New Guidance on Use of Diabetes Drugs for CVD Risk Reduction: ACC Experts

Care of patients with type 2 diabetes has shifted with the introduction of new glucose-lowering agents that reduce the risk of cardiovascular events and, with that in mind, the American College of Cardiology (ACC) has published a new decision pathway to guide physicians in the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists.

Historically, glucose-lowering agents were not the domain of cardiovascular specialists. But with multiple studies over the past several years showing the SGLT2 inhibitors and GLP-1 receptor agonists reduce the risk of major adverse cardiovascular events and progression of diabetic kidney disease, as well as data showing the SGLT2 inhibitors curb heart failure hospitalizations, this has shuffled some of the traditional roles for physicians managing patients with type 2 diabetes.

We cardiologists need to be comfortable prescribing these drugs to help our patients achieve their best outcomes, even if this is a bit out of our previous comfort zone. Sandeep Das

“Things have morphed [since] the drugs were initially approved to lower glucose to now, when many of them have cardiovascular indications—the prevention of heart failure, prevention of cardiovascular death,” writing committee co-chair Brendan Everett, MD (Brigham and Women’s Hospital, Boston, MA), told TCTMD. “We wanted to help cardiologists understand the benefits and risks of different medications, how to prescribe them, and how to monitor them going forward.”

Co-chair Sandeep Das, MD (UT Southwestern Medical Center, Dallas, TX), made a similar point.

“Their effects on blood glucose are, to me, much less important than their cardiovascular and renal benefits,” he told TCTMD. “We cardiologists need to be comfortable prescribing these drugs to help our patients achieve their best outcomes, even if this is a bit out of our previous comfort zone. It is really exciting to have these new tools in our kit. We want to help people get more familiar with these drugs and more comfortable using them as recommended by this decision pathway and the current [American Diabetes Association (ADA)] standards of care.”

The 2020 expert consensus decision pathway, which is endorsed by the ADA, was published August 5, 2020, in the Journal of the American College of Cardiology.

Benefits Beyond Glucose-Lowering

The SGLT2 inhibitors include empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly), canagliflozin (Invokana; Janssen Pharmaceuticals), and dapagliflozin (Farxiga; AstraZeneca), which were tested in EMPA-REG OUTCOME, CANVAS/CANVAS-R, DECLARE-TIMI 58, CREDENCE, and DAPA-HF. In EMPA-REG OUTCOME, for example, empagliflozin reduced the risk of MACE, heart failure hospitalization, and cardiovascular mortality. While the MACE outcomes varied in the trials, all SGLT2 inhibitors reduced hospitalizations for heart failure and had a positive effect on renal outcomes.

The GLP-1 receptor agonists include lixisenatide (Lyxumia; Sanofi), liraglutide (Victoza; Novo Nordisk), oral and subcutaneous semaglutide (Rybelsus/Ozempic; Novo Nordisk), exenatide (Byetta; AstraZeneca), and dulaglutide (Trulicity; Eli Lilly). In LEADER, liraglutide reduced the risk of cardiovascular death, MI, or stroke, as did semaglutide in SUSTAIN-6 and dulaglutide in REWIND. The drug class didn’t reduce the risk of heart failure hospitalizations, but many of the drugs had a positive effect of renal outcomes.

Where is the money best spent? For the clinician and patient, that’s going to be the difficulty. Brendan Everett

For treatment, the ACC experts state that if an adult patient with type 2 diabetes has atherosclerotic cardiovascular disease (ASCVD), heart failure, or diabetic kidney disease or is at high risk for ASCVD, physicians should recommend starting an SGLT2 inhibitor or GLP-1 receptor agonist with proven cardiovascular benefit (in addition to lifestyle changes and optimizing guideline-directed medical therapy).

With both drug classes, the decision pathway outlines the recommended doses, indications, dose modifications, contraindications, cautions, and potential adverse effects.

Everett said the two drug classes aren’t used interchangeably, but rather should be selected based on patient-specific factors and comorbidities. Thus far, the SGLT2 inhibitors as a class have demonstrated a more-consistent effect on heart failure outcomes, as well as the composite endpoint of heart failure hospitalization and cardiovascular mortality.

“I would say that if you have a patient that has either developed heart failure, or is at high risk for heart failure, clinicians should probably steer towards a SGLT2 inhibitor with some important caveats,” said Everett. “For example, kidney function has to be reasonable and they can’t have peripheral artery disease, which could potentially put them at risk for serious complications. A patient with predominantly atherosclerotic cardiovascular disease, who might also be obese, might be a better candidate for one of the GLP-1 receptor agonists with demonstrated cardiovascular benefits, such as liraglutide, dulaglutide, or semaglutide.”

No Turf War, Just Collaboration

One of the challenges going forward will be affordability given that there are a number of available drug classes with proven cardiovascular benefit in patients with ASCVD, many of whom have diabetes, said Everett. In addition to the SGLT2 inhibitors and GLP-1 receptor agonists, other treatments might include PCSK9 inhibitors or low-dose rivaroxaban (Xarelto; Janssen Pharmaceuticals), a factor Xa inhibitor now approved for the prevention of cardiovascular events. In addition, icosapent ethyl was recently shown to reduce the risk of ischemic events and cardiovascular mortality in REDUCE-IT.

“Where is the money best spent?” asked Everett. “For the clinician and patient, that’s going to be the difficulty.”

In terms of any potential “turf war” between cardiologists or endocrinologists, Everett said he doesn’t see it that way, noting that the ADA fully endorsed the decision pathway.

“I would say it’s the reverse,” he commented. “This gives the potential for more collaboration in terms of care with the patient in the middle of that collaboration. These are medications that have dual indications. When you prescribe it, for what indication, and who’s managing the dosing: there will be many different models for how to collaborate. We don’t describe what we think should happen but I think as opposed to there being a turf war, I think this is an opportunity to work together.”