Cardiologist as a cardiometabolic specialist

1. INTRODUCTION

The prevalence of the so‐called “cardiometabolic risk” and its interrelated components, such as diabetes, heart disease, obesity, and metabolic syndrome (MetS), is increasing globally. Especially in developing countries, the new estimates of diabetes in adults confirm its large burden, while recent data demonstrate the progress of the obesity pandemic.1 According to the epidemiological research, in 2013, worldwide, 382 million people had diabetes and this number is expected to rise to 592 million by 2035.2 Among patients with diabetes mellitus (DM), cardiovascular (CV) disease remains the main cause of morbidity and disability, typically occurring 14.6 years earlier, with greater severity and with more diffuse distribution compared to individuals without diabetes.3, 4 Also, CV morbidity and mortality are higher among patients with type 2 DM.5 According to a study with 20 years of surveillance, although the rates of atherosclerotic CV diseases, myocardial infarction, stroke, and end‐stage renal disease are decreasing in diabetic subjects, they are still higher than in persons without DM.6 Of note, a meta‐analysis, including 87 studies with 951 083 patients, showed that MetS was associated with a more than 2‐fold increased risk for atherosclerotic CV morbidity and mortality.7

The recently reported increase in the risk of cardiometabolic multimorbidity (at least two from the following: type 2 DM, coronary heart disease, and stroke) with increasing body mass index, from double in overweight people to more than ten times in severely obese people, compared with individuals with a healthy body mass index, underlines the need for special attention from the clinicians regarding the screening for diabetes in overweight patients and the prevention of CV disease in obese diabetic individuals.8 These considerations along with the promising results from the recently published randomized CV outcome trials of the new antidiabetic drugs have reinvigorated the interest in the appropriate management of all the clinical conditions that lie in the cardiometabolic field. With this review, summarizing recent evidence from the literature, we aim to address the issue of the role of the cardiologist in the current management of patients with cardiometabolic disease.

2. THE CARDIOVASCULAR EFFECTS OF NEW ANTIDIABETIC DRUGS

In patients with type 2 DM, the intensive glucose lowering has shown an apparent reduction in microvascular disease, but has a smaller effect on CV events or mortality.9 In 2008, the US Food and Drug Administration required that all new agents for the treatment of type 2 DM should be evaluated in terms of CV safety, due to the serious concern over increased CV morbidity associated with rosiglitazone use.10 This has led to the conduction of several large double‐blind, placebo‐controlled trials on CV outcomes related to the new antidiabetic drugs, giving birth to a new age in the “cardiometabolic management” of patients. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors did not provide a CV benefit and produced mixed results on heart failure.9 Since then, diabetologists and cardiologists alike have focused on the CV disease risk reduction of diabetic patients that appeared at last to be feasible with the identification of two newest drug classes, namely sodium‐glucose co‐transporter 2 (SGLT2) inhibitors and glucagon‐like peptide (GLP)‐1 receptor agonists.

It was in 2015 that the Empagliflozin Cardiovascular Outcome Event Trial in type 2 DM patients (EMPA‐REG OUTCOME) changed our point of view, showing for the first time a significant and unexpected proof of macrovascular benefit with empagliflozin, a SGLT2 inhibitor.11 The trial reported a 14% risk reduction in the primary composite outcome (death from CV causes, non‐fatal myocardial infarction, or non‐fatal stroke), primarily due to a 38% reduction in death from CV causes. The other important finding was a 35% reduction in the risk for hospitalization for heart failure. Two years later, the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, evaluating canagliflozin, another SGLT2 inhibitor, reported a 14% reduction in major adverse CV events, along with a 33% reduction in hospitalization for heart failure and a 40% reduction in the risk for the composite outcome of a 40% reduction in eGFR, renal replacement therapy, or death from renal causes.12 Both EMPA‐REG and CANVAS were conducted among patients with DM who had established atherosclerotic disease or were at high risk for CV disease. Consequently, American Diabetes Association recommended the use of SGLT2 inhibitors for the reduction of CV death in such patients.13 Moreover, the DECLARE‐TIMI 58 CV outcomes trial included only patients who were at risk but not with established CV disease and demonstrated that dapagliflozin, another SGLT2 inhibitor, did not have benefit (or harm) in the risk for major CV events. However, like EMPA‐REG and CANVAS, it reported a significant reduction in the risk for heart failure hospitalization (by 27%) and in the risk for the renal composite (by 24%).14 The robust benefits of SGLT2 inhibitors on reducing hospitalization for heart failure and progression of renal disease regardless of existing atherosclerotic CV disease or a history of heart failure, as shown in a recent meta‐analysis,15 have triggered the beginning of a series of studies in heart failure also in non‐diabetic subjects, with reduced or preserved ejection fraction, and their results are eagerly anticipated.16

The new antidiabetic drugs seem to possess a variety of actions and exert pleiotropic effects.17, 18 First of all, SGLT2 inhibitors reduce pre‐load through their diuretic effect. Moreover, by reducing afterload, they affect favorably blood pressure and arterial stiffness.16 Of note, SGLT2 inhibitors are the first class to show reductions in CV disease mortality and slowed chronic kidney disease progression in diabetics, and they are effective even in stage 3 chronic kidney disease, where the osmotic and glucose lowering effects are attenuated.19, 20 Other favorable effects include the delay of micro‐ and macroalbuminuria, the reduction in inflammation, the weight loss, the improvement in glycaemia, and the reduction in epicardial adipose tissue and uric acid levels. Α crucial action of SGLT2 inhibitors is the improvement in efficiency of cardiac mitochondrial energy output, which is considered largely responsible for the cardioprotection and the reduction of heart failure.21

Regarding GLP‐1 receptor agonists, the potential cardioprotective effect of incretin‐based therapies is attributed to their multiple non‐glycaemic actions in the CV system, including changes in insulin resistance, weight loss, reduction in blood pressure, improved lipid profile, as well as direct effects on the heart and vascular endothelium.22 Liraglutide, semaglutide, and albiglutide (analogues of the human GLP‐1) have been demonstrated to reduce the risk of major adverse cardiac events, whereas lixisenatide and extended‐release exenatide had a neutral effect. Thus, it is conceivable that there are different drug‐specific properties across the class of GLP‐1 receptor agonists.

3. MULTIDISCIPLINARY APPROACH

The finally proven connection of the new antidiabetic agents with the improvement of CV and renal outcomes has resulted in debates between diverse health professionals regarding the role of each one in the management of patients with cardiometabolic risk. Today, cardiologists are asked to deal with an increasing proportion of patients with coronary artery disease, MetS and type 2 diabetes. The complexity of managing patients with DM and CV disease requires a dialogue between diabetologists and cardiologists as well as joint actions for the optimal clinical management of this rapidly growing population. For cardiologists, the emergence of new classes of medications creates the additional need to learn and understand how these agents work and how they interact with other aspects of diabetes management. The collaboration and interplay between cardiologists and endocrinologists/diabetologists seems to be really promising. It should be clarified that it is not the case that each specialist runs its own target organ system. However, health professionals should pay particular attention in finding ways to improve all of the key components that can make people with diabetes to live longer and with better quality. In fact, the care of patients with diabetes and CV disease is a teamwork. MetS is a complex pathophysiological condition that comprises a cluster of risk factors. It is associated with serious and extensive comorbidity, and it is still clinically under‐recognized.23 Therefore, primary care physicians, also, should be engaged in its primary prevention and become familiarized with the management of related clinical issues, such as blood pressure, lipids, and glucose metabolism. On the other hand, complicated clinical scenarios in subjects with established CV disease justify an integrated care across general practitioners and specialists and the creation of a team of experts, including cardiologists, endocrinologists, and nephrologists, if renal disease co‐exists, in order to find the best way to manage these patients.

4. THE CARDIOMETABOLIC SPECIALIST

The strong CV benefit of SGLT2 inhibitors and GLP‐1 receptor agonists has led many experts to describe the dawn of a new cardiometabolic era,24 in which the cardiologist could play a critical role integrating and coordinating the efforts for the reduction of CV and renal outcomes in subjects with increased cardiometabolic risk. A new field of expertise arises, that of the cardiometabolic specialist, who will be responsible for the management of CV risk in people with DM. And this is primarily the domain of a cardiologist, given that subjects with DM still die from cardiovascular causes.25 This point of view is strengthened by the idea that the beneficial effects of new antidiabetic drugs could possibly be extended in the reduction of heart failure in non‐diabetic subjects, although we are still waiting for the results of the respective ongoing trials.16

The results of the CV outcome trials of SGLT2is and GLP‐1 receptor agonists have led to changes in clinical practice and guidelines. The fact that European guidelines on CV disease prevention and the European Society of Cardiology recommend empagliflozin for the prevention or the delay of the onset of heart failure and for the prolongation of life of diabetic patients, as well as the cardioprotective effects of GLP‐1 receptor agonists, reinforce the use of these new drug classes as part of the cardiologist's armamentarium in his endeavors to succeed in his main goal, the reduction of CV death of subjects with DM and CV disease.26, 27 Therefore, it seems reasonable that SGLT2 inhibitors or GLP1 receptor agonists, like empagliflozin or liraglutide, should be prescribed in most diabetic subjects with established CV disease, if there is no contraindication. Cardiologists become progressively more and more familiar with these medications and feel capable to initiate such drugs in patients, alone or in collaboration with other related specialists (diabetologists, nephrologists, or primary care physicians). Cardiologists could either play a more advisory role in the use of these new medications in every day clinical practice or take on a coordinating role as cardiometabolic specialists in the overall management of diabetic patients with increased cardiometabolic risk (successful modification and management of the most CV risk factors, including smoking, hypertension, dyslipidemia, and DM).28 The multiple aspects of a patient's cardiometabolic profile that a health professional must deal with call for a specialized and targeted education. A cardiometabolic specialist should have knowledge of internal medicine, cardiology, and endocrinology, focused in the metabolic diseases. Of note, this is not the case of the management of blood glucose levels and glucose control, for which the expert opinion of a diabetologist is needed, but of the management of CV risk.25

5. CONCLUSIONS

After the impressive results of the large trials of new antidiabetic drugs, cardiometabolic health has been placed in the center of scientists' and health professionals' interest. Therefore, it is mandatory to implement a new care model for patients with increased cardiometabolic risk, focusing on an integrated management. Cardiometabolic disease is a continuum of clinical conditions ranging from insulin resistance, obesity, dyslipidemia, hypertension, and MetS to the established DM and finally to the major cardiovascular and renal unfavorable outcomes. The cardiologist as a cardiometabolic specialist could take the leading role in coordinating a team of experts who will target, with a multidisciplinary approach, on the reduction of the burden of CV complications in patients with cardiometabolic disease.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Katsi V, Andrikou I, Tsioufis C, Tousoulis D. Cardiologist as a cardiometabolic specialist. J Clin Hypertens. 2019;21:1432–1435. 10.1111/jch.13636