New Insights into Prescribing of SGLT2 Inhibitors and GLP-1 Receptor Agonists by Cardiologists in 2020: Major Barriers Limiting Role
Rishav Adhikari, BS; Michael Blaha, MD, MPH

KEYWORDS
diabetes; CHD prevention; SGLT2 Inhibitors; GLP-1 receptor agonists

Introduction - Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in patients with type 2 diabetes (T2D).^1,2 Adults with T2D are two times more likely to die from heart disease or stroke than those without diabetes.³ While diabetes itself is a major risk factor for cardiovascular (CV) mortality, that risk is doubled for patients with T2D who also have established CVD.³ Despite these elevated risks, most patients with T2D do not meet treatment goals for traditional CV risk factors, and intensive glucose therapy alone does not appear to mitigate macrovascular outcomes.^4,5 Thus, as the global prevalence of diabetes continues to escalate, projected to reach 700 million by 2045, targeted strategies to better manage cardiovascular health in this vulnerable population are urgently needed.⁶

A wave of cardiovascular outcomes trials (CVOTs) over the past five years for two classes of drugs, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA), has shifted the landscape of CV risk management in diabetes patients.⁷ These drugs were originally approved as antihyperglycemic agents, but have since proven to be even more useful for their CV benefits. Meta-analyses of CVOTs suggest that in patients with T2D, GLP-1 RA reduce major adverse CV events in patients by 12%, while SGLT2i reduce the risk of CV death and hospitalization for heart failure by 23%.^8,9 In fact, two recent clinical trials show that not only are SGLT2i effective in primary prevention of heart failure in patients with T2D, but also in secondary prevention to treat heart failure, regardless of whether patients have diabetes.^10,11 Thus, SGLT2i and GLP-1 RA have become powerful tools in physicians' arsenal to combat CVD in patients with T2D.  Updated guidelines by the American College of Cardiology (ACC), American Diabetes Association (ADA), European Society of Cardiology (ESC), and European Association for the Study of Diabetes (EASD) all strongly recommend an SGLT2i or GLP-1 RA in patients with T2D who already have or are at high risk for CVD.^7,12,13

Recent study by Hamid et al. - Design - Recently, Hamid et al. examined SGLT2i and GLP-1 RA prescribing patterns in the University of Mississippi Medical Center from January 2013 - June 2019.¹⁴ Data from electronic health records were analyzed retrospectively for patients with T2D (n=66,368) as well as the subset of high-risk patients (n=21,173) who had both T2D and clinical manifestations of CVD, defined as any instance of chronic ischemic heart disease, stroke, myocardial infarction, unstable angina, or peripheral vascular disease. The authors characterized the demographics of patients receiving SGLT2i or GLP-1 RA therapy, including insurance status, and examined trends in prescription volumes over time, prescribing of other antihyperglycemic agents, and the specialty of the prescribers for SGLT2i/GLP-1 RA agents.

Are patients receiving SGLT2i/GLP-1 RA therapy? - The researchers found that among patients with T2D and CVD, only 1.4% received an SGLT2i and 1.6% received a GLP-1 RA. These fractions were much smaller than the percentage of patients prescribed insulin (60%), biguanides (20%), sulfonylureas (10%), or dipeptidyl peptidase-4 inhibitors (7%). The most popular SGLT2i and GLP-1 RA were empagliflozin (52%) and liraglutide (66%), respectively. For these two drugs, the authors observed an increase in new prescriptions following expansion of their US Food and Drug Administration (FDA) labels to include a CV risk reduction indication. Prescriptions for all other SGLT2i and GLP-1 RA agents did not increase appreciably over the study period (January 2013 - June 2019). Interestingly, an equivalent percentage of patients with T2D and CVD were prescribed an SGLT2i or GLP-1 RA as compared to all patients with T2D. Most guidelines unambiguously recommend these drugs for patients in the former high-risk subgroup but provide less definite recommendations for use in the broader T2D population. Combined, these results suggest that the vast majority of patients with T2D and CVD are not being prescribed optimized treatments to manage their high risk for adverse CV outcomes.

Because this study was restricted to patients at a single institution, the results may have limited generalizability. For example, unlike national demographics, most patients in this registry were black (56%) and very few were Hispanic (0.2%) or Asian (0.4%). Of the patients with T2D, 28% in this cohort were uninsured, while that number is estimated to be 10% nationally.¹⁵ However, the general conclusions of this study are consistent with multiple prior investigations suggesting that less than 15% of patients in the United States with T2D and CVD are receiving an SGLT2i or GLP-1 RA.^16-18

Are cardiologists prescribing these cardioprotective therapies? - CVOTs demonstrating the unexpected CV benefits of SGLT2i and GLP-1 RA have generated significant buzz within the CV community, with cardiologists finally armed with targeted tools to specifically improve CV outcomes in their vulnerable patients with T2D and CVD. Concurrently, many high-profile publications and most professional guidelines strongly encourage cardiologists to embrace a more active role in screening for T2D and initiating these evidence-based treatments.^7,13,19 However, the data suggest that, so far, cardiologists have played only a minor role in deploying SGLT2i and GLP-1 RA therapies. For example, a survey of cardiology providers at Duke University reported that over 80% had never prescribed drugs in either class.²⁰ Vaduganathan et al. observed that within the Partners Healthcare system in Boston, cardiologists accounted for only 5% of the prescriptions for SGLT2i and GLP-1 RA.^21,22 Similarly, Hamid et al. found that cardiologists prescribed only 6% of the total SGLT2i and 1% of GLP-1 RA in their academic hospital system.¹⁴ Rather, primary care providers accounted for the largest share of prescriptions (45% of GLP-1 RA and 53% of SGLT2i), followed by endocrinologists (45% of GLP-1 RA and 30% of SGLT2i). While cardiologists comprise only a small fraction of prescribing, estimates suggest that a patient with T2D and CVD is four times less likely to encounter an endocrinologist, and equally as likely to encounter a primary care physician, as they are a cardiologist in a given year.²³ Nationally, less than 15% of diabetes care is provided by endocrinologists.²⁴ These data suggest that cardiologists are well-positioned to improve access to these cardioprotective agents.

What are the main barriers to more widespread usage? - Most discussion in the literature about reasons for the slow uptake of SGLT2i and GLP-1 RA, especially among cardiologists, has been largely speculative. Some of the hypothesized barriers to uptake include medication cost, lack of physician familiarity with the drug classes, injection phobia for GLP-1 RA, concerns about overstepping traditional specialist boundaries, and natural "clinical inertia" delaying adoption of new therapies for chronic diseases. Hamid et al. noted that because comparably priced DPP4i were prescribed four times more frequently than GLP-1 RA or SGLT2i and because one-fourth of SGLT2i and GLP-1 RA prescriptions were written for uninsured patients, cost may not be the most significant barrier to access. However, rigorous quantitative analyses or systematic ethnographies to pinpoint the most important barriers are scarce.

Two recent surveys about cardiologists' attitude towards these novel therapies provide some insight. A 2019 survey in the United Kingdom of 103 consultant cardiologists showed that only a minority of the respondents felt very familiar with the outcomes data for SGLT2i (30%) or GLP-1 RA (20%).²⁵ Only 11% believed that they were best suited to deliver diabetes treatment to a hypothetical inpatient post-acute coronary syndrome with T2D, and only 5% would initiate a guideline-recommended SGLT2i or GLP-1 RA for that patient. Instead, most preferred to refer to a diabetes specialist. Results from another small survey of providers corroborate these findings. Yumin et al. surveyed 41 primary care providers, 17 endocrinology providers, and 32 cardiology providers in the Duke University Health System in North Carolina.²⁰ They found that while endocrinology and primary care providers cited cost and nonapproved prior authorizations as their major barriers to prescribing these drugs, the cardiology providers reported that their main obstacles were lack of knowledge about the medications, concerns of introducing confusion into the diabetes care plan, and a sentiment that it is not a cardiologist's responsibility to prescribe "diabetes medications." Taken together, these studies suggest that among cardiologists, the major hurdles to more widespread usage are lack of familiarity with these therapies and the perception that management of diabetes is beyond their purview.

Conclusion - While recent well-designed CVOTs revealing the cardioprotective benefits of SGLT2i and GLP-1 RA have provided a much-needed strategy to reduce the excess risk of adverse CV events faced by patients with T2D, multiple studies, including the recently published results by Hamidet al., show that adoption of these medications for the patients who could most benefit has been slow.^14,16,17 Disappointingly, while the primary benefit of these drugs is CV risk management, cardiologists continue to account for a minute role in initiating their prescriptions.^14,21,22 Among the many possible obstacles to more widespread uptake by cardiologists, lack of knowledge about these therapies and perceptions that diabetes care is best left to other specialists may be the major impediments.^20,25 Therefore, initiatives directly addressing these factors may be most effective at transforming clinical practice. These include recently published treatment pathways to simplify prescribing, educational programs for clinicians and patients such as the ACC's "Succeed in Managing Cardiovascular Risk in Diabetes" (SIM-CVRiD), and cross-disciplinary coordinated models of care to re-evaluate traditional boundaries between medical specialties.^7,12,13,26 In addition, the medical community would benefit from adapting language norms to refer to SGLT2i/GLP-1 RA not just as diabetes medications but rather as cardiometabolic drugs useful particularly for CV risk reduction. Recent data demonstrating dramatic reductions in heart failure risk from SGLT2i, even among patients without diabetes, further underscore the need to stop regarding these drugs simply as diabetes treatments. Nationally representative studies characterizing SGLT2i/GLP-1 RA prescribing patterns as well as larger surveys of cardiologist's knowledge of and attitudes towards these cardiometabolic medications are also needed to better diagnose the persistent barriers to progress in this area.

References