CASE PRESENTATION

J.F. is a 74-year-old man with coronary artery disease (CAD) status post 13 stent placements. He also has had two cardiac valves replaced and has heart failure with reduced ejection fraction (HFrEF; EF of 20%). Additionally, he has obesity (body mass index [BMI], 31.4 kg/m2) complicated by hypertriglyceridemia, hypertension, nonalcoholic fatty liver disease (NAFLD), obstructive sleep apnea, and type 2 diabetes (T2D) with A1c of 6.7%. He is referred for secondary prevention.

Medications include atorvastatin (Lipitor) 40 mg/day, eplerenone, carvedilol, furosemide, lisinopril, aspirin, and prasugrel. On exam, blood pressure is elevated at 176/99, and he is noted to have acanthosis nigricans and lower-extremity pitting edema. Laboratory results are significant for a triglyceride level of 1894 mg/dl, urine microalbumin of 50 mg, high-sensitivity C-reactive protein of 6.93 mg/L, 25-hydroxyvitamin D of 29 ng/ml, homocysteine level of 9.8 μmol/L, and thyroid stimulating hormone of 1.38 mIU/L.

A diet history reveals that he has two servings of fresh fruit and vegetables per day, but primarily consisting of pineapple and oranges.

DISCUSSION

This case presentation and panel discussion took place during the virtual course, Comprehensive Nutritional Therapy: Tactical Approaches in 2021 (Part 1, March 19, 2021; Part 2, March 20, 2021), which was organized by the American Society for Parenteral and Enteral Nutrition (ASPEN) Physician Engagement Committee and preceded the ASPEN 2021 Nutrition Science & Practice Conference. The moderator for this session was Jeffrey I. Mechanick, MD, and the panelists were Christopher D. Still, DO; Mohamed Al-Kazaz, MD; and Timothy Garvey, MD.

1. DrMechanick: What is the overarching diagnosis and context within cardiometabolic preventive medicine?

DrStill: So, as an obesity medicine specialist, everything goes back to obesity. Even though you have described his obesity as mild, or class I (Table 1), I really think that it is affecting a lot of his cardiometabolic issues. Therefore, my focus would be to state that obesity is driving a number of his other comorbid medical problems and to set up realistic expectations for him that his multiple issues can be managed through a focus on obesity treatment.

TABLE 1. Obesity classification and risk stratification Waist circumference and comorbidity risk Classification BMI, kg/m2 Men, ≤40 in (102 cm); women, ≤35 in (88 cm) Men, >40 in (102 cm); women, >35 in (88 cm) Underweight <18.5 Normal weight 18.5–24.9 Overweight 25–29.9 Increased High Obese class I 30–34.9 High Very high Obese class II 35–39.9 Very high Very high Obese class III ≥40 Extremely high Extremely high Abbreviation: BMI, body mass index.

Dr Mechanick: As you review this case, Chris, you are prioritizing the various key mechanistic drivers, and in your opinion, you are judging that obesity and abnormal adiposity are really the primary drivers. Also, by focusing on that, some of the other risk factors come into line; is that correct?

Dr Still: Yes, absolutely, Jeff. What was not listed there is his waist circumference; you know, that is a very important issue, in my opinion, to individualize someone's risk (Table 1). So, irrespective of his BMI, really his waist circumference would be nice to know, because I think that could be a driving factor.

Dr Mechanick: Well, then, how would you manage him differently based on the waist circumference?

Dr Still: From a cardiometabolic standpoint, just a 10% decrease in body weight has a significant 25%–30% reduction in visceral adipose tissue. So, on evaluation, he probably has an android body type given the number of metabolic comorbidities. We usually do not see that with a gynoid body type with higher subcutaneous adipose tissue in lower extremities.

2. Dr Mechanick: How would you classify this patient's obesity, and what would be your approach?

Dr Garvey: I go back to the American Association of Clinical Endocrinology (AACE) obesity treatment guidelines and Chris is right, this is class I obesity (Table 1).1 However, the BMI is really not what is relevant here. It is what the degree of adiposity is doing to his health. And he already has multiple end-stage manifestations of cardiometabolic disease (hypertriglyceridemia, hypertension, NAFLD, obstructive sleep apnea, and T2D). So we are really in a tertiary prevention mode here, and we have to actively treat all of these complications. We could also classify him to be in stage 2, because he has severe complications, as opposed to stage 1, which is mild to moderate, or stage 0, which has no complications.

So AACE would recommend more-aggressive treatment, structured lifestyle intervention, weight loss medicines, and to consider bariatric surgery, but we have got a patient here that is 74 years old. The AACE guidelines also say that we do not have a lot of data for treating obesity in the elderly. And we really need to have clear health-related goals in mind.

Now, it is true that weight loss will help his blood pressure, diabetes, obstructive sleep apnea, hypertriglyceridemia, and NAFLD and may even be renal protective, resulting in a reversal of his microalbuminuria. However, I would be kind of cautious as to how aggressively I would treat the obesity here. I would definitely start with a structured lifestyle intervention, including a reduced-energy diet. Next, I would focus on his diabetes and be selective with medications that improve his A1c and produce weight loss or at least are weight neutral. I do not think I would progress to weight loss medications immediately given his severe heart disease, despite the fact that his CAD is stable.

Another factor that needs attention right away is his hypertriglyceridemia, as it is in a range at which he is at risk of developing hemorrhagic pancreatitis. So I think, yes, obesity is underlying a lot of these problems. However, this is a very complex case, and I think we have to move cautiously and manage all of these end-stage complications in concert with each other. As we make management decisions, we have to keep in mind that these comorbidities all affect each other and the treatment for each individual disease will impact the treatment of the other.

Dr Mechanick: So let me just hone in a little bit more, because for the audience, thinking about managing a complex patient with significant comorbidities is kind of scary. This patient really represents the extreme of cardiometabolic risk. My question back to you, Tim, is do you approach this patient with the presumption that there is one main driver of disease and that is where you should focus? Or do you approach this patient—that in fact there are the three, four, or five drivers of disease and should be approached concurrently?

And given that context, what is the role of first optimizing his lifestyle, and particularly the nutrition aspect, including the types of foods that he is consuming and the granularity of the nutrition recommendations within the context of all those different metabolic syndrome traits? I know it is a complicated question, but unfortunately, this is the reality of managing a patient like this in your practice, with perhaps a visit that is limited to 15 min.

Dr Garvey: Yes, he has multiple drivers, including adiposity-based chronic disease, dysglycemia, and insulin resistance, just to name a few. However, they have now all come to a head in this elderly individual and require aggressive management, active management of his heart disease, blood pressure, hypertriglyceridemia, diabetes, NAFLD, and renal function, including microalbuminuria. We have to work together on the management of all of these diseases and treat them aggressively. Of course, lifestyle will be important and favorably impact all of these, so that is definitely something we want to do. We would start with a reduced-energy diet and perhaps even present him with a healthy meal plan. In terms of the dietary composition, a Mediterranean pattern would be ideal given his comorbidities.

3. Dr Mechanick: How would you manage this patient's T2D?

Dr Garvey: He has an A1c in the diabetes range, and I would just confirm that with a fasting blood glucose. Once confirmed, most of the guidelines would state that the first-line medication would be metformin. However, we would also want to consider constellations of comorbidities, especially congestive heart failure, cardiovascular disease, or renal disease, and consider starting with a medicine that can address those issues as well as his diabetes. Keeping that in mind, I would think about two classes of medications. The first would be Glucagon-Like Peptide 1 (GLP-1) receptor agonists, and the second would be Sodium-Glucose Co-transporter-2 (SGLT2) inhibitors.

Now, certain GLP-1 receptor agonists have been shown to be cardioprotective, particularly liraglutide, semaglutide, and dulaglutide. These drugs can also prevent adverse renal outcomes. Although GLP-1 receptor agonists should be considered, these drugs do not decrease hospitalizations for congestive heart failure, which is a major problem in this patient.

The SGLT2 inhibitors, by contrast, are cardioprotective and renal protective and will also lower the blood pressure and decrease the risk of hospitalization for congestive heart failure. So, given this patient's complex list of medical problems, I would probably start him on an SGLT2 inhibitor, either canagliflozin or empagliflozin, which have been shown to be cardioprotective in cardiovascular outcomes trials. Dapagliflozin could also be considered because treatment is associated with benefits regarding blood pressure, congestive heart failure, and renal function. Although dapagliflozin did not quite achieve superiority for the composite major adverse cardiac events (MACE) outcome in the DECLARE study, it was shown to reduce the risk of cardiovascular disease events in those patients with long-standing diabetes.2 I would start with a low dose, because this class of medications will decrease plasma volume. This patient's hemodynamics are questionable, as his EF is 20% and he is on a number of other medications. So I might start with either 10 mg/day empagliflozin, 5 mg/day dapagliflozin, or 100 mg/day canagliflozin, in addition to the lifestyle modifications. That is probably how I would address his diabetes.

Dr Mechanick: So let me just challenge this a little bit. We have heard that obesity is the main driver here, although we are taking care of all the different comorbidities together. We know that there is more weight loss with the GLP-1 receptor agonists compared with SGLT2 inhibitors. So why are we prioritizing the heart failure over the weight loss?

Dr Garvey: Yes, I am prioritizing two things, but one is definitely his congestive heart failure. The cardioprotection is about the same with both classes of drugs. There is a hazard ratio of approximately 0.86, translating to a reduction in cardiovascular events by 13% or 14% for both of these drug classes. However, the severity of CAD (13 stents), the valvopathy (two valve replacement), and the congestive heart failure (EF ∼20%), despite being medically optimized, are what could kill him. Because of this, I want to prioritize medications that address heart failure and diabetes. It is only because of his age and his advanced and precarious cardiovascular disease status that I would not pursue highly aggressive weight loss, at least not immediately.

4. Dr Mechanick: What is the relevance of the severe hypertriglyceridemia, and how would you manage it? Specifically, is his hypertriglyceridemia a driver or is it a marker? How aggressively would you manage this, and should you still focus on low-density lipoprotein (LDL)?

Dr Al-Kazaz: It is very important to point out that this man has CAD that is extensive, and he is currently taking atorvastatin 40 mg/day. Additionally, hypertriglyceridemia is independently associated with cardiovascular events. However, whether hypertriglyceridemia is categorized as a main driver or as a marker has always been controversial. I believe this back-and-forth debate really occurs because reduction of hypertriglyceridemia with medications such as fibrates on the background of statins has never been shown to change cardiovascular outcomes. A recent clinical trial evaluated the reduction of triglycerides in high-risk patients with diabetes or CAD using eicosapentaenoic acid (EPA; as icosapent ethyl [IPE]). The placebo in the trial was, unfortunately, mineral oil, which has its own tolerance problems. There was clinical benefit in that trial, with reduction of triglycerides in the background of optimal LDL reduction medication with statins.

So there is definitely some benefit in treating his hypertriglyceridemia with EPA. Additionally, in a patient with CAD, one of our goals is to address the residual risk and whether it is targeting inflammation, hypertriglyceridemia, or lipoprotein(a), among many other things. So it is not something we ignored.

However, the first line of defense for hypertriglyceridemia, which I cannot emphasize more, is lifestyle modification resulting in weight loss. Hypertriglyceridemia is driven by high–glycemic index foods, alcohol intake, and medications, as well as other conditions such as thyroid disease. So controlling all of these variables prior to initiating pharmacotherapy directly targeting hypertriglyceridemia is very important. In his case, his triglyceride level is severely elevated well over 1800 mg/dl. So, in addition to cardiovascular risk, we also have to consider his risk of pancreatitis. Despite this risk, I have seen, in many cases with a triglyceride level above 1000 mg/dl, if there is modification of diet including stopping consumption of “junk” food, decreasing sugar intake, and decreasing alcohol consumption, we can see dramatic improvement in triglycerides, especially if dietary changes result in weight loss.

In addition to lifestyle modification, I also want to ensure that LDL level is optimized. LDL is the main cardiovascular risk factor, and in someone with known CAD, we use high-dose statins to ensure the LDL level is <70 mg/dl. Actually, with data from recent trials using proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) inhibitors, there is a big movement to consider lowering the LDL to <55 mg/dl.

After lifestyle modification and optimization of LDL, if the triglycerides remain elevated, then most likely we are dealing with a genetic predisposition or disorder with mendelian inheritance. In this situation, we then can use medications targeting hypertriglyceridemia. We can consider fish oil, such as EPA/IPE or fenofibrate, which I prefer over other fibrates, to minimize the risk of liver and/or muscle injury when combined with statins.

To summarize my treatment approach, lifestyle and risk factor modification with dietary changes and increases in physical activity level, along with optimization of LDL, remain the first line. If triglycerides still remain elevated, then consider medications targeting hypertriglyceridemia.

5. Dr Mechanick: How would you manage this patient's hypertension?

Dr Al-Kazaz: As I mentioned earlier, this man obviously has a high risk for cardiovascular death and/or readmission to the hospital from a coronary artery and heart failure standpoint. So controlling high blood pressure is important to prolonging his life, as well as to improve his quality of life. So, obviously, after we exhaust lifestyle interventions, I would optimize his blood pressure medications by utilizing medications that have been shown to be effective in patients with HFrEF. Assuming he has ischemic cardiomyopathy, because he is on carvedilol, eplerenone, and lisinopril, I would utilize new-generation drugs for diuresis because he has pitting edema and his blood pressure is elevated. This will improve his blood pressure and help reduce his sodium retention. Once he is euvolemic, we can start introducing new agents that have demonstrated improved outcomes.

As an example, instead of being on lisinopril, I would recommend him switching to a combination of sacubitril (a neprilysin inhibitor) and valsartan (an angiotensin receptor antagonist). Both of these are antihypertensive medications but have also been shown to help with remodeling and antifibrotic effects on the heart, along with some diuretic effects. This allows us to obtain multiple benefits including blood pressure control, as well as mortality benefits and a reduction in hospitalization in patients with HFrEF. Additionally, the combination of sacubitril and valsartan has been shown to reduce hospitalization in those with heart failure with preserved EF.

We would also target his other medications as well. As an example, dapagliflozin in patients with HFrEF has been shown to decrease hospitalization for heart failure and decrease cardiovascular mortality.3 Dapagliflozin, like other SGLT2 inhibitors, would also have some blood pressure effect, and this would be ideal to start at low doses, such as 5 mg/day.

To summarize, I would start by using guideline-directed medical therapy for heart failure, which includes optimizing his carvedilol to the highest dose possible, switching from lisinopril to a combination of sacubitril and valsartan, optimizing eplerenone, and having him undergo diuresis, as well as adding an SGLT2 inhibitor. With these changes, we hope to optimize his volume status, achieve blood pressure reduction, and modify his risk factors, resulting in improvement in both quality and quantity of life.

Dr Mechanick: Great; thank you, Mohamed. So we can see that these pleiotropic effects of these new agents not only have metabolic effects but also have effects directly on the cardiovascular system, strategically help everything to converge, and take care of multiple metabolic syndrome traits. I think the point that I want to get across is that although it is very onerous, when you hear about this at the beginning with multiple risk factors and drivers, because we have interventions that sort of affect each of the various nodes in this cardiometabolic network, we are able to help the patient.

6. Dr Mechanick: Is progression of the coronary heart disease reversible, not only the atherosclerotic but the myocardial component as well?

Dr Al-Kazaz: Yes, it is reversible. Of course, the earlier we intervene, the better the outcome we have. The later-stage advanced cardiomyopathies or advanced CAD require more-intensive therapies, such as left ventricular assist device, heart pumps, or transplant. However, for the majority of the population who are not this far advanced, coronary heart disease can be reversible, controllable, and modifiable by addressing risk factors with lifestyle changes and secondarily using pharmacological therapies that have been proven, with large trials, to change outcomes.

For example, let us look at ischemic cardiomyopathy with low EF, such as in this man with an EF of 20%. We have seen many cases in which you optimize carvedilol to 25 mg twice per day, sacubitril/valsartan 97/103 mg twice per day, and eplerenone to 50 mg once per day, as well as adding SLGT2 inhibitors; you achieve not only blood pressure benefit but also hemodynamic effects and, in turn, help with left ventricular (LV) remodeling and antifibrosis, leading to a reduction in LV size. Even in cases when there is not a reduction in LV size, patients can feel better and stay out of the hospital longer. So I would say that coronary heart disease is reversible—it is preventable. The earlier the better.

We just need to be aggressive and address all of the drivers of the heart failure, which, in this patient, could be his obesity leading to diabetes, dyslipidemia, hypertension, and eventually coronary heart disease. We need to make sure we address the risk factors that can lead to progression of CAD, including lowering LDL, controlling inflammation, controlling diabetes to the lowest possible point without side effects, and using agents with multiple benefits, as discussed previously. It is also essential to do this through a multidisciplinary approach and not just targeting a drug for cardiology or endocrinology or calling in a weight loss specialist. It is in the pleiotropic drugs that have inotropic effects that we all get comfortable using them and help each other to reach a stage at which we maximize those medications in the background of aggressive lifestyle modification. It is those drugs that have been shown to help stop the progression of disease and even regress it and improve heart outcomes.

Dr Garvey: To add to what Mohamed is saying, a triglyceride level near 2000 mg/dl already implicates a genetic contribution, so I would be more aggressive initially. I would utilize a more potent statin, either maximal-dose atorvastatin or rosuvastatin. I would also add fish oil (EPA/IPE) right away, along with intensive lifestyle modifications. Assuming that this patient is not consuming a great deal of alcohol, how much benefit can we achieve through lifestyle modifications?

Dr Al-Kazaz: With this degree of hypertriglyceridemia, there is a strong genetic component, and thus, I would agree with you in that we should be quite aggressive from the beginning. He already has severe indications for high-dose statins, whether it is atorvastatin 80 mg/day or rosuvastatin 40 mg/day. He also meets the criteria from the REDUCE-IT (Reduction of Cardiovascular Events With EPA—Intervention Trial) trial to initiate EPA/IPE.4 So I would start with these medications along with intense lifestyle modifications and see what happens to his triglyceride level. Adding fenofibrate to this drug combination may not change the cardiovascular risk profile; however it might lower the triglyceride level enough to provide protection from pancreatitis. In this situation, lifestyle modifications alone would not be sufficient; however, it is important for us to emphasize that these medications work best on top of a foundation of a healthy lifestyle. So lifestyle modifications must be our first-line treatment.

7. Dr Mechanick: Thank you, Mohamed. This is a patient I have been following for some time. We did initiate high-dose EPA/IPE from the very beginning and continued with the atorvastatin. The triglycerides came down to 732 mg/dl and plateaued there. Additionally, the LDL remained at 144 mg/dl. Would you now consider transitioning this patient to evolocumab or alirocumab?

Dr Al-Kazaz: On a maximum dose of atorvastatin or rosuvastatin, based on data from the IMPROVE-IT trial, you would add ezetimibe 10 mg/day.5 It has a small benefit of reduction in LDL and improvement in cardiovascular outcomes. However, if despite use of maximal-dose statin along with ezetimibe, LDL continues to remail high, then we do need to transition to using PCSK9 inhibitors to achieve an LDL goal of <70 mg/dl if not as low as 55 mg/dl. In my interpretation of data from PCSK9 inhibitor clinical trials, it is safe to achieve that low of an LDL level, and it helps with plaque regression.

8. Dr Mechanick: What would be your approach to implementing structured lifestyle change? Can you provide three or four of the most important aspects regarding intensive lifestyle intervention or structured lifestyle change for this particular patient with very severe cardiometabolic disease?

Dr Still: First, I think everyone is in full agreement that lifestyle modifications are going to be very important. So, as Dr Garvey alluded to initially, focusing on the Mediterranean diet would be very important and beneficial for this gentleman. I would have him work with a registered dietitian to really understand why it is important for him and to begin implementing the Mediterranean diet in a manner that he can adhere to.

Second, I think avoiding all energy-dense beverages, especially alcohol, will be very important because of their association with insulin resistance, T2D, and hypertriglyceridemia.

Third will be to decrease how sedentary he is and try to increase physical activity as much as possible. I would recommend doing so in a way that he will be successful. What I mean by that is often when people think of increasing physical activity, they try to reach their goal of 30 min per episode or 150 min of moderate intense activity per week right away. This can lead to failure or injury. So I usually recommend starting by assessing what his current exercise tolerance is. Then, if the goal is 30 min per day, I would recommend breaking it up into smaller episodes such as 10 min three times per day or even 5- or 6-min intervals multiple times per day. I think that is much better tolerated, more realistic, and something he can adhere to in the long term.

Fourth would be to make sure his other obesity-related comorbidities are optimized, especially his obstructive sleep apnea. That is one disease that is often underdiagnosed and undertreated and can have tremendous ramifications for his cardiovascular disease, his daytime hypersomnolence, and overall well-being.

9. Pat Anthony asks a question from the audience: What about fruit consumption, especially fruits that have a high glycemic index? Should he be allowed to consume as he desires, or would that lead to overeating or worsening of his diabetes, obesity, etc?

Dr Still: This is a key question, as we need to focus on diet quality and not just reduction in energy consumed. That is why I previously recommended working with a dietitian not just to receive a meal plan but to have the patient understand the key components of a Mediterranean diet and how it can improve the diseases he has. Lifestyle modification is a two-way street, and we have to make sure there is buy-in from the patient. If we simply say this is what you should and should not eat, it will not be followed long-term without the patient understanding the “why.”

10. Dr Mechanick: Is there sufficient clinical evidence that a Mediterranean diet is going to be able to have significant benefit for this patient, including a reduction in inflammation, improvement in adipokines, and decrease in insulin resistance?

Dr Garvey: We do have data on reduction in adipose tissue cytokines. We do not have real rigorous data on insulin resistance but do have some data indicating that a Mediterranean diet can prevent progression of diabetes, which really implies a beneficial effect on insulin sensitivity. The two robust clinical trials I am thinking of are the PREDIMED study6 and the Lyon Diet Heart Study.7 There have also been some semirandomized clinical trials showing that the Mediterranean diet pattern can be cardioprotective and prevent diabetes. However, it is difficult to conduct large-scale, randomized prospective studies in free-living individuals over a period of 10 years. That is the real challenge in evaluating the long-term benefits of diets. Despite these drawbacks, I do feel that a Mediterranean diet has the best data we have available.

11. Dr Mechanick: What about the polyphenol content in the Mediterranean diet and effects on sirtuins and other molecules? Are there sufficient data to support this mechanistic benefit?

Dr Garvey: To be honest, we do not really know what the mechanisms are that translate into these benefits with respect to outcomes. There are significant data available with isocaloric substitutions of one macronutrient for another regarding insulin sensitivity via clamp trials. When I review these data, dietary fiber, long-chain fatty acids, and especially polyunsaturated fatty acids (PUFAs) are the key components of dietary intake. In an isocaloric manner, when you substitute PUFAs for saturated fatty acids, whole grains for refined grains, and high fiber for low fiber, you can improve insulin sensitivity significantly. A Mediterranean diet incorporates these key principles.

Dr Still: Another option we should consider is a vegan diet. It can be harder to adhere to for some individuals but can also have significant benefit.

12. Dr Mechanick: Is there a role for a bariatric procedure, and if so, which one and why? Also, would his age or heart disease impact your decision to recommend bariatric surgery?

Dr Still: If we start with age, we have done bariatric surgery in 74-year-old patients, and so age is no longer a contraindication to bariatric procedures for me. With a current BMI of 31 kg/m2, this gentleman does not meet the current recommended criteria for bariatric surgery: BMI ≥40 or ≥35 kg/m2 with obesity-related comorbidities. However, if he were a bit heavier, then I would consider bariatric surgery.

There are other procedural options such as the intragastric balloon (IGB). However, IGB tends to be short-term, as it needs to be removed after 6 months and there can be side effects such as significant nausea early on.

Dr Mechanick: Let me push back a bit in light of the STAMPEDE (Surgical Therapy And Medications Potentially Eradicate Diabetes Efficiently) trial8; not withstanding the economics, as he can pay out of pocket, would you reconsider your answer? There has been some improvement, but he has not been able to lose weight despite our recommendations. So would you reconsider a sleeve gastrectomy or Roux-En-Y gastric bypass?

Dr Still: To be honest with you, I would not modify my answer. I just think he is pretty high risk because of his cardiovascular status, and so I would not recommend surgery. I would try to be more aggressive with his lifestyle modification and consider adding antiobesity medications such as a GLP-1 receptor agonist and see how much weight loss we can achieve.

13. Dr Mechanick: What is needed to prevent cardiometabolic disease progression on a population scale?

Dr Garvey: That is a good question, and I think we have to consider the drivers of cardiometabolic disease. To me, it begins with insulin resistance and the insulin-resistant state, which incorporates an inflammatory portfolio of processes affecting vascular reactivity, adipose tissue function, dysregulated secretion of adipokines, and the accumulation of ectopic fat in muscle and liver. Then, of course, obesity can further exacerbate insulin resistance and the insulin-resistant state. So, if we consider those as the primary drivers of cardiometabolic disease, then for primary disease prevention we have to focus on public health messaging on maintaining a lean BMI, appropriate physical activity, and healthy dietary patterns. All of these can prevent further disease progression.

Over much of the life cycle, the insulin-resistant state is subclinical. However, eventually, it does give rise to certain clinical diseases, such as metabolic syndrome or prediabetes. When prediabetes occurs, we then add a glycemic driver in addition to perhaps dyslipidemia associated with insulin resistance, prehypertension or hypertension, and ventral adiposity, as well as hepatic steatosis. Now, we are in secondary prevention mode. In these individuals, who are often overweight or obese, 10% weight loss is maximally protective and effective in preventing disease progression. We also have to aggressively treat other risk factors such as LDL and blood pressure.

However, when we have progressed to end-stage manifestation of cardiometabolic disease process, such as diabetes, we know that we are at risk for developing all of the other ones and have to engage in aggressive prevention. Unfortunately, in this man, we are at end-stage manifestation, as he has CAD, poorly controlled hypertension, diabetes, dyslipidemia, and NAFLD. Now, we are at the stage of tertiary prevention at which we have to manage all of these end-stage manifestations because the presence of one feeds back and exacerbates the others. For example, diabetes worsens CAD atherogenesis as well as NAFLD, which itself increases cardiovascular risk. So, in this state, it is really aggressive active management of all of these processes together, as we have been discussing.

Dr Mechanick: Great, thank you. All right, with that, I would like to close out this session and thank our speakers, Dr Chris Still, Dr Mohamed Al-Kazaz, and Dr Tim Garvey; and hopefully, everybody has found this to be a worthwhile program.

FUNDING INFORMATION

The content of this article was presented during the virtual course, Comprehensive Nutritional Therapy: Tactical Approaches in 2021 (Part 1, March 19, 2021; Part 2, March 20, 2021), which was organized by the ASPEN Physician Engagement Committee and preceded the ASPEN 2021 Nutrition Science & Practice Conference. The author(s) received a modest monetary honorarium. The conference recordings were posted to the ASPEN eLearning Center https://aspen.digitellinc.com/aspen/store/6/index/6.

AUTHOR CONTRIBUTIONS

Manpreet S. Mundi, Jeff I. Mechanick, and Jayshil J. Patel contributed to conception or design. Manpreet S. Mundi contributed to acquisition, analysis, or interpretation of the data. Manpreet S. Mundi drafted the manuscript. Jeff I. Mechanick, Jayshil J. Patel, Mohamed Al-Kazaz, W. Timothy Garvey, and Christopher D. Still critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.