Q&A Sessions on Cardiometabolic Risk: Lipid Disorders, Diabetes, Obesity, and Hypertension
Introduction
As the chair for the Cardiometabolic Risk Summit, which will be held this coming September in Las Vegas, I am very excited about this meeting and our partnership with Consultant and NACCME (North American Center for Continuing Medical Education) in making it successful. We think those who attend will get an up-to-date, pragmatic view of how to address cardiometabolic risk factors and syndrome in the primary care setting. We’re focusing on family physicians, general internists, and physicians who are generalists, as well as nurse practitioners, physician assistants, and anyone else who has a strong interest in helping patients deal with the cardiometabolic risks that are so common today.
Cardiometabolic risk and metabolic syndrome have many similarities. Metabolic syndrome highlights five areas: waist circumference, blood pressure, blood glucose, high-density lipoprotein cholesterol (HDL cholesterol), and triglycerides.1 Cardiometabolic risk involves not only these five areas, but also family history, tobacco use, obesity, low-density lipoprotein (LDL) cholesterol, nutrition, and physical activity. This conference will provide an overview of the cumulative impact of all these factors on cardiometabolic risk.
The meeting will be divided into four sections. The first section will be a general discussion of cardiometabolic risk: we will review the epidemiology and look at ways we can assess risk and debate the cost-effectiveness of the more advanced testing options.
The next morning, we will undertake an in-depth review of diabetes and pre-diabetes. That will be followed in the afternoon by discussion of hypercholesterolemia and the dyslipidemias. The following morning we will look at hypertension. And then that afternoon we will close out the conference with a review of obesity, which underlies or is involved with all of these risk factors.
The conference will feature great workshops, Q&A sessions following the plenaries, and an audience-response system to give attendees the chance to participate and to interact. So, there will be plenty of opportunities for all attendees to ask questions and be involved. Because of the way the meeting has been set up, I think that everyone will have a very stimulating and entertaining time. But, most important, they will go home with pragmatic solutions to some very challenging problems. Our goal is to have all attendees leave with a comprehensive knowledge of how to understand and treat cardiometabolic risk.
They will also learn how to help at-risk patients help themselves. Patient involvement is crucial to the effective management of cardiometabolic risk. The sessions at the conference will show primary care clinicians how to provide information to their patients—in terms patients can understand—that can enable and empower them to manage their risk factors.
Here, in this series of interviews, I and two of the faculty members at the conference, Dr Tara Dall and Dr Steven Milligan, will answer some frequently asked questions about lipid disorders, diabetes, obesity, and hypertension. We will go into these topics in much greater depth at the Cardiometabolic Risk Summit.
References
1. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
Lipid Disorders With Edward Shahady, MD
Q: What is the most effective means of reducing low-density lipoprotein (LDL) cholesterol levels?
A: The foundation of any treatment plan is lifestyle changes: exercise and nutrition. However, nutrition influences only about 25% of LDL-C levels, so patients who have additional risk factors, such as diabetes and hypertension, need something in addition to lifestyle changes. That’s where the statin drugs come in: they are most effective in lowering LDL. We have excellent studies—epidemiological, observational, as well as randomized, controlled trials—that demonstrate that if we reduce LDL, we reduce cardiovascular risk. So, lifestyle changes plus statins are the key way to lower LDL.
Statins not only reduce LDL, but they also help with the inflammatory process that is rampant in every one of the elements of cardiometabolic risk. Lifestyle changes also reduce inflammation. Paying attention to saturated fats and trans fats is the key, so we try to help our patients understand that and encourage them to eat a reasonably healthy diet in addition to taking statins and other drugs if the statins don’t work, or if they can’t tolerate statins, to reduce LDL.
Q: What are some of the obstacles to the use of statins?
A: Statins in general are associated with a very small risk of diabetes, which we will discuss in a workshop at the Cardiometabolic Risk Summit on the risks and benefits of statin therapy. As for cost, a number of statins are now available as generics, such as atorvastatin, simvastatin, lovastatin, and pravastatin, so we have great opportunities for treatment at low cost.
Because myopathy is common in people who have chronic diseases, especially diabetes, and in those who are obese, the first thing we have to do is educate patients. Is the myopathy secondary to the statin? If the patient believes this, many times we can just switch the statin and that seems to eliminate much of the problem.
Occasionally, we have patients who are unable to tolerate statins. We have other drugs that we can use to reduce cholesterol, such as ezetimibe and some of the bile acid resins, but unfortunately they are not associated with any data that demonstrate risk reduction in cardiovascular events, even though they will lower LDL. With the first dose of a statin we can get a 25% to 35% reduction in LDL level; with ezetimibe it comes out to about 18%.
Q: Under what circumstances is non–high-density lipoprotein cholesterol (non-HDL cholesterol) a more precise therapeutic target than LDL cholesterol?
A: I am very interested in helping clinicians understand the value of non-HDL cholesterol, which is simply total cholesterol minus HDL. Why is that of value? Since 2001 the NCEP (National Cholesterol Education Program) has emphasized non-HDL as a target when the triglyceride level is over 200 mg/dL.1 And we’ve now had recent data published in JAMA in March of this year that show non-HDL cholesterol is a better predictor of cardiovascular events than LDL-C and apolipoprotein B.2
What we’re trying to do is to identify not just the amount of lipid levels that are toxic but the small dense LDL, the more atherogenic LDL, and non-HDL is a good surrogate for the small dense LDL. And that’s the LDL that can get into the artery wall and that can lead to more plaque.
What happens is that an inflammatory environment exists in patients with diabetes, with hypertension, and with obesity; this inflammation permits the LDL to get into the artery wall and cause plaque to form. So statins not only reduce LDL levels and inflammation, they also stabilize the plaque.
Q: What is the best approach for lowering non-HDL cholesterol?
A: It’s the same approach we use to lower LDL: statins and lifestyle changes. The goal for non-HDL-C is 30 mg/dL higher than the goal for LDL-C. So if my LDL goal is 100 mg/dL, my non-HDL goal is 130 mg/dL.
Because most of the time we obtain the LDL-C level through a calculated LDL-C, the LDL may be low—say, it will 100 mg/dL—when patients have high triglycerides, but the non-HDL-C will be 150 or 180 mg/dL as a result of the elevated triglycerides. So, lifestyle changes and statin therapy are the best way to get non-HDL-C down. Of course, you can lower the triglycerides in patients who have diabetes by treating the hyperglycemia. It’s a multifactorial issue we have to deal with.
Q: What is the optimal strategy for raising HDL levels?
A: That has been the challenge for us as clinicians for a long time. We know that lifestyle modification is a great way to do it: exercise, moderate alcohol intake, not smoking, and decreasing dietary fat raise HDL. We also have some medications that help: niacin increases HDL. One of the problems is we don’t know if that HDL is what we call functional. In fact, over the last year or two we have begun to appreciate functional and nonfunctional HDL. If we have a patient who has very high HDL, but is hypertensive, smokes, and has diabetes, the HDL may be nonfunctional. That’s because it exists in an inflammatory environment that may decrease the reverse cholesterol function of HDL.
A recent study raises questions about the value of increasing HDL with a medication (niacin): the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health) study.3 The patients in the study were given a statin and ezetimibe if needed to reduce LDL levels to less than 70 mg/dL. We will discuss the results of this study at the conference. The AIM-HIGH bottom line was that niacin does not make a difference in lowering mortality. This raises the question of whether you can still obtain a benefit once you drive LDL down very low.
We also have some new drugs called CETP (cholesteryl ester transfer protein) inhibitors. Unfortunately, one drug in this class, torcetrapib, caused more mortality. However, for the new drugs in this class, initial studies show positive effects in the small numbers of people who were treated. We will look at larger studies that are now being conducted, which may show these drugs can raise HDL tremendously. We are all excited about that potential, and we’ll talk about it at the conference.
Q: Looking ahead, what are your thoughts about the coming update to the ATP NCEP III?
A: The ATP (Adult Treatment Panel) NCEP III guidelines were published in 2001,1 and then there was an addendum in 2004.4 A new recommendation is supposed to be released this year. We think non-HDL is going to be much more highly emphasized, and we are probably going to look at new ways to assess risk. Hopefully, it will be published by September, and we’ll be able to discuss highlights of the new recommendation at the conference.n
REFERENCES:
1. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
2. Boekholdt SM, Arsenault BJ, Samia Mora S, et al. Association of LDL cholesterol, non–HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA. 2012;307(12):1302-1309.
3. The AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255-2267.
4. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110(2):227-239.
Diabetes With Edward Shahady, MD
Q: What is the role of beta cell regulation in the initiation of type 2 diabetes?
A: That is really the key question because what we have learned over the past 10 to 20 years is that beta cell failure leads to diabetes. In type 1 diabetes, it’s a complete failure of the beta cell, or close to a complete failure. In type 2 diabetes, it starts with resistance to the effects of insulin.
In many patients with type 2 diabetes, insulin resistance is related to obesity, although not always. The basic cause is genetic: patients have a predisposition and become inactive and obese, or at least gain weight, and their beta cells start to produce more insulin. Because their body is resistant to insulin, they produce more. Over time, the beta cell becomes exhausted, but not completely exhausted. At a certain point patients no longer produce enough insulin to overcome the insulin resistance. And that’s when the blood glucose level becomes elevated.
We are now beginning to understand more clearly the role the alpha cell plays in the development of type 2 diabetes. Glucagon secreted by alpha cells raises blood glucose levels. Incretins inhibit glucagon release from the alpha cells, and we will discuss incretin-based therapy with GLP-1 (glucagon-like peptide-1) agonists and DPP-4 (dipeptidyl peptidase 4) inhibitors in adults with type 2 diabetes at the conference.
We used to think that beta cell failure was inevitable in type 2 diabetes and that all patients would eventually need insulin. We now believe that some drugs may slow or forestall progression, and this is something we are going to discuss during the conference.
Q: Is there a role for beta cell preservation in therapeutic strategies for patients with type 2 diabetes?
A: The clear data we have come from animals, so we have to be careful, although some human studies seem to indicate we can preserve function. We now have better tools, most of them research tools, to evaluate beta cell function. Animal studies indicate that the following drugs may help preserve beta cells: GLP-1 agonists, such as exenatide and liraglutide; and the DPP-4 inhibitors, such as sitagliptin, saxagliptin, and linagliptin.
Q: What is the role of the newer drug classes in therapy today, and when should they be started?
A: Diabetes treatment should start with lifestyle changes and metformin. The newer classes like GLP-1 agonists and DPP-4 inhibitors can be added as the second drugs. The DPP-4 inhibitors aren’t quite as powerful as the GLP-1 agonists in reducing hemoglobin A1c (HbA1c) levels: you might get a 0.5% or 0.6% reduction in HbA1c with them versus about a 1% drop (say, from 8% to 7%) with the GLP-1 agonists, depending on the level of the baseline HbA1c .
After you start the patient with lifestyle changes and metformin, it depends on how much of a further decrease in HbA1c is needed. If only a 0.5% decrease is needed, I think a DPP-4 inhibitor is a good addition. If you need more than 0.5%, I would use a GLP-1 agonist, especially if the patient is overweight.
One of the other exciting areas is the use of GLP-1 agonists with basal insulin. Both exenatide and liraglutide have recently been approved by the FDA to be used with basal insulin. Insulin use is often associated with hypoglycemia and weight gain. Combining a GLP-1 agonist and insulin will decrease the incidence of hypoglycemia and decrease weight gained with insulin.
GLP-1 agonists increase insulin release from the pancreatic beta cell and decrease glucagon secretion by the alpha cell. Glucagon increases hepatic production of glucose, and in type 2 diabetes glucagon secretion is inappropriately increased. These drugs are also associated with a reduction of lipids and blood pressure.
Q: How should cardiovascular risk be considered when choosing an antihyperglycemic regimen?
A: The ACCORD (Action to Control Cardiovascular Risk in Diabetes) study was supposed to show that we can reduce cardiovascular risk by reducing HbA1c. In fact, the ACCORD study showed the opposite: there was an increase in cardiovascular risk.1 The ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) study2 and the VADT (Veterans Affairs Diabetes Trial)3 had neutral results, but they didn’t show a hoped-for reduction in cardiovascular mortality.
The UKPDS (United Kingdom Prospective Diabetes Study), published in the late 1990s, did show a reduction in cardiovascular risk.4 Here’s the key: patients in the UKPDS had newly diagnosed diabetes, while all three of the other studies—ACCORD, ADVANCE, and VADT—were conducted in patients who had had diabetes for a longer time.
So, what we now know is that if a patient has newly diagnosed diabetes and if they have no cardiovascular risk factors, are not frail, and have good resources, we want to get the HbA1c down as low as we reasonably can. But if the patient is older, frail, has co-morbidities, and prior cardiovascular events, the HbA1c goal will be higher. However, if a patient is in a nursing home, we don’t want the HbA1c to be very high, because hyperglycemia causes polyuria. In an older, frail patient, an HbA1c of 8% is acceptable, whereas in others, it should be reduced to 7% or 6.5%. Safe HbA1c reduction to avoid hypoglycemia, especially when using insulin, is critical. Patients who have been diabetic for several years may have hypoglycemia unawareness; in other words, they are not aware their blood glucose is approaching dangerously low levels.
Again, you can’t treat any one of these factors in isolation. In addition to hyperglycemia, patients may have high blood pressure and dyslipidemia, and they may be obese. To have two of these four risk factors at the same time is not unusual, and this is something that we’re going to be stressing at the conference: the interplay of these factors in cardiometabolic risk.
Q: What are some of the barriers to initiation and intensification of diabetes therapy?
A: We do have barriers, and I prefer to use the term “barriers” rather than “compliance.” One of the speakers at the conference, Martha Funnell, will discuss this further. She published an article in which she said that words like compliance are dysfunctional in diabetes, because they indicate blame.5
One of the reasons patients don’t want to start insulin is that they believe they’ve failed, because we say to them, intentionally or unintentionally, “If you don’t get your blood sugars under control, we’ll have to start you on insulin.” The patient then feels like a failure.
Diabetes involves dramatic lifestyle changes: the patient will probably have to be on multiple medications and they are going to have to follow dietary restrictions and an exercise regimen, so it takes time, maybe a year or even 2 years, to really educate the patient. That’s why we need diabetes educators, and well-educated office staff, to help us. It’s a tough disease, and it’s very difficult to overcome.
Sometimes we as clinicians experience what we call clinical inertia; when we face these barriers, we become frustrated. We feel that nothing further can be done. We need to have confidence in our patients and help them deal with their issues and understand that it’s a very difficult process.
I like to say that it takes a village to care for a patient with diabetes. It’s not only me and my office staff, but the family and all the other people who are involved: the pharmacist, the diabetes educator. We have to function as a team, and the most important player on the team is the patient.
So, we need to empower patients. And we’re going to address that a great deal at the conference because adherence to everything we have talked about—medication, exercise, nutritional changes—is critical.
REFERENCES:
1. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559.
2. ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.3. Duckworth W, Abraira C, Moritz T, et al; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-139.
4. Holman RR, Paul SK, Bethel MA, et al. 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-1589.
5. Anderson RM, Funnell MM. Compliance and adherence are dysfunctional concepts in diabetes care. Diabetes Educ. 2000;26(4):597-604.
Obesity With Tara Dall, MD
Q:What is the relationship between obesity and other conditions, such as cancer, diabetes, cardiovascular disease, and premature mortality?
A: There is an obesity epidemic in the United States and indeed throughout the world. If we look at the CDC statistics on obesity, very closely following the footsteps of this obesity trend is a diabetes pandemic, so we know that it is very closely related.
At the root of type 2 diabetes is insulin resistance. We also recognize that insulin resistance contributes to many other diseases, including cardiovascular disease, cancer and even Alzheimer’s disease.
Q: What are some effective strategies for identifying and treating secondary causes of obesity, such as various medical conditions and medications?
A: At our clinic, Advanced Lipidology, one of the first things we do is try to identify secondary causes of patients’ weight problems, as well as genetic lipid and metabolic disorders. The root cause of obesity may in part be a “brewing insulin resistance syndrome,” or prediabetic state, or potentially an underactive thyroid, and there are many ways we can then intervene once the root cause is understood.
Often, people are eating the wrong kinds of foods: for example, they are eating a significant amount of carbohydrates. Although a low-fat diet is very commonly recommended, we found that, clinically, it actually doesn’t work that well for patients with insulin resistance and obesity. In fact, a low-carbohydrate diet works much better, so one of the things we need to look at is diet and we certainly need to assess the patient’s level of physical activity.
But part of what we do—and I think the magic of what we do—is to identify with blood testing insulin resistance, especially at the early stages. If we can identify insulin resistance 10 to 15 years before it becomes diabetes, that is where we can make a big difference.
So, we do a number of things: we look at traditional glucose numbers and we also do lipid testing and some advanced lipoprotein analysis, which really begin to tell us the story of insulin resistance years before you see any other numbers. And that is very powerful because intervention for insulin resistance is low-carbohydrate diet, exercise, weight loss, and inexpensive medications, such as metformin.
Q: Could you expand on the interventions for insulin resistance?
A: Insulin resistance is associated with disease states such as obesity, cancer, diabetes, and cardiovascular disease, and early intervention with medications—commonly used metformin—and certainly low-carbohydrate diet and exercise can really make a big impact.
There aren’t any drugs that are specifically indicated or approved by the FDA for the treatment of insulin resistance, but we have a scientific data sets and population studies that show the safety and efficacy of very inexpensive medications such as metformin. For example, the Diabetes Prevention Program looked at lifestyle changes and exercise, as well as metformin, and clearly showed a benefit.1 Certainly, the lifestyle benefit is even greater than the drug benefit if you can get patients to adhere to a very aggressive regimen.
We also know from patients who have polycystic ovarian syndrome—which affects at least 10% of reproductive-age women and is one of the most common endocrinologic disorders in women—that at the root cause of this disease is actually insulin resistance. And the standard of care for polycystic ovarian syndrome is metformin. But what is metformin doing? It’s addressing insulin resistance. And what makes a woman with polycystic ovarian syndrome and insulin resistance an appropriate candidate for metformin? They all are. How is that patient any different from a patient with insulin resistance who does not have polycystic ovaries or other reproductive problems. Or a man with insulin resistance? Nothing, metformin clearly has a benefit in all these disease states.
In our clinic, we prescribe as much metformin as we do lipid drugs, and we’re technically considered a “lipid clinic.” But in order to address cardiometabolic risk, we really have to treat the root cause aggressively—and diet and exercise are better than any drug. We put great effort in helping patients with that; we have dietitians on site and therapists working with patients to address barriers to lifestyle change. Sometimes, certain medications can also be appropriate.
Being able to identify insulin resistance as early as possible is key to long-term success. And with some of the additional lab tests that we do, we can arrive at that answer much earlier on.
REFERENCE:
1. Knowler WC, Barrett-Connor E, Fowler SE, et al, Diabetes Prevention
Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.
Hypertension With Steven Milligan, MD
Q: For which patients with elevated blood pressure is a trial of diet and exercise appropriate—and for how long?
A: A trial of diet and exercise is appropriate for all patients. It should be continued even after drug therapy is started. The trial can be as long as a couple of months; it could be only for a couple of weeks. You should see some difference within 2 to 4 weeks in their blood pressure; however, every patient should have diet and exercise as part of their regimen even if they are receiving medication.
Q: What is the best approach to the evaluation of patients with hypertension that is refractory to treatment?
A: First, you need to decide whether this is resistant hypertension or hypertension that is just not adequately controlled because of compliance. The biggest problem we have is the cost of medications. Any time you use multiple medications with multiple dosing regimens, blood pressure becomes difficult to control because patients do not take their medications as scheduled.
The best approach is to try to find out whether patients are actually taking their medications and how well they are taking them. Ask whether they can afford the regimen. If the regimen is multidrug taken multiple times a day, patients may just be noncompliant because they are unable to take the medication 3 times a day. So, the best approach is to engage the patient, and try to either simplify the regimen or encourage the patient to become more compliant with the regimen.
Q: What are the most effective ways to address the problem of nonadherence to drug therapy?
A: This is the point at which you and the patient need to talk about what they can afford, how well they can take their medications, and how often they can take their medications. Ask if they are having side effects, because they may not take the medication because of that. You need to open a dialogue with the patient.
Q: What is the definition of resistant hypertension?
A: Truly resistant hypertension is blood pressure that is not adequately controlled on 3 or more medications taken in optimal or adequate doses. So, that would be a patient who is on 3 different medications at the proper dosage, and we can guarantee that they are compliant with the regimen—that is someone who has resistant hypertension.
Q: Which patients are most likely to exhibit resistant hypertension?
A: Patients who have resistant hypertension are often those who have other comorbidities, such as obesity, sleep apnea, renovascular hypertension—to name just a few.
Q: What is the relationship between hypertension and other aspects of cardiometabolic risk, including obesity and dyslipidemia?
A: The metabolic syndrome is a spectrum that includes hypertension, diabetes, hyperlipidemia, obesity, and sleep apnea. The key issue is weight: the higher the weight goes, the more likely the patient is to have hypertension, diabetes, and lipid disorders. As we will discuss at the conference, we need to treat the whole patient.