In Focus: Cardiodiabetology: Endocrinologists and Cardiologists Working Together to Improve Clinical Outcomes | Nathan D. Wong, PhD, FACC

CardioSource WorldNews | With atherosclerotic cardiovascular disease (ASCVD) and its complications (i.e. heart attacks, strokes, chronic kidney disease and heart failure) among the principal causes of death in persons with type 2 diabetes mellitus (T2DM), the field of cardiodiabetology prompts a close collaboration between the practicing endocrinologist and cardiologist notes Nathan D. Wong, PhD, FACC, of the University of California, Irvine. In addition, it is important to have other diabetes treatment experts, including nephrologists, exercise physiologists, nutrition experts (i.e. registered dieticians), podiatrists, and not uncommonly, cardio-thoracic and other vascular surgeons, along with the referring primary care physicians, to be part of the team aimed to improve patient outcomes, longevity and quality of life notes Paul D. Rosenblit, MD, PhD, of the University of California, Irvine.

Several lines of evidence support the necessity of a multidisciplinary approach, especially in the secondary prevention setting when the cardiologist is most often initially involved in patient care. First, we know that few patients with T2DM, even in the US, despite its sophisticated healthcare systems, attain guideline directed goals for the conventional cardiovascular risk factors including lipids, blood pressure, blood glucose, and weight, and when inadequately controlled, lead to significant residual risk for cardiovascular complications, notes Norman Lepor, MD, FACC, of Cedars-Sinai Medical Center.

Wong and colleagues previously published data from the US National Health and Nutrition Examination Survey noting that while approximately 50% of patients with T2DM may reach targets for glycated hemoglobin (HbA1c), blood pressure (BP) or low density lipoprotein (LDL)-cholesterol, the likelihood that all three risk factors together are at target is only 25%. In addition, only 10% had a normal body mass index (BMI); i.e. below 25 kg/m2, and only 4% attained all four targeted goals.1 The STENO-2 trial showed that controlling multiple modifiable CV risk factor measures can reduce the risk of future cardiovascular disease (CVD) outcomes by nearly 60%.2 Wong and colleagues recently also demonstrated from a pooling of diabetes subjects from 3 major prospective epidemiologic studies (MESA, ARIC, and Jackson) that those who met all three guideline-based goals for targeted HbA1c, LDL-C, and BP had 60% lower CVD event risks compared to those who met none of the goals.3

Barriers to achieving targeted goals include a perceived lack of unifying recommendations among stakeholder organizations, regarding the actual goals and the methods for their achievement, and even the perceived necessity of achieving those goals. Other barriers may include the increasingly available numbers and classes/types of pharmaceutical agents to control lipids, blood pressure, blood glucose and weight, along with a complexity of choice decisions; these decisions become particularly difficult in the settings of secondary prevention, where co-morbidities (i.e. CKD, heart failure, liver abnormalities) often limit the choice(s) or dose(s) of many agents within multiple classes that may be required for control of modifiable risks.

The association of hyperglycemia with microvascular complications [i.e. retinopathy, neuropathy, nephropathy (CKD)] and with ASCVD events has been demonstrated in many epidemiologic studies. Randomized clinical trials (RCTs) have clearly demonstrated that reducing hyperglycemia reduces onset and progression of microvascular disease. But, while the multifactorial role of hyperglycemia in unfavorably modifying the atherosclerotic environment has been recognized for decades, RCTs, historically, have failed to demonstrate that glycemic control reduces ASCVD events significantly. Post-hoc analyses, however, do support an approximate 16% reduction of ASCVD events for each 1% reduction of A1C. Furthermore, even with the perhaps ethically-driven inadequate between-group A1c differences from several trials, a legacy or memory effect, has been noted like that observed long after trials have been completed using lipid lowering agents (i.e. niacin, fibrate, statins); suggesting early treatment can have long-term positive effects.

Special cardio-protective properties, beyond glucose control, have been suggested for metformin, with uncertain mechanisms of action, as observed in sub-group analyses of the UKPDS. While metformin is the first line agent in global diabetes recommendations, proper use becomes challenging and complex, with the potential for progressive CKD, heart failure, or chronic atrial fibrillation. The thiazolidinedione (TZD) pioglitazone, among high risk secondary prevention patients, in PROACTIVE, CHICAGO and PERISCOPE, reduced nonfatal myocardial infarction, stroke, and all-cause death, reduced carotid intimal media thickness, and coronary artery plaque volume. Another unique TZD property is beta cell preservation that has been demonstrated in multiple studies, including those dedicated to diabetes prevention. The TZD benefits are attributed to a considerable reduction in insulin resistance. Pioglitazone was added to the 2008 European Stroke Organization recommended agents for secondary stroke prevention in patients with type 2 diabetes (Class III, Level B). While TZDs also affect visceral fat reduction, this benefit may be offset by the known potential overall side effect of weight gain, from both water retention (edema) and increased subcutaneous fat weight gain. In secondary prevention, and even primary prevention, a challenge is the potential risk for heart failure, associated TZD-induced fluid retention, in the susceptible patient with pre-existing ventricular dysfunction; therefore, careful observation and close collaboration between the practicing endocrinologist and cardiologist is often required.

Of significance, in the past 15 months, outcome trials of two more classes of anti-hyperglycemic agents have demonstrated reduced cardiovascular outcomes in patients with T2DM, again, with special cardio-protective properties, beyond glucose control. The EMPA-REG trial4 showed the sodium glucose transporter-2 (SGLT2) inhibitor, empagliflozin, to significantly reduce the primary outcome of myocardial infarction, stroke, and cardiovascular death, and the reductions in heart failure hospitalizations, cardiovascular and total deaths were particularly impressive. The MOA responsible for these benefits seen with empagliflozin are likely multifactorial. Other SGLT2 inhibitor cardiovascular trials, CANVAS with canagliflozin, DECLARE with dapagliflozin, and NCT01986881 with ertugliflozin, are underway to evaluate the potential for a class effect. More recently the LEADER5 trial showed a significant reduction in the composite cardiovascular events (cardiovascular death, non-fatal MI and stroke) and a reduction of cardiovascular mortality with the GLP-1 RA, liraglutide, that has nearly 100% homology to human GLP-1. And in the SUSTAIN-6 trial, use of semaglutide reduced a composite of cardiovascular events and a reduction of non-fatal MI and stroke6. Also of note involving the thiazolidinedione pioglitazone, the Insulin Resistance Intervention After Stroke Trial (IRIS) trial dedicated to individuals with prediabetes and prior stroke showed subsequent CVD events to be reduced in the pioglitazone treated group7, as observed in secondary endpoint analyses from the PROACTIVE clinical trial of patients with T2DM.

One-third or more of cardiovascular patients having T2DM, and another third being pre-diabetic with impaired glucose tolerance or impaired fasting glucose, as well as the other characteristics of the metabolic syndrome (i.e. HTN, dyslipidemia). Therefore, it is critical, especially in the secondary prevention setting, where decisions become much more complex, cardiologists must not only collaborate with endocrinologists and other providers managing patients with diabetes, but must also get accustomed to decisions made by the endocrinologist/diabetologist and/or take greater responsibility for the management of diabetes, and understand the value that these newer therapies for glucose, cholesterol and BP control may have to be mutually coordinated for maximal reduction of cardiovascular outcomes guided by information gleaned from clinical trial results. Also endocrinologists/diabetologists need be especially suspicious of the likelihood of subclinical or clinical ASCVD and work with cardiologists in both the primary prevent and secondary prevention setting. The American Association of Clinical Endocrinologist (AACE) and the American Diabetes Association (ADA) both have annualized updated guidelines for management of blood glucose, HTN and dyslipidemia. The National Lipid Association (NLA) serves as a training ground for educational expertise in the complexities of lipid management.

Finally, to help in the effort to better combine forces between cardiologists and diabetologists, the ACC, in partnership with the American Diabetes Association, American College of Physicians, American Association of Clinical Endocrinologists, and Joslin Diabetes Center has created the first worldwide collaborative diabetes registry (thediabetesregistry.org) that is designed to track and improve the quality of care of diabetes and those with the metabolic syndrome across the continuum of primary and specialty care and encourage the participation of primary care physicians, endocrinologists, cardiologists, and other healthcare providers managing diabetes. In addition, the ACC seeks to promote physician education through article reviews and hot topic discussions via its clinical topic collection on diabetes and cardiometabolic disease on ACC.org.

Address correspondence to: Nathan D. Wong, PhD, FACC, FAHA, Heart Disease Prevention Program, C240 Medical Sciences, University of California, Irvine, email: ndwong@uci.edu

References:

  1. Wong ND, Patao C, Wong K, et al. Diab Vas Dis Res 2013; 10: 505-513.
  2. Gaede P, Lund-Andersen H, Parving HH, et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 58):580-91.
  3. Wong ND, Zhao Y, Patel R, et al. Diabetes Care 2016; 2016;39:668–676.
  4. Wanner C, Inzucchi SE, Lachin JM, et al. EMPA-REG OUTCOME Investigators. N Engl J Med 2016; 375 (4):323-34.
  5. Marso SP, Daniels GH, Brown-Frandsen K, et al. N Engl J Med 2016; 375:311-22.
  6. Marso SP, Bain SC, Consoli A, ET AL. sUSTAIN-6 Investigators. N Engl J Med. 2016 Sep 15 (e-pub ahead of press).
  7. Inzucchi SE, Viscoli CM, Young LH, et al. Diabetes Care 2016; 39: 1684-92.
Read the full December issue of CardioSource WorldNews at ACC.org/CSWN

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: CardioSource WorldNews, Atherosclerosis, Diabetes Mellitus, Type 2, Heart Failure, Myocardial Infarction, Nutritionists, Physicians, Primary Care, Quality of Life, Renal Insufficiency, Chronic, Stroke, Surgeons


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