The elephant in the room: Why cardiologists should stop ignoring type 2 diabetes☆

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Abstract

Type 2 Diabetes (T2D) is a growing public health threat that is evolving into a global pandemic with debilitating, expensive and often lethal complications. Even when hemoglobin A1c (HbA1C) levels are well controlled, and concomitant cardiovascular (CV) risk factors are effectively treated, two out of every three patients with T2D are destined to die from CV complications.

Several large randomized controlled trials (RCT) indicate that two classes of glucose-lowering medications, oral sodium-glucose cotransporter type 2 inhibitors (SGLT2-i) and injectable glucagon-like peptide-1 receptor agonists (GLP-1RA), confer significant CV benefits, including reductions in: hospitalizations for heart failure (HF), progression of diabetic kidney disease, atherosclerotic CV events, and (with some agents) CV death. These CV benefits appear to be independent of the glucose-lowering effects of these agents. These compelling findings are triggering a fundamental paradigm shift in T2D management whereby the focus is no longer on HbA1c alone, but instead on implementing a comprehensive CV risk reduction strategy prioritizing the use of these evidence-based therapies (along with other evidence-based treatment strategies) with the objective of reducing the risk of morbid complications, and improving the quantity and quality of life of patients with T2D.

Cardiologists are uniquely positioned to become more involved in the management of T2D and established CV disease, which at this time should include initiation (either by prescribing or by making recommendations) of agents proven to reduce CV risk. Specifically, SGLT2-is and/or GLP-1RA have now been shown to have a favorable risk-benefit balance, and are being increasingly emphasized by the practice guidelines as preferable treatment options in vulnerable patients with T2D. The cardiology community should collaborate with other care providers to ensure that when and where appropriate these new T2D therapies are used along with other evidence-based therapies to improve patient outcomes.

Introduction

During the past 60 years the number of people in the United States (US) with diabetes mellitus has risen 10-fold, up from 2.5 million in 1959 to 25 million today.1,2 Even when hemoglobin A1c (HbA1C) levels are well controlled and concomitant cardiovascular (CV) risk factors are effectively treated, two-thirds of patients with type 2 diabetes (T2D) are destined to die from CV complications.1,3,4 Recent statistics from the Centers for Disease Control and Prevention indicate that after several decades of progress, the rates of CV complications in patients with T2D have plateaued, and in younger patients are on the rise.4

The first effective drug for lowering hyperglycemia was discovered by Dr. Frederick Banting in 1921, when he isolated insulin from the pancreas of fetal calves and began using it for treating his patients with diabetes. Now approximately 100 years later, 12 classes of glucose-lowering agents are available, comprising hundreds of different medications that have been approved by the US Food and Drug Administration (FDA) for the treatment of diabetes. Yet, until 2015, when the EMPA-REG Outcome study using a sodium glucose cotransporter 2 inhibitor (SGLT-2i) empagliflozin (an insulin independent glucose lowering therapy) in patients with established atherosclerotic CV disease was published, not one of these T2D medications had been proven to lower the ominously high risk of major adverse cardiovascular events (MACE), defined as CV mortality, myocardial infarction (MI), and stroke, or reduce hospitalizations for heart failure (HF) – another common and morbid CV complication of T2D.5

Section snippets

Landmark SGLT2-i CV outcome trials

Drugs in the sodium-glucose cotransporter type 2 inhibitors (SGLT2-i) class act in the proximal tubule to increase urinary excretion of glucose and sodium, resulting in modest but significant reductions in HbA1c, weight, and blood pressure (BP).5., 6., 7., 8. A large and consistent body of data from randomized controlled trials and large observational real-world studies indicates that SGLT2-i are effective in the prevention of atherosclerotic CV disease (ASCVD) events (among patients with

Landmark GLP-1 RA CV outcome trials

Recent large CV outcome trials show that glucagon-like peptide-1 receptor agonists (GLP-1RA) also confer cardio-protection for patients with T2D.14., 15., 16., 17. A meta-analysis of four RCTs reported that GLP-1RA compared with placebo showed a hazard ratio (HR) for MACE of 0.90 (95% confidence interval [CI] 0.82 to 0.99; p = 0.033).18 Since that meta-analysis, two additional large CV outcome trials of GLP-1RA have reported results. Harmony Outcomes trial assessing albiglutide,15 and the

Why cardiovascular specialists should take an active role in T2D management

Patients with T2D in the US see a cardiologist as often as they see their primary care provider, and are three times more likely to see a cardiologist than an endocrinologist.20 Cardiologists are accustomed to having large randomized outcome trials to guide many of our clinical decisions, rather than simply treating surrogate laboratory targets. Accordingly, we tend to deploy therapies that have been proven to lower risk of morbid events such as MACE, and hospitalizations for HF. The SGLT2-i

Lack of cardioprotection of traditional T2D therapies

Physicians managing T2D have traditionally been incentivized to focus primarily on management of HbA1c, which will improve microvascular outcomes (retinopathy, neuropathy, etc.) but have modest (if any) impact on cardiovascular outcomes.1,9,25., 26., 27., 28., 29. Consequently, the majority of patients with T2D remain on therapies that have not been proven to reduce CV events (such as MACE or hospitalizations for HF). An analysis of 313 institutions showed only 5% of T2D patients who met

Safety of GLP-1RA and SGLT2i

In contrast, the GLP-1RA and SGLT2i agents do not commonly cause hypoglycemia (except when co-administered with insulin and/or SU), are associated with weight loss, and generally have favorable safety profiles with infrequent serious adverse events.31 A systematic review and meta-analysis of all RCT data published to date on the safety of SGLT2-i showed no increased risk of harm compared to placebo or active comparators with respect to acute kidney injury, diabetic ketoacidosis, urinary tract

CV event reduction agents that coincidentally lower glucose

The hypothesis that aggressive glucose management using traditional glucose-lowering agents can reduce MACE and lower CV mortality has been disproven in multiple large RCTs.27 Moreover, the mechanisms driving the cardio-protective effects of GLP-1RA and SGLT2i appear to be unrelated to reductions in HbA1c and/or blood glucose levels.9,25., 26., 27.,29 A large body of evidence emerging from RCTs has forced us to re-think the traditional paradigm of T2D, which should not be viewed simply as a

SGLT2-i and GLP1-RA endorsed by national guidelines

Recent guidelines from the American College of Cardiology, the American Heart Association, and the American Diabetes Association all strongly endorse the use of SGLT2-i and/or GLP1-RA for patients with T2D and established ASCVD.25,26,29 Of note, most trials that demonstrated reduced MACE with SGLT2i and GLP-1RA were comprised of patients who were already on metformin as the first-line therapy. So metformin, if it is tolerated and not contraindicated, should be considered as an option in the

Call to action for cardiologists

Dr. William J Mayo taught that “The best interest of the patient is the only interest to be considered.”33 As cardiologists, our raison d'être is to prevent and/or treat CV disease and improve our patients' quantity and quality of life. After decades of futility we finally have glucose-lowering agents that significantly improve the CV prognosis for our diabetic patients.21 Cardiologists can take ownership of this issue by deploying these new evidence-based therapies in appropriate T2D patients

Statement of conflict of interest

Dr. James O'Keefe declares that he is on the speaker's bureau for Amgen, AstraZeneca, Boehringer Ingelheim, Proctor & Gamble, and Sanofi.

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    Statement of conflict of interest: see page 368.

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