ACC Consensus on New Diabetes Drugs to Reduce CV Outcomes

November 27, 2018

The American College of Cardiology has issued an Expert Consensus Decision Pathway aimed at educating cardiologists on the use of two major new classes of diabetes drugs — sodium-glucose cotransporter type 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs) — which have been shown to reduce adverse outcomes in patients with both cardiovascular (CV) disease and diabetes.

"The main aim for this report is to educate cardiologists, who might not otherwise think about prescribing diabetes drugs, about these two new classes of medications that have important cardiovascular benefits for their patients," cochair of the writing committee for the new consensus document, Brendan Everett, MD, assistant professor of medicine, Brigham and Women's Hospital, Boston, commented to theheart.org | Medscape Cardiology.

"We hope to help them understand which of their patients might benefit, and to help them understand how to prescribe these new drugs appropriately to their patients with both atherosclerotic cardiovascular disease and diabetes."

The document is published online November 26 in the Journal of the American College of Cardiology, and is endorsed by the American Diabetes Association.

He explained that the overall impetus for the consensus document was the realization that there are a number of new agents now available that reduce the risk for cardiovascular outcomes in patients with diabetes and atherosclerotic cardiovascular disease. "Many patients with atherosclerotic disease have diabetes so there is a large population who could potentially benefit from these new drugs."

Everett noted that typically, cardiologists do not get involved in glucose control, leaving that to endocrinologists or primary care doctors. "But because these two new classes of drugs have been shown to reduce cardiovascular outcomes in patients with heart disease and diabetes, cardiologists should be aware of them and their benefits."

"The SGLT2 inhibitors and GLP-1 agonists can be considered as both diabetes and cardiovascular drugs. The key point is that the cardiovascular benefits of these drugs appear to be independent of their glucose-lowering effects," Everett said.

"I don't think cardiologists are comfortable using these drugs yet," he said. "The goal of this consensus document was to produce an easy-to-read document setting out evidence-based pathways that would be useful for practicing clinicians. I hope we have achieved that."

The document includes summaries of the major CV outcome trials with two SGLT2 inhibitors (empagliflozin and canagliflozin) and four GLP-1RAs (liraglutide, semaglutide, exenatide, and lixisenatide).

CV Outcome Trials
  Hazard Ratio (95% CI)
Trial, Drug MACE* CV Death HF Hospitalization
SGLT2 inhibitor trials
EMPA-REG, empagliflozin 0.86
0.74–0.99)
0.62
(0.49–0.77)
0.65
(0.50–0.85)
CANVAS, canagliflozin 0.86
(0.75–0.97)
0.87
(0.72–1.06)
0.67
(0.52–0.87)
GLP-1 receptor agonist trials
LEADER, liraglutide 0.87
(0.78–0.97)
0.78
(0.66–0.93)
0.87
(0.73–1.05)
SUSTAIN-6, semaglutide 0.74
(0.58–0.95)
0.98
(0.65–1.48)
1.11
(0.77–1.61)
EXSCEL, exenatide 0.91
(0.83–1.00)
0.88
(0.76–1.02)
0.94
(0.78–1.13)
ELIXA, lixisenatide 1.02
(0.89–1.17)
0.98
(0.78–1.22)
0.96
(0.75–1.23)
*Major adverse CV events of MI, stroke, and CV death

It does not, however, include the recently published CV outcomes trials of the SGLT2 inhibitor dapagliflozin (DECLARE-TIMI 58) or the GLP-1RA albiglutide (Harmony Outcomes), which were published after the consensus document was in press.

In addition, topline results of the PIONEER 6 CV outcomes trial, reported November 26 by Novo Nordisk, showed an oral form of the GLP-1 agonist semaglutide produced a reduction in CV and all-cause mortality, but did not significantly reduce the overall composite primary end point of major adverse CV events (MACE).

Which Class to Choose?

On whether to choose a SGLT2 inhibitor or a GLP-1RA, Everett said that "the general perception is that SGLT2 inhibitors are better at reducing heart failure hospitalizations and GLP-1 agonists are better for reducing atherosclerotic events, such as MI and stroke, but there is a lot of crossover."

Liraglutide has shown "particularly impressive" results among the GLP-1RAs, with large reductions in MI, stroke, and CV death, he said. "By contrast, the two SGLT2 inhibitors included in this document have shown striking reductions in heart failure hospitalizations, but less consistent reductions in atherosclerotic cardiovascular events such as MI or stroke."

The consensus document notes that the SGLT2 inhibitors appear to reduce both MACE and HF risk but increase the risk for genital mycotic infections, whereas GLP-1RAs offer reductions in MACE but are associated with transient nausea and vomiting. Both classes of agents have benefits in reducing blood pressure and weight and have a low risk for hypoglycemia.

Differences in the route of administration (oral for SGLT2 inhibitors, subcutaneous injection for GLP-1RAs) might influence patient and physician decision making; however, the GLP-1RAs are given with a small needle and pen device to ease administration and patient acceptance, it adds.

Summary of Priorities for Considering the Two Classes
SGLT2 Inhibitor GLP-1RAs
Reducing MACE and CV death Reducing MACE and CV death
Preventing heart failure hospitalization Substantial weight loss
Reducing blood pressure Therapy when glomerular filtration rate consistently <45mL/min per 1.73 m²
Oral administration Once-weekly subcutaneous dosing
Consider alternative agent if:
  • significant chronic kidney disease

  • history of amputation, severe peripheral arterial disease, neuropathy, or diabetic foot ulcers (avoid canagliflozin)

  • history of recurrent genital candidiasis

  • History of diabetic ketoacidosis

  • history of osteoporosis (avoid canagliflozin)

Consider alternative agent if:
  • persistent nausea

  • history of pancreatitis

  • history of gastroparesis

  • history of multiple endocrine neoplasia type 2 or thyroid cancer

  • history of proliferative retinopathy (semaglutide)

Empagliflozin Preferred SGLT2 inhibitor

The document states that, "among the SGLT2 inhibitors, empagliflozin is currently the preferred agent based on the available evidence and overall benefit-risk balance."

It notes that canagliflozin has been associated with increased risk for lower limb amputation (6.3 vs 3.4 amputations per 1000 patient-years), prompting the US Food and Drug Administration to add a black-box warning to the prescribing information.

A numerical increase in amputations has also been seen in a phase 3 trials with another SGLT2 inhibitor, ertugliflozin, which has not yet completed a CV outcomes trial. However, no increase in amputations has been seen with empagliflozin or dapagliflozin to date, it reports.

"Whether amputation risk represents a class effect remains unclear, but vigilance is suggested in those with a history of amputation, peripheral arterial disease, neuropathy, or diabetic foot ulcers," the consensus document says.

Liraglutide Preferred GLP1RA

The document also recommends that, "among the GLP-1RAs with demonstrated CV benefit, the most convincing data for CV benefit are for liraglutide, which should currently be the preferred member of this class for CV event reduction until additional information becomes available."

On where dapagliflozin and albiglutide might fit in, Everett said that "the results of the DECLARE trial with dapagliflozin and the HARMONY trial with albiglutide are consistent with the other trials for each drug class. Based on my interpretation of those two trials, I think they reinforce the recommendations in this consensus decision pathway."

He noted that the DECLARE trial with dapagliflozin was the first study of SGLT2 inhibitors to have also included a substantial number of diabetes patients without established CV disease but with additional risk factors, "but this consensus document is aimed at cardiologists and the focus is therefore on patients with established cardiovascular disease."

"While DECLARE did not show such a strong signal in reducing atherosclerotic cardiovascular outcomes — which may have been because it included a lower-risk population — like the other trials with other SGLT2 inhibitors, it showed a striking reduction in heart failure hospitalization," he said. "So this is completely in line with our recommendations that these agents are most suitable for patients who already have heart failure or are thought to be at risk of developing heart failure."

The authors of the consensus document conclude that the evidence for specific agents in these classes is still emerging, and other CV outcomes trials in patients with type 2 diabetes are currently underway.

"As such, this area of care for affected patients is likely to continue evolving rapidly," they write. "We anticipate that the algorithms proposed here will change as new evidence emerges, but that the overarching goal of improving CV outcomes in patients with type 2 diabetes and clinical atherosclerotic cardiovascular disease will remain consistent."

"Although Decision Pathways have a new format, they maintain the same goal of Expert Consensus Documents: to develop clinical policy based on expert opinion in areas in which important clinical decisions are not adequately addressed by existing trials," the authors note. "Expert Consensus Decision Pathways are designed to complement the guidelines and bridge remaining gaps in clinical guidance. In some cases, topics covered by Expert Consensus Decision Pathways will be addressed subsequently by ACC/American Heart Association (AHA) guidelines as the evidence base evolves."

Everett reports grants from Novartis, the NHLBI, and consulting for Roche Diagnostics, the FDA, the NIDDK, and Abbott.

J Am Coll Cardiol. Published online November 26, 2018. Abstract

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