Jaime Burkle, MD, Director of the Center for Cardiovascular Prevention, Metabolism & Lipids at Georgia Heart Institute. Dr. Burkle presents as a Cardiovascular Grand Rounds speaker during the CME lectures for 2022. Dr. Burkle discusses cardiometabolic therapies and gives a post interview with Habib Samady, MD answering questions from live viewers. To receive CME credit for this presentation, please visit the survey link.
Good morning and welcome to Georgia heart Grand rounds. This program is provided by Georgia Heart Institute. With support from our industry partners. The planners have disclosed no relevant financial relationships with commercial interests. The presenter has financial relationships and will disclose in his presentation to claim cmI credits today. Answer the survey evaluation. The link will be put into the chat. If you have a question for the presenter please type it in the chat section and we will read it at the end. And now dr Habib Samity president of Georgia Heart will introduce Dr Jamie Burkle. Thank you very much. Suzanne Suzanne McNeil is our educational coordinator and has helped organize this wonderful series. Well it gives me great pleasure to introduce our cardiovascular Grand Round speaker. DR Jamie Burkle is going to talk to us about cardio metabolic therapies. Doctor Burkle received his medical degree at La Salle University in Mexico city where he graduated with honors. He then completed internal medicine residency at the Famous Mount Sinai Medical Center in Miami, where he served as Chief Medical resident in 1996 and was granted the Howard Kane Resident award of the year and teacher of the Year award as you all know Miami was the hotbed of preventive cardiology all the way back to then he then completed his cardiovascular fellowship at Mount Sinai and received advanced Proctor Ship and echocardiography at massachusetts General Hospital in boston. Additionally he had a teaching position at Mount Sinai and the trans esophageal echocardiogram department. DR Burkle specializes in cardiovascular prevention lipid disorders and cardiac imaging. He holds multiple boards including internal medicine and every cardiovascular specialty known to mankind. In addition, his fellow of the American College of Cardiology and of the National lipid Association. He's been an instructor for advanced cardiac life support to many physicians, nurses and allied health care professionals on the behalf of the American Heart Association. It's really a testament to his passion and his teaching abilities across the board. He has published numerous scientific journals, articles and journals, medical book chapters as well as an active principle investigator and numerous national and international clinical trials. Mostly focused around his passion of preventive cardiology. DR Burkle joined the atlantic cardiology group way back in 2000 and then became one of the founding members of the Piedmont Heart Institute in 2007 where he served for 14 years as a prolific cardiologist and really a person that was sought after across the greater Atlanta area for cardiovascular prevention. We are absolutely delighted that he joined the Georgia Heart Institute very recently as our lead preventive cardiologists and lipid ologists. Now, if that's not enough, Jamie and his lovely wife, Kristi Burkle have five Children and I just don't know how they do it. But we're absolutely delighted you've joined us Jamie and to give this cardiovascular grand rounds. Thank you for being here. Thank you really appreciate the invitation. Alright, well thank you everyone for joining us today. We're gonna be talking about today, a very exciting topic which is cardio metabolic therapies. And these are my disclosures. So we're going to start by the definition cardio metabolic syndrome is a combination of metabolic dysfunctions, mainly characterized by insulin resistance, impaired glucose tolerance. This lipid e mia hypertension and central capacity. It's important to recognize that 58% of patients with coronary artery disease have more than three metabolic risk factors in terms of the metabolic syndrome, Hypertension disease. Epidemiology, diabetes account for 92% of morbidity and mortality amongst coronary artery disease patients. This is a disease that peaks at the age of 50-59 in males and over the age of 70 in females. And these are patients that have key cardio metabolic risk factors including visceral fat, insulin resistance, pathogenic disease. Epidemiology including high triglycerides, low HDL and small, dense LDL cholesterol, hypertension, glucose intolerance, including both impaired glucose tolerance and type two diabetes Impaired for analysis, including increased levels of plasminogen activator inhibitor one and fiber in again, these patients have chronic inflammation manifested as elevated high sensitivity crp many of these patients have the Pecos syndrome or polycystic ovarian syndrome with a decrease on sex hormone binding globulin and increased free testosterone and many of these patients have also concomitant nonalcoholic fatty liver disease. So we put this all together from the multitude of risk factors that we know that increased cardiovascular risk, including smoking hypertension age, race, sex, family history, abnormal lipid metabolism. The presence of insulin resistance in the metabolic syndrome, whether you have that or pre diabetes diabetes, physical activity, overweight or obesity significantly increase their cardiovascular risk. So when we deal with patients with the cardio metabolic syndrome, what our treatment goals first and foremost reduction of mortality and reduction of major adverse cardiac events. We need to concentrate on lipid and blood pressure control. We need to focus on organ protection, particularly kidneys and eyes. And finally we're going to focus on glucose control and weight control. However, the most important factor for us cardiologists when dealing with these patients is apply what we've learned from large perspective randomized clinical trials which now have instituted what is called evidence based medicine for the management of patients with cardio metabolic syndrome. So if we focus on what large clinical trials have taught us, the major drugs that we have to use on these patients include ace inhibitors or arbs. Because the trials have demonstrated a reduction of 13-15% in all cause mortality and 17-20% in cardiovascular mortality Statins. Going back to the forest trial in the 90s have shown a decrease in all cause mortality from 32 to 34% and a reduction in cardiovascular mortality between 21-24%. This is the reason why all diabetics should be treated with ace inhibitors and statins unless contraindicated. If we move forward Now to the past five years, two major drugs have made major advances in the management of these patients and these are the GLP one receptor agonists and the S. G. L. T two inhibitors. The use of GLP one receptor agonist and are patients with metabolic syndrome and diabetes have resulted in a 13 to 26% reduction in cardiovascular death or stroke and introduction of SGL T two inhibitors in clinical trials have resulted in a 17 to 38% reduction in cardiovascular death and a 7 to 14% reduction in cardiovascular death or stroke. Making this again. Drugs that are key in the armamentarium of treatment of patients with metabolic syndrome and diabetes. So how did we get here if we go back to 2008 following the much publicized cardiovascular safety concerns with rosiglitazone or Avandia. This drug, as you might remember, resulted in a significant increase in cardiovascular mortality including heart failure related hospitalizations. So in 2008 the FDA mandated that every single diabetes drug on investigation had to include a parallel arm for major adverse cardiovascular events on their clinical trials. In order to demonstrate safety and the upper limit of the 95% confidence interval for the hazard ratio had to be less than 1.8 for pre marketing study and less than 1.3 for post marketing studies. So as a result, every drug in development since 2008 have studied cardiovascular safety. So it was really by accident that we learned that these drugs not only were safe for patients with cardiovascular disease but had a significant improvement in cardiovascular outcomes. So there are four new classes of anti diabetic drugs the T. C. D. S. Or solid indians that end in glitter zone, the DPP four inhibitors that end in glitch in the GLP one receptor agonist that end in blue tide and the S. G. L. T two inhibitors that end in blood flows in from these four classes of drugs. The last two have demonstrated clear cardiovascular benefits in large perspective clinical trials. So let's focus first on GLP one receptor agonists. There are seven G. O. P. One receptor agonists that have been approved for the treatment of top two diabetes in the United States. And these include Senate tied tied Lexus, senate tied tight stomach, tight, oral, semi tied and Albig low tide. From all these three have demonstrated improved cardiovascular outcomes. How do these work drugs work? They work in the in creating system that is after we eat the food reaches the small intestine. This triggers a secretion in GLP one in response to food, which has mostly three mechanisms of action. The first is at the level of the brain by decreasing appetite. The second is the slow gastric emptying and the third and most important one is at the level of the pancreas where these drugs stimulate insulin secretion and suppress Glueck agan secretion. All these benefits will result in lower glucose levels, decreased appetite and weight loss. So three major randomized prospective clinical trials have demonstrated benefits of GLP one receptor agonist and cardiovascular outcomes. The regular type trial was called the leader trial demonstrated a 13% reduction in the primary outcome of cardiovascular death. Nonfatal mi or stroke for the regulated compared to placebo. The sustained six. And the pioneer six trials with some magnetite demonstrated at 26 and 21% reduction respectively in their three component maze of cardiovascular death, non fatal or nonfatal stroke. And finally the harmony outcomes trial with all big low tide demonstrated a 22% reduction in the primary outcome of cardiovascular death, nonfederal mind or stroke. So how does how does this work drugs work. The mechanisms for cardio protection include renal protection, lowering chronic inflammation, glucose reduction and a reduction in ectopic fat deposition, which is known to affect incident resistance and to associate with cardiovascular risk. These drugs are administered daily or weekly by injections with or without food. They're tight traded for a one C reduction but their cardiovascular protection effects are observed from the starting dose. These are the four most commonly used GOP one receptor agonist in clinical practice. I recommend my referring physicians to familiarize with one of them dozing tight rations and so on. So in summary GLP one receptor agonists Result in a 13-26% reduction in cardiovascular death or stroke in patients with diabetes and the metabolic syndrome. Moving on now to the two inhibitors. We recognize these drugs now as the new statins because of their significant impact not only in glucose control but also an improvement in cardiovascular outcomes. Four G. L. S. G. L. T two inhibitors have been approved for the treatment of Type two diabetes in the United States. And these include empathy, flows in or guardians definitely flows in or for siga can only flow sonoran volcano and electrically flows or state lateral. How do these drugs work? So there is an S. G. L. T. Two receptor in the proximal tubules of the NEF Ron that is responsible for greater than 90% of the renal glucose reabsorption. In other words, most of the glucose that reaches the proximal to bill is absorbed through this receptor and just like the name says sodium glucose co transporter, he's in charge of re absorbing both sodium and glucose. The sodium is absorbed and then through the sodium potassium at P. A. S. Is brought into the bloodstream as an exchange for potassium. Whereas the glucose is absorbed through the glucose T two receptor into the bloodstream. As you can conclude inhibition of this SGL T two receptor and two inhibitor will result in both glue creases and natural resources. So these drugs result in a significant increase in urinary excretion. The patients lose over 400 calories in the urine when taking these drugs. The result in natural resources and as a result intravascular volume contraction. They lower blood pressure. They contribute to weight reduction and to hemoglobin A one c reduction all the things that we tell our diabetic patients should do. So. There are three major drugs that have been investigated in large perspective clinical trials for cardiovascular outcomes. These are the Empire red trials for the canvas trial with Canada and the declare timI 58 trial with Dapa Cliff Lawson. This is the emperor trial with Cliff Lawson that demonstrated in the primary outcome of the three point maze of cardiovascular death, nonfatal mi a nonfatal stroke and resulted in a 14% reduction in this three component maze. Most impressively the key secondary endpoint of cardiovascular mortality alone demonstrated that addition of empathy that flows in two patients with type two diabetes compared to placebo, resulted in a 38% relative reduction of cardiovascular death. This really shocked the investigators and the cardiovascular community in general because to this date, since the Cliff Lawson trial was published in 2015, we have never seen a drug with such an impact in cardiovascular outcomes in cardiovascular medicine. The canvas trial with also demonstrated a significant improvement in death from cardiovascular causes in nonfatal stroke and non fatal M. I. With all of them reaching statistical significance. And the declared team of 58 trial with that flows and also demonstrated a reduction in cardiovascular death and heart failure hospitalization by 17% a 7% reduction in major adverse cardiac events And most impressively the reduction in cardiovascular death or stroke and most importantly cardiovascular death and heart failure. Hospitalization was significantly reduced with hostile ratios in the 1.65 range. So in summary SGL T two inhibitors results in a 17 to 38% reduction in cardiovascular death and a 7 to 14% reduction in the triple component maze of cardiovascular death or stroke. Making these drugs key components in the management of type two diabetes. And obviously these drugs should be administered to all patients with type two diabetes on this country indicated however, the initial trial studies that the benefits of these drugs go beyond cardiovascular death or stroke. In fact these trials have shown us just like the declared to me 58 trial. I just showed you a significant reduction in heart failure even in non diabetics, an improvement in renal outcomes, patients with chronic kidney disease and even improved outcomes in patients with peripheral arterial disease or atrial fibrillation. So let's focus on heart failure now So we know that this SGL22 inhibitors prevent the development of heart failure in type two diabetes according to the clinical trials. But the question is can they be used to treat patients with established heart failure? And the second question behind this was the benefits of A. G. L. T. Two inhibitors, maybe glucose dependent but can GLT two inhibitors be used to treat patients without diabetes. And with these two premises to clinical trials were conducted. The Dapa HF trial with data and the emperor reduced trial with empathy. The Dap ugly flows in trial or DaPA HF included patients with symptomatic heart failure, 11 trigger ejection fraction less than 40% and an N terminal pro Bmp greater than 600 with an exclusion criteria of a G F. R less than 30 symptomatic hypertension or systolic blood pressure, less than 95 or the presence of type one diabetes. And these are the results of the Dapa HF. Trial. Addition of data flows Two patients with type two diabetes compared to placebo resulted in a 30% reduction in worsening heart failure event And an 18% reduction in cardiovascular death. The key secondary endpoint of cardiovascular death or heart failure. Hospitalization was reduced by 25% when adding that flows into patients with heart failure with or without diabetes. And you can see the curve separated early on the trial and remain separation for the duration of the trial All cause death was reduced by 17%. The Emperor reduced trial This trial was presented by Milton Packer, the American College of Cardiology meetings last year. Similarly to Dapa HF, demonstrated that addition of empathy flows in To standard of care, patients with heart failure with reduced ejection fraction resulted in a 25% reduction of the primary endpoint of cardiovascular death or heart failure hospitalizations And these are the primary outcome right here of estimated cumulative incidence of the primary endpoint was a reduction of 25%. And this is the first and recurrent hospitalization for heart failure outcome, which also resulted in a 30% reduction as a result of these two large randomized clinical trials. The 2020 A. C. C. H. A. Heart failure guidelines are now recommending the use of S. G. L. T two inhibitors to all our patients with heart failure with reduced ejection fraction defined as an ef less than 40%. And the way they describe their algorithm is you have to always start with an ace art or an army as your first line with an addition of an evidence based beta blocker. And subsequently you would add mineral accord accord receptor agonist for those patients who meet criteria or an S. G. L. T. Two inhibitor or diuretics. For patients who have congestion or hydra, listen and nitrates for patients who are not target blood pressure or african americans. Or finally evaporating for those patients who have persistent elevated heart rate despite despite maximally tolerated beta blockers. So these are now what our heart failure colleagues call the four pillars of heart failure with reduced ejection fraction treatment the finance and ejection fraction less than 40%. All our patients with heart failure with reduced ejection fraction should be on a razz blocker, Ace inhibitor, ARB or Arnie A beta blocker, an M. R. A. And S. G. O. T. Two inhibitor. And we should strive to keep our patients. And this quadruple therapy. But now the question is, what about heart failure with preserved ejection fraction? So the emperor preserve trial was presented at the american heart association meetings. This past november was a phase three randomized double blind placebo control, event driven trial in which patients with type two diabetes and non type two diabetes age 18 years or older with new york heart association class 2 to 4 ejection fraction greater than 20 greater than 40% elevated anti prom Bmp and structural heart changes. Documented heart failure with preserved ejection fraction. Within the past 12 months, patients were excluded if they had symptomatic hypertension or a G. F. R. As low as 20 and were randomized to receive impact flows and 10 mg a day versus placebo with a composite primary endpoint of time to first event or adjudicated cardiovascular death or heart failure, hospitalization and key secondary endpoints of first and recurrent adjudicated heart failure, hospitalization or a slope of change in E. G. Fr from baseline. When the emperor preserved trial shown us was for the first time we have a therapy that is effective in patients with heart failure with preserved ejection fraction demonstrated a 2021% reduction in the primary outcome of cardiovascular death or heart failure hospitalizations and the preserved HF trial with data flows in which was presented the heart failure society of America last year. Also included patients with heart failure with preserved ejection fraction. That is ejection fraction greater than 40% 162 patients were randomized to the chosen 162 were randomized to placebo. And the trial resulted in again significant improvement in their cardiovascular outcomes. Starting with the Kansas city quality of life questionnaire showed an improvement in cardiac symptoms, a decrease in cardiovascular death or hospitalization for heart failure, hospitalization for heart failure alone, cardiovascular death and all cause mortality in patients with or without established cardiovascular disease. So again, these drugs are becoming now key in our armamentarium for the management of patients with heart failure with preserved ejection fraction as well. Well, how about renal function? S. G. L. T. Two inhibitors have a significant impact in renal function and grow Merrill filtration rate and have significant him a dynamic effects. Starting with physiological changes including an increase in glucose urea and natural resources with a decrease in protein urea. Therefore, renal protection. Long term they have significant glamorous him a dynamic effects including an increase in the different arterial or vessel constriction, increase in tupelo glamorous feedback and most importantly, a decrease in the intra glamorous air pressure which preserve kidney function in the long run and finally has systemic economic him a dynamic effects including lowering blood pressure, lowering plasma volume, lowering arterial stiffness and possibly improved energy utilization. This is a meta analysis published published at the Lancet a couple of years ago that showed that SCL 22 inhibitors will actually prevent kidney failure in patients with Type two diabetes and the Forest Plus will show you that the major randomized clinical trials using these drugs, The Credence Trial declared to me 58 the canvas program and the emperor, including the three most commonly used SGL T two inhibitors have consistently shown a significant improvement in renal function when used long term in patients with Type two diabetes. And what we have observed with these drugs is similarly to an ace inhibitor. When you start an H two inhibitor in a patient with CKD, you will see an initial drop in the G. F. R. Which is expected as a result of the hemo dynamic effects in the glow Marylise. But subsequently, as you can see in the data flows in curve here in the Dapa CKD trial, the renal function will be preserved in the long run as opposed to patients on placebo in the red because you can see that they experience a progressive decline in renal function. And I'm telling you this because it's important for you to know that you should expect to see a slight drop in the G. F. R. When you start these drugs in a patient with CKD and you should not stop the drug as a result but just monitor them because in the long run they will experience the benefit. These are the Dapa CKD trial outcome results by based on cardiovascular disease. The primary endpoint of the DaPA CKD trial, or data flows in patients with CKD showed that the primary endpoint of a G F R declined more than 50% and stage kidney disease, or kidney or cardiovascular death was significantly improved when using data and compared to placebo in both patients with or without cardiovascular disease, and the key secondary endpoint of heart failure, Hospitalization or cardiovascular death was also decreased in both patients with or without established cardiovascular disease. Similarly, the Emperor wreck trial showed that addition of flows into patients with chronic kidney disease resulted in a slight drop in G Fr at first followed by stabilization of renal function in the long run compared to a progressive decline in renal function on patients who are on placebo. And now there's an ongoing impact kidney trial, which is a randomized double blind placebo controlled trial of impact life lesson versus matching placebo. In 6000 patients with chronic kidney disease with or without diabetes, it will continue for about 3 to 4 years and will assess if frozen, reduces the risk of kidney disease progression or cardiovascular death. The results of this trial will be presented in october of this year. Moving on to atrial fibrillation. We now have significant evidence that addition of SGL T two inhibitors will result in a significant reduction of new onset atrial fibrillation or atrial flutter. This is data from the declared timmy 58 trial with flossing that showed a significant 19% reduction in new onset atrial fibrillation or atrial flutter will administer these drugs to patients with diabetes. And once again the forest plots show that subgroup analysis showed that this decrease in the incidence of nuanced or a flutter was independent of whether the patient had a history of this in the past presence of atherosclerotic cardiovascular disease or presence or absence of heart failure all patients benefited the same. So the question is how can they have multiple cardiovascular benefits? Well we have three proven mechanisms. One is volume contraction. These drugs like I said, result in natural resources and as a result volume contraction. Therefore pre low reduction. These drugs clearly lower blood pressure as a result of after the reduction. And there's also a significant decrease in glamorous pressure which sends signals to the brain to decrease sympathetic outflow. And there are three mechanisms under investigation. One is proposed by pharaoh Ninny at all from U. T. San Antonio. He is considered the father of myocardial, energetic and his research very interestingly has shown that S. G. L. T. Two inhibitors actually induce mild ketosis and ketosis is good for the body. It increases the levels of beta hydroxybutyrate that turns out to be a better fuel to myocardial than glucose. Then you have Subodh verma. And investigators that proposed that the mechanism by which the LT2 inhibitors provide cardiovascular benefit is due to volume contraction and an increase in erythropoietin release and this increase increases him adequate by 2-3%, resulting in improved oxygen delivery. And then we have David Charney from University of Toronto and his group of investigators that say that it's all about the kidney that the renal protective effects resulting improved aerodynamics vessel dilation, lower intravascular volume and therefore improvement in cardiovascular morbidity and mortality. Finally recently it has been shown that S GLP one receptors are found in the myocardial and these promote oxidative stress, apoptosis and fibrosis very similar to Augusta rhone. So possibly possibly inhibition of S. E. L. T. One and T. Two receptor will result in improved cardiovascular outcomes as well. So in summary, we have all these potential direct and indirect effects in the cardiovascular system. We have a decrease in the sodium hydrogen exchange. We have a decrease in the calcium. Can modeling protein kinase two. We have an increase in mythology and auto faggy and very importantly these drugs have shown a significant reduction in the N. L. P. N. L. R. P. Three inflammatory which you might remember the cantos trial with candy cockney mob which is a drug that actually activates the NLP three inflammatory by reducing interleukin six, a very important pro inflammatory drug and is associated with improved outcomes in cardiovascular disease by decreasing inflammation indirect effects of these drugs improving the function, increased vascular progenitor cells increase epoetin decrease sympathetic nervous system activation and improve energetic all of these effects appear to be the reason why these drugs are so beneficial in the cardiovascular system. So how are these drugs dosed? Most of these drugs are administered once daily with or without food. And the tight tray shin of the dose is for a one C reduction but not for cardiovascular protection. In other words, you will experience the cardiovascular protecting benefits from the starting dose. These are the three most commonly as yell T two inhibitors used in cardiovascular medicine doses of 10 or 25 mg a day in five or 10 mg a day and can only flows in 100 or 300 mg per day. The most common side effects observed with these drugs are hypertension and volume depletion. Like I said, these drugs clearly cause natural recess and volume contraction. So be very careful with your patients who have borderline blood pressure or our Ortho static in the office pre renal ischemia can be observed in the patient does not adequately hydrate when using these drugs. And because bacteria love glucose urinary tract infections and vaginal yeast infections are commonly seen not commonly seen but are seen as potential side effects in patients with guilty to inhibitors, particularly the poorly controlled diabetics in uncircumcised males. Candida vaginitis has also been observed stressing the importance of hygiene. These drugs is important to know. Do not cause hypoglycemia by themselves unless they are combined with a cell phone Elyria or insulin. So it's important to educate our patients and explain to them why we, as cardiologists are adding another quote anti diabetic drug to their armamentarium because of their cardiovascular benefits. It's critical to stress hygiene and hydration. It's important to also consider adjusting diuretic doses. In my practice. I typically lower their baseline diuretic doses in half because these drugs will have additional diuretic effect. You want to also communicate with primary care doctors our endocrinologists and clarify that you're not taking over the management of diabetes. That continues to be the responsibility of the primary care physician or endocrinologist. And you want to monitor G fr every 3-6 months especially when starting therapy. So who are the patients that benefit the most. These are all diabetics with atherosclerotic cardiovascular disease. You should prescribe these drugs unless country indicated most heart failure, patients with heart failure with reduced ejection fraction and E. G. F. R. Now initially recommended greater than 30% greater than 30. But now we can go as low as 20 obese patients or patients who have significant fluid overload or edema. These are the patients who benefit the most of the altitude inhibitor therapy in which patients we should avoid prescribing this. Those patients who have marginal blood pressure or those patients who are Ortho static or volume depleted because obviously these therapies will just exacerbate that. So this is a recommended protocol that wants to institute in our um group first we start with. Does the patient have established established a CBD. And remember this can be the presence of coronary cerebral vascular or peripheral vascular disease. If the answer is no then the further treatment of diabetes to PCP or endocrine. Or does the patient have at least one of the following this epidemiology, hypertension or tobacco use? The answer is no. Referred to PCP or endocrine. If the answer is yes, we're going to look for any contra indication for SGL T two inhibitor patient allergic to this. Does the patient have type one diabetes? Does the patient have D. K. A. Hypoglycemia? G. F. Are less than 30 history of necrotizing fasciitis or recurrent UTI. Or genital yeast infections or presence of hypertension. The answer is yes to any of these. You want to avoid an S guilty two inhibitor. If the answer is no you should immediately prescribe an S guilty two inhibitor or Canada which have all demonstrated improved cardiovascular outcomes. Additionally you may consider adding metformin and finally consider important points including assessment of volume status avoided. The patient is volume depleted. I routinely do Ortho statics in my office before prescribing these drugs to make sure these patients are not volume depleted. You educate a patient on hygiene and hydration. Key of this too because that will prevent complications. You want to adjust. Diuretic doses like I said I typically drop their diuretic doses in half to prevent volume depletion and you monitor G. Fr every three months. Finally consider raising the dose if additional hemoglobin a one c reduction is desired. So his closing remarks I recommend to all my cardiology colleagues to take ownership. Remember these are cardiovascular drugs with anti diabetic effects and not anti diabetic drugs with cardiovascular effects. Clinical trials have clearly shown that. Remember also that patients see a cardiologist four times more often than their endocrinologist. I recommend all of you guys to familiarize with one or two drugs from each class, those tight rations etcetera and get comfortable prescribing and if in doubt ask but don't withhold these lifesaving drugs and I want to thank you for your attention. Fantastic Jamie. What a wonderful overview of cardio metabolic therapies. And you know when you hear that title for cardiovascular grand rounds initially you wonder if you're you should be in endocrinology or diabetic grand rounds. But I think you've certainly convinced me and many of our viewers that we have to take ownership of this. Well maybe what I could do is ask Suzanne McNeil. If there are any questions from the audience Suzanne questions in the chat first question for healthy younger patients but with high family risk factors. What age do you recommend they be evaluated and proactively treated? Yeah. So that's a very good question. What I recommend is everyone started with your 10 year A. S. C. B. D. Risk calculation. So I hope that all my colleagues have that app on their phone and you calculate that as your first step because if you're patient has a greater than 20% 10 year risk of CVD events. They should aggressively be treated with secondary prevention factors including aspirin, a statin and cardio metabolic therapy. If they have diabetes or the metabolic syndrome For patients less than 5%, then you can probably just stick to lifestyle modifications. And for those patients between five and 20%, what we use as the tiebreaker is a city calcium score. Thank you. We have another question In clinical practice. What side effects if any do you see in patients taking GTL two inhibitors over a long period of time? Thank you for that question. Very important. So the most common side effect we see is hypertension uh and a drop in the G. F. R. Initially. So for the hypertension is very important that you stress the patient to remain well hydrated to make sure you lower the diuretic doses in half if they are heretics, it's sometimes necessary to even adjust antihypertensive therapy to prevent hypertension. So I try to avoid and my patients who have systolic blood pressures below 100. Um once you re evaluate them after starting therapy after three months, they come back to the office and you want to check Ortho static vital signs. You want to do a G. F. R. And B. M. P. To make sure there's no significant drop in G fr. You expect a mild decrease in the G. F. R. And very importantly you screen for urinary tract infections or vaginal yeast infections. So as a cardiologist I never thought that I would ask my patients if they were circumcised or not. But now I'm asking them that because again we've seen cases of Candido, ballon itis and uncircumcised males who have started these therapies. Thank you. A few more questions. Can you comment on the anti inflammatory effects of these drugs and their role if any in treatment of patients with significant inflammatory disease? States great question. And there's actually a lot of research in this area because of the significant effects on like I was saying the inflammatory reduction and interleukin six and C. R. P. And many other markers of inflammation are significantly decreased with these drugs. So there's a lot of ongoing clinical trials in the rheumatology area now on SCL T two inhibitors to see if these drugs drugs will have an impact in chronic inflammatory states. So we know that clearly they reduce Crp and other MPO and other inflammatory markers in cardiovascular medicine. But the question is can also can also be used in patients with chronic inflammatory conditions that will have additional benefits. So the answer to that question is stay tuned because there's a lot of data coming out of that. Okay I was going to say that these are wonderful questions. I want to just take a step back and ask you the question as a cardiologist. It is sort of almost dizzying the number of various therapies out there. The cost of some of these therapies as well as the potential for drug drug interactions as you increase therapies. Um so um is there is there some advice you have for people that want to embark on this journey that it sounds like we all have to embark on obviously listening to grand rounds getting educated on it. But how do you? Is there is there an age cut off that you rethink these drugs or give us some advice on how you clinically approach this? Myriad of challenges. So, thank you for the question. And obviously poly pharmacy is a very important issue that we're dealing with on our daily, in our clinics on daily basis. And this is something that we as cardiologists, we need to use our judgment. Right. And so the perfect example is as guilty to inhibitors the impact on cardiovascular event reduction is so strong that should really take priority over other drugs. So many of my patients that come see me for cardiovascular prevention who are diabetics are taking three or four other glucose lowering drugs and none of them have cardiovascular protective benefits. They all just lowering a number. But in the long run they're not getting any benefit. So I start by having a wide open communication with the primary care physician or the endocrinologist and explain to the patient that some of these drugs need to be changed and perhaps start by eliminating the non lifesaving drugs and simplify the regimen to them? So rather than taking an insulin credit dog, soften Ilaria insulin. And those drugs that all they're doing is lowering the number, replace those by S G L T two inhibitors or GLP one receptor agonists that have demonstrated cardiovascular outcome benefits. So start from there, then evaluate your other drugs, right? Because polly pharmacy and cost is the other issue. So, I was just showing you, for instance, in the heart failure world, all our heart failure colleagues are trying to push hard the use of SGL T two inhibitors again because the data on Dapa, HF and Emperor reduced are so strong that we've never seen drugs having this impact. In fact, the data is even stronger than the use of a C inhibitors. So you could make a point of saying, well if these drugs are more powerful than its inhibitors, why don't we start with an two inhibitor upfront and a newly diagnosed heart failure reduced ejection fraction patients. And the answer is yes, probably we should be doing that. So the idea here trials were that were done were all in addition to ace inhibitors beta blockers, correct that on top of maximum medical therapy, which in this case our ace inhibitors beta blockers and an Mra but the question is okay but if you have a patient with new answered heart failure and say that they have marginal blood pressure, are you going to start all full drugs at the same time? Are you gonna start one or two at first an uptight trade and adjust. So most of our heart failure colleagues will recommend start one or two at first to prevent hypertension, side effects and so on. So the question here becomes okay. So you start with the rats blocker, you start with two inhibitor. So it's interesting the way that this paradigm is changing is shifting. So we'll see very soon. I mean ideally, yes, you want to have these patients on quadruple therapy right? Like the four pillars we were talking about. But in clinical practice you should really pick and choose which drugs have the greatest impact in the cardiovascular outcomes of your patients. Fantastic. Really, really good practical advice that any additional questions from the audience had several questions in regard to insurance coverage. Can you comment on insurance coverage for SGL T two inhibitors? Yes. So most of these drugs, actually when you prescribe them, they will offer you a $10 copay for a 90 day supply. So for your commercial patients is very affordable for $10.90 day supply for Medicare part D patients. Obviously there are so many and so variable that it really depends on the particular plan of the patient for prescription coverage. But in my experience, the cost of these drugs have dropped significantly over the past two years as a result of a new clinical data coming out on clinical trials and be insurance companies and Medicare payers realizing the importance of these drugs as preventative for heart failure, hospitalizations and recurrent heart failure hospitalizations which as you know is our number one DRG and a big problem here nationwide. So coverage is much better for Medicare Party patients in my practice. Their maximum copay or the average copay is anywhere between 50 to $120 a month. Very very good practical advice. And as you all know dr Antonio Rios is our head of population health at Northeast Georgia health System. And he's really passionate in teaching us about kind of changing our paradigms. Is physicians and advanced providers to really think of the continuum of health care. And you sort of touched on the cost aspect. But the idea of preventing this level of cardiovascular death, hospitalizations etcetera could have an enormous impact on our health care costs. And so it may be an investment worth question is who Foots the bill? And I'm sure that's a complicated question and that's where all the insurance companies and third party payers and Medicare are seriously looking at that Jamie talk to me a little more about the GLP one agonists because it seems like you kicked off your wonderful talk with that. And then the S. E. L. T. Two inhibitors really kind of stole the show. So okay so we talked a lot about what sorts of patients and I know you covered this. but just to summarize what sorts of patients would you reach out for a GLP one agonist is the answer. Those who have a contraindications for two inhibitor or an allergy. And the reason is these are by far the two most important cardio metabolic therapies we have in cardiovascular medicine right now. But the winner consistently is the DLT two inhibitor. And all clinical trials have demonstrated a greater impact in cardiovascular, more video mortality compared to the GLP one receptor agonist who come in second but still better than metformin and any other glucose lowering agent out there. Right. So I use GLP one receptor agonist only when there's a contra indication for CRT two inhibitor or when my patient has a demonstrated allergy to it. So otherwise my SGL two inhibitor is always going to be first line again because of a greater magnitude reduction in CV events. Okay. And this is for and I was thinking that you could take your patients and put them into the secondary prevention bucket and the existing heart failure would reduce the bucket. And then just the type two diabetics that you're seeing. So for all three of those buckets you would start with an S. Absolutely absolutely. Because again the data is very consistent. So if I was to summarize this I would say so start with your diabetics. So if you are a cardiologist you see a diabetic first thing in your mind should be. Well I'm a cardiologist patient likely has established atherosclerotic cardiovascular disease of some sort right vascular vascular coronary. So that patient must be on an two inhibitor on this country indicated period end of story now for your heart failure reduced ejection fraction patient. If they are already on triple therapy, beta blocker, a rat's blocker and M. R. A. Then consider using an two inhibitor so that you have the four pillars and then you can provide that additional cardiovascular benefit for your half path patient. This is really truly the only class of drugs that have proven benefit all the other drugs that we've used in half of patients really have very weak data. The top cut with mineral cortical receptor antagonist Was the closer to get to reach statistical significance but didn't really reach statistical significance. So we should start with T. two inhibitors in patients and then add the other drugs as needed. So again, we want to use always the drugs that will provide you with the greatest cardiovascular benefit up front and then add on other drugs that don't have a significant or powerful effect. So I would love if we had our active audience which we're going to restart our cardiovascular grand rounds in person as soon as we can with the pandemic. But if I were to wager a bet I would say the majority of our cardiovascular doctors and aps minus maybe the heart failure doctors. And also some of the prevention experts don't have a lot of experience with these drugs. So you've given us a lot of practical tidbits. How do you simplify? How do you think of these patient groups now? You did also say that there are three different drugs that have had cardiovascular benefit. So what recommendations do you have? You said find one get comfortable with the dozing. Like anything we take on. Can you give us anymore advice on that in terms of how to pick and then how to get comfortable with dozing and so forth. That's right. So I tell my referring doctors on my cardiology colleagues pick one drug. Just one familiarized with the starting dose and the obliteration and start prescribing it and get comfortable prescribing it, remembering also. Educating your patient is key telling your patient a hydration, hygiene, hydration, hygiene is very, very important to stay well hydrated. These drugs can actually dehydrate you if you don't drink enough water and practice hygiene. Report symptoms of urinary tract infection early. That's really the extent of your education you're going to do because you're not taking over anti diabetic diabetic management. You're only providing them with the cardiovascular protective benefit that they need as a cardiologist. That's our number one responsibility. And that's why I started with my first light saying first and foremost when trading our patients with diabetes or metabolic syndrome. The first responsibility for us is reduction of cardiovascular mortality and reduction of May's events. So you have to start with that. Get comfortable prescribing it and you'll see that it's not that difficult. I mean there are very few drugs in cardiovascular medicine have this side effect profile that really very safe drugs start with. Like I said get familiar with one drug. Get familiar with the starting dose and we bring them back in three months recheck Ortho statics. Ask them about you TR or yeast infections and get a G. F. R. As simple as that. And then I know you mentioned this but just to reiterate for the clinicians that want to embark on this journey there. Subcutaneous li injected or oral. So all the T. Two inhibitors are oral once daily with or without food. That's simple. And the only way you you stay at the starting dose and I typically lead the primary doctor and endocrinologist uptight trade if additional A one C. Is desired. But that's in their field that's for just a one C reduction my responsibilities reduction of cardiovascular morbidity mortality. I stick to the starting dose period for the GLP one receptor agonists. The only one that is orally available is oral. Some magnetite all the others are injection once a week and it's a small subcutaneous injection. Most of these patients are used to injections because of the finger sticks or insulin anyway and it's very well they're very well tolerated as well. So let's think again. I think I'd like us to thank for the next two minutes about diabetics, right? Because most clinical trials and in our practice we know that diabetics, probably our third of our patients. So it's a huge chunk of our patients. And obviously their outcomes are so poor and their outcomes are driven by cardiovascular mortality and renal disfunction and stroke. So if you have a diabetic in your office that is coming to you maybe with metabolic syndrome but does not have established known cardiovascular or cerebral vascular disease. So my first question to you is do you actively screen them with imaging for vascular disease? And if so, what's your go to screen. Thank you for your question. So I have to say that if you have a patient that has been diabetic for more than five years and you think that the patient does not have a CBD is because you haven't dug deep enough. Most of the patients that have Type two diabetes for over five years will have some form of subclinical atherosclerosis. So these are the patients that ice cream with carotid ultrasounds with city calcium scores. And with A. B. I. S. And I'm going to say that greater than 75% of them will come back with an abnormality on any of those three. They will show some carotid plaque. Perhaps not critical stenosis but they will show some carotid plaque. They will have probably an elevated calcium score above 100 which is really now in the secondary prevention level. Or they might have an abnormal A. B. So if I have any of these three automatically move that patient from a primary prevention to a secondary prevention strategy. So I'm going to be focusing more on a stronger LDL reduction, stronger A one C better blood pressure control and anti platelet therapy. Talk to me about we haven't touched on LDL reduction much passe. That's old news. Right? But talk to me a little bit about where you are with that. You've got let's say you've got your diabetic that you've looked at. Let's say their calcium scores 300 and they may have a little carotid plaque. There may be hemoglobin a one C. Is eight and say their LDL is 140. How do you approach the lipid aspect to that? Something we've learned from recent clinical trials is that we used to say LDL lower is better. We no longer say that we say LDL lowest is best because we have not reached a point where further LDL reduction will not result in additional cardiovascular benefit. So in that regard, in my practice I have just three strata. I want in my first strata, which is LDL below 100. I want all my patients, irrespective of other side effects. I mean, other concomitant common abilities to be an LDL below 100. Now, patients with stable CHD or diabetics or multiple risk factors. They should be on an LDL below 70 goal. Okay. And finally the third group is the patients that have a recent my or patients that have recurrent events for those. The LDL goal should be less than 55. So moving back to the diabetics, I treat them as a secondary prevention because pretty much their outcomes just like you said are very similar to patients with established a CBD prior cabbage prior P. C. I. So those patients should be treated to an LDL below 70 And I treat them with obviously first statins at the maximally tolerated dose. But something that we need to learn as cardiovascular specialist is that we should be using additional drugs for LDL lowering. Because it turns out that only about 40% of patients who take statins reach SDL goal less than 70. So 60% are still they take their status but they're still not a goal. So we need to use secondary agents the same way we do with hypertension. We have the patients on two or three drugs the same thing we do for diabetes. There are two or three drugs turns out when it comes to lipids. We only use statins. And for that reason we think that we're doing our job but we're not we're falling short. So I encourage everyone to use combination therapy with like acid PCSK nine monoclonal antibodies And now the PCSK nine silencers that have recently approved by the FDA. Wonderful. Well listen there's so much more that we can discuss and talk about Suzanne, we have a few seconds left. Any one last question from the audience. One last question related to some points that you just recently made our PCP and endocrinologists regularly prescribing SGL T two inhibitors. Or should patients with type two diabetes also be seeing a cardiologist regularly for evaluation? Yes, Thank you for that question. So the short answer is no. Unfortunately neither PCP nor endocrinologists are using enough DLT two inhibitors. So that falls into our area. Cardiologist should be actually the leaders and the owners of these drugs because of the major cardiovascular benefits. But we are as a team. Right? So we should work as such. And we should communicate with our PC PS and endocrinologist and making sure all of us are on the same page, making sure that we make it clear to them we are not taking over management of diabetes. This is a historical issue because if you ask nine out of 10 cardiologists will be hesitant to use these drugs because of the concern of hypoglycemia. Right? And we were taught this in training. No, no, no, no. This just leave the diabetes management to the endocrinologist. But these drugs truly don't cause hypoglycemia unless you use along with insulin or a secret agog. So yes. The short answer to your question is unfortunately, the PC PS and endocrinologists are not prescribing this enough. They should definitely see a cardiovascular specialist that we take ownership. Well with that said I do want to put a plug in for our student to be launched Wellness prevention and lipids metabolic center that yourself and Dr. Dave Okey dr super. Mainly in many of our wonderful cardiologists are going to be involved with DR Win. And I just want to thank you for really an incredible talk. I know that not only as clinicians but as patients, we all want to come see you and your colleagues. So thank you very much for that. And we look forward to a lot of future collaborations and wonderful work. Thank you for the invitation.
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