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New Renal, HF Results Seen in 2020 ACC Pathway on CV Risk Reduction

Value Based Cardiology™October 2020

The American College of Cardiology updates guidance on prescribing SGLT2 inhibitors and GLP-1 receptor agonists to patients with type 2 diabetes and cardiovascular disease or CV risk.

Cardiologists should consider screening patients who have heart failure (HF), diabetic kidney disease (DKD), or atherosclerotic cardiovascular disease (ASCVD) for type 2 diabetes (T2D) once a year if they meet the criteria for prediabetes, according to an updated American College of Cardiology (ACC) document on new drug classes developed for T2D that have shown a range of benefits in cardiovascular care.

Regular screening is just one recommendation in the 2020 Expert Consensus Decision Pathway (ECDP) on Novel Therapies for Cardiovascular Risk Reduction With Type 2 Diabetes, published today in the Journal of the American College of Cardiology. It comes nearly 2 years after the inaugural document discussed 2 groups of therapies—sodium glucose co-transporter 2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists—that have transformed T2D treatment and are now changing the way physicians prevent heart and renal failure.

“An important paradigm shift in the care of patients with diabetes and cardiovascular disease is underway,” Sandeep R. Das, MD, MPH, FACC, co-chair of writing committee for the ECDP, said in a statement. “Patients and physicians can now choose from a number of medications that have important proven benefits on cardiovascular and renal outcomes, in addition to their effects on blood glucose.”

Among key updates in the 2020 ACC pathway:

  • The authors say the need for patients to get started on SGLT2 inhibitors or GLP-1 RAs upon discharge after a heart attack “must be weighed” when hospitals decide what drugs to put on formulary.
  • Unlike the 2018 pathway document, which singled out one therapy from each class as “preferred,” the 2020 version makes no such distinctions, but some approved drugs in each class are not discussed in language on therapy initiation.

Both the SGLT2 inhibitor and GLP-1 RA classes were first approved to lower blood glucose, but they were found to have other benefits, including the ability to prevent heart attacks, strokes, renal decline, or cardiovascular death; or to reduce heart failure for hospitalization. The benefits were revealed in the first wave of cardiovascular outcomes trials, which were required by FDA and led to publication of the initial pathway in November 2018.

Since then, leaders of ACC have sought to educate members about the value of prescribing these drug classes in patients with heart failure or who have demonstrated ASCVD. However, cardiologists sometimes have resisted using drugs that were first approved for diabetes, in part because they don’t want to “own” responsibility for a patient’s glycated hemoglobin level (A1C), a quality measure that can get reported to Medicare.

In a forthcoming interview to be published with The American Journal of Managed Care®, Darren K. McGuire, MD, MHSc¸ of UT Southwestern Medical Center, said there’s been a rapid embrace of new evidence among the fellows he trains at the cardiology clinic at Parkland Hospital in Dallas, Texas. But among cardiologists generally, he said uptake has been “dismal.”

“It’s important that we disconnect the benefits of both the SGLT2 inhibitors and the GLP-1 receptor agonists. The cardiovascular benefits that have been demonstrated are completely independent of glucose control,” McGuire said, and guidelines in both the United States and Europe reflect this.

“It doesn’t require the need for more glucose control,” he said. “You simply use the risk of the patient to prescribe the medication. It’s not that you’re forgetting the glucose control. That’s still going to be left up to the providers who’ve been managing it all along, but we’ll be adding these.”

September will mark 5 years since the scientific community was stunned with results from the EMPA-REG OUTCOME trial, which was the first to show a drug to lower blood glucose, empagliflozin, could also provide cardiovascular (CV) benefits. The race was on among competitors in the 2 emerging drug classes to show which individual therapy was more likely to reduce heart attacks, CV death, or heart or renal failure. In the 2018 pathway, the ACC authors singled out empagliflozin (Jardiance, Eli Lilly/Boehringer Ingelheim) among the SGLT2 inhibitors and liraglutide (Victoza, Novo Nordisk) among the GLP-1 RAs as “preferred,” on the strength of CV outcomes trial results reported at that time.

New evidence. Since then, more clinical trial findings have been reported, and this has increased available data across the 2 classes for the ECDP Writing Committee and the Solution Set Oversight Committee to evaluate. Among the newer studies, the DAPA-HF trial found that the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca) reduced the risk of worsening HF or CV death for patients with HF with reduced ejection fraction (HFrEF), regardless of diabetes status. CREDENCE found that the SGLT2 inhibitor canagliflozin (Invokana, Janssen) could reduce the risk of renal decline or renal death in patients with T2D and chronic kidney disease (CKD).

More recently, the DAPA-CKD trial was stopped early, and sponsors of the EMPEROR-Reduced trial for empagliflozin in HRrEF say it has achieved all primary and secondary endpoints.

Among the treatment recommendations, the authors write:

  • An SGLT2 inhibitor with demonstrated CV benefit is recommended for patients with T2D and HF, especially reduced ejection fraction (HFrEF).
  • Diagnosis of T2D, when ASCVD, DKD, or HFrEF is present, or a diagnosis of ASCVD when any of the other conditions are present, “offers the opportunity to begin the patient-clinician discussion” about taking an SGLT2 inhibitor.
  • GLP-1 RAs are recommended for those patients with established or very high risk ASCVD.
  • Decisions on prescribing these medications for CV or kidney risk reduction “should not be contingent” on a patient’s A1C level; however, the document stops short of saying metformin is not needed, and in fact, says most patients will likely take it.

In the new pathway, authors write, “Although canagliflozin, dapagliflozin, and empagliflozin have differences in their FDA-approved CV indications, they appear to have broadly similar CV and renal benefits.”

Among the GLP-1 RAs, the authors write, “data support the use of dulaglutide, liraglutide or injectable semaglutide as having demonstrated CV benefit to reduce the risk of [major adverse cardiovascular events].” Based on REWIND, dulaglutide (Trulicity, Lilly) won a label indication for reduction of MACE in patients with and without established CV disease. This class is also considered more effective for weight loss, ranging from 2% to 4%of total body weight for dulaglutide, exenatide, and liraglutide. The authors note that existing studies suggest that the GLP-1 RA class may offer “modest renal benefits,” but this has not been confirmed in a trial with a primary renal outcome.

The document gives dosing recommendations; with GLP-1 RAs, generally, physicians should start on a low dose and titrate up to avoid gastrointestinal reactions. With SGLT2 inhibitors, cardiologists should use the lowest dose tested in CV and renal outcomes trials.

Authors speak to recent concerns about diabetic ketoacidosis among users of SGLT2 inhibitors outside a clinical trial setting, and note that physicians should advise patients about the dangers of dehydration with a drug whose mechanism of action leads to volume depletion—the drugs expel excess blood glucose through the urine.

Unanswered questions. The authors discuss whether the 2 classes should be used together; they note there is guideline support for this, “even though such combination therapy has not been studied for CV risk reduction.” Patient out-of-pocket costs might be a factor here, they note.

Among other questions: What is the role for these drug classes among patients “who do not have DKD or established ASCVD but are at high risk?” How should drugs be prioritized and sequenced? How do these therapies fit it with others, such as icosapent ethyl (Vascepa), PCSK9 inhibitors, and antiplatelet therapies?

The cardiologists’ role with T2D patients requires working with others, said Brendan M. Everett, MD, MPH, FACC, co-chair of the writing committee. “We should consider thesenew medications important tools to reduce cardiovascular morbidity and mortality in patients,” with T2D, he said. “We can work together with our patients and other members of the care team to decide whether the patient would benefit from these therapies, and to initiate therapy if appropriate.”


Ras DR, Everett BM, co-chairs, for the Writing Committee of the American College of Cardiology Solution Set Oversight Committee. 2020 Expert Consensus Decision Pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes. Published online August 5, 2020. J Am Coll Cardiol. doi: 10.1016/j.jacc.2020.05.037

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