So, I will talk about diabetes. This is the title of the lecture that JP chose for me. So, and this is also, I also try to keep our topics relative to the parts of the guidelines that each one of us, you know, were primary authors. So, I had the pleasure of writing a little bit about diabetes for the guidelines. And, you know, diabetes is very problematic. It's a major risk factor, increases mortality from heart disease from two to four times. There's systemic endothelial dysfunction, accelerated atherosclerosis. There's more diffuse and extensive CAD. The vessels are smaller, they're more difficult to treat with stents. I mean, these are very different patients and diabetics have a high mortality and higher need for repeat procedures after revascularization. And patients on insulin even have a worse prognosis. So, these worlds here are showing how the diabetic epidemic will continue to grow and will continue to be a problem. And here, there are some of the mechanisms, there's increased thrombosis, increased risk stenosis, and increased risk to these patients. So, over time, we have conducted a number of trials comparing PCI versus CABG that have enrolled patients. So, there are three trials highlighted in yellow here that enroll exclusively diabetic patients, being FREEDOM, the most important one, EXCEL, NOVAL, and PRECOMBAT. They published their diabetes sub-analysis, and the others, we haven't seen the diabetics sub-analysis. So, most of the data are drawn from these studies, but the major study, as everybody knows, is the FREEDOM trial conducted, published now 10 years ago. And, you know, time goes by very quickly. And this trial took a long time to be conducted, and this was the comparison between two strategies. One strategy was bypass surgery using a LIMA, and the interventional strategy was using dragolitic stents at the time that this trial was conducted were relatively novel. And the stent used in this study was a CYPHER study that is no longer in the market, but used serolimus. So, a total of 1,900 patients were actually consented and randomized, and these are the results of the study. So, this is a composite outcome of death, stroke, and myocardial infarction. As you can see, the curves cross over at about one year, so one thing to keep in mind. They remain relatively together for two to three years, and then they start diverging late. So, this is an important aspect that we have to consider when we are deciding one or the other, you know, the expected mortality, unexpected survival of the patient, maybe for other reasons. So, as we can see on the side table that all-cause mortality was higher with PCI. Myocardial infarction was probably what drove most of the outcome difference, and then cardiovascular death was not statistically significantly different. Here we have the difference in myocardial infarction with CAVG versus PCI. Here is all-cause mortality that is statistically significant, and then the opposite happened with stroke. So, that's another thing to keep in mind, that strokes may be increased with the use of bypass, and all has to go into the decision-making process when we're treating these patients. And then, one topic that we discussed before is the syntax score, and we can see here that there was no interaction with syntax, and the same trends were observed across these three categories of syntax score, low, intermediate, and high. So, the syntax investigators are to be commended because beyond the median three and a half years of follow-up that the patients in the measure study had, they did a follow-on study, a long-term survival at a median time of seven and a half years, and that showed that the curves continued to diverge, and we can see here that the mortality at seven and a half years is statistically significantly different with one strategy versus the other. Now, I think that this trial was not quoted in the previous revascularization guidelines because the CAVG and PCI guidelines were published more than 10 years ago before the publication of this study. So, this study, I think, is very informative for the decision-making diabetic patients. So, we have to note a few things about the FREEDOM trial, that it was a highly selected population that included left main disease, so it does not apply to patients with left main. Mortality was similar in the first two years, so as I mentioned before, we have to be careful when we make those decisions. There were no differences in cardiovascular mortality. There's been issues that we have been discussing at NOSYN for many years about adjudication of MI, and that has probably…we learned about this type of adjudication in the conduction of newer trials like EXCEL. We observed more severe strokes in the CAVG arm, and the difference stayed significant for the duration of the follow-up, and there was no interaction between the syntax score and treatment, and this is one of the reasons why the chairs were adamant about not giving a Class 1 recommendation to the syntax score. Subsequently, there's the HEDMET analysis published in Lancet in 2018, and there's a significant interaction between diabetes and the modality of revascularization, and you can see…I mean, you could actually say that the difference in mortality between CAVG and PCI is mostly driven by diabetes. This included 11,000 patients looking at 5-year-old cause mortality. This was a meta-analysis based on individual patient data, and here again, we look at the…and this is for the whole cohort. We can see that there was no…the interaction for syntax score survival and benefit with PCI or CAVG was not statistically different, even though you can see that there's no difference in the lower and middle partiles, and there's a significant difference favoring CAVG in the upper partile, but the overall interaction is nonexistent. Therefore, our guidelines gave it the Class 2B recommendation with the level of evidence B. In terms of how do we treat left-main in diabetics, the EXCEL trial showed that in the main…in the primary endpoint, there were no differences at the end of the 3-year follow-up, and this is the left-main sub-analysis published from EXCEL, although all-cause mortality preferred and favored bypass surgery. You have to keep in mind that the difference in all-cause mortality was driven by non-cardiac death, mostly because cardiac mortality was similar in the EXCEL trial between CAVG and PCI. Then we have this meta-analysis that was published after we finished our writing of the guidelines and shows that combining syntax, pre-combat, novel, and EXCEL, the mortality at 5 years is similar. It's not statistical. There's no statistical differences. And then when they looked at different interactions, when they looked at the interaction with diabetes, there was no interaction with diabetes, and that also supports the type of recommendation we also provided in our guidelines. We spoke about strokes, and this is the stroke meta-analysis for the different comparisons, and there's an interaction between diabetes and stroke and treatment, so that's important to take in consideration. Most of the strokes occurred during the first year, and subsequently, this landmark analysis shows no differences in subsequent strokes. In the ISCHEMIA trial, diabetic patients had similar survival and microbial infarctions with medical therapy versus revascularization, so there was no differential effect of diabetes in the outcome. The only thing that we can learn from the ISCHEMIA trial is that diabetic patients are higher-risk patients, as we mentioned before, and because they are higher-risk patients, we have to sharpen and we have to learn on how to manage diabetics, even in the cardiology clinics. You know, we don't have the time or the expertise to manage the glycemia day-to-day, but we understand, I mean, there are new drugs that are maybe not that new, the SGLT2 inhibitors and GLP-1 agonists that have shown that they improve the cardiovascular outcomes, as given the mandate in 2008 that all new drugs for diabetes have to improve cardiovascular outcomes, and we need to learn in our clinics how to use these drugs, and they don't cause hyperglycemia, which are the drugs that can increase cardiovascular mortality. So, these are the recommendations in summary. So, based mostly on the FREEDOM trial, in patients with diabetes and multivessel CAD, with involvement of the LAD, who are appropriate candidates for CABG, with a limit to the LAD, is recommended CABG with a limit to the LAD is recommended in reference to PCI to reduce mortality and repeat revascularizations, and that's a class 1A. In patients with diabetes who have multivessel disease amenable to PCI and an indication for revascularization or candidates for surgery, maybe PCI can be useful to reduce long-term ischemic outcomes, and you have to look and you have to read between lines because there's a difference when we talk about mortality ischemic outcomes, so you have to be able to read the guidance. And then finally, we address the issue of left main stenosis in low and intermediate complexity CAD in the rest of the coronary atomy. PCI can be considered an alternative to CABG to reduce major adverse cardiovascular outcomes, and that's an indicate class 2B indication based mostly on the results of the randomized trials and the excel trial. And I would like to thank everybody for the attention and for having and to SCI for sponsoring this webinar. Thank you.

diabetes

cardiovascular health

risk factor

bypass surgery

PCI