Cardiologists play expanded role in the management of cardiometabolic issues

The prevalence of diabetes, metabolic syndrome, obesity and other cardiometabolic issues is increasing worldwide. The complex association between cardiometabolic disorders and heart disease and the shortage of endocrinologists and primary care providers to manage these disorders bring many patients directly to the cardiology community.

Cardiology Today assembled a distinguished panel of experts to discuss the topic of cardiometabolic issues and the emerging community of cardiologists who are becoming experts in metabolic issues. Additionally, the American Diabetes Association and the American Heart Association released in August a new scientific statement on prevention of CVD in adults with type 2 diabetes, an update to a 2007 statement. This new document summarizes recent literature, new guidelines and clinical targets, including screening for kidney disease and subclinical CVD, appropriate for the current management of patients with type 2 diabetes that underscores the need for aggressive risk factor management.

This expert round table tackles topics including BP and blood glucose control, cholesterol management, weight loss, lifestyle modification and more. Read on for insight from some of the leading experts in this area.

Rising rates

Pepine: Let’s begin this discussion by reflecting on our patients. What changes are you seeing in your practice?

Ferdinand: I practice in the South at Tulane University in New Orleans. In our clinics, we have seen an increase in patients with a combination of hypertension, diabetes and CVD, including heart disease, stroke and peripheral artery disease. I believe this is likely related to lifestyle.

Wenger: I agree that lifestyle is a major adverse contributor to what we are all observing in our practices. In the South, we see an unhealthy diet that has become even worse over time, with more saturated fat, nonrefined carbohydrates, a huge amount of salt and calories, and very little physical activity.

Plutzky: On a population basis, the rising incidence of cardiometabolic disorders is alarming and should give clinicians pause. We are now seeing type 2 diabetes in adolescence. One report published in The New England Journal of Medicine suggested that the increasing incidence of diabetes among increasingly younger people may result in this being the first generation in which individuals may not outlive their parents. Whether that will turn out to be true, only time will tell, but it does focus our attention on the long term, chronic impact of cardiometabolic disorders.

Pepine: It has been my observation that these metabolic issues disproportionately affect women and certain races/ethnicities. Is this true of your practices?

Wenger: Metabolic issues have a disproportionate effect in women. Diabetes is called the “great equalizer” because women with diabetes essentially have the same coronary risk as men. Women have worse outcomes overall; there is a robust body of literature showing that women with diabetes are far less likely to have their coronary risk factors detected and managed, both in hospital and clinic settings. However, there is no good explanation why.

The various risk factors differ substantially among African American women, Hispanic women and white women. I have been involved with the NHLBI’s Heart Truth campaign and the American Heart Association’s Go Red for Women campaign, and the penetrance of those messages into the minority community of women has been minimal. It has improved from one-third in the whole population of women to about half, but that has plateaued over the last few years. We have unfortunately not made any significant inroads.

Ferdinand: In particular, African American women are at high risk for CVD. The life expectancy for African American women, based on the U.S. statistics, is similar to that of a white man and is driven primarily by CVD. In fact, the survival curves overlap.

Kosiborod: The South Asian population tend to be relatively lean, but have diffuse vascular disease and metabolic syndrome. There are limited data on Asian women and a need to acquire more.

Source: David Braun Photography, Inc.

Pepine: My perception, living in the South and seeing a lot of Hispanic women at our institution is that somehow, although they present with characteristics of metabolic syndrome, they are somewhat protected from CVD. Has that also been your impression?

Wenger: Yes, and the data show the same. It has been called the “Hispanic paradox.” Some of the problem derives from the characterization of “Hispanic.” That characterization has nothing to do with biology or genetics — it’s a language.

Ferdinand: This paradox has been looked at in the NHLBI-led Hispanic Community Health Study / Study of Latinos, which analyzes various Hispanic populations based on geography. It appears that the BP effect is higher in Dominicans and Puerto Ricans than Cubans, and there are higher rates of diabetes in one group vs. another. The reason why Hispanics are lumped into one group is a historical anomaly of National Health and Nutrition Examination Survey data, which first looked at Mexican Americans mainly in Southern California. A lot of this was carried forth and generalizations were made about Hispanics, meaning Spanish-speaking or Spanish culture, and did not nuance Dominican, Puerto Rican, South American, Cuban and so on.

The human genome is 99.5% the same. We need to pay more attention to differences in culture and lifestyle.

Kosiborod: We are talking about an epidemic of diabetes and CVD, but there’s another concomitant epidemic: chronic kidney disease (CKD). Another part of metabolism are the issues that arise with CKD, such as acidosis, that we know are detrimental, but don’t quite know how to manage. Many of these people have never seen a nephrologist.

Ferdinand: In the African American community, progression to end-stage disease is three to five times more than that in the general population. Once a person has been on dialysis, the costs are paid for Medicare up to $82,000 to $100,000 per year. This is not a social issue; it’s a health, economic and survival issue. In most places, progression could have been prevented by effective control of comorbid conditions of diabetes and hypertension.

Impact of hypertension

Pepine: What about hypertension, the most prevalent CV risk factor?

Ferdinand: Hypertension remains a potent driver of risk. Looking at metabolic syndrome as a cluster of risks, the hypertension risk likely exceeds that above some of the others. African American men can keep a fairly robust HDL greater than 50 mg/dL and have severe CVD. Obese African American women, on the other hand, have been reported to have the “triglyceride paradox” — low triglycerides, with a relatively robust HDL. The low triglycerides may be related to some differences in lipoprotein lipase (LPL), the enzyme responsible for clearing triglyceride-containing particles from the circulation. Perhaps, LPL activity is higher in non-Hispanic blacks than whites.

One of the criticisms of the American College of Cardiology/AHA Cardiovascular Risk Calculator, which I utilize on a regular basis, is that it will drive, for instance, a 65-year-old African American with total cholesterol of 190 mg/dL and HDL of 50 mg/dL to moderate-to-high intensity statins. What more could he do if he is already doing well with his lipids? I’m not speaking against the calculator and I’m not speaking opposed to using more statins in that population — in fact, I think they’re underutilized in both African Americans and Hispanics — but we should not forget the critical impact of BP. Hypertension drives much of the increased CVD risk calculated in blacks.

Pepine: Should we adopt a lower BP threshold for patients with diabetes or prediabetes? Should we be treating prehypertension in those who appear dysmetabolic?

Ferdinand: The International Society on Hypertension in Blacks states that more robust BP lowering is appropriate because of the increased risk. The ACC/AHA calculator gives additional risk points for African American descent, which is not driven by higher LDL but rather by more hypertension in the way of stroke. It is reasonable for us to be very cautious about undertreating hypertension in older blacks, especially as a recent guideline liberalized the thresholds for intervention and treatment for patients aged older than 60 years.

More cardiologist involvement

Kosiborod: Cardiometabolic issues impact many decisions for cardiologists. As the epidemic of diabetes and prediabetes has taken off, cardiologists cannot relegate management of these conditions to PCPs and endocrinologists. We have to take partial ownership because cardiologists are many times the first frontier when patients come in with CV issues, or we are the ones who actually diagnose them with diabetes or, frequently, we are the sole providers. For a long time we, as a profession, have not viewed ourselves as responsible for managing glucose metabolic abnormalities, prediabetes and diabetes. But that position needs to change.

Looking at some recent data from the ACS population, only 30% of patients who present with ACS have normal glucose metabolism. Seventy percent of these patients have either known diabetes, diabetes that is unrecognized or pre-diabetes. Beyond the fact that an overwhelming majority of our patients have abnormal glucose metabolism — and that we need to be aware of how to address it, if patients have prediabetes or diabetes we might manage their CVD differently. From that standpoint, if you think about a patient with multivessel coronary disease and diabetes, you might offer bypass surgery over multivessel PCI, for example, or perhaps prescribe a beta-blocker that may have less of an impact on glucose metabolism.

We need to think about greater involvement in the management of diabetes from the CV standpoint, which involves strategies that may be more favorable for the glucose and diabetes management. We need to stop looking at cardiometabolic issues only as a comorbidity that we, as cardiologists, have nothing to do with.

Plutzky: There is certainly a need for more cardiologist involvement. There has been a lot of interest in “deputizing cardiologists.” In considering approaches to this, one recurring refrain has been that cardiologists don’t feel trained for managing diabetes. They are worried about how to do diabetic teaching and implement everything that a PCP or diabetologist would do in starting and adjusting therapy. However, there are ways around that. We have seen cardiology practices bring in an endocrinologist, which is a clever solution. A PCP within a cardiology practice might also handle that. We have started such integrated approaches in both fellow training and patient management at our center. Identifying the hurdles for cardiologists that have kept them from becoming more involved in the management of cardiometabolic issues will be helpful.

Kosiborod: The first thing we could be doing is diabetes screening of all patients who present to us with an array of CV conditions. Patients with HF should also be screened for diabetes. HF is a big risk factor for the development of diabetes; the more severe the HF, the greater the risk for diabetes. Another example is patients with ACS. European guidelines recommend universal diabetes screening among patients admitted with ACS. The current U.S. guidelines do not recommend that, but I think that recommendation is overdue.

Changing management, treatment

Pepine: How have you been involved in the treatment of patients with cardiometabolic issues? There are a number of large CV outcomes trials with the new glycemic drugs (Table 1). Are you starting glycemic drugs in these patients?

Source: Adapted from figure provided by Pepine CJ and information from ClinicalTrials.gov.

Ferdinand: If a patient’s primary problem is related to his or her elevanted glucose, I inform the patient to ensure the primary provider address this problem and possibly refer them to an endocrinologist, especially if they need intensive insulin therapy. But the first step for many of these patients, along with lifestyle change, is metformin. Metformin is fairly easy to prescribe.

Some of the newer antidiabetic agents, like glucagon-like peptide-1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, may have a beneficial effect on CV risk, especially BP. With the SGLT2 inhibitors, one can lose approximately 300 to 400 calories per day along with osmotic diuresis. These therapies also may be associated with a decrease in CV events; although data from the outcomes studies have not yet been reported, it points in the right direction. In fact, recent positive, top-line results were announced from a long-term clinical trial investigating CV outcomes for empagliflozin in more than 7,000 adults with type 2 diabetes at high risk for CV events. We have done ambulatory BP monitoring on patients who are using GLP-1 agonists such as dulaglutide (Trulicity, Eli Lilly), liraglutide (Victoza, Novo Nordisk) and exenatide (Byetta, AstraZeneca). In a Hypertension study published in 2014, my colleagues and I reported a BP-lowering effect with dulaglutide; at that time, its use was investigational, but it has since been approved. The 2-mm to 3-mm decrease in BP that we observed in that study doesn’t sound like a lot, but across a large population those small changes in BP do have an outcome benefit.

Pepine: I’m impressed that you said your first action is to refer these patients to an endocrinologist. Even at an institution where we have a full staff of endocrinologists, it is difficult to get these patients seen within a reasonable time.

Kosiborod: I am comfortable prescribing oral glucose-lowering medications. Once you get into multi-dose regimens with multiple insulin injections, that is out of the realm of most cardiologists and it belongs in the endocrinology clinic.

Plutzky: We will initiate anti-diabetic therapy in our clinic and certainly adjust doses of already prescribed medications. A concern for some cardiologists is over hypoglycemia, which can be a serious issue, including cardiovascular complications. However, some anti-diabetic agents are less likely to cause hypoglycemia, certain risk factors for hypoglycemia are known, like use of insulin. and decisions to intervene can be made based on the given patient.

Wenger: We have a large diabetes clinic at Grady Memorial Hospital that has an educational program incorporated, with a large presence of nurse practitioners who do the follow-up. In cardiology, we commonly start a patient on oral agents, but patients who require insulin are cared for in the diabetes clinic.

Pepine: While many randomized controlled trials have confirmed benefit of intensive glycemic control on microvascular outcomes, there are now three trials documenting benefit on macrovascular outcomes long after the trials were completed. These trials, and their HbA1c goals, are: UKPDS 33 (7% vs. 7.9%); DCCT/EDIC (7.2% vs. 9.1%); and VADT (6.9% vs. 8.4%). These findings provide support for the concept of “metabolic memory.”

Wenger: Particularly related to women, we’ve tried to involve the obstetrician/gynecologists in this risk estimation. They function in a prevention-mode with Pap smears and mammograms, but not in a CV preventive mode. The last decade has seen an explosion of information on women who have complications of pregnancy — hypertensive disorders, preeclampsia, eclampsia and gestational diabetes. Depending on the study, women with these complications have increased risk for subsequent development of coronary disease, cerebrovascular disease, peripheral vascular disease and so on. A study from Canada also showed an increase in atrial arrhythmias, pulmonary emboli, deep vein thrombosis and other issues. It is unusual that most obstetrician/gynecologists refer these patients to cardiology or do the CV risk-factor screening because they assume the hypertension subsides, the preeclampsia disappears with delivery of the placenta. But we have some very potent evidence that the endothelial dysfunction persists. It has persisted by measures of endothelial function and it has been associated with an increase in coronary artery calcium.

Images: David Braun Photography, Inc.

These women should participate in an intensive education and screening program, and probably deserve a referral. We are emphasizing within our women’s preventive program at Emory to see that a complete pregnancy history is part of the risk ascertainment for women. That’s where we have to broaden our circle of involvement.

Kosiborod: Another emerging concept that I hope will gain more traction in the future is the idea of comprehensive diabetes care centers in the outpatient setting, where a patient with type 2 diabetes can come in and see all of the specialists they need in a one-stop shop — ophthalmologists, cardiologists, diabetologists and so on. It requires a multispecialty approach to diabetes because it is a multispecialty disease.

Fat, benefits of weight loss

Pepine: One area that we haven’t touched on yet is adiposity. What are the contributions of body fat and dietary fat to cardiometabolic disorders?

Plutzky: Visceral fat is an important culprit in driving cardiometabolic complications. Ultimately, the issue is one of energy balance, as our bodies are programmed to store energy. As the need for storage expands, this can extend beyond subcutaneous fat, which may be protective against some cardiometabolic issues, with subsequent increases in visceral fat. We now know there are many different kinds of fat. Subcutaneous fat may actually be protective against cardiometabolic issues. In fact, patients with lipodystrophy can have diabetes because of a lack of fat depots. Brown fat, which releases energy rather than storing it, may also protect against obesity and diabetes — a topic my laboratory has been interested in. There is considerable interest in understanding how more “brown fat-like” properties may be induced in white fat. In contrast to these depots, visceral fat appears especially dangerous. Fat in the viscera is very biologically active, in secreting hormones that are pro-inflammatory, pro-diabetic and pro-atherogenic, helping drive the process of complications that develop later. What’s fascinating is that you can see this scenario early, years before a diagnosis of diabetes or coronary disease might be made. Such patients are often referred to our Lipid Clinic because of hypertriglyceridemia.

Pepine: What is the effect of weight loss? Where do weight loss and drugs fit into your practice? Are you writing prescriptions for weight-loss drugs?

Plutzky: Sometimes. It has been very helpful to partner with our weight-management specialists in endocrinology. I think many cardiologists have been hesitant to prescribe weight-loss drugs in part because of prior controversies with such agents. The current drugs can also have issues — like questions about their effects on heart rate. At the same time, many of these agents are well tolerated and can have a major impact. We also have more in the way of other interventions involving endoscopy and surgery. Interestingly, and consistent with our prior discussion, some of these weight-loss agents have shown a major impact on conversion to diabetes among those with prediabetes. Weight loss can also have a significant impact on issues like sleep apnea, also linked to CV risk. Often the people who are prescribed such drugs are younger and often female, with CV risk that would make it hard to show CV benefit in a study. But the benefits of avoiding the development of diabetes would be assumed among most clinicians.

Ferdinand: I have started anti-obesity drugs in some patients and I think the profiles have improved over time. The question with weight loss is not whether you can lose weight, but whether you can maintain the weight loss. Weight-loss medications clearly help in terms of weight maintenance. I don’t go all the way to bariatric surgery with most of these patients, although it appears that the gastric sleeve is relatively safe and well tolerated. When you look at most trials of weight loss, it takes a very intensive lifestyle-modification program to lose weight, but when looking at the curves they tend to drift back over time. If you look at free-living people in the usual one-on-one doctor practice, telling patients they have to lose weight just does not work in itself. It has to be an integrated program, often with the assistance of medication, and in some cases even surgery.

Kosiborod: Weight-loss therapies are very reasonable in selective cases. It seems to me that widespread use of weight-loss medications is premature because we don’t know enough about the impact on outcomes. There is no question that weight loss is important, but just like lowering glucose or LDL, it matters to some extent how you do it. With lifestyle interventions that we know have essentially no downside, there is still a struggle to show outcome differences. When prescribing medications, the question is whether you are really improving life expectancy or quality of life. We need evidence from clinical trials to show that is the case. That will likely shift the paradigm with cardiologists potentially using weight-loss therapies more widely, but as of right now we still don’t have those data.

Plutzky: It is worth mentioning that although the mean weight loss with these agents can be more modest, there are many patients who have quite robust responses. If a patient does not respond with weight loss, it is also important to stop the drug. At the same time, one of the more impressive responses we see in clinic is how dramatically many CV risk parameters change in response to relatively modest changes in weight.

Ferdinand: Additionally, there is a weight-loss approval for the GLP-1 agonist liraglutide (Saxenda, Novo Nordisk), which is indicated as an adjunct to lifestyle for weight management in patients who are obese or overweight and have at least one weight-related comorbidity including diabetes, dyslipidemia or hypertension.

Take-home messages

Ferdinand: Treat the whole patient. Don’t isolate yourself to being a CV specialist and not recognize the importance of lipids, glucose and weight and, of course, hypertension.

Wenger: We can’t continue to just treat one risk factor. Multifactorial screening and intervention are requisite. We must take ownership of recommending lifestyle interventions.

Adapted from: Farkouh ME, et al. J Am Coll Cardiol. 2013;doi:10.1016/j.jacc.2013.01.044.

Kosiborod: The main message in my mind is start with screening patients you see in CV practice for diabetes and prediabetes. Participate in decision making when it comes to diabetes management because many patients will not see a subspecialist such as an endocrinologist or nephrologist; don’t just assume they’ll take care of it.

Pepine: The educational issues for our trainees are critically important. Each week when I’m in clinic, someone presents with complicated coronary disease, HF and/or valve disease and there is a metabolic risk factor, often high HbA1c, which is not controlled. Our trainees’ usual response is, “Someone else is taking care of it.” When, in fact, no one is taking care of it. We need to get over such barriers. Perhaps this means training another generation of cardiologists to be much more comfortable with the metabolic side of things. Perhaps CVD fellows should spend time with the diabetologist when they come to a lipid or cardiometabolic clinic.

I am reminded of an analysis by Farkouh and colleagues published in the Journal of the American College of Cardiology in 2013 that evaluated the control status of four risk factors among patients with diabetes in three federally funded randomized trials (COURAGE, BARI 2D and FREEDOM) purporting “optimal” or “maximal” medical care. Examined from the patient perspective, fewer than 20% of the diabetes patients had all four risk factors (smoking, BP, LDL, HbA1c) at goal by 1 year despite protocolized instructions for risk factor management (Table 2).

Plutzky: A root contributor, if not cause, of many of the issues we often deal with as cardiologists relates to energy imbalance, excess energy intake and inadequate energy expenditure. Getting at that can also get at a lot of these factors driving diabetes and complications of CVD. There are opportunities in terms of lifestyle and therapeutics that cardiologists need to be engaged in, helping in understanding the existing and emerging data, and being part of this important discussion.

• References:
• Farkouh ME, et al. J Am Coll Cardiol. 2013;doi:10.1016/j.jacc.2013.01.044.
• Ferdinand KC, et al. Hypertension. 2014;doi:10.1161/HYPERTENSIONAHA.114.03062.
• Fox CS, et al. Diabetes Care. 2015;doi:10.2337/dci15-0012.
• Goff DC Jr, et al. Circulation. 2013;doi:10.1161/01.cir.0000437741.48606.98.

• For more information:
• Carl J. Pepine, MD, MACC, is division director emeritus, eminent scholar emeritus and professor of medicine in the division of cardiovascular medicine at University of Florida College of Medicine, Gainesville. Keith C. Ferdinand, MD, is professor of clinical medicine at Tulane University School of Medicine, immediate past chair of the National Forum for Heart Disease and Stroke Prevention and Cardiology Today Editorial Board member. Mikhail N. Kosiborod, MD, is professor of medicine at Saint-Luke’s Mid America Heart Institute and University of Missouri-Kansas City School of Medicine. Jorge Plutzky, MD, is director of preventive cardiology at Brigham and Women’s Hospital and Harvard Medical School. Nanette K. Wenger, MD, is professor of medicine (Cardiology) emeritus in the division of cardiology at Emory University School of Medicine, consultant at Emory Heart and Vascular Center, director of the cardiac clinics at Grady Memorial Hospital and Cardiology Today Editorial Board member.

Disclosures: Ferdinand reports receiving support from Boehringer Ingelheim and Eli Lilly and consulting for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Sanofi. Kosiborod reports receiving support from AstraZeneca, Eisai, Genentech, Gilead and Sanofi and consulting for Amgen, AstraZeneca, Edwards Lifesciences, Eli Lilly, Genentech, Gilead, GlaxoSmithKline, Glytec, Regeneron, Roche and Takeda. Pepine reports no relevant financial disclosures. Plutzky reports consulting and/or advising for Arena/Eisai, Ember Therapeutics, Janssen, Merck, Novo Nordisk, Orexigen, Sanofi and Vivus. Wenger reports receiving grants/contracts and/or serving on committees/boards for Alnylam, Gilead, NHLBI, Pfizer and the Society for Women’s Health Research; she also reports consulting for Amgen, AstraZeneca, Gilead and Merck.