I don’t have access to the full paper, but following the link, I’m trying to understand the claims. The claim of carotid occlusion or stenosis is specific to empagliflozin and dapagliflozin, but not other SGLT2i?
That’s how I’m reading it, unless I’m misunderstanding something.
That’s rather odd. Empagliflozin and dapagliflozin, together with canagliflozin are some of the most studied SGLT2i. If these two cause carotid stenosis (at least in t2 diabetics), then it’s possible that all SGLT2i do, but we haven’t studied these other ones sufficiently to turn the non significant effect of 12% higher risk into a significant effect upon more data.
However, carotid stenosis is caused by atherosclerotic plaque at those locations. There are several risk factors for plaque deposition. The general effect of SGLT2i, including empa and dapa is some slight lowering of BP, or at least not raising BP, so that particular risk factor falls away. Lipid levels are effected very slightly if at all, so it’s unlikely that elevated lipids are the mechanism here. Inflammation is lowered rather than raised, and endothelial function seems to benefit and not be impaired by either of those SGLT2i. The question is: by what mechanism do these two increase carotid stenosis?
The Role of SGLT2 Inhibitors in Atherosclerosis: A Narrative Mini-Review
“We first review the underlying mechanisms of SGLT2-is on the development and progression of atherosclerosis, including favorable effects on lipid metabolism, reduction of systemic inflammation, and improvement of endothelial function. We then discuss the putative impact of SGLT2-is on the formation, composition, and stability of atherosclerotic plaque. Furthermore, we evaluate the effects of SGLT2-is in subclinical atherosclerosis assessed by carotid intima media thickness and pulse wave velocity. Subsequently, we summarize the effects of SGLT2-is in ASCVD events, including ischemic stroke, angina pectoris, myocardial infarction, revascularization, and peripheral artery disease, as well as major adverse cardiovascular events, cardiovascular mortality, heart failure, and chronic kidney disease. Moreover, we examine factors that could modify the role of SGLT2-is in atherosclerosis, including sex, age, diabetes, glycemic control, ASCVD, and SGLT2-i compounds.”
“PubMed and Google Scholar were searched to identify relevant publications on SGLT2-is and atherosclerosis. Key words included the following: “SGLT2 inhibitor, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin, sotagliflozin, tofogliflozin, atherosclerosis, carotid intima media thickness, plaque, ankle-brachial index, coronary artery calcification score, pulse wave velocity, transient ischemic attack, ischemic stroke, coronary heart disease, angina pectoris, acute coronary syndrome, myocardial infarction, coronary revascularization, renal artery stenosis, and peripheral artery disease.” All types of articles were considered, including clinical trials, animal studies, in vitro observations, reviews, and meta-analyses. Since this is a narrative mini-review, we prioritized the most clinically relevant and up-to-date articles in the current literature.”
I don’t want to quote the whole paper here, but the bottom line is that examining all commonly accepted risk factors for atherosclerosis, they find that SGLT2i, and empa and dapa too, either lower the risk factors or are neutral across multiple studies, including studies focused specifically on empa or dapa. When it came to plaque burden and size, canagliflozin was least effective at amelioration of plaque, so if we are to blame empa and dapa, you’d expect cana to be even worse, and yet, that’s not what the Chinese paper claims (and to be clear cana is at least as extensively studied).
Carotid stenosis or occlusion results in the clinical outcome of stroke. So how do empa/dapa/SGLT2i do with stroke? If they significantly increase carotid occlusion, you would expect to see increased incidence of strokes:
“Stroke and TIA. Several meta-analyses and reviews reported that SGLT2-is, including canagliflozin, dapagliflozin, and empagliflozin, do not affect the risk of stroke (Milonas and Tziomalos, 2018; Zheng et al., 2018; Sinha and Ghosal, 2019b; Sinha and Ghosal, 2019a; Zhu et al., 2020). In line, the empagliflozin and placebo arms in the EMPA-REG OUTCOME trial did not differ in the risk of TIA (Zinman et al., 2015). Further investigations evaluating the role of SGLT2-is in ischemic stroke are needed.”
Without reading the full Chinese paper, I am not going to attempt to evaluate it, but given my reading of the literature in the past few months, I find their claims rather puzzling and contrary to generally accepted clinical experience.
