New ESC Guidelines for CVD in Patients With Diabetes Cover Wide Ground

The European Society of Cardiology (ESC) has issued new guidelines that span the intersection between diabetes and cardiovascular disease, with lessons for screening, risk stratification, and management.

Released at last week’s ESC Congress 2023 and published in the European Heart Journal, the current iteration is the most recent since 2019 and is informed by studies published up through January of this year. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists continue to take a lead role, one that’s expanded even further for certain subgroups thanks to the arrival of fresh data from randomized controlled trials.

Nikolaus Marx, MD (RWTH Aachen University, Germany), who chaired the 2023 ESC guidelines along with Massimo Federici, MD (University of Rome Tor Vergata, Italy), told TCTMD: “The overarching goal is to implement a person-centered, evidence-based approach to reduce the burden of disease and to improve the prognosis and quality of life.”

With the hope that as many people as possible get the care they need, “we covered a broad spectrum of patients in risk categories,” he added.

Screening and Risk Stratification

The writing group’s recommendations encompass two main areas: screening and cardiovascular risk stratification as well as the treatment strategies available for people with type 2 diabetes who have comorbid atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or chronic kidney disease (CKD).

The overlaps among “these comorbidities in a given patient have a major impact not only on the prognosis, but also on the treatment strategies, because we have now validated evidence-based strategies to reduce cardiovascular risk in this high-risk population. And so we recommend that all patients with cardiovascular disease, so basically all patients that we as cardiologists see, are screened for the presence of diabetes . . . by measuring fasting plasma glucose and HbA1c,” said Marx. Both of these tests are “very easy tools that the physician can, as a tick box, order from the lab.”

From the other direction, he continued, “we recommend that every patient with diabetes should be evaluated for the presence of atherosclerotic cardiovascular disease by assessing the history and symptoms.”

One new element to the guidelines is that patients with type 2 diabetes should be evaluated at each clinical encounter for signs and symptoms of HF, given that risk of developing the condition is very high and worsens prognosis if it does occur. Additionally, “every patient with diabetes should be screened regularly for the presence of chronic kidney disease. Because if chronic kidney disease is present, it again has an impact on the prognosis, and chronic kidney disease itself is a driver for cardiovascular disease,” said Marx. To screen for CKD, clinicians just need to collect a spot urine test from patients and measure the urinary albumin-to-creatinine ratio, he noted.

And finally, for the first time, the guidelines advise screening for atrial fibrillation among patients with diabetes who are 65 years or older.

The overarching goal is to implement a person-centered, evidence-based approach to reduce the burden of disease and to improve the prognosis and quality of life. Nikolaus Marx

For patients who have diabetes, but none of the above comorbidities, “we introduced a new risk score called SCORE-2 Diabetes,” Marx highlighted. Using both conventional CV risk factors and diabetes-specific details, the score can estimate the 10-year risk of MI and stroke in patients with type 2 diabetes.

Marx predicted the score, which can be downloaded on the ESC CVD Risk Calculation App, will see wide clinical use. “It's easy to use, and this will really help because before we could only have a rough estimate by saying, ‘Okay, this patient has target organ damage.’ . . . Now it's based on numbers,” he said, adding that this information can be helpful when urging patients to take steps to improve their health.

Darren K. McGuire, MD (UT Southwestern Medical Center, Dallas, TX), a co-author on the ESC guidelines, also drew attention to SCORE-2 Diabetes. The risk model has been validated across several cohorts and can be adapted to geographic regions. “It works beautifully at predicting risk,” he said. “What we don’t know is: will it predict response to therapy? So we propose to use this model, which is the best model available today, to predict the risk of the patient [and use that knowledge] to dictate the medical therapies, just like we do for statins.”

Treatment of ASCVD, HF, and CKD

In terms of treatment, the guidelines go into considerable detail on comorbidities, particularly ASCVD, HF, and CKD. “For these three large groups of patients, we give a clear flowchart on how to treat and what to do,” said Marx.

First, there’s the matter of how to manage patients who have existing ASCVD on top of diabetes.

“Glucose-lowering medications can be prescribed with two mutually exclusive intentions,” the document specifies. One is to improve CV outcomes and safety, while the other is to control glucose.

SGLT2 inhibitors and GLP-1 receptor agonists each get class I recommendations. “Ideally, patients should receive both of them, because they have different modes of action to reduce cardiovascular events,” said Marx. This benefit is independent of glucose control, he added.

If the HbA1c is not at target, Marx explained, “we provide a list of agents with proven safety and proven potential benefit. . . . We want to prioritize those with a benefit, and if someone is on a drug without proven benefit, we even recommend to switch it.”

At the top of the list are several GLP-1 receptor agonists (liraglutide, semaglutide s.c., dulaglutide, and efpeglenatide) and SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, and sotagliflozin). Further down are glucose-lowering agents with suggested CV benefit: metformin (class IIa) and pioglitazone (class IIb). “Once SGLT2 inhibitors and GLP-1 receptor agonists are implemented, and if then additional glucose control is needed, there are some suggestions that metformin has a benefit, but it has never been proven in this population with vascular disease,” said Marx. “And so we gave it a IIa, but not to reduce cardiovascular risk: to control blood glucose.”

Rounding out the list are the glucose-lowering agents with proven CV safety but not benefit, as well as those that haven’t been evaluated for safety.

For McGuire, a key message is that both classes of drugs—GLP-1 receptor agonists and SGLT2 inhibitors—have “proven cardiovascular efficacy.” The American Diabetes Association, he pointed out, “continues to use as first-line recommendation ‘either/or’ language, so either a GLP-1 receptor agonist or an SGLT2 inhibitor. Previously, [the European guidelines] had ‘and/or’ as a choice, but we’ve taken out all that language and encouraged people to consider them [as a possible combination] just like we do for heart failure with reduced ejection fraction medications.”

The thinking initially had been that the only reason to add a GLP-1 receptor agonist on top of an SGLT2 inhibitor, or the other way around, would be if that first drug hadn’t been enough to achieve glucose control, said McGuire.

“But that’s not how the trials were designed or conducted. The trials were designed as adding one of these medications versus placebo on whatever background therapy there was, which could include the other class of medication,” he observed. “As we’ve gone through time, increasingly an SGLT2 inhibitor trial has had more and more people on a GLP-1 receptor agonist, and vice versa. That’s given us an opportunity after each trial to do stratified analyses to see if there’s any suggestion that there’s treatment effect modification in the absence or presence of the other medication, and we can’t find any.”

Treatment of heart failure, meanwhile, is for the first time seeing in-depth discussion in the guidelines, said Marx. “Here it is recommended that all patients with [the two diseases], independent of glucose control and independent of ejection fraction, should be treated with an SGLT2 inhibitor to reduce heart failure-related events” with a class I recommendation on the basis of DAPA-HF, EMPEROR-Reduced, DELIVER, EMPEROR-Preserved, and SOLOIST-WHF.

For CKD, the guidelines offer “treatment strategies to reduce both cardiovascular risk and kidney failure risk, because you don't want to have your patient ending up on dialysis,” said Marx. “We recommend an SGLT2 inhibitor and the nonsteroidal mineralocorticoid receptor agonist finerenone” with a class I recommendation on the basis of CREDENCE, DAPA-CKD, and EMPA-KIDNEY, as well as FIDELIO-DKD and FIGARO-DKD. “And this treatment with these two agents should be [on top of] a statin regimen, ACE inhibitors or ARBs, and blood pressure control, which is standard of care,” he added.

Also in the document are new recommendations pertaining to lifestyle (weight reduction, increased physical activity, smoking cessation), blood pressure, lipids, and antithrombotic therapies. Beyond this, the guidance covers the need for a multipronged strategy in patients with diabetes; the management of patients with atrial fibrillation and peripheral vascular disease; and advice on type 1 diabetes, among other topics.

Just ESC This Time

Notably, unlike the 2019 version and those that came before it (in 2013 and 2007), the latest guidelines were drafted by the ESC alone, not in collaboration with the European Association for the Study of Diabetes (EASD).

As for why the EASD didn’t participate this time around, Marx said it just came down to the two professional societies having different processes for evaluating the quality of data.

“The European Society of Cardiology has a very rigorous process for how evidence is looked at, how evidence is weighted, and how this translates into recommendations,” he said, adding that the EASD’s approach is a little different. “We negotiated in the beginning, but it turned out that the processes need to be aligned. And since we had to get the work started, we said, ‘Okay, the two societies will, in the future, figure out how to make this possible,’ but for this one it was just a matter of time that it didn't work out.”

Among the co-authors of the 2023 ESC document are several of Europe’s leading diabetologists, he pointed out. For most aspects of management, “what we propose now is pretty much in line with the [EASD] and American Diabetes Association recommendations, so there's no longer discrepancy, which is good.

Chantal Mathieu, MD, PhD (Katholieke Universiteit Leuven, Belgium), president of the EASD, and Richard Holt, MA, MB BChir, PhD (University of Southampton, England), chair of the EASD Committee on Clinical Affairs, elaborated on why the organization did not work on this particular guideline document. 

“The EASD was unable to participate because doing so risked undermining the consistency of its consensus reports, position statements, and guidelines," they told TCTMD in a written statement. “The EASD is hopeful that the two organizations can work together effectively in the near future for the benefit of people with diabetes.”