Metabolic Basis of CVD Prevention

Hi, I'm Bob Eckel. I’m a professor of medicine and physiology and biophysics at the University of Colorado Anschutz Medical Campus. That's in Aurora, just east of Denver. And I have joint appointments in the divisions of endocrinology, metabolism and diabetes, and also division of cardiology. So I'm kind of a what hat wears well today versus what one wears well tomorrow. But I, I have a clinic in cardiology, which is a lipid clinic, but it focuses on all metabolic disorders. And my science is really in the endocrine division. So anyway, it's a bit of a background. Let's go ahead with the seminar. A few duality of interests worth mentioning up front. Merck and Novo Nordisk do not relate really to what I'm going to be presenting today. These are consulting roles for those two companies. And UniCure is a recently completed gene therapy protocol evaluating the role of LPL gene therapy in patients with LPL deficiency. Again, no interaction whatsoever in what I'm going to be talking about today. In medical education's all CME related stuff, kind of like this programs. All right, let's go ahead. I'm going to present a case upfront that we're going to be using as a beginning of a more complicated discussion of the metabolic basis of cardiovascular disease. So this is a 55 year old guy presents for routine care, and he's not really been seen by anybody for a number of years. And besides being a little bit overweight, he's fairly sedentary, but he's otherwise healthy by his report. He's not on any medications and there's no family history of coronary heart disease. It's no regular exercise program, and he doesn't eat a heart healthy diet. He really just eats what he wants. And mostly fast food, not a diet that we would be really content with in terms of reducing his risk for heart disease. He's a nonsmoker and drinks alcohol occasionally and his review of systems is entirely negative. So this is kind of a kind of a boring 55 year old guy who just shows up in clinic and we got to deal with it. So let's go ahead and examine him. His blood pressure is 138 over 88, a bit on the higher side, his weight’s 188 and BMI at five foot nine calculates at 27 kilograms per meters squared. His weight circumference is 41 inches, but otherwise his exam is normal. So the question I might ask all of you, are you measuring weights circumferences routinely? And as you know, I'm sure the metabolic syndrome is effectively diagnosed by three of five components, including waist circumference. It's elevated. And for men that circumference is 40 or above. So he does meet that criteria for the metabolic syndrome. Let's look at his labs. And total cholesterols 199, the triglycerides are 245. His HDL cholesterol is 38 milligrams per deciliter and his LDL cholesterol is 112. Fasting glucose was 135, elevated. His hemoglobin A1c was 7.0%, elevated and sufficient to make a diagnosis of type 2 diabetes, particularly if validated by a second measurement. And his high sensitivity C-reactive protein is 1.5, which puts him in kind of that gray zone in terms of inflammation and risk. So what steps do I need or do you need to take to reduce his cardiovascular disease risk? And where is the evidence? So now addressing the metabolic basis of increased atherosclerosis, these are the things that should enter our mind. First of all, the metabolic substrates that are involved in intermediary metabolism that relate to atherosclerosis, including glucose, fatty acids and lipoproteins which are lipid fuel delivery vesicles. Increases in inflammation, which was alluded to a few minutes earlier in terms of his HSCRP elevation. Oxidative stress, which also involves glycoxidation when glucose levels are elevated. Endothelial dysfunction, pro thrombosis, which is an increase in the thrombotic state because of increases in platelet aggregation and coagulation factors that promote thrombosis and also defects on the other side of clot formation, meaning defects in fibrinolysis. Now today we're going to concentrate mostly on the first 4 items: glucose, fatty acids, lipoproteins and inflammation. I'm going to comment on blood pressure because that has a metabolic relationship also. But we're not going to cover in detail the following topics. So let's start with a diagram and I think the metabolic syndrome, which again is high triglyceride above 150, low HDL, below 40 for men and 50 for women, systolic hypertension or actually diastolic hypertension in and or antihypertensive medications and big waist circumference and then impaired glucose tolerance either by an impaired fasting glucose or type 2 diabetes. Although to be honest with you, I think the metabolic syndrome is best applied to patients who have no diabetes because a large percentage of people with type 2 diabetes already have the metabolic syndrome. So let's begin here with kind of central obesity. And I'm showing in the middle of this slide a fat mass. When the fat mass increases, particularly in the visceral or, ??? we have an increase in lipolysis. And when those lipolysis products, meaning free fatty acids, go to the liver, we see a lot of downstream effects, including the accumulation of lipid droplets in the liver, hepatic steatosis and the overproduction of very low density lipoprotein, which include ApoB 100, ApoC2 as the LPL activator and ApoC3, which appears to carry additional risk for atherosclerosis. And associated with this higher level of triglycerides or VLDL are reductions in HDL cholesterol and the presence of more small dense LDL, which some people consider to be pro atherogenic. Now in addition, free fatty acids that reach the systemic circulation that don't go directly to the liver can also impact insulin action and peripheral tissues. And here I'm showing muscle. And most of insulin sensitivity in the periphery relates to insulin mediated glucose uptake by muscle. And when the fatty acids are elevated, the work of Jerry Shulman from Yale and others has shown that the insulin resistance in muscle relates to a defect in glucose uptake by the skeletal muscle. And therefore we have a reduction in glycogen stores and a tendency to increase triglyceride stores in the muscle leading to the insulin resistant muscle. And in that setting, oxidation of fat is is somewhat reduced and ultimately the oxidation of carbohydrates preferential. Again, glycogen is the major source of insulin action in the muscle taking glucose and putting in the glycogen, and when glycogen is depleted and fat’s accumulating the muscle can do really nothing but oxidize carbohydrate. And let's go on. Ultimately, in the adipose tissue there is this pro-inflammatory release of molecules that also have a paracrine effect to increase rates of Lipolysis. IL-6 and TNF Alpha are among those factors, but these factors also can give rise to more systemic insulin resistance peripherally. So here are levels of pro-inflammatory cytokines produced to a large extent by adipose tissue that go to the muscle and further inhibit insulin mediated glucose uptake. But in addition, these pro-inflammatory cytokines gets systemically circulate and go to the liver where they increase the production of the pro-inflammatory biomarker C-reactive protein. Moreover, the adipose tissue release releases an inhibitor of fibrinolysis called PAI-1, and when PAI-1 is increased, the Prothrombotic state is representative of the defect in fibrinolysis. And then there are many other alterations related to resistance that relate to increases in fibrinogen production and also in many alterations and other coagulation cascades that we call normal in terms of conformation and clot lysi that leads to, I think, increased cardiovascular disease risk. Now when we go to the adipose tissue from another perspective, the adipose organ is the organ of origin of adiponectin. And adiponectin, unlike the pro-inflammatory cytokines, is an anti inflammatory factor or cytokine. So when these levels are reduced as are present in the insulin resistant situation, the effects on systemic insulin sensitivity in the liver and more so in the muscle are modified adversely. And then finally, of the upper right of this slide is the hypertensive component of the metabolic syndrome. Here, IL-6 has a direct effect. Insulin itself may have a direct effect and moreover, fatty acids and activation of the sympathetic nervous system also may play a role. So if we think of the metabolic syndrome lipids, glucose elevation, ultimately waist circumference here we can come up with really an agenda that really relates including blood pressure, the three, four, five components of metabolic syndrome. And I want to point out to you that these are all manifestations of insulin resistance. Let's go ahead now and going forward, I'm just going to comment a little bit on the work of Mike Brownlee, who's shown through a variety of studies how hyperglycemia and the setting diabetes drives oxidative stress and the process of glycoxidation is shown on the bottom. So when we have hyperglycemia, that leads to an increase in PA Ribose Polymerase which is involved in the transcription of multiple genes. And one of those is, uh, reversely effects. In other words, there is a inhibition of the transcription of glycerolaldehyde phosphate dehydrogenase. And with falls in GAPDH, we see a number of downstream effects that relate to the complications of diabetes, perhaps not only microvascular complications that Michael Brownlee studied, but also microvascular disease through atherosclerosis and that includes increases in the polyol pathway, increases in methylglyoxal, which increase the production of reactive advanced glycation end products and ultimately protein kinase C activation, which leads to a proinflammatory effect. And finally, the hexosamine pathway. All that relate to the micro and perhaps also the macrovascular complications of diabetes. Now if we look at studies in terms of glucose lowering and we're looking at four studies predominantly here of the UKPDS was the first among four studies that have looked at an intensive insulinization, a more aggressive treatment in diabetes to see if it reduces the complications of diabetes. And the primary end point for these studies were cardiovascular disease outcomes, typically a three point race, myocardial infarction, stroke and death from cardiovascular disease. And the UKPDS is kind of unique in that it started with patients who had early onset type 2 diabetes who were untreated. So ultimately that data showed over the first part of the study a benefit in reducing microvascular complications which were measured in terms of the kidney and the retina. And ultimately in the second phase of the study, this so this sustained a benefit, a more intensive control with insulin or even sulphonylureas or metformin was additionally shown. But the primary outcome of cardiovascular disease was not favorably affected in the first study, but over a legacy period of years after the study. Ultimately, that outcome became favorably influenced although the P-Value really didn't show much difference between this first phase of the study and the second phase of the study. Now all cause mortality or cardiovascular disease related mortality was not changed. But in the legacy, the further follow up these patients after the trial had been concluded did show a statistically significant benefit. Now the ACCORD, ADVANCED, and VAD, the VADT studies and the Veterans Administration cohort all showed that more intensive insulinization, and most of these trials were insulinization only, showed a reduction in microvascular disease, and that was mostly due to reductions in proteinuria. But the primary outcome, which is our topic here today of atherosclerosis and related events, there were was no benefit here. But on the downside is the ACCORD study showed actually an increase in all cause mortality, which was multifactorial. But some people thought that because the patients were so intensely treated that ultimately more hypoglycemia ensued, that that was the reason that there was more mortality. That increase in hypoglycemia also occurred in these two trials. But in this trial I find it kind of interesting because the people who in fact did not have better control with more insulin intensification appeared those to be at greater risk for cardiovascular and all cause mortality. So kind of interesting that if you can't control your patients with diabetes with more intensive insulinization you need to relax your goals. And that's consistent with all the current recommendations of all the international organizations that set guidelines or recommendations for the treatment of type 2 diabetes. Now, if you look at all these trials put together, there are two kind of meta analyzes that I've looked at a similar cohort in terms of the patients that were included. And if you look at the men analytical approach about more intensive insulin therapy for diabetes and its effect on cardiovascular disease, you see no effect on CVD death, you see no effect on all cause death and you see more severe hypoglycemia, but look here, if you look at the confidence intervals for the primary outcome, more intensive insulin therapy still shows a statistically significant benefit. However, is this a clinically significant benefit? And I think in your practice you just have to weigh this benefit with this risk down here and no benefit for CVD death and all cause death in terms of the decisions you make going forward. Now what about the newer therapies for type 2 diabetes? We could take, you know, several hours in addressing all these clinical trials and the details. But what I have chosen to do is summarize a lot of data that relates to the classes of drugs we commonly used to treat type 2 diabetes. Insulin, I'm going to say a yes based on the meta analysis, but again, that is an equivocal yes based on the risk of hypoglycemia and the lack of benefit for all cause mortality or CVD death. Suflonylureas, I think we can pretty much unequivocally say no benefit. We use them because they're cheap and they have a clinical benefit in terms of reducing glycemia. But this reduction in Glycemia has not proven itself favorable in the trials in which suflonylureas have been utilized. Metformin is entirely driven by UKPDS data. But the number of events that occurred in the metformin treated patients in UKPDS were few, and many people are questioning whether this use of metformin is the primary therapy to treat type 2 diabetes is really justified based on the absence of sufficient data to make that claim. Acarbose, again limited data, but the one trial that was presented that showed that Acarbose reduced cardiovascular disease events is highly quoted, but never validated and of course Acarbose in the state, we don't use too much of that drug because of some of the gastrointestinal adverse effects that are related to Acarbose therapy. Now pioglitazone, I'm going to say the TZDs in general, the PIOs, where that data comes from, probably are beneficial. I'm going to relate both to the active study where Pioglitazone affected the secondary outcome that did not include the amputatation, but the primary outcome included amputation, which seemed like an unusual primary outcome. But the secondary outcome without amputation was favorably affected, and the most recent IRIS study were in fact pioglitazone versus control, meaning placebo, were randomized to patients following a cerebrovascular accident or stroke. In that trial pioglitazone had an impressive effect on cardiovascular disease risk to follow. Now a couple of cautionary notes with Pio, of course, the weight gain is there. Much of that subcutaneous weight gain. And so that may be less concerning in terms of CVD risk, but patients don't like it. But the bone disease, I think, could be limited to some extent by keeping the dose at 15 or 30 milligrams rather than 45 milligrams. And the whole issue of bladder cancer is still a little unclear, but most of the analysis have shown no increase in risk of bladder carcinoma. The estriol T2 inhibitors have surfaced of recent to show clinical benefit. And kind of the interesting thing about these studies, EMPA-REG and CANVAS recently completed is that these drugs don't do too much to glucose lowering but appear to have extra glycemic effects on accruing benefit. Many of these effects seem to relate to the potential diuretic effect of the drug, although that is claimed to wear off in about a week to ten days on admissions to the hospital for heart failure. Whereas the GLP-1 receptor agonists liraglutide and semaglutide appear to effect more the atherosclerotic process and maybe not so much the heart failure risk and that makes sense in terms of the way the SGLT2 inhibitors work versus the GLP-1 receptor agonist. I should point out in passing that just a recent paper in the Lancet Endocrinology Diabetes this week showed that the amputation risk in cana is really a risk perhaps uniquely related to this molecule. And when the investigators in that study looked at empa, cana and dapagliflozin, whose clinical trial is yet to be completed, over 80% of all amputations occurred with cana and only 20% with the rest of these agents. So I'm a bit uncertain as to why this molecule canagliflozin should be likely to be causing amputations where the other ones are not causing those amputations because the all these drugs in this class work by the similar mechanism of increasing glucose excretion in the kidney by inhibiting the sodium glucose LT2 transport protein. All right. Let's turn now to approaching the metabolic basis of cardiovascular disease by affecting lifestyle. So this is the most recent report from the AHA and the ACC, released in November of 2013 and published in July of 2014, as shown here in the bottom. So the charge of the lifestyle work to review the evidence, review on diet and physical activity in the absence of weight loss, which could be integrated with the recommendations for blood cholesterol and high blood pressure panels going forward with their own recommendations. So the overall heart healthy diet or actually, I think a cancer healthy diet and the diabetes healthy diet is one of them. Lots of fruits and vegetables, lots of whole grains, lean poultry and fish, legumes, nuts and beyond. All right. So let's look at those those recommendations. So the recommendations that came forth for our examination of the data that related to LDL cholesterol lowering was to advise adults who would benefit from LDL cholesterol lowering to consume a DASH or a Mediterranean style diet. Aim for a dietary pattern that achieves 5 to 6% of calories from saturated fat. Typically, Americans are eating between ten and 11% of saturated fat. So cutting that in half, reading food labels to see what the saturated fat content is and finally reducing the percent of calories from trans fat. This last issue is a fairly easy one nowadays because the food manufacturing companies have attempted to substantially reduce their trans fat content in processed food, so we're doing better in that regard, but often the trans fat are being replaced by saturated fats, so you have to watch your labels fairly carefully there. The evidence here was unequivocal. A strong 1A average for these types of dietary patterns and this type of saturated fat restriction. I should say parenthetically, that getting a food history for your patients is a worthwhile exercise in the clinic, and you can use that as a teaching moment to favorably modify diet in terms of the number of servings of fruits and vegetables and whole grains a day. And ???? sugar, well, if you're eating a weight maintaining diet that’s DASH or Mediterranean style, you don't have a lot of room for discretionary calories that have a lot of sugar. Let's go ahead now to dietary cholesterol. This has been a mystery for some time. And I grew up thinking that cholesterol restriction was important to reducing LDL, but if you look at this systematic review and in our own search of the data, when we wrote the guideline, there wasn't enough evidence to implicate dietary cholesterol restriction to lower LDL. So I'm quoting the conclusions here. This group of authors said that the reviewed studies were heterogeneous and lacked the methodologic rigor to draw any firm conclusions regarding the effects of dietary cholesterol on cardiovascular disease risk. That means not only LDL lowering but heart attacks and stroke to follow that that effect on dietary cholesterol. And carefully adjusted well-conducted cohort studies are needing to be done to look at the relative effects on dietary cholesterol on CVD risk. Keep in mind, you know, if you have a patient who likes omelets, why not eat an egg white omelet that doesn't have, you know, 600 milligrams of cholesterol in it. I mean, but despite the data, I think we can't overly advise cholesterol restriction as a way to reduce cardiovascular disease risk. Now, what about the Mediterranean style diet We don't have outcome data for the DASH diet. We'll have a lot of risk reduction data, but no outcome data. But the PREDIMED study carried out in Europe is one which we turn to often and if you will, the Spanish approach to modifying dietary composition and look at outcomes. And in one of the first reports of outcome data, we're looking at a controlled diet which had a reasonable amount of saturated fat, like in the 11 to 12% range versus the Mediterranean diet with either extra virgin olive oil as an additive or nuts as an additive showing this reduction in risk over the study period of five and a half years. Then when we turn to patients with diabetes, the same PREDIMED program tends to share the same kind of benefit in patients with diabetes, here at the bottom, as you saw in younger and older men and women above. So overall, I think the PREDIMED program, which is very similar to a Mediterranean diet that's usually prescribed, is one which has merit in terms of cardiovascular disease risk. And these studies had biomarkers for controlling for dietary compliance over the interval of study. And what about the gut microbiome and preventive cardiology? Just a week ago I was at a week long meeting and they all that dealt with the gut microbiome and its effects on bile acid metabolism. So let me show you a data from one of the speakers who was out of there, Stan Hazen, actually from the Cleveland Clinic. So what Stan’s done is his research has looked at dietary sources of phospholipids and here specifically phosphatidylcholine with higher consumptions of red meats, hard cheeses and eggs. This phosphatidylcholine is broken down by phospholipases in the gut forming choline. And choline leads to betaine, which is part of carbon fragment metabolism. But more important is how choline is handled by the gut flora. So these are the types of microbials that we have in our large intestine and maybe to a little bit in our small intestine that leads to the metabolite production trimethylamine. And this may itself not be so harmful, but when levels are produced in high quantities, it goes to the liver where ??? mono oxidizes, oxidized this product and lead to trimethylamine N oxide. And this is a bad actor leading to atherosclerosis and many outcomes that are related to that. Let me show you a little data. This is a Kaplan-Meier estimate of major atherosclerotic cardiovascular disease events according to TMAO levels in plasma. So over here are people with the highest quartile and here are the people with the lowest quartile. As you see, there's up to a 2 to 2 and a half fold increase in risk comparing Quartiles one over quartiles for controlled for many other variables. And then here's the subsequent report. And people with peripheral vascular disease were in fact the first quartile. Now we're looking at freedom from death over five years. First quartile, fourth quartile, again showing now may be up 2 to 2 and a half to three fold difference between the two quartiles. So overall, I think we can conclude that your gut microbiome has something to do with the way we handle dietary phospholipids, specifically phosphatidylcholine to increase risk of an atherosclerotic event through the production of the oxide of Trimethylamine. Now let's turn to blood pressure for a second. So in blood pressure in terms of dietary modification, we want people to eat less sodium. And you know, this is a bouncing ball on both sides of the court. But in general, yes, there's a U-shaped curve. But in general, for people that have pre hypertension or hypertension, restricting dietary sodium leads to a reduction in blood pressure. The evidence for that is very, very strong. So the recommendations were modified a little bit and suggesting that around 2400 milligrams of sodium per day will reduce your blood pressure. But if you can reduce that even further by another gram a day, you'll get an even greater reduction in blood pressure. And even without these goals, ultimately the strength of the observation of decreasing sodium intake by just a gram a day is going to have a moderately strong recommendation for lowering blood pressure. And combining the Danish dietary pattern with reduced sodium intake was even a stronger benefit. So let me pause here. Even without reducing dietary salt by eating a Danish dietary pattern, you can lower your blood pressure. Now, if we add modest to moderate restrictions of dietary sodium, we can see even a better effect on blood pressure. So what am I going to eat? Well, I'm into natural foods, Joe, And give me a martini with a soybean in it. That's pretty natural. I think It's not certainly anything we want to recommend going forward here. But maybe you're as confused as this woman is. Fat free food, cholesterol free food, salt free food, food free food is probably the best outcome. But we're not suggesting prolonged fasting to reduce atherosclerosis. But fat free food is wrong. I mean, mono and polyunsaturated fats are perfectly fine and associated with maintaining good lipid levels. Cholesterol free food, we've made a comment about that. We're not so concerned about that. Salt free food, I think depends on whether you're pre hypertensive or hypertensive. And there I think sodiuim restriction may be more important to seriously consider. Let's turn to physical activity now. Here are the guidelines and what we're recommended based on our drilling down to the evidence supporting physical activity increases to reducing LDL cholesterol, non HDL cholesterol and blood pressure. We're talking about advising adults to engage in aerobic physical activity, 3 to 4 sessions per week, averaging 40 minutes possession involving moderate to vigorous intensity, physical activity, and basically you have to sweat. Now, if you can't exercise that much and there are limitations, there are other ways to get out of the sedentary lifestyle. So these are really strongly recommended, but not quite at the 1A level, the 2A level because outcome data for the impact of modifying blood pressure, now this is for lipids and blood pressure, are insufficient at this point to really make it a stronger recommendation. But physical activity benefits LDL, non HDL and blood pressure, and this is something we should really recommend to our patients going forward. And now some good news. I've got a bunch of smiling faces here leading to the next slide, and that's the MESA study. The MESA study is an NIH funded study that looks at the multi ethnic study of atherosclerosis, which is a medical research study involving more than 6000 men and women and different communities around the United States, and its strength is its diversity in terms of the kinds of participants it took place in terms of Hispanics, African-Americans and Caucasians. And here are the centers that participated in MESA In fact, the trial is still ongoing. This is not an intervention, but it's an observational study that ultimately has provided important information. So the food frequency questionnaire and nutrients databases is the food frequency questionnaire used by the Harvard School of Public Health. And ultimately let's look at some data that have come from there. So for assessing the probability and hazard ratio of death all cause mortality over a seven and a half years based on lifestyle, and this included basically smoking, physical activity. and nutritional control. Ultimately, we're looking at scores of 3 or 4, meaning higher scores that really related to a about a two fold difference in events compared to people who didn't have adequate control of any of the 4 components of lifestyle related risk. So this provides encouraging information about the importance of physical activity, dietary quality, body weight, and smoking in relationship to outcomes of atherosclerosis relationship, and not only that, but all cause mortality. Let's turn to weight loss as as a related entity that was included in the evaluation. So weight loss in patients with a higher risk for cardiovascular disease and type 2 diabetes was addressed by the LOOK AHEAD study. So let's look at the primary objective that was to assess the long term over 11 and a half year effects of an intensive weight loss program over a 4 year intervention period in overweight and obese subjects with type 2 diabetes. Some 5000 men and women, 16 study centers. So weight loss was the aggressive intervention versus support in education, which didn't discourage weight reduction but was not the intent of that control design. Age range shown. BMI all above 25. Primary outcome, major CVD event. Secondary outcomes were many and the study was stopped early for no benefit on the primary outcome, a major CVD event. So here are the data hazard ratios at the bottom over over the period of study over 11 years. And here's the intervention group. Again, no hint of any benefit over the time period despite weight reduction and successful weight reduction. I don't have that data in there, but you have to trust me there. However, when in additional analysis this is post-hoc and for any post-hoc analysis, you got to weigh it with a grain of salt. But what we're looking at here is the weight change categories from gain or stable, small weight loss 2 to 5%, medium loss between 5 and 10%, and large loss greater than 10%. And this is during the first year of study. And now we're looking at the primary outcome. And now down here we're looking at the secondary outcome. And if you look at the benefit now we're looking at major cardiovascular disease events. We're seeing a reduction of the P of .04 value for the unadjusted ratio. And with the adjusted ratio, even a stronger benefit of losing a lot of weight if you have type 2 diabetes and reducing your cardiovascular disease risk. Now just a pause. A post hoc analysis needs another study. It's really a subgroup analysis that even though it may have been a prespecified end point, the amount of weight loss, it really needs to be studied and validated for a separate study. So let's turn to another outcome. Here we're talking about changes in fitness and how they related to the outcome. So I'm going to turn your attention to the bottom of the slide of gain. Those people who gained in terms of mets or of exercise capability gained more than two mets. Look at their benefit, very strong. People who gained less, if we move this far to the left, we'd see some benefit here. So if you're more fit either a medium gain or particularly with a large gain in fitness, that benefit is accrued. Again, secondary analysis and we have to be careful about overly generalizing this to people who were were randomized and had no impact on the primary outcome with the intervention. Now let's turn our attention as we move towards the finish yard, to lipids and Lipoproteins. So we know that atherosclerosis is LDL getting out of the artery. It's pro-inflammatory and through chemokines make some circulating monocytes come on in there. We have the ingestion of the LDL by the monocytes. So they become macrophages and they in turn reduce reactive oxygen species. And through that process and the generation of oxidized LDL, we increase inflammation and the process becomes circuitous with more LDL, more inflammation and more atherosclerosis. So here's the report of the 2013 ACC/AHA guideline, and that debate is basically related to the predicted five year benefit on major cardiovascular events coming through 27 randomized controlled trials of statins versus placebo or statins versus other statins or other agents. So here's the group on the bottom with a greater LDL decrease with statins and here's the group for the higher five year risk, anywhere from less than 5% to greater than 30%. And I think you see nicely with me this platform effect, let me get back to that slide, this platform effect, no matter what your risk is, that the more LDL reduction you have with statins, the better the outcome. And this is also true of cardiovascular disease death. Again, 5 year benefit, higher risk versus lower risk, less reduction versus more reduction. And we're seeing, again, the staircase relationship, no matter where you're LDLs at or what your overall risk gets to benefit for more LDL cholesterol reduction. So that led to the guidelines that recommend statin therapy. Secondary prevention is for everyone with known atherosclerosis, meaning heart attack, stroke in general, in terms of defining atherosclerotic cardiovascular disease, patients with diabetes between ages 40 to 75 with LDL is in this range. And the reason in this range is because above 190 we have a condition called familial hypercholesterolemia, which should be treated independent of having known atherosclerotic cardiovascular disease. And patients with diabetes it's recommended that kind of a moderate dose statin be used as it should be in people above the age of 75, because the clinical trials only involve this age range from 40 to 75. Then for primary prevention, ultimately we're looking at moderate intensity statin therapy for people with lesser risk and high intensity, fixed statin therapy for people with greater risk, and that's an LDL range here and an ACVD risk of above 7.5%. So this is important because if you're above 71.5%, there's good reason to think about primary prevention, even though event has not previously ensued. And this is always a conversation between you as the health care provider and your patient at the follow up. I point out when the risk is between 5 and 7.5%, the guidelines recommend using some tiebreakers to decide whether statin therapy may be worthwhile. And without reviewing all those tiebreakers with you I think a coronary artery calcium score in an asymptomatic patient may be the best tiebreaker. And really that's what MESA is about. MESA is evaluating coronary calcium scores as part of their overall clinical design. Looking at the impact of other noninvasive imaging techniques on detecting disease. So here is the intensity of statins. Here's the high intensity. 40 of 80 of Atorva, 20 of 40 of Rosuva and here are statins and doses that all fall within this moderate intensity standard therapy range. The low dose I think we only turn to now if patients are statin intolerant. But there is residual risk and these are the populations that may need more aggressive therapy. The FH population, genetic disorder, 1 in 200, and untreated LDL is typically 190 and above. 80% of these people are not at a reasonable goal of less than 100. Then there's the high and very risk CVD risk populations that have had a previous event and multiple risk factors including diabetes, difficult to achieve. And if you're using 100 as your goal, 20% of people here still don't achieve the goal. And if you want to go under 70, which is what many of us want to do now in people with previous disease, it's only 60% of people who are not a goal, meaning only 40% are at goal, but 60% are not at goal. And then finally, statin intolerant patients. I see a lot of these people and most of them can't get the goals even if you set them at 130, 170 or even below if they're statin intolerant. So as stated here, nearly all patients need additional cholesterol lowering here in this particular group. So we're going to talk about the PCSK9 monoclonal antibodies. These antibodies bind to this PCSK protein that allow the LDL receptor following internalization to be recycled to the membrane and function continues. I could put in many more slides showing in the absence of the antibody, the receptor now gets degraded in lysosomes and does not get returned to the cell surface to carry out its function for LDL binding and degradation. So the PCSK9 monoclonal antibodies are an important step forward in modifying LDL cholesterol in a major way. So here are the trials that are out there. FOURIER has recently been completed and published. ODYSSEY Outcomes is going to be done at the end of this calendar year and reported early next spring or late next winter. The SPIRE program has been discontinued despite the potential benefit of bococizumab. The reason for that is that there were neutralizing antibodies that came up against bococizumab and a bit less LDL lowering that we're seeing with FOURIER or Evolocumab or Alirocumab. And therefore we're not going to have the privilege of seeing those trials completed. But we'll have two drugs that are competing one versus the other to use clinically based on clinical trial data that now is complete for FOURIER. So FOURIER took high risk patients and used a five point outcome, which is the primary outcome which included a bypass surgery or hospitalization for an acute coronary syndrome. And as you see, when Evolocumab was added to statin therapy, almost all of these people are on appropriate statin therapy, there's about a 15% reduction in the primary outcome shown here. And when we look at a three point outcome, actually the secondary end point was a three point outcome that was influencing them a little bit better with a 20% reduction. Now keep in mind these statin treated patients were already well controlled, but the Evolocumab effect went beyond the statin therapy alone or even other lipid altering drugs. So we're seeing benefit now from the FOURIER trial done over a fairly short interval here. We're talking about, you know, up to three years. But but this is an important outcome that relates to even lower LDL cholesterol levels. And we're used to gaining in terms of benefit. And this slide points that out. No matter where you started in terms your your baseline LDL cholesterol or the placebo treated group, look where you end up here. So even if you started high or placebo group was high in the fourth quartile here, you're down here. But if you started quartile one, your LDL baseline were like at 75 and they fell to levels around 20, but still benefit and not necessarily a benefit that related to this being a flat line and comparing one group to the other here, I don't think you can really do. But I think the additional trials, particularly with Alirocumab, may show us a result that relates to what levels the maximum benefit ensues. And here's an important slide that I'll not spend much time on. But if you look at people to develop very low levels of LDL under 25 milligrams per deciliter, and this is with Alirocumab now, not Evolocumab, there doesn't appear to be any increased risk versus placebo or in patients that are treated, our patients treated with Alirocumab. So right now there's a safety net around this. We don't want to get overly cocky about this over 10 to 15 years of treatment, but right now it seems okay to get that LDL cholesterol well below 70 and even as low as perhaps in the 30s without any inverse effects. I'm just going to talk briefly about triglyceride rich particles. They may relate to atherosclerosis, either by creating lipolysis products that have access to the arterial wall or ultimately the remnant particles that are formed after LPL acts on the triglyceride rich particles. Both of these hypotheses have support for them, but we don't at this point know exactly the reason triglyceride rich lipoproteins or triglycerides fight the heart disease. I should say this and this is parenthetical and kind of my opinion, it's people that have hypertriglyceridemia that have higher number of atherogenic particles versus those that just have too many triglycerides but have a normal number of particles that may relate to the increased risk, but this has not been unequivocally proven and we don't have clinical trial data to really support your measurements ApoB on a regular basis. And keep in mind, if you measure ApoB, LDL carries most of the ApoB so if LDL is up above 100, much above 100, much of your ApoB is going to be coming from your LDL. So let's kind of summarize where we're at with lipids here in 2017. I scroll down this fairly quickly. Statins, Yes, unequivocally. I didn't show you the IMPROVE-IT data, but the IMPROVE-IT data, despite levels of LDL of 53 versus 69, still had a beneficial effect. But that study took about eight years to get done with lots of patients, but yet the benefit was still there. Cholestyramine, our bile acid sequestrant, was the first drug used to lower LDL with a medication that showed benefit. We can't forget about that early trial. But now of course, Colesevelam was an easier form of this class of drugs to give. But outcome data with Colesevelam are not yet available. The PCSK9 inhibitors, I think FOURIER says yes, we're going to have to wait for ODYSSEY outcomes now to validate that effect of a class of molecules that we call PCSK9 inhibitors. Fibrates variable. I'll just say in passing that if you have hypertriglyceridemia where they're on an existing statin therapy, you may see benefit. And most of those analyzes that have shown that are secondary analysis. So we're going to have to wait for that right fibrate trial to be done yet. Omega-3 fatty acids. Interesting enough, I saw yesterday that the REDUCE-IT trial with Vascepa still ongoing and 80% of the data are in. So we know that that means no substantial harm and likely means no substantial benefit. But the outcome with omega -3s is yet to be accrued and we're going to need to be patient there maybe for another year, year and a half to see the outcomes. The JEALOUS trials often quoted the Japanese trial that showed benefit of omega-3s both in primary and secondary prevention, but in today's world, the statin therapy in those patients needed to be more optimized than was present. And I think any any more I think we would not tend to want to lower triglycerides until the statin prescription is ultimately considered and optimized. Niacin, I think retrospectively way back perhaps, but the more recent trials have shown no benefit. And the CETP inhibitors, I'm putting a question mark here now because work to be presented in Barcelona in a couple of weeks by Chris Cannon, the REVEAL trial is positive, but here we're talking about drugs that raise HDL, but the CETP inhibitors also lower LDL. We're going to have to look at the data until we're sure exactly how these drugs work. And in terms of modifying lipoproteins and risk and where they fit into the overall equation. Let's turn briefly now to blood pressure. And I'm going to turn to the concept of individualizing therapy, where we look at goals. Some people say 150 over 90 is where the data is, and many other people like lower blood pressures. And if you look at two of the big trials, ACCORD done in diabetes and SPRINT done in the absence of diabetes, and you look at summary of intensive treatment versus standard of care, yes, there is a benefit. And I think in general the more aggressive blood pressure lowering is something we ought to think about, particularly in terms of of of stroke. Now here’s stroke, a little bit stronger than the overall primary outcome, but the variability here is wider, and SPRINT showed no benefit where ACCORD. So I think I think we have to ultimately be careful in overly generalizing data that needs to be even further validated. But in general, with diabetes, I think we should think about lower blood pressures despite the fact that the primary outcome in ACCORD was not fulfilled here. But, you know, there's always a but isn't there? In JAMA Cardiology, just a couple of weeks ago, we see this gradient relationship and what we're looking at here a, systolic blood pressure reduction and risk. And here are people who started at 120 to 124 versus starting at greater than 160. And we're looking at ultimately the reduction in blood pressure over this range and the impact on cardiovascular disease events favors lower blood pressure. So the the my that so when we're looking here, we're looking at those individuals who are compared to the control group that were 160 that have blood pressures lowered. Here are this group who compared to the control group are 125 over 129 who were at this level, an effect over that gradient range. So the more blood pressure reduction you have, the greater the benefit, and that's a reduction now, a lesser reduction to 130 and a reduction to 140 and a reduction to 150. So as you see on the top, more reduction, better outcomes in terms of CVD risk, and this is 42 trials, 140,000 patients and of course the more reduction you get compared to the control group, the more drugs you have to use. So that's an important consideration. But nevertheless, I think it just shows that blood pressure still an important predictor of outcome and being more aggressive carries more risk, carries more costs. But it's something we need to seriously think about in making decisions going forward. So last, inflammation. I mentioned inflammation here before and I'll mention it here again, it's part of the atherosclerotic process. And there are two ongoing trials actually. One I think is is just going to be presented very soon again in Barcelona. The first is the Cardiovascular Inflammatory Reduction Trial or CIRT, using methotrexate in high risk patients. And of course these people are already statin treated. And the second is CANTOS, or the Canakinumab Anti-Inflammatory Thrombosis Outcome Study. Interleukin 1B inhibition is the approach using a monoclonal antibody and these are high risk people with hsCRPs above 2, have for maximum risk reduction. And what's recently been published is that the Phase 3 CANTOS study met the primary endpoint, which is the reduction in cardiovascular disease events and cardiovascular disease death, a composite of heart attack, stroke and death, showing that canakinumab in combination with standard of care therapy reduces CVD risk in people with a prior heart attack and inflammatory atherosclerosis. So this is going to add even more complexity to our evaluation treatment of patients and hopefully that data is going to be convincing enough that we maybe should start to think about measuring hsCRP. I'm not advocating that now. I haven't seen the study yet, but that'll be, I'm sure, hitting the newspapers in a couple of weeks when that data is presented in Barcelona. So I'm going to conclude in terms of this cardiovascular disease risk. It relates to the metabolic predictors of cardiovascular disease. In terms of any kind of prevention, if you changed nothing, nothing will change. And I think overall we need to take a more aggressive approach to evaluation of our patients and the risk and multiplying the risk factor assessment to not assess one, two or three, but all the potential ones that relate to cardiovascular disease and modifying favorably to evidence based outcomes to achieve the maximum reduction in cardiovascular disease, that's a death. I'm going to thank you so much for joining me. This is the campus where I work overseeing the Rocky Mountains in the background of downtown Denver and more before me. And I want to thank you for joining a webinar and thank you for your attention.