I don’t know the trial - was it representative of all CVD?
There any many cases where one specific trial fails and the mechanism later is proven out in a powerful way and helps thousand of people
Is colchicine a complete representation of offset inflammation?
See comment above, I don’t know the literature here - did a lot of other trials for other parts of CVD also show no results?
I think what you quoted contains the answer: as mediated by colchicine. It’s a comment on colchicine, not some other molecule and the possibility of some other molecule impacting inflammation and then in turn inflammation impacting CVD outcomes. Just colchicine. And furthermore, not even impact on inflammation, but on a particular inflammation biomarker. Think of it as a series of venn diagrams from the biggest to the smallest: CVD end points–>inflammation–>inflammation biomarkers–>inflammation biomarker–>colchicine. If colchicine only affects a given inflammatory biomarker, you don’t therefore assume that it must affect all inflammatory biomarkers (just the subset), and in turn, just because inflammatory marker(s) are affected doesn’t mean actual inflammatory processes are affected, and even if inflammatory processes are affected, doesn’t mean CVD end points must be affected. So as can be seen there are multiple leaps (steps) between colchicine and CVD outcomes, and a breakdown can occur at any of those steps, i.e. any of those steps can be a wrong assumption.
Yes, you guys are correct in that there are different types of inflammation. So, I should’ve probably said it puts the ‘colchicine and inflammation’ issue to bed in regards to CVD.
Does anyone remember the difference in ApoB and LDL lowering if you take 5 mg Atorvastatin every day vs EOD? Thanks in advance.
Association of sodium-glucose cotransporter-2 inhibitor with regression of coronary plaque burden 2024
In the SGLT2i group, the non-calcified plaque burden [(39.86±14.30)% vs. (36.84±13.86)%, p=0.002)] and low attenuation non-calcified plaque burden (6.62 [4.11,10.13]% vs. 5.78 [3.40,9.28]%, p=0.042) were significantly decreased between two CCTA images. Whereas, in the non-SGLT2i group, there was no difference with regard to non-calcified and low attenuation non-calcified plaque burden between two CCTA images (all p>0.05). Moreover, changes of total plaque burden and non-calcified plaque burden were higher in the SGLT2i group than the non-SGLT2i group (all p<0.05). Importantly, SGLT2i was associated with total plaque volume (odd ratio=0.594, p=0.024) and non-calcified plaque volume regression (odd ratio=0.619, p=0.042) after adjusting for confounding factors.
SGLT2i significantly regresses coronary plaque burden, in particularly non-calcified plaque. These findings might explain the observed cardio-protective effect of SGLT2i in large trials.
Wow, Antoine, where the heck do you dig up these studies?! This one is a doozy. One thing always puzzled me, because I’ve read that SGLT2i can raise LDL levels, yet they were considered heart healthy. I just figured it must be some other non-lipid mechanism that was responsible for the heart protective effects of these drugs. Same way statins increase the calcification score (CAC), yet diminish MACE, because by calcifying the plaque they stabilize it and so it doesn’t rupture and cause blockages. But this study says the opposite, that SGLT2i can actually diminish plaque and they speculate that it is this that might be responsible for the heart protective effect. Very bizarre. How can you regress plaque while also raising LDL levels? I don’t get it. But hey I’m happy, as long as these results are real over the long term.
I check ALL SGLT2i papers 
Yes but… not really. See: SGLT2-inhibition increases total, LDL, and HDL cholesterol and lowers triglycerides: Meta-analyses of 60 randomized trials, overall and by dose, ethnicity, and drug type 2024
Overall, changes were modest and not likely to be of clinical relevance.
Overall, using random effects models, SGLT2-inhibitor treatment increased total cholesterol by 0.09 mmol/L (95% CI: 0.06, 0.13), low-density lipoprotein (LDL) cholesterol by 0.08 mmol/L (0.05, 0.10), and high-density lipoprotein (HDL) cholesterol by 0.06 mmol/L (0.05, 0.07), while it reduced triglycerides by 0.10 mmol/L (0.06, 0.14).
For LDL, +0.08 mmol/L (0.05, 0.10) means… +3 mg/dL! So basically nothing.
OK, but they don’t lower LDL levels, so they must reduce plaque by some other mechanism than lowering LDL levels. But plaque regression in studies is always accomplished by lowering LDL, high intensity statins lower LDL, ezetemibe combos, PCSK9i lower LDL - that’s how all of them regress plaque, by lowering LDL. SGLT2i don’t lower LDL - so how do they reduce plaque? I start to wonder how real this result is.
Vascular disease is multifaceted, but the low hanging fruit are:
Blood pressure, Insulin Sensitivity and Lipid optimization.
So minimally increasing LDL while lowering blood pressure and increasing insulin sensitivity, like occurs with the SGLT2-i on balance gives benefit. Also, I’d guess most individuals on one of these drugs is managing/optimizing their lipids anyway.
Here’s what Vera-Health.ai says on SGLT2-i and insulin sensitivity and BP.
SGLT2 inhibitors, primarily used for managing type 2 diabetes mellitus (T2DM), have been shown to both lower blood pressure and increase insulin sensitivity, offering benefits beyond glucose control.
Blood Pressure Lowering: SGLT2 inhibitors have a significant blood pressure-lowering effect, which is dose-independent and comparable to low-dose hydrochlorothiazide 2. This effect is primarily due to natriuresis and osmotic diuresis, which reduce blood volume and subsequently lower blood pressure 9. Additionally, these drugs improve vascular function by reducing oxidative stress and inflammation, further contributing to their blood pressure-lowering effects 4.
Insulin Sensitivity: SGLT2 inhibitors have shown potential in improving insulin sensitivity. For instance, empagliflozin has been demonstrated to improve hypothalamic insulin sensitivity in patients with prediabetes, suggesting a potential reversal of brain insulin resistance 1. The mechanism involves reducing glucose reabsorption in the kidneys, leading to glucosuria and a decrease in blood glucose levels 1. This reduction in glucose levels can improve insulin sensitivity by decreasing the need for insulin secretion and improving β-cell function. Furthermore, SGLT2 inhibitors promote weight loss and modulate adipocyte function, which also enhances insulin sensitivity 1.
In summary, SGLT2 inhibitors effectively lower blood pressure through mechanisms involving natriuresis and vascular improvements, while also showing potential to enhance insulin sensitivity by modulating glucose levels and adipocyte function. These effects make SGLT2 inhibitors a valuable therapeutic option for managing T2DM and its associated comorbidities.
OK, so if you already have low/optimal BP, and have good insulin sensitivity and glucose levels, SGLT2i are useless /jk/
It’s just one Chinese paper (but from a good uni and in a good journal) so it might be incorrect. However another paper suggests the same thing (at least in diabetic mice, a you say for those with “low/optimal BP, and have good insulin sensitivity”: no one knows): Glucose lowering by SGLT2-inhibitor empagliflozin accelerates atherosclerosis regression in hyperglycemic STZ-diabetic mice
Thanks. Yeah, one Chinese paper. I would be much happier if there are more papers confirming this result from different unis in more countries. Would be fantastic if true.
Another paper by the same Chinese team in a good journal: Longitudinal assessment of coronary plaque regression related to sodium-glucose cotransporter-2 inhibitor using coronary computed tomography angiography 2024
These papers might explain the mechanism:
Again, in diabetic mice and humans.
Follow up here, in June for Eric Topol - top cardiologist and one of the most cited physicians on the planet.
Don’t think that one trial result should lead to that conclusion in @DeStrider s post.
There are 6 other generally large trials showing results in the right direction…
(My inflammation is always super low (eg hs-CRP below or at the lowest bound) so I’m not going to read up more on this at this point, but wanted to share a more holistic and I believe actually view of potential here.)
Yesterday a new randomized trial of colchicine, a potent anti-inflammatory agent, to prevent events after stroke, was published in The Lancet. Over 3,100 patients with a non-severe, non-embolic stroke or TIA were randomly assigned to 0.5 mg colchicine per day plus usual care vs usual care only. The primary endpoint was the composite of heart attack, stroke, cardiac arrest, or hospitalization for unstable angina.
In the colchicine group, the event rate by intention-to-treat was 9.8% vs 11.7% in controls, a 16% reduction that was not statistically significant (upper bound 95% confidence interval 1.05). Colchicine led to a significant reduction of high sensitivity C-reactive protein (hs-CRP) at all time points assessed (Figure below). By a pre-specified on-treatment analysis, the primary endpoint was reduced from 11.7% to 8.0%, a 20% reduction, which was statically significant.
The new colchicine trial comes after 5 preceding ones that were subject to a meta- analysis. To summarize the 5 trials, the Table below shows 2 were large, each about 5,000 participants, one in chronic coronary artery disease and the other after heart attack, both with about 2-year follow-up.
There was a very consistent reduction of heart attack, stroke and coronary revascularization, as seen below.
Visual summary
See full discussion here
I was doing great till the very end where it shows no improvement in cardiovascular death. How can it improve MI and stroke by so much and not improve death? Because strokes don’t kill? My great uncle had one, lived a couple more years in a nursing home, then just died. Not a good 2 years. Is that what they’re talking about?
Either it doesn’t decrease MI and stroke by enough to cause a statistically significant reduction in acm or alternatively colcichine increases death by other causes as a side effect which resuls in a net zero benefit.
Probably both, that MI and stroke don’t usually kill just make you unproductive, and it lowers immunity or something by killing inflammation. Rats, it seemed like such a nice drug.
A great interview with Columbus Baptiste, a heart surgeon. He pretty much confirms a plant based diet is best along with keeping cholesterol low.
