I work in the trenches. I am not an academic physician, I do not do research, and I spend all my time in patient care. I am an internist in a busy office as part of an outpatient setting of a large hospital network. My father2 and mentor, an internist and keen diagnostician, made my focus in approaching each patient very easy. He said “whenever you see a patient, narrow down your approach to one question. What variable can you change that will improve the quality or length of his/her life?” He also said, “Be careful, every 7 years, half of what you know will change… However, you do not know which half”.
This led me to the study of cardiometabolics. I realized that unfortunately many patients were being treated as if time stood still in medicine. Cardiologist were treating cholesterol, endocrinologist were treating sugars, and exercise was “going for a walk”. Lipid issues were treated with the advice, “watch your diet” and many patients were told “be careful you have borderline diabetes”. Unfortunately, death rates, though modestly improved, were still unacceptably high. High-profile people were getting ill and dying with traditional care. Tim Russert’s death at 58 years old of a myocardial infarction with an LDL less than 70 mg/dL and a normal stress test 6 weeks earlier is a prime example, as well as Bill Clinton’s bypass and subsequent stenting 2 years later. Both of these men had metabolic issues which should have initiated a full cardiometabolic work-up today.
Diabetes is not about sugars alone. In fact, glucose is the fourth variable I will look at with diabetes. The first is overall cardiometabolic health including percent body fat, exercise patterns, and fitness. The second is evidence of cardiovascular disease. The third is lipid patterns, especially the triglyceride to HDL ratio indicating atherogenicity. Last is the hemoglobin A1C level. Why is so much attention paid to glucose when other variables predict morbidity and mortality to a great extent? Unfortunately, many patients were told that if they did not improve their sugars, they would have a heart attack or stroke. This was proven wrong by the UKPDS3, ACCORD4, ADVANCE5 and VADT6 trials. In fact, overall mortality increased slightly! CVD-real7, EMPA- reg8, CANVAS9, DECLARE10, LEADER11 and SUSTAIN-612 trials, to name a few, have all changed our “goal” when treating diabetes mellitus. The goal should not be hemoglobin A1C, but reducing the cardiovascular morbidity. Most clinicians do not know that the definition of diabetes with a hemoglobin A1C of 6.5% was defined based on diabetic retinopathy and not the associated cardiovascular disease.
Cardiologists must now remove their blinders when it comes to cardiovascular prevention. Lowering a diabetic’s LDL from 90 to 70 mg/ dL after a cardiovascular event with ezetimibe as in the IMPROVE-IT trial13, resulted in a 2% absolute risk difference after 7 years and is minimal compared with the risk reduction of discontinuing the sulfonylurea, adding an SGLT-2 inhibitor as well as a GLP-1 agonist and considering pioglitazone when appropriate. Additionally, as most patients with type 2 diabetes have elevated triglycerides, adding icosapent ethyl has been associated with a 25% to 30% risk reduction14. Bromocriptine, in its safety study15 has been associated with a decreased cardiovascular composite endpoint by 40%, although further large-scale studies need to be undertaken. In statin intolerant patients or those not at LDL goal, a PCSK–9 inhibitor should be added. When a patient has progression of atherosclerosis, one has to change a variable besides mechanically opening up the vessel to prevent it from happening again. Frequently, this is not done especially if the lipid levels are “within normal limits”. Einstein said it best with his definition of insanity, which is doing the same thing multiple times and expecting a different result.
All patients with evidence of diffuse inflammatory vascular disease should get a 2-hour glucose tolerance test, regardless of normal fasting blood sugar or normal hemoglobin A1C16. I have coined the term EUGLYCEMIC DIABETES MELLITUS to describe those patients that have a normal fasting blood sugar or hemoglobin A1C but have an abnormal 2-hour glucose tolerance test. The increased cardiometabolic risk demonstrated did not correlate with the degree of glucose abnormality, whether it was present on not. It’s like being a little pregnant, you are or you are not. This is frequently seen in those patients who have early onset or diffuse atherosclerosis as this is a leading cause of atherogenic dyslipidemia and subsequent cardiovascular disease. Patients that scare me the most are those with diffuse cardiovascular disease. I label these the inflammatory vasculopathy as opposed to the discrete lesion. Diabetic heart disease is frequently seen as Diffuse Luminal irregularities or diffuse areas of atherosclerosis rather than the discrete lesion. Cardiac surgeons are seeing much more complex disease with the obesity epidemic seen today. Many have strong family histories of cardiovascular disease and many have normal or near normal LDL levels. I have seen these patients put on low-dose statins because “the cholesterol is normal”. However metabolic issues in these patients related to insulin resistance and genetic variability play an even greater role. We need to recognize this vulnerable patient prompting a full cardiometabolic workup. Furthermore, new noninvasive imaging techniques are being used to identify these high-risk patients. These include computed tomography (CT) coronary calcium score, computed tomography angiogram (CTA) coronary arteries, and the fractional flow reserve (FFR) which helps predict the degree of stenosis and which patients would benefit from subsequent coronary angiography. The CTA coronary arteries with FFR not only show structure but demonstrate function as well. I predict that with the higher accuracy and a much lower radiation dosage, this test may ultimately surpass the nuclear stress imaging in cardiac risk stratification.
When it comes to exercise, I say, “less is more, and failure is success”. High intensity interval training is superior to moderate intensity continuous training at improving cardiometabolic risk17. A program of less time but higher intensity leading to muscle failure is easy to achieve and leads to successful improvement in cardiovascular risk. Walking should be the baseline, exercise the goal.
The lack of recognition of the cardiometabolic syndrome has led to a failure of clinicians in looking at metabolic variables in heart disease as opposed to just “aggressive” statin lowering. An example of this is when one of my surgical colleagues, a 67-year-old non-smoker African-American male of above average physical condition and shape had chest pain and had a CABG x4 as well as a carotid endarterectomy. Triglycerides were 90 mg/dL, LDL was 86 mg/dL and HDL was 48 mg/ dL. His coronary angiogram demonstrated at least 8 separate 90% stenotic lesions. He had a strong family history of cardiovascular disease. When he returned back to work, I was shocked to find out he was prescribed 10 mg of atorvastatin because his cholesterol was “fine”. That was the dose that he had prior to his cardiac event! As a friend, I took control and I called the cardiac surgeon. I asked if his heart appeared to be a diabetic or inflammatory type of heart and he said definitely yes. As a matter of fact, he commented over the past 10 years the bypass surgical cases were becoming more complex as there were less discrete lesions and a lot more inflammatory type lesions. I ordered a 2-hour glucose tolerance test which revealed a 2-hour of 108 mg/ dL with an average insulin response. His advanced lipid testing was significant for considerably reduced large HDL. Because of this, I started my friend on rosuvastatin 40 mg as obviously he did require a high intensity statin, icosapent ethyl 2 g twice daily as per the data from the REDUCE-IT trial, and pioglitazone 30 mg based on the IRIS trial18. There was no recognition of the metabolic state by his internist, cardiologist, vascular surgeon, cardiac surgeon or the hospital team taking care of him. Unfortunately, this is the rule rather than the exception. Prior to his diagnosis of advanced atherosclerosis, he was on atorvastatin 10 which was his discharge dose! Obviously, no one thought of changing a variable to prevent it from happening again.
I see 25-30 patients daily and I try to keep my focus simple--change variables to improve outcomes. Like most physicians, I use EMR and barely have time to take a deep breath. However, as Jack Nicholson said in the movie A Few Good Men “…you need me on that wall…protecting you. I have a greater responsibility”. I feel I must be constantly vigilant in my role as a physician and coordinator of my patients’ care. I am wary of the cardiologist who ignores metabolic issues in cardiovascular risk reduction, as well as the endocrinologist whose main focus is glucose lowering ignoring the metabolic issues related to insulin resistance and cardiovascular disease. Cardiometabolic issues involve not only lipids and diabetes but exercise, obesity, nutrition, brain health, inflammation, kidney disease, and even cancer. This list I am sure is not complete. Treating variables is easy but recognizing which ones to change is the difficult task. As Robert Eckel19 told me “…the more we learn the more we realize what we do not know! “. Never lose focus and never stop learning as patient lives are in our hands.