SGLT-2 inhibitors and GLP-1 agonists recommended as first-line therapies

The 2019 European Society of Cardiology Congress in Paris, France brought exciting news at the intersection between diabetes and heart health.

Two of the biggest stories are significant updates to the European Society of Cardiology’s treatment guidelines, and impressive study results showing the heart protective benefits of Farxiga dapagliflozin in people with and without type 2 diabetes.

The European Society of Cardiology released updated treatment guidelines for diabetes, prediabetes, and heart disease. These guidelines provide healthcare professionals with recommendations for diabetes care. 

In big news, SGLT-2 inhibitors and GLP-1 agonists are now recommended as first-line drugs in people with type 2 diabetes who have heart disease or a high risk for heart disease. First-line drugs are those that health care professionals prescribe first for a certain condition - in this case, for heart failure.

Why is this important? This is the first time a major guideline has recommended first-line usage of a drug other than metformin for type 2 diabetes. With strong data showing the heart and kidney health benefits of SGLT-2 inhibitors and GLP-1 agonists, starting with these drugs can protect the heart and kidneys and lower blood glucose.

The European Society of Cardiology Congress showcased the results of DAPA-HF – a trial that examined the heart health benefits of SGLT-2 inhibitor Farxiga (spelled Forxiga in Europe) in people with and without type 2 diabetes. An enthusiastic, standing-room only crowd applauded for the results:

  • Farxiga reduced significantly heart-related death or worsening heart failure by 26% compared to placebo (a “nothing” pill).
  • The heart benefits were the same in people with diabetes and without diabetes type 2.

Dr. John McMurray from University of Glasgow presented the results. He highlighted that Farxiga “does everything we want a new heart failure drug to do:

1) reduce hospital admissions;

2) increase survival; and

3) improve symptoms – the three key objectives of treatment.” 

Farxiga is now the first SGLT-2 inhibitor to show use as a treatment for heart failure and to demonstrate beneficial effects in people without diabetes. 

The majority (67%) of participants without type 2 diabetes in the trial did have prediabetes. This highlights the potential of these therapies to help people with heart failure and prediabetes – it would also improve blood glucose to prevent type 2 diabetes.


ESC Diabetes and CVD Guideline: New Evidence

PARIS — The European Society of Cardiology (ESC) in collaboration with the European Association for the Study of Diabetes (EASD) has released new guidelines for the management and prevention of cardiovascular disease (CVD) in patients with diabetes or prediabetes.  

Recommendations in the document reflect recent positive findings from large cardiovascular outcome trials (CVOTs) of new classes of diabetes drugs and other new developments.  

The guideline updates the 2013 version: It not only provides advice about new classes of diabetes drugs based on groundbreaking CVOTs but also removes metformin from its place as initial diabetes therapy for all. They further stratify CV risk into medium-, high-, and very-high-risk levels rather than primary prevention and secondary prevention.

The document reflects "an unprecedented increase in the evidence base available for practicing healthcare professionals to refer to in their daily consultations," write Francesco Cosentino, MD, PhD, Karolinska Institute and Karolinska University Hospital in Stockholm, Sweden, and Peter J. Grant, MD, University of Leeds, United Kingdom, respective ESC and EASD co-chair chairs of the writing task force.


Cosentino and Grant presented the guidelines here at the ESC Congress 2019, and the document was simultaneously published online August 31 in European Heart Journal and on the ESC website.

What's New?

"The last 5 years has been the most exciting time in diabetes research ever," said Cosentino, "since for the first time in the history of type 2 diabetes, we have data from several CVOTs that indicate CV benefits from the use of glucose-lowering drugs in patients with CVD or at very high/high CV risk."

The guidelines incorporate evidence that has emerged from the trials of sodium-glucose co-transporter-2 (SGLT2) inhibitors — the EMPA-REG OUTCOME trial of empagliflozin (Jardiance, Boehringer Ingelheim/Lilly), the CANVAS trial of canagliflozin (Invokana, Janssen), and the DECLARETIMI 58trial of dapagliflozin (Farxiga/Forxiga, AstraZeneca) — and from glucagon-like peptide-1 (GLP-1) receptor agonists: notably the LEADER trial of liraglutide (Victoza, Novo Nordisk), the SUSTAIN-6 trial of semaglutide, the Harmony Outcomes trial of albiglutide, the REWIND trial of dulaglutide (Trulicity, Lilly), and the PIONEER 6 trial of semaglutide.

The guidelines classify patients with diabetes as follows:

  • Medium CV risk If they are young, lack other CV risk factors, and have had diabetes for less than 10 years;

  • High CV risk if they have had diabetes for more than 10 years and have at least one other risk factor, but no target-organ damage; and

  • Very high CV risk if they have CVD or target-organ damage or have had type 1 diabetes for more than 20 years.  

Trial evidence strongly suggests that these new drugs should be recommended for patients with type 2 diabetes and prevalent CVD or very high/high CV risk, such as those with target-organ damage or several CV risk factors, whether they are treatment naive or already receiving metformin.

"We are really facing a major paradigm shift" in the use of metformin, said Cosentino. For drug-naive patients with type 2 diabetes and established CVD, very-high-risk patients, the guideline advises immediate initiation of an SGLT-2 inhibitor or GLP-1 receptor agonist or adding this to existing metformin therapy.   


"This is important," Grant told | Medscape Cardiology in an email, "because until now, all guidelines have recommended metformin as first-line therapy in all cases of type 2 diabetes. The strength of evidence shows this is no longer the correct strategy."


The guideline also notes that the benefits seen with GLP-1 receptor agonists "are most likely derived through the reduction of arteriosclerosis-related events," while SGLT2 inhibitors seem to reduce endpoints related to heart failure.


The "huge changes in the management of diabetes in the last 5 years or so," said Grant, "is probably the greatest achievement since the discovery of insulin in 1924."


Grant drew attention to the following key updates in the current guideline iteration:

  • "We should no longer talk about primary and secondary prevention," he said, but instead classify patients with diabetes as having moderate, high, or very high risk for CVD.

  • A new aspirin CVOT (ASCEND) in moderate-risk diabetes led them not to recommend aspirin in moderate-risk patients but to use it in high- and very-high-risk patients on an individual basis.

  • Two trials of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors —including one with a diabetes substudy — led them to recommend PCSK9 inhibitor therapy in very-high-risk patients who have persistently high low-density lipoprotein cholesterol levels despite maximal statin and ezetimibe treatment or with statin intolerance.

  • The COMPASS trial of rivaroxaban plus aspirin in patients with stable coronary artery disease led to the recommendation for its use in dual antiplatelet therapy in longer-term prevention of CVD.


At the same time, "glycemic control should not be forgotten," Grant cautioned, because it helps prevent microvascular complications to the eyes, nerves, and kidneys.


The guidelines advise aiming for a hemoglobin A1c level below 7%, especially in young adults who have not had diabetes for long.


The document also recommends lipid targets of 2.5 mmol/L, 1.8 mmol/L, and less than 1.4 mmol/L for patients with diabetes who are at medium, high, and very high risk for CVD disease, respectively.


In addition, it advises that PCSK9 inhibitors are clearly needed in patients with diabetes classified as being at very high risk for CV events and that aspirin may be considered for such patients, but not for patients at moderate risk for CV events.  


Cross-Discipline Guidelines 

Invited to comment, Robert H. Eckel, MD, University of Colorado, Denver, past president of the American Heart Association (AHA, 2005 to 2006), and soon to be co-president of the American Diabetes Association (ADA, January 2020) told | Medscape Cardiology In an email that, in general, US healthcare practitioners turn to Standards of Medical Care from the ADA/EASD for diabetes care advice and to guidelines and position statements from the AHA and American College of Cardiology for cardiology care advice.


This version of the ESC/EASD guidelines for patients with diabetes and CVD shows the importance of SGLT2 inhibitors and GLP-1 receptor agonists based on CVOTs, he said, "including placing them as primary therapy vs. metformin for patients at high or very high risk for CVD — which is a new way to classify patients instead of classifying them as patients being treated for primary prevention or secondary prevention of CVD."

European Society of Cardiology (ESC) Congress Aug 31 2019.


Eur Heart J. Published online August 31, 2019. Full text



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