Hello, Colleagues. I’m professor Subodh Verma, from the University of Toronto in Toronto, Canada, and I’m delighted to be here today to discuss with you GLP-1RA Clinical Benefit to Clinical Practice Guidelines. Shown in this slide are my disclosures. As you all know, diabetes adversely affects the cardiovascular system. Several pathophysiological mechanisms have been described through which diabetes increases the risk of cardiovascular events. For example, oxidative stress, inflammation, insulin resistance, vasculopenia, they lead to increased rates of atherosclerotic cardiovascular events, an important cause of cardiovascular death. These mechanisms are also critical in, you know, promoting increased rates of heart failure. And in fact, heart failure is an increasingly recognized, you know, risk factor in people with diabetes. Furthermore, diabetes affects the, the kidney, and we’ve now learned quite clearly that renal disease is an important risk amplifier for atherosclerotic events as well as for heart failure. So essentially, when we think about the cardiorenal spectrum in people with diabetes, we think about the pump, i.e., heart failure, the pipes, MACE events, and the filter, renal events. And these three tend to occur either independently or coincidentally with each other in patients with diabetes with a lot of crosstalk between these three endpoints. And in fact, it’s that background and the richness of the clinical trial dataset that has led to a change in clinical practice guidelines. And on this lecture series you’ve already heard in great detail, you know, a discussion around the ESC Guidelines that have suggested that in people with ASCVD at high or very high CD risk that physicians can go straight to either an SGLT2 inhibitor or a GLP-1RA as a monotherapy in drug-naïve patients ahead of metformin, recognizing the dual benefits of these therapies to improve not only A1c but to improve cardiorenal risk. Let me again remind all of you that a high-risk patient according to the ESC is someone with diabetes of greater than 10-year duration with an additional risk factor, and the very high-risk patient is someone with established cardiovascular disease, someone who has target organ damage, or someone who has three or more risk factors. And this has now been well established in the ESC Guidelines that SGLT2 inhibitors on the left, Class IA recommendation for reducing cardiovascular events, and a Class IA recommendation on the right for GLP-1RA, specifically liraglutide, semaglutide, or dulaglutide. One guideline that you haven’t heard about is the recent expert consensus decision pathway from the ACC, and that was recently published addressing this issue for cardiologists. And that is that if you have patient with type 2 diabetes who’s over the age of 18 who either has ASCVD or who has heart failure or has diabetic kidney disease or has multiple risk factors that put them at high risk, cardiologists or cardiovascular specialists are encouraged to address both their glycemic risk as well as their cardiovascular and renal risk concurrently. And as you walk down this algorithm to the right lower quadrant, in orange you see that either an SGLT2 inhibitor or a GLP-1RA is recommended in those patients for cardiorenal risk reduction. Last year there was an important guideline from the American Heart Association and American College of Cardiology, the primary prevention guidelines for cardiovascular disease. And an excerpt from that speaks to how SGLT2 inhibitors or GLP-1RAs may be considered even in primary prevention for reducing not just A1c but also cardiorenal effects. This is a busy slide. The important aspect here is that the right lower sort of portion of this slide in the orange and circled box that talks a bit about how these newer therapies may be used in primary prevention as well for cardiorenal risk reduction in people with diabetes. Now, you’ve heard a lot about guidelines today. I just want to call your attention to the fact that there are some differences between ESC and ADA ESD Guidelines and there are differences. There are some similarities as well. The biggest difference being that metformin is not required as first-line by the ESC Guidelines, and also, differences exist between the hierarchy of a GLP-1 and a SGLT2 inhibitor. The ADA ESD suggesting that a GLP-1RA and an SGLT2 inhibitor should be used in that order in people who have diabetes where ASCVD is the predominant phenotype whereas an SGLT2 inhibitor or a GLP-1RA in that order be used in people where heart failure or CKD is the predominant phenotype whereas that’s not necessarily the case with the ESC guidance. I’m delighted to share with you our recently updated Diabetes Canada Guidelines, and they have suggested the sort of similar kind of approach to, to the prior guidelines from the ESC and ESD and ADA saying that people with diabetes we must look at whether they have established cardiovascular disease, heart failure, or kidney disease, and then choose the appropriate strategies. So, you can see here this matrix involves not just the phenotype of patients but also you see on the Y-axis it involves what specific outcomes are being affected by these therapies. So, a patient with ASCVD who has diabetes, a GLP-1RA or an SGLT2 is Grade A evidence, and then Grade B evidence for, you know, SGLT2 inhibitors and for the outcomes of either MACE, heart failure, or progression to nephropathy. When we think about heart failure, patients who have heart failure, we have again for the outcome of hospitalizations for heart failure or progression to renal disease, Grade A evidence with SGLT2 inhibitors. In patients who have chronic kidney disease and diabetes, Grade A evidence for SGLT2 inhibitors to reduce hospitalizations for heart failure, and in people who are high-risk primary prevention, Grade A evidence for GLP-1RAs to reduce MACE events, and Grade B evidence for, you know, SGLT2 inhibitors for renal and heart failure outcomes. I know this is a very complicated matrix, but essentially you see that these new therapies have come of age in the vast majority of patients with diabetes. Now, in some of the clinical trials that we’ve been involved in, one important aspect that comes up is that these agents not only prevent the time to first event but also recurrent events. And this is an analysis that we did from the LEADER Trial in which we highlighted the fact that the first events were reduced by liraglutide but then recurrent events which included recurrent rates of fatal or nonfatal events were also reduced by liraglutide versus placebo such that total events were reduced by over 14 percent which was statistically significant. I think this is an important message for patients that a patient who’s had a myocardial infarction these therapies reduce recurrent events and death. And if a patient has not had a prior event, they reduce the first event, and therefore, the total burden of ischemic events and CB death are reduced with these therapies. There have been several GLP-1RA studies that are being conducted. There’s some differences in the molecules and there’s some differences in the inclusion criteria within these trials. For example, the REWIND Trial which was one of the latest employed dulaglutide in largely a primary prevention population. Thirty-one percent of these patients had established cardiovascular disease in contrast to studies with albiglutide in HARMONY outcomes or SUSTAIN 6 or PIONEER 6 where the majority of patients were so-called secondary prevention. However, the way in which primary and secondary prevention patients was defined was slightly different between trials, and therefore, in this analyses that we presented recently, we attempted to recalibrate or reclassify the pooled SUSTAIN 6 and PIONEER 6 dataset through the lens of the inclusion criteria of REWIND. And when we did that, you can see on the right that the original distribution of primary and secondary prevention patients in the pooled SUSTAIN 6 and PIONEER 6 datasets changed such that now 67 percent of patients had established cardiovascular disease and 33 percent of patients were in primary prevention. And we then evaluated the overall dataset from SUSTAIN6 and PIONEER 6 to ask the question did people with established cardiovascular disease or those with risk factors derive a consistent benefit? And the answer was yes, that semaglutide either oral or once weekly had a consistent benefit to reduce MACE events in people with established cardiovascular disease or those with multiple cardiovascular risk factors. How do these agents reduce ischemic events has been a topic of great discussion. And shown here are the so-called direct effects of GLP-1RAs on the vascular biology to improve endothelial function, to reduce vascular smooth muscle cell proliferation and migration, to reduce vascular inflammation, to reduce lipid accumulation, all of which seem to be very important in the atherosclerotic process. And in addition to that, there are the indirect effects of these agents on blood pressure, weight, and A1c. But personally, the benefits of these strategies on ischemic events are largely independent of blood pressure, weight, and glycemic control per se. So, finally, let me just leave you with what we’ve learned cumulatively with respect to the class of GLP-1RAs for meta-analyses that suggest that cumulatively there is a significant reduction of about 12 percent with respect to major adverse cardiovascular events with these agents. There’s a reduction in about 12 percent in cardiovascular death that is also statistically significant with GLP-1RAs. GLP-1RAs reduce by about 9 to 10 percent the rate of fatal or nonfatal myocardial infarction. And then when we look at the rate of fatal or nonfatal stroke, there seems to be a significant 16 percent reduction in this outcome. So, when cardiologists, endocrinologists, diabetologists, family doctors, or internists or anyone really taking care of patients with diabetes is thinking about reducing cardiorenal risk in addition to lipid-lowering, in addition to blood pressure-lowering, triglyceride-lowering with icosapent ethyl, we should be really including GLP-1RAs and SGLT2 inhibitors as an important tool in our toolbox to reduce cardiovascular risk, heart failure risk, and renal risk. There are many exciting trials ongoing. There’s the SOUL Trial with semaglutide which is a study in people with diabetes. There’s the FLOW Trial with semaglutide at renal preservation. And then there’s the SELECT Trial that I’m involved in which is a trial of 17,500 patients with established ischemic disease, prior MI, stroke, PAD with a BMI of over 27 who are being randomized to semaglutide 2.4 mg once weekly versus placebo in an event-driven trial to reduce primary and secondary outcomes of MACE and the secondary outcome of, you know, CV death, or all-cause mortality. So, this is a very exciting trial in patients without type 2 diabetes with semaglutide. So, let me try to bring today’s session to an end and say the following, that just be cognizant that there is new guidance from the ESC that has prioritized these therapies even ahead of metformin in many cases in patients with diabetes with or without established disease, and that no matter who we are in terms of our specialty, just think diabetes as an opportunity to reduce cardiovascular and renal risk. Now, all of these wonderful data that have accumulated with GLP-1RAs and SGLT2 inhibitors and all the great guidelines you’ve heard about from me and other speakers through this program, you know, are really of no value if they’re not translated into clinical care. And I think that is our biggest enemy and that is clinical inertia, therapeutic inertia to do something different in our patients with diabetes. And I hear a lot about this that my patient has mild diabetes or my patient is quite stable. In a patient with diabetes who has two or three risk factors I don’t really think that’s a stable patient, you know. If you think that that patient is at high risk of developing an MI, then how is that patient stable? Or my patient has mild diabetes. Is it mild until they have retinopathy or heart failure or, you know, CKD? You know, why should I change anything? I think he’s doing just fine on this current regimen. You know, it may be inconvenient for him or her. Finally, it’s probably more work for me. So just be cognizant that all of us do this and think about ways to overcoming clinical inertia as one of our biggest impediments in knowledge translation. Well, I hope, friends, you’ve enjoyed today’s presentation. I really enjoyed spending some time with you. Thank you very much for the opportunity, and I wish you the very best in the future.

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