AJMC®: Can you discuss the recently published American College of Cardiology (ACC) Expert Consensus Decisions Pathway, and how it will guide clinical decision-making for the management of patients with type 2 diabetes with cardiovascular (CV) disease?
Desai: The recent ACC Expert Consensus Decision Pathway for patients with CV disease and diabetes helps practitioners synthesize a wide body of evidence that emerged over the past several years. [The new guidelines] highlight emerging therapies that demonstrated significant benefits with regards to CV events, such as CV death, myocardial infarction, and stroke. Patients with diabetes and established CV disease or at increased risk for CV disease face substantial morbidity, mortality, and healthcare spending. Cardiologists and endocrinologists have traditionally been very siloed in the management of these patients; each discipline focusing on selective risk reduction strategies. Over the past 3 years, however, we have seen a real need emerge for more global and holistic comprehensive management of patients with CV disease and diabetes. The guidelines went a really long way toward reinforcing and reinvigorating some of those topics and some of those points.
The most important things that came out of the guidelines—beyond summarizing the data for [sodium-glucose cotransporter-2] (SGLT-2) inhibitors and glucagon=like peptide 1 receptor agonists (GLP-1)—is an emphasis on the practical and pragmatic; to enable providers not just to synthesize data, but to distill it and figure out how to best apply it to patients. The most exciting thing that we have seen over the last couple of years are agents that were traditionally thought of as glucose lowering therapies—both SGLT-2 inhibitors and GLP-1 agonists have demonstrated that they are not only safe from a CV standpoint, which is what the trials were first designed and conceived to do, but also that they are associated with reduction in adverse CV events. I think that is a profound change in the way that we think about the interplay between “diabetes medications” and CV risk. The Expert Consensus Decision Pathway was the start of what I am sure will become a long conversation [regarding what] people think about these therapies and the risk that our patients have in a different way.
AJMC®: Can you reflect on the historical differences in approach regarding treatment of type 2 diabetes and CV disease between endocrinology and cardiology?
Desai: The nature of the way that healthcare has been organized over the past couple of decades has reinforced a “jurisdiction” type of thinking when it comes to medical care. There were 2 distinct domains of comfort in jurisdiction; cardiologists traditionally dealing with coronary artery disease, lipids, etc., and endocrinologists focusing on hemoglobin A1C and microvascular complications. The new evidence for SGLT-2 and GLP-1 agonists forces us to [acknowledge] that we cannot continue to operate in these silos and traditional ways of thinking, and that we must think broadly about risk reduction strategies for patients who have CV disease and diabetes. Moreover, there needs to be some integration and a coming together, to think about the global risk and different strategies that need to be in place to reduce that risk. It is not about whether 1 person is comfortable doing 1 thing and another person is comfortable doing something else—it is about what they are comfortable doing together to meaningfully advance the care of the patient.
The whole conversation around SGLT-2 inhibitors and GLP-1 agonists is ironic in the sense that, while they were developed as “diabetes medications,” they have quite modest effects on hemoglobin A1C and pretty dramatic benefits on CV outcomes. So, the question is: should these even be thought of as diabetes medicines? For patients with both diabetes and CV disease, an interdisciplinary plan should be created to address the risk of the patient, integrate the best evidence that we have, and then apply it to the patients that we are seeing.
AJMC®: What is the evolving role of SGLT-2 inhibitors in the management of patients with type 2 diabetes with CV disease?
Desai: It is important to remember some of the history of this. It is unfortunate, but just over a decade ago, there were concerning signals for some of the diabetes medicines that we had gotten comfortable using, such as rosiglitazone. There appeared to be an adverse CV signal for some of these therapies that can reduce hemoglobin A1C. To be fair, in reality that has not turned out to be true, but as a consequence of that potential signal the FDA mandated manufacturers to do large, long-term safety trials to prove there was no excess in risk from a CV standpoint for drugs that were potentially going to be used as glucose-lowering therapies. Thus, many manufacturers set out to conduct large-scale CV safety trials with their therapies, and I think everyone was quite surprised that SGLT-2 inhibitors were not only safe from a CV safety standpoint, but these agents actually yielded quite dramatic benefits.
There are some important differences between the drugs. I think the Expert Consensus Decision Pathway does a nice job of integrating all of that evidence and synthesizing it, but we’re beginning to see a new paradigm and that these drugs are doing a good job differently than what we were accustomed to. Historically, we have seen drugs that lowered hemoglobin A1C and I think what we saw there was a nice correlation between reducing hemoglobin A1C and reducing microvascular complications, eye disease, kidney disease, and neurological dysfunction versus very modest effects on macrovascular complications, including CV events. In contrast what we saw in the EMPA-REG OUTCOME trial for example, which was the first trial, is relatively modest effects on hemoglobin A1C. It had a [fairly] dramatic reduction in CV events, including a reduction in CV mortality. I think that this finding, in some ways, has been mirrored by the CANVAS program, with canagliflozin, and the recently release DECLARE trial with dapagliflozin.
All the SGLT-2 inhibitors seem to have some benefit, different in magnitude, character, and quality. I think there are some differences there that deserve to be highlighted. For the most part, we are seeing, essentially, what nobody had probably expected, which is now we have drugs that don’t do a lot for hemoglobin A1C but have this pretty dramatic benefit on the CV side. And I think, frankly, the mechanism for that remains unclear. I do not think we have a full or a complete understanding of what the mechanism of that benefit is. But this has been observed now in multiple trials, so it makes you quite confident that there is something about the SGLT-2 mechanism that is unique, that is concurring, and a CV benefit.
AJMC®: What do you see as the next steps in research regarding SGLT-2 inhibitors?
Desai: I think that there are probably 2 important domains of additional trials that we know are in some stage of either being designed or are actually being launched. There is 1 set of analyses—more translational science, if you will—seeking to help explain the benefit that has been observed in these trials. What are the mechanistic explanations for it? Is this a blood pressure lowering effect? Is this a sympathetic tone modulation effect? An antiarrhythmic effect? Is it an antiinflammatory effect? What exactly is causing the findings that have now been observed? I do think that many of the companies are involved in developing those types of scientific portfolios where they want to explore the potential mechanisms and get some better explanation for what is driving the benefit that we’re seeing and what might the lessons learned from that be. In parallel, most of the work that’s been done thus far, and that includes the EMPA-REG, CANVAS, and DECLARE—has been done in patients that either have established CV disease, or patients that have multiple risk factors for sporadic CV disease. A really important signal that has emerged in all of these data is a pretty significant reduction in heart failure hospitalization. It is probably not too surprising, given the fact that SGLT-2 inhibitors do have a mild diuretic affect. They cause glucose loss in the urine, and with that follows water. Given this diuretic effect, it would not be a huge surprise that there might be an effect in heart failure and so what we saw in the trials was a pretty dramatic reduction in the rates of heart failure hospitalization. But it is important to remember, that this result was observed in patients that did not actually have a history of congestive heart failure, or they might have had a history of heart failure but that wasn’t a requirement for entry into any of the current trials.
There is a lot of work being done right now with many of the SGLT-2 inhibitors, [with researchers] looking at the impact of these drugs on patients that have heart failure, whether they have diabetes or not. Can these drugs actually be thought of in the broader armamentarium of patients that have congestive heart failure, whether that is with reduced ejection fraction, or preserved ejection fraction? There are [several] trials that are being done right now looking at the impact of these drugs in patients with heart failure. So that’s a second, but very important, domain of those trials and clinical research that is currently underway.
AJMC®: What factors should physicians weigh regarding treatment selection?
Desai: I do think there are elements of the three drugs empagliflozin, canagliflozin, and dapagliflozin that are class affects. These are drugs that belong in the same general therapeutic class that probably have overlapping mechanisms. They have overlapping pharmacologic effects, but we also saw in the trials [that there were] some important differences between these agents. For example, in the EMPA-REG outcomes trial that enrolled patients with a prior history of CV disease, everyone had a prior a MI, prior stroke, or peripheral arterial disease. We saw in that trial very dramatic reductions in the rate CV death, MI, and stroke, as well as a very profound effect on CV death, heart failure hospitalizations. We did not see the same magnitude of effect with canagliflozin, and there was an adverse safety signal seen in canagliflozin that wasn’t seen with EMPA-REG outcome surrounding a significantly increased risk of lower extremity amputation.
The most recent data that we saw was with dapagliflozin, where there didn’t seem to be a significant reduction on the 3-point composite endpoint of CV death, MI, and stroke. There was a pretty significant reduction in the rate of CV death and heart failure hospitalization. Providers [as a] whole, should be reassured that these drugs certainly do not have an adverse safety signal on CV events. If anything, there is probably a benefit. I think there is a range of benefit on the low end for dapagliflozin. Probably the most dramatic effect was seen with empagliflozin and the one additional caveat for canagliflozin, being the risk of amputation. Practitioners are trying to make decisions about the patients they are seeing. They should be trying to reflect on the evidence that we have about what are the sort of patients that were studied, what are the sort of benefits that you can expect, what are the trade-offs, and what are the risks that accompany that therapy. When you put all of that together, it may enable you to kind of select across the 3 drugs, and why, in certain cases, you may choose 1 over the other. It is worth noting that the ACC Expert Consensus Decision Pathway sort of highlights empagliflozin as the preferred SGLT-2 inhibitor, just given the fact that it had very robust efficacy and didn’t seem to have any significant safety concerns or safety events, such as the amputation risk with canagliflozin.
Regarding selection of agents, providers will have to make some of those calls [when] they begin to select across these 3 therapies, and I think it is worth reemphasizing that the ACC Expert Consensus Decision Pathway does note that empagliflozin is the preferred SGLT-2, given its robust efficacy and [that] there did not seem to be any adverse safety concerns.
AJMC®: As the cardiology and endocrinology communities continue to process recent findings regarding the clinical utility of SGLT-2 inhibitors, how do you envision the research spectrum and treatment landscape taking shape over the next several years?
Desai: There is a lot of new science that we are going to see in the next 6 to 12 months, such as longer-term data regarding efficacy and safety, different populations, and different clinical settings. That will be an important stage for us to watch as we think about putting these various pieces of the puzzle together to get a better picture of what these drugs are and what they are doing. Frankly, what I am excited about is to start thinking about how we implement this data into clinical practice. How do we drive clinical adoption of what seems to be very effective, high-value therapies for patients who have a substantial burden of morbidity and mortality? Obviously, those patients that have CV disease and diabetes have very high rates of adverse coronary events and other CV complications, so how do we best work together with our endocrine colleagues, engage patients, and ensure shared decision-making so patients are informed of the various treatment options that are available to them and the various risks and benefits that come with those therapies? How do we work on the science of moving much more rapidly to the adoption and implementation phase and not have such a lag between these trials coming out [and] these guidelines coming out? Should there be specialized clinics where patients with CV disease and diabetes are seen at the same time by both a cardiologist and an endocrinologist? Are there other models of care that might prove to be highly effective at optimizing clinical care for these patients?
I think that there is much more important work to be done, and I think that some of that stems from getting cardiologists, endocrinologists, and primary care physicians to work together, to think differently about the patients that they are serving, and to also find ways to help structure care differently.