SGLT1 and SGLT2 are co-transporters that move glucose and Na+ into the tubular lumen. SGLT2 is responsible for 90% of glucose reabsorption, while SGLT1 is responsible for 10%, and also found on intestinal epithelial cells.
SGLT1 and SGLT2 are co-transporters that move glucose and Na+ into the tubular lumen. SGLT2 is responsible for 90% of glucose reabsorption, while SGLT1 is responsible for 10%, and also found on intestinal epithelial cells.
3/ The Beginning
Phlorizin, found in the root bark of an🍎, was first isolated in 1835. But we have to fast forward to 2013, when the FDA approved Canagliflozin in 2013 for DM2 treatment, followed by Dapagliflozin and Empagliflozin in 2014.
Phlorizin, found in the root bark of an🍎, was first isolated in 1835. But we have to fast forward to 2013, when the FDA approved Canagliflozin in 2013 for DM2 treatment, followed by Dapagliflozin and Empagliflozin in 2014.
T4/ The Heart
EMPA-REG-OUTCOME (2015): first large trial to investigate a CV benefit. 7,020 patients with T2DM and CV risk ➡️placebo vs. 10 or 20 mg empagliflozin daily, followed for 3 years.
Outcomes: 1° (CV death, nonfatal MI, nonfatal stroke),
2° (1° + UA hospitalization)
EMPA-REG-OUTCOME (2015): first large trial to investigate a CV benefit. 7,020 patients with T2DM and CV risk ➡️placebo vs. 10 or 20 mg empagliflozin daily, followed for 3 years.
Outcomes: 1° (CV death, nonfatal MI, nonfatal stroke),
2° (1° + UA hospitalization)
T5/ Outcomes of EMPA-REG-OUTCOME
Empagliflozin group showed:
↓ Lower rates of death from CV causes (3.7% vs. 5.9%, 38% RRR) ↓
↓ Lower HF hospitalizations (2.7% vs. 4.1%, 35% RRR)
↓ Lower death from any cause (5.7% and 8.3%, 32% RRR)
Empagliflozin group showed:
↓ Lower rates of death from CV causes (3.7% vs. 5.9%, 38% RRR) ↓
↓ Lower HF hospitalizations (2.7% vs. 4.1%, 35% RRR)
↓ Lower death from any cause (5.7% and 8.3%, 32% RRR)
T6/ The Story Continues
EMPA-REG-OUTCOME was impressive. DAPA-HF (2019) was the first large trial to evaluate an SGLT2i (dapagliflozin) in high-risk CV patients (n=4,700) +/- T2DM, finding a relative risk ⬇️of 26% for a 1° outcome = worsening HF or CV death at 18 months.
EMPA-REG-OUTCOME was impressive. DAPA-HF (2019) was the first large trial to evaluate an SGLT2i (dapagliflozin) in high-risk CV patients (n=4,700) +/- T2DM, finding a relative risk ⬇️of 26% for a 1° outcome = worsening HF or CV death at 18 months.
T/7 The Recent Updates
This year’s EMPEROR-Reduced found similar benefits for empagliflozin in CHF patients (EF<40%) with and without T2D, suggesting CV benefits are a class effect across SGLT2 inhibitors.
This year’s EMPEROR-Reduced found similar benefits for empagliflozin in CHF patients (EF<40%) with and without T2D, suggesting CV benefits are a class effect across SGLT2 inhibitors.
T/8 Other Names to Know
Other big trial names you might hear: CANVAS (Canagloflozin), DECLARE-TIMI (Dapagloflozin), VERTIS-CV (Ertugloflozin) have all analyzed patients with T2DM and found SGLT2i-related CV benefits.
Other big trial names you might hear: CANVAS (Canagloflozin), DECLARE-TIMI (Dapagloflozin), VERTIS-CV (Ertugloflozin) have all analyzed patients with T2DM and found SGLT2i-related CV benefits.
T9/ The Next Frontier
Most of the previous work has been in HFrEF, and there are many recently concluded and ongoing trials, some of which take on HFpEF as well. They include EMPEROR-Preserved, EMPERIAL-Preserved, and DELIVER in this hard to treat patient population.
Most of the previous work has been in HFrEF, and there are many recently concluded and ongoing trials, some of which take on HFpEF as well. They include EMPEROR-Preserved, EMPERIAL-Preserved, and DELIVER in this hard to treat patient population.
T/10. Mechanisms.
So what are the underlying mechanisms behind this SGLT2i magic in heart failure? How does this pharmacology actually benefit patients?
A quick overview in the image below, before we dive in.
So what are the underlying mechanisms behind this SGLT2i magic in heart failure? How does this pharmacology actually benefit patients?
A quick overview in the image below, before we dive in.
T11/ The "Smart Diuretic"
SGLT2i are thought to block NaCl reuptake in prox tubule➡️sensing cells (macula densa) in distal tubule ⬇️blood flow to the glomerulus and ⬇️GFR. This ⛔️ the “hyperfiltrative" DM nephropathy, protecting the kidney and potentially also HF progression.
SGLT2i are thought to block NaCl reuptake in prox tubule➡️sensing cells (macula densa) in distal tubule ⬇️blood flow to the glomerulus and ⬇️GFR. This ⛔️ the “hyperfiltrative" DM nephropathy, protecting the kidney and potentially also HF progression.
T12/ Erythropoiesis
SGLT2i have also been shown to ⬆️ hematocrit through erythropoiesis via a variety of mechanisms. This may occur by ⬇️cytokine mediated damage to fibroblasts (below), ⬆️ expression of hypoxia-inducible factors that ⬆️ EPO and improve O2 delivery.
SGLT2i have also been shown to ⬆️ hematocrit through erythropoiesis via a variety of mechanisms. This may occur by ⬇️cytokine mediated damage to fibroblasts (below), ⬆️ expression of hypoxia-inducible factors that ⬆️ EPO and improve O2 delivery.
T13/ The "Thrifty" Substrate
There may be putative benefits in the heart, one that SGLT2 is a “thrifty substrate”. Normally, myocytes use FFA and glucose for energy, but both are toxic to damaged myocardiocytes.
There may be putative benefits in the heart, one that SGLT2 is a “thrifty substrate”. Normally, myocytes use FFA and glucose for energy, but both are toxic to damaged myocardiocytes.
T14/ The "Thrifty Substrate" ftw
SGLT2 inhibitors reduce FFA oxidation and lower glucose levels. This means that cardiomyocytes must use ketones, which are more energy-efficient and improve contractility. They also protect against remodeling and further injury + hypertrophy.
SGLT2 inhibitors reduce FFA oxidation and lower glucose levels. This means that cardiomyocytes must use ketones, which are more energy-efficient and improve contractility. They also protect against remodeling and further injury + hypertrophy.
T15/ NHE1 Hypothesis
SGLT2i may also strengthen damaged myocytes. This hypothesis suggests that SGLT2i ⛔️Na+/H+ exchange in myocytes that normally is ⬆️ in heart failure. ⬇️Na+, Ca++ intracellularly ⬆️ ATP production and in animal models, has been shown to ⬇️injury + remodeling
SGLT2i may also strengthen damaged myocytes. This hypothesis suggests that SGLT2i ⛔️Na+/H+ exchange in myocytes that normally is ⬆️ in heart failure. ⬇️Na+, Ca++ intracellularly ⬆️ ATP production and in animal models, has been shown to ⬇️injury + remodeling
T/15 We "Lept" In to another pathway (🥁)
One other mechanism is via leptin, a hormone related to adipose tissue. Through mechanisms shown below, this causes fluid retention and volume overload. SGLT2i by ⬇️ visceral fat tissue, ⬇️leptin levels helping ⛔️this increase.
One other mechanism is via leptin, a hormone related to adipose tissue. Through mechanisms shown below, this causes fluid retention and volume overload. SGLT2i by ⬇️ visceral fat tissue, ⬇️leptin levels helping ⛔️this increase.
T16/ Summary
So, what do we know for sure? There's a lot of cool ways SGLT2i may help as a "smart diuretic", "EPO" protector, "thrifty" substrate, myocyte enhancer, and the leptin inhibitor.
Many more are theorized, and we encourage you dive into references below!
So, what do we know for sure? There's a lot of cool ways SGLT2i may help as a "smart diuretic", "EPO" protector, "thrifty" substrate, myocyte enhancer, and the leptin inhibitor.
Many more are theorized, and we encourage you dive into references below!
Trial Summaries provided by The Scope Medicine app
References:
Lytvyn, Yuliya, et al. "Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials." Circulation 136.17 (2017): 1643-1658.
References:
Lytvyn, Yuliya, et al. "Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials." Circulation 136.17 (2017): 1643-1658.
Packer M. Do sodium-glucose co-transporter-2 inhibitors prevent heart failure with a preserved ejection fraction by counterbalancing the effects of leptin? A novel hypothesis. Diabetes Obes Metab. 2018;20(6):1361-1366. doi:10.1111/dom.13229
Verma, Subodh, and John JV McMurray. "SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review." Diabetologia 61.10 (2018): 2108-2117.
Packer, Milton, et al. "Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action." JAMA cardiology 2.9 (2017): 1025-1029.
Image References:
link.springer.com/article/10.100…
onlinejacc.org/content/73/15/…
ahajournals.org/doi/full/10.11…
frontiersin.org/articles/10.33…
ahajournals.org/doi/full/10.11…
link.springer.com/article/10.100…
onlinejacc.org/content/73/15/…
ahajournals.org/doi/full/10.11…
frontiersin.org/articles/10.33…
ahajournals.org/doi/full/10.11…
If you have any more insights or clarifyications, let us know, #MedTwitter! We know this is an expansive and rapidly changing topic!
• • •
Missing some Tweet in this thread? You can try to
force a refresh
