The rise of SGLT2 inhibitors: the time is now for cardiovascular specialists to lead the charge

KEYWORDS:

• SGLT2 inhibitors
• morbidity
• mortality
• cardiovascular diseases
• diabetes
• outcomes

Cardiovascular (CV) disease continues to be the leading cause of death and disability across the globe and is especially burdensome on patients with diabetes mellitus (DM) [1]. Numerous cellular and molecular pathophysiologic factors have been identified in the development and progression of atherosclerosis in DM that not only contribute to the unrelenting progression of atherosclerotic vascular damage but also the development of heart failure (HF) [1]. It is crucial, based on our current knowledge, that measures are instituted to prevent CV disease among diabetic patients and conversely, to avert the development of DM in individuals with diagnosed CV disease [1,2].

Type 2 DM is a polygenic disease characterized by defects in both pancreatic insulin secretion and variable defects in the action of insulin in peripheral tissues [2]. Consequently, traditional DM treatments have been mainly centered on increasing pancreatic insulin secretion, increasing peripheral insulin sensitivity or reducing the absorption of carbohydrates in the intestinal tract [2]. Yet as stated by the American Diabetes Association, “despite the approval of more than 40 new diabetes treatment options since 2005, as well as advancements in guidelines and treatment algorithms, we still haven’t been able to make a meaningful difference in improving glycemic control in people with type 2 diabetes. In fact, between 1999 and 2014 the percentage of diabetes patients with an A1C over 9% actually increased“ [3]. Furthermore, most type 2 DM patients do not meet treatment goals for traditional CV disease risk factors and unfortunately, outside of metformin, traditional DM treatments and intensive glucose control has not been shown to reduce macrovascular complications [4].

The DM treatment landscape was altered with the advent of two new classes of medications including inhibitors of renal sodium–glucose cotransporter-2 (SGLT2) and glucagon-like peptide-1 (GLP-1) receptor agonists [5]. While they were originally approved for their antihyperglycemic effect, since their introduction a surge of CV outcomes trials over the last 5 years have made it clear that these medications provide CV benefits beyond their glucose-lowering ability [6,7].

Recent studies not only have shown that SGLT2 inhibitors improve CV morbidity and mortality outcomes in patients with HF and DM but also in patients without DM [8]. Specifically, SGLT2 inhibitors in patients with DM also protect against renal function deterioration [9] while in patients without DM, SGLT2 inhibitors have shown improvements in body weight and blood pressure control [8]. However, the most consistent benefit of the SGLT2 inhibitors as a class has been their capacity to reduce the risk of CV deaths and HF hospitalizations for both DM and non-DM patients [6–9].

This hesitancy seen among CV providers [10,11,12] is particularly troublesome when less than 15% of all DM care across the US is provided by endocrinologists [13]. To specifically address these critical issues, data from Gao and associates might be useful in identifying these concerns. After conducting a very small sampling survey using a questionnaire administered to 90 providers of a single large academic health care system, these investigators noted that for endocrinology and primary care providers, cost and non-approved prior authorizations were the most notable main barriers, while lack of knowledge on how to use these medications, concerns of potential interference with DM care, and plain discomfort on how to start and follow these DM medications were additional barriers, mainly identified by CV providers [14].

Although cost and delays due to non-approved prior authorizations might be insurance-related issues currently hindered by local US-centric regulations, on a more realistic global scale, low-income and middle-income countries must face the real financial burden of these drugs due to their exorbitant cost per patient. Even when these medications hold great promise to reduce the overwhelming number of attributable chronic complications due to untreated DM, these medications also improve management of HF.

Unfortunately, to reach their full therapeutic potential, SGLT2 inhibitors need to meet common price targets. Results from a recent cost analysis study suggested that to reach that goal in the real-world in low- and middle-income countries, a cost reduction of approximately 17% needs to occur for SGLT2 inhibitors to be cost-effective and be used by type 2 DM patients in these countries [15]. In a follow-up commentary article, also published in The Lancet – Diabetes & Endocrinology, by Unnikrishnan and Mohan, these investigators from the Madras Diabetes Research Foundation in Chennai, India, not only concurred with this proposed cost reduction but also found this as a feasible target once these agents go off patent [16]. In fact, they have found that other generic products, in India, would usually by 50% cheaper than the brand counterparts [16].

It is well-known that diabetes and CV disease are interrelated disorders, and most diabetes-related morbidity and mortality comes from CV events. Therefore, a significant share of patients cared for by a CV specialist will have DM (diagnosed or undiagnosed). Likewise, a patient with DM is very likely to be treated by a CV specialist. In fact, a patient with DM and coexisting coronary artery disease will have 5-fold more outpatient encounters with a CV specialist than an endocrinology specialist [17]. With coexisting HF, a DM patient will have 8 times more encounters with a CV specialist than an endocrinology specialist [17]. This alone puts CV specialists in the foremost position to take ownership of the optimization of CV protecting therapies in these patients, which means expanding the treatment armamentarium and including SGLT2 inhibitors into day-to-day practice.

HFrEF is the disease state that can be the initial focal point for CV specialists to expand SGLT2 inhibitor use. As mentioned, SGLT2 inhibitors improve outcomes in patients with HFrEF, independent of DM status and irrespective of HF duration and symptom burden at baseline [6–9]. Consequently, the American College of Cardiology, recognizing the overwhelming benefit of the SGLT2 inhibitors, now considers them as a foundational therapy in HFrEF regardless of a patient’s glycemic status [18]. In fact, an estimated four out of five HFrEF patients in the U.S. are proposed to be candidates for SGLT2 inhibitor therapy [19]. Furthermore, the role of SGLT2 inhibition in HF continues to quickly evolve as data presented by the SOLOIST-WHF [20] and SCORED [21] investigators suggest that SGLT2 inhibitor benefits extend into the acute HF setting and could also offer benefit in HF with preserved ejection fraction [22].

As health care providers we ought to do better, DM not only is associated with substantial chronic complications but also adverse CVD outcomes. In addition, DM causes overwhelming financial burdens not only to patients but also, to health-care systems, here in the US and all around the world. Therefore, we need to improve screening of patients with or at high risk for DM as well as continue optimizing care for already diagnosed DM patients by not only by treating their CV risk factors but also by addressing all their CV needs [23]. In terms of cardiologists we need to routinely measure the urine albumin/creatinine ratio to better risk stratify our DM patients. Albuminuria is a useful biomarker that can be used to identify individuals who are candidates for SGLT2 inhibitors, regardless of background DM or CV disease status [24,25].

As William Gibson once said, ‘The future is already here. It’s just not evenly distributed yet’

It is time to fight the natural inertia and resistance that usually comes along side implementation of new practice guidelines. Changes are certainly difficult. However, in the case of SGLT2 inhibitors, we must abandon our comfort zone and become more active in prescribing these agents. Current data is overwhelmingly robust showing improved CV outcomes [6–9,19–22]. So far, cardiologists continue to account for a minute force when it comes to initiating their prescriptions despite the primary benefit of these drugs regarding CV risk management [26]. Surely, we have cited many potential hurdles; however, lack of knowledge about these therapies and perceptions that DM care is best left to other specialists might be the most significant impediments [27]. New initiatives that can clearly address these issues are most needed. Specifically, if these initiatives could help us in transitioning this knowledge into clinical practice, even more important. To reach these goals, easy to read publications that can simplify treatment pathways are a must [28]. Furthermore, increasing the number of educational programs for clinicians and patients as well as coordinating multidisciplinary forums to ease boundaries between medical specialties would also be a reasonable strategy [29].

In conclusion, aside from what we have already stated, we recommend two additional strategies. First, certainly the medical community in general would benefit if we all adopt a different language when referring to these SGLT2 inhibitors not just as DM medications but rather as cardiometabolic drugs, useful in reducing CV risks. Second, for all of us cardiologists, the use of a practical guide that will ensure a better understanding on who, when and how to prescribe SGLT2 inhibitors that simplify in a stepwise-approach a very comprehensive visual aid that eases patient selection, guide to initiation, monitoring, and patient counseling would certainly ease any reluctance, clarify any potential misunderstandings, and build confidence in how to follow patient’s response would be of great help. Maybe this approach should be adopted by other specialties.

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No potential conflict of interest was reported by the author(s).

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Funding

The authors have no funding to report.