2018 American College of Cardiology ECDP Encourages Collaboration Among Specialists and PCPs

AJMC^®: What has changed in the landscape of treating type 2 diabetes that may have influenced the recent publication of the ECDP?

Ganda: A lot has happened in the past few years. We have seen a number of important clinical trials published in the area of drugs that lower blood glucose, and, initially, we did not think they had any advantage in patients with cardiovascular disease. However, the results of studies conducted in the past 4 years have spurred interest in cardiologists and endocrinologists [mainly diabetes specialists] working together to treat patients in an appropriate manner. We never thought that some of the drugs that are designed for glucose reduction in patients with diabetes would also have, in some cases, very exciting cardiovascular benefits.

This idea [of specialists working together] is taking off throughout the country and the world.

AJMC^®: Are you already seeing increased collaboration among these specialists?

Ganda: I think it is a little too early to tell. The decision pathway appeared in the cardiovascular brief only a few months ago. The American Diabetes Association has been revising these guidelines with the ACC since the beginning of last year. Now that they are published in the cardiovascular literature, I am sure they will encourage many cardiologists to seek collaboration with diabetes specialists in the coming years.

Those of us at Joslin Diabetes Center have met a few times with the Beth Israel Deaconess Medical Center cardiology department to discuss the details of this new decision pathway and how to collaborate with primary care physicians (PCPs). Most patients with diabetes are ultimately followed by PCPs, so we have to think of this as a multispecialty collaboration among PCPs, cardiologists, and diabetologists.

AJMC^®: How has the introduction of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists changed your treatment approach, if at all?

Ganda: When a patient is [given a diagnosis of] diabetes or has had diabetes for some time, the first drug that we use is metformin because lifestyle changes alone generally do not allow patients to meet their goal for adequate blood sugar control. Following metformin, if the goals are still not met, then the provider will consider a second drug. So far, that second drug has been any of 6 different classes of medications. But now there are 2 classes of medications that seem to have an advantage [in addition to] metformin, when metformin alone is not enough to provide the desired benefits for a patient with diabetes.

Based on the exciting results of the recent studies on both GLP-1 agonists and SGLT2 inhibitors…the 2018 ADA guidelines and other guidelines, including the ECDP, [recommend] that if you have a patient with atherosclerotic cardiovascular disease, you should preferably use either one of these 2 classes of agents. In addition, if a patient has a history of heart failure or is at increased risk of heart failure, that patient should preferably be started on an SGLT2 inhibitor, although both classes of drugs are recommended for reducing cardiovascular events in the future.

The first question you want to ask when a patient presents with cardiovascular disease and diabetes together is whether they have had, for example, myocardial infarction, a stent, coronary artery bypass grafting, bypass surgery, a history of stroke, or a history of peripheral arterial disease. These patients, preferentially, should be given 1 of these 2 new classes of drugs, unless it is contraindicated or the patient does not fulfill the criteria. This is because cost is still a factor when prescribing these drugs, as they are not yet generic. Some patients may find that the cost [of these medications] is a limiting factor because they may have a higher co-pay.

However, the cost issue aside, these 2 classes of drugs provide additional benefits, in addition to blood sugar control, so that we [as providers] do not need to be thinking about 4 other classes of drugs we can use to lower blood sugar. Lowering blood sugar is one thing, but reducing the risk of cardiovascular disease is another. Overall, both the SGLT2 inhibitors and the GLP-1 agonists seem to have advantages in patients at risk of cardiovascular events, particularly among patients who have already had cardiovascular events.

AJMC^®: Are you seeing adverse effects with SGLT-2 inhibitors and GLP-1 agonists that are comparable with those of other drugs?

Ganda: There are positives and negatives for every drug that we use; adverse effects are seen not only in these classes of drugs. Some of these adverse effects may stem from the mode of administration. For GLP-1 agonists, for example, as a provider you want to ensure that the patient understands that it is an injection. Whereas for the SGLT-2 inhibitors, it’s a pill. Usually we find that most patients, when given the choice, would rather take a pill.

Other points to consider are that, in the beginning, the GLP-1 agonists can give you gastrointestinal adverse effects, particularly nausea and vomiting; however, these effects normally subside over the course of several weeks.

On the other hand, with SGLT2 inhibitors, there is the possibility of increased urination. In most cases, however, this has not been a problem. In my experience and my colleagues’ experience, no [patients have] said they were going to stop taking the drug because they were going to the bathroom a lot. That is a transient phenomenon that is not seen in every patient.

The risk of genital infections is indeed a concern, particularly in women, in whom it is more than twice as common to occur [as in men]. Even so, only about 10% to 12% of women will have that adverse effect [compared with] about 3% to 5% of men. Not everyone will experience the same adverse effects.

Of the 3 SGLT2 drugs that have been studied in clinical trials, only canagliflozin has been associated with increased risk of lower extremity amputations, particularly the feet, up to the ankle. No one yet understands why that is, yet, so far, both empagliflozin and dapagliflozin trials did not show that effect. However, with canagliflozin, the rate of amputation was quite small, so we cannot say that it is a common adverse effect, and there are risk factors for that adverse effect. For example, patients who have a previous history of amputations, neuropathy, or vascular disease are more prone to have these distal fractures.

AJMC^®: What are some of the unknowns that still exist around SGLT2 inhibitors and GLP-1 agonists?

Ganda: First of all, we really do not yet understand the mechanism by which these drugs reduce the risk of cardiovascular outcomes. [The drugs have been] approved for use in individuals who have preexisting cardiovascular disease, based on trials that were completed in patients with cardiovascular disease. The big question is: What about those patients who do not have cardiovascular disease?

In the DECLARE[-TIMI58] trial with dapagliflozin, the largest trial so far—with 17,000 patients—about 10,000 patients, or two-thirds, did not have prior cardiovascular disease. One of the most distinguishing features of this study is that those individuals who did not have a prior history of heart failure or cardiovascular disease still had a reduced rate of cardiovascular outcome in primary prevention, particularly heart failure. There is something unique about the SGLT2 inhibitors in that they reduce the risk of heart failure, and at least in DECLARE, even the primary prevention group, who did not have prior cardiovascular disease, still saw a benefit in the reduction in heart failure, which is an exciting new finding.

AJMC^®: What would you say to your colleagues who might be hesitant to prescribe these new medications?

Ganda: First and foremost, it is a matter of education. Diabetes is a serious disease, and many people have the disease and do not yet know it. More than 90% of patients with diabetes are seen by PCPs. Patients go to a specialist only when they have advanced complications in the majority of cases. As specialists, we want to prevent that from happening. We want patients to start these medications as soon as they are [given a diagnosis of] cardiovascular disease, and that is not happening yet.

At our center, and other centers, the patient registries have indicated that less than 20% of patients who have had a prior cardiovascular episode—and should be on either an SGLT2 inhibitor or a GLP-1 agonist—are currently on these drugs.

A shift in practice takes time. Every time a new finding comes out, even an exciting new finding like this one, it takes a few years for everyone to get on board. The message that we want to convey to PCPs is to please try to send your patients with type 2 diabetes and cardiovascular disease to us soon after they get a diagnosis, and then we will work with you conjointly. We do not have time to see every patient and follow them forever; we want to see them only a few times to get them on the right path and then send them back to the PCP.

It is a 3-way street, in a way, with the specialists and the PCPs all working together. Cardiologists want to work with the PCPs and diabetologists too. They see patients with diabetes who have been sent to them for, let’s say, a myocardial infarction. The cardiologist would like to work with us as diabetologists to decide which drug is best for the patient because all these drugs have secondary effects. For example, SGLT2 inhibitors might lower a patient’s blood pressure, so we may have to modify their blood pressure medication, or in many patients on insulin, dosage adjustments may be necessary to prevent hypoglycemia.

AJMC^®: What are you currently doing at the Joslin Diabetes Center to increase communication with PCPs in your area?

Ganda: We have a large primary care group at the Beth Israel Deaconess Medical Center with hundreds of PCPs. We want to first start working with those physicians and then branch out to educate PCPs in our state. This will require more continuing medical education, more grand rounds, roundtables, etc. That is the direction we are planning in right now.

AJMC^®: What does the future hold for the SGLT2 inhibitors and GLP-1 agonists?

Ganda: Because of the great success with SGLT2 inhibitors in patients with diabetes who have heart failure and their ability to reduce heart failure, there are now several trials studying the impact of these drugs on heart failure risk in patients with and without diabetes, and that is exciting news.

Furthermore, a new finding from all the SGLT2 trials [and some of the GLP-1 trials] is that these drugs all seem to reduce the rate of the progression of kidney disease. Kidney disease is a serious and common complication in patients with diabetes; 1 of 3 patients with diabetes will develop some type of kidney disease, and many may progress to the need for dialysis and transplantation. These drugs have been shown to have a rather impressive benefit in reducing the progression of kidney disease and there are 3 separate trials currently in progress that are looking at just the kidney disease endpoint as the main endpoint. These trials are the CREDENCE trial,² the Dapa-CKD trial,³ and the EMPA-KIDNEY trial.⁴

References:

1. Das SR, Everett BM, Birtcher KK, et al. 2018 ACC expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2018;72(24):3200-3223. doi: 10.1016/j.jacc.2018.09.020..
2. Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE). clinicaltrials.gov/ct2/show/NCT02065791. Updated January 25, 2019. Accessed January 30, 2019.
3. A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease (Dapa-CKD). clinicaltrials.gov/ct2/show/NCT03036150. Updated January 23, 2019. Accessed January 30, 2019.
4. The Study of Heart and Kidney Protection With Empagliflozin (EMPA-KIDNEY). clinicaltrials.gov/ct2/show/NCT03594110. Updated February 4, 2019. Accessed February 7, 2019.