TLDR:This is about endotoxin-induced heart inflammation and what Vinay Prasad knows.
Revascor didn’t keep patients out of hospital for decompensated HF but showed significantly reduced risk of hospitalisations for MACE and stroke in a prespecified subgroup.
Since Dream, there’s been widespread adoption of SGLT2 inhibitors which, as suggested by a very knowledgeable poster leftyahoo I tagged below, have changed the baseline playing field for CHF. I’ve looked into this and my take is that’s not the case at all. If anything, these drugs reinforce just how good our results are.
So many new drugs for RA and IBD have flooded onto the market in recent years but that doesn’t change the playing field for our IBD therapy. It’s an indication things IMO are out of control. As in the case of IBD (where the underlying cause is dysregulation of the microbiome), we need something to address the root cause of heart disease and HF.
Mostly, I based my argument on information from physicians and scientists I’ve identified as fair-minded who have made good points. My intention isn’t to bash drugs but to show cardiology is IMO the discipline under the most intense pressure (some of that frustration and cynicism coming from within). VP has been a major source of that pressure. He’s made a rod for his own back IMO and, given the current context, the administration needs to deliver more than for end stage HF.
As always, I welcome corrections.
Endotoxin-Induced Heart Disease
I’m a paid subscriber to Australian scientist Dr. Geoff Pain. He’s written a lot about endotoxins. I took the following mechanism from one of his articles. It sounds plausible (likely, actually) to me:
Mucosal permeability - bacterial translocation - endotoxemia - systemic inflammatory response
(Endotoxins can contribute to mucosal permeability)
My thinking is that a systemic response could manifest as MIS-C/A, secondary hemophagocytic lymphohistiocytosis (sHLH, which is also known as macrophage activation syndrome) or other inflammatory conditions.
(Relevant to us: Remestemcel-L was trialled for a systemic inflammatory response induced by Covid (MSB’s own report on ARDS compared the inflammatory response to HLH) and the same product was used for MIS-C, which often has cardiac involvement).
MSCs’ positive action on endotoxins has been known for many years. Professor Caplan’s (RIP) talk is on YT.
Vinay Prasad - Endotoxin Expert
I also took the above title from one of Geoff’s articles.
Geoff says endotoxins can lead to a cytokine storm which can cause heart damage. He gives a link to a paper published in 2014 co-authored by Vinay Prasad to demonstrate that VP is (Pain says) fully aware of endotoxin (LPS) Induced heart disease:
https://www.ahajournals.org/doi/10.1161/ATVBAHA.113.303153
The aim of the study was to identify macrophage inflammatory markers in the setting of subclinical carotid artery disease in women with HIV or hepatitis C virus infection. Endotoxin-induced macrophages can play a key role in atherosclerosis. The study confirmed results by examining arteries in deceased patients.
Authors say:
“Atherosclerosis is characterized by infiltration of monocytes into the wall of large and medium-sized arteries, where they form atherosclerotic plaque. These monocytes differentiate to macrophages and foam cells, some of which undergo apoptosis and secondary necrosis, forming a necrotic core that makes plaque vulnerable to rupture and clinical events like myocardial infarctions and stroke.”
Further:
“Atherosclerotic lesions contain macrophages with phenotypic characteristics of M1 and M2 polarization. In general, M1 macrophages are thought to be associated with inflamed, vulnerable plaques, and M2 macrophages are considered to be with a thick fibrous cap and less with risk of rupture.”
(One thing I learned early is that MSCs can change the phenotype from M1 to M2)
https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.122.320877
The study identified biomarkers but more recent studies have identified IL-6 as a key biomarker. AI overview confirms the gist I got from Dr. Perin’s report in that IL-6 is a closer biomarker to macrophages than CRP, primarily because macrophages are a major source of IL-6 production, while CRP is primarily produced by the liver in response to IL-6 signaling.
There are many published studies on circulating IL-6 as a predictor of carotid plaque severity, vulnerability, and progression and the important role it plays in atherosclerosis:
https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.122.320877
https://pubmed.ncbi.nlm.nih.gov/39589436/
This is a narrative review (2024) of studies on IL-6 as a biomarker to predict cardiovascular death, MACE and stroke:
https://pubmed.ncbi.nlm.nih.gov/39589436/
Authors say:
“Higher levels of IL-6 are associated with a higher risk of cardiovascular death, major adverse cardiovascular events, myocardial infarction, stroke, peripheral artery disease, and heart failure. Imaging studies have also shown an association between IL-6 and carotid intima-media thickness progression, carotid plaque progression, severity, and vulnerability. These observations have been consistent across a wide range of study populations”
Authors go on to suggest IL-6 blocking as a potential therapy when it’s well known that this cytokine can be good or bad depending on the context! (A friend of mine who works for a pharma once explained to me IL-6 wasn’t ‘bad’. It was a lot more detailed than what I’ve read in published literature. I don’t recall exactly what he said but will ask when I next see him.) Stat published an article on IL-6 blocker Actemra increasing the risk of heart attacks. My own theory is its known GI side effects may increase gut permeability, leading to bacterial translocation. IMO Malhotra appears to know this because in one of his lectures he refers to VIoxx causing GI effects.
Dream HF
Perin et al. say of inflammatory biomarkers:
“Thus, MPC treatment significantly lowered the risk of cardiovascular death in HFrEF patients with inflammation regardless of whether hsCRP or IL-6 was used as the biomarker of inflammation. Together, these results suggest that high plasma levels of hsCRP and IL-6 can be used interchangeably as markers to both disease activity and response to MPC treatment.”
What they say is supported in prespecified subgroups finding reduced risk of MACE and stroke. (VP should be interested in this IMO.)
MPCs reduced intestinal permeability in the LVAD trial, which would impede translocation of endotoxins. (They must surely have imaging of the cells’ ability to restore intestinal barrier function or SI wouldn’t have mentioned repair of vessels that were friable and leaky?). The MOA is obviously multifactorial (M1- M2) and the cells are also surely able to communicate with the host microbiome, which plays a key role in the central nervous system.
https://pmc.ncbi.nlm.nih.gov/articles/PMC5788145/
SGL2 Inhibitors
I recall in one interview SI was asked about the “weird effect” of patients still having to be hospitalized and he explained they needed to go in to be diuresed (I never heard that verb before) meaning having fluid removed.
These two posts by @LeftYahoo7936378079369951IMO give a very good explanation. Reading them gave me a much clearer picture of what was going on.
A fraction of participants on Dream were taking SGL2i but since then, they’ve been widely prescribed. My understanding is that these drugs remove excess glucose and the rationale is that improving kidney function will improve heart function?
(The diet Malhtora is promoting would IMO have the same effect.)
I don’t dispute that SGL2 inhibitors could reduce hospitalisation for HF but I just don’t see how they can have an effect on MACE, strokes or mortality benefit.
Further, any drug that inhibits or blocks can cause downstream effects (The AEs of Ruxolitinib are well acknowledged; it also affects metabolism, which is why so many patients report weight gain on it). We come along with a big JAK hammer and block off the street. The traffic just goes down the other side. How long does the beneficial effect last anyway?
Cesar Ernesto Lam-Chung
Endocrinologist Cesar Ernesto Lam-Chung has written a review of the various SGLT2 inhibitors’ efficacy through their diuretic mode of action in diabetic patients.
IMO this young man does a really good job. He used reports (and quotes) from the FDA and EMA. He says they’re on the websites for anyone to read (I inferred from this statement that they’re not widely read)
https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1174692/full
Dr. Lam-Chung says:
“We think that this review would be very helpful to every physician treating diabetic patients to better balance belief and reality of SGLT2i prescription effects.”
Belief vs reality. Please note below my extreme cognitive bias. I love this guy already!
The first section is about the side effects flagged by the FDA and, in the case of dapagliflozin, FDA reviewers proposed to use the lowest dose available. The side effects flagged are IMO consistent with online reviews I’ve read.
The gist I got from reading this review is that these drugs work through a diuretic effect:
“Whatever the hypothesis, SGLT2i have been clearly identified as a diuretic by both the FDA and EMA. Looking at EMPA-REG clinical and biological results, an additional mode of action does not seem to be needed. Acting on kidneys through osmotic diuresis, empagliflozin favors glucose extraction, reducing glycemia and HbA1c, but only on the short term, as this whole effect rapidly plateaued and then diminished, making SGLT2i a «modest» anti-diabetic agent, as defined by the EMA”
Empa Reg
The Empa REg trial (empagliflozin) exclusively enrolled patients with type 2 diabetes and atherosclerotic cardiovascular disease.
Dr. Lam-Chung says MACE excluded silent MI (which online literature tells me is relatively common in diabetic cardiovascular disease). He says this was found to be statistically superior to placebo with an upper limit of 0.99, 0.86 (0.74–0.99), p = 0.04. “However, the secondary primary endpoint for efficacy, CV death, non-fatal MI (excluding silent MI), non-fatal stroke, or unstable angina, was not significant and closed the hierarchical testing.”
He continues with quotes from the FDA Report:
“Regarding the hospitalization for heart failure endpoint, FDA reviewers commented that, «as previously noted, hospitalization for HF and other HF-related endpoints were not included in a plan to control the overall Type 1 error; hence, all of these analyses are exploratory», explaining that, «because of its diuretic effect, it is certainly plausible that empagliflozin could reduce the risk of HF hospitalization (in patients with a preserved or reduced EF); however, we believe this hypothesis should be confirmed in a well-designed and well conducted trial in patients with HF»
EMPEROR-Reduced
This trial focused on patients with heart failure and reduced ejection fraction (HFrEF).
The correspondence on the results published in the NEJM is IMO a lot more forceful than I usually come across and worth reading.
The following extract is from a letter by Mayooran Shanmuganathan, M.R.C.P. and Rohan M. Goswami, M.D. from the University of Oxford:
“EMPEROR-Reduced, empagliflozin therapy led to a 25% lower risk of the primary composite outcome (cardiovascular death or hospitalization for heart failure) than placebo among patients with heart failure with reduced ejection fraction. However, this difference was driven mainly by a lower risk of hospitalization for heart failure over a median follow-up of 16 months. Although multiple explanations are proposed for the beneficial effects of empagliflozin therapy,1 it is known that empagliflozin induces diuresis.2”
They give further details to support their argument that the benefit is potentially due to the diuretic effect and ask for specific raw data on the diuretics used.
Debdatta Bhattacharyya, M.D., C.C.S.T. and Ayan Kar, D.N.B.(Med.), D.N.B.(Card.) of Rabindranath Tagore International Institute of Cardiac Sciences Kolkata, India say the results should be interpreted with caution:
“The trial showed a significantly lower risk of the composite outcome of cardiovascular death and hospitalization for heart failure, which was powered by hospitalization for heart failure alone, with no significant between-group difference in cardiovascular mortality. This finding prompts us to speculate that the beneficial effects of the drug could be limited to its osmotic diuretic effect in a subgroup of patients with inadequate decongestion.”
DECLARE–TIMI
This was a trial in dapagliflozin in cardiovascular efficacy and safety in people with type 2 diabetes.
The report was published in the NEJM (Wiviott et al.)
A letter on the report from Piero Baglioni, M.D. Prince Charles Hospital Merthyr Tydfil, United Kingdom:
“Wiviott et al. (Jan. 24 issue)1 found that dapagliflozin did not result in a lower incidence of the composite of major adverse cardiovascular events (MACE) — defined as cardiovascular death, myocardial infarction, or ischemic stroke — than placebo (hazard ratio, 0.93; 95% confidence interval [CI], 0.84 to 1.03). There was no between-group difference in the incidence of cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17), and the incidence of death from any cause was not lower in the dapagliflozin group than in the placebo group”
Dr. Baglioni goes on to point out the disparity between Declare and Empa Reg but the authors reply that comparisons should not be made because only a minority of patients in the DECLARE–TIMI trial had atherosclerotic cardiovascular disease.
DAPA HF
This was a trial in dapagliflozin in HF with reduced EF.
From the correspondence on the report published in the NEJM:
Harry Peled, M.D. of St. Jude Medical Center Fullerton, CA and Nhu‐Quyen Dau, Pharm.D. of
Marshall B. Ketchum University Fullerton, CA say:
“The DAPA-HF trial on the benefit of dapagliflozin in patients with heart failure suggests to us that a benefit may have been obtainable by simply increasing the dose of diuretic. SGLT2 inhibition promotes natriuresis and osmotic diuresis.”
(Authors go on to suggest tests for biomarkers which could be consistent with an effect that is potentially related to diuresis only.)
Claudio Borghi, M.D. Arrigo F.G. Cicero, M.D. University of Bologna, Bologna, Italy:
“Current data indicate that high serum uric acid levels are associated with worse myocardial function2
and with a doubled risk of death from any cause among patients with heart failure.3 However, sodium–glucose cotransporter 2 (SGLT2) inhibitors are associated with considerable reductions in serum uric acid levels.”
(Authors go on to support their argument that cardiac effects are due to a reduction in serum uric acid levels by referencing a large meta analysis. They conclude by saying: “ In our opinion, this effect is relevant to the observed effect with dapagliflozin treatment.”)
Conclusion
If widespread use of SGLT2is has impacted us, it’s only to reinforce how remarkable our results from Dream are.
None of the current therapies on the market addresses the root cause of heart disease and HF. Evidence points increasingly to inflammation as the underlying cause. That inflammation is likely caused by endothelial dysfunction. That ED is likely a result of endotoxins which cause mucosal permeability, particularly in the gut, and then circulate throughout the body. Surely this leads to organ damage if the process goes unchecked?
At the time of writing, we have a reasonable chance of AA for end stage. LVADs (I don’t know the exact statistics) are often used as a bridge to transplant but the transplant industry has been recently impacted (whether through belief or reality). Further, what is there to help people with class II or III among whom the death rate is very high?
I’ve been following VP for almost a decade and mentioned him in several posts here since 2017. A consistent theme of his is how bad the status quo is. He has written and spoken extensively on heart therapies and is himself a source of intense pressure. In one of his YT videos, he directly addresses clinical practice in cardiology:
“Keep going with your p*ss poor homeopathic dose of Entresto”
VP isn’t impressed very much so it’s perhaps good he’s impressed by PK. Like I’ve said, Geoff Pain says VP knows and that Malhotra also knows. If Malhotra knows, then so does RFK because they’re close friends. VP obviously read the comments on his Substack articles because he occasionally replied. I assume he read the comments on his YT presentations too.
(20min delay)