New ESC guidelines zero in on lipids, diabetes, and more

The European Society of Cardiology (ESC) has released five new guidelines at the ESC Congress 2019, recommending an even lower LDL-C* target in patients at very high risk for cardiovascular disease (CVD), and the use of SGLT2** inhibitors and GLP-1*** receptor agonists as first-line treatments in those with diabetes to reduce their CVD risk.

Other guidelines focus on the management of chronic coronary syndrome, pulmonary embolism, and supraventricular tachycardia.

Dyslipidaemia: Lower is better still holds

The ESC guideline on dyslipidaemia, updated in collaboration with the European Atherosclerosis Society (EAS), specifically sets the absolute LDL-C treatment target at <55mg/dL (<1.4 mmol/L) for very high-risk patients and <70 mg/dL (1.8 mmol/L) for high-risk patients. For patients at the very highest risk with multiple recent events, the target is even lower at <40 mg/dL (<1.0 mmol/L). [Eur Heart J 2019;doi:10.1093/eurheartj/ehz455]

Patients with familial hypercholesterolaemia (FH), atherosclerotic cardiovascular disease (ASCVD), or who have another risk factor, are treated as very high-risk, and those without ASCVD or other risk factors as high-risk.  

“Lower is better, and while this has been generally recommended for some time, we are saying this still holds right down to very low levels of LDL-C,” said the guidelines taskforce co-chair Dr Colin Baigent from the University of Oxford in Oxford, UK. “In the highest risk patients, LDL-C should be lowered, if possible, at no lower limit.”

On top of the LDL-C target of 1.4 mmol/L, a 50-percent reduction in LDL-C from baseline is recommended for the highest risk patients to ensure they achieve the greatest LDL-C reduction possible, a target which is lower than the previous target of 1.8 mmol/L or a 50 percent reduction.

“This means that if a patient has an uncontrolled LDL of 1.5 mmol/L, getting a 50 percent reduction and a <1.4 target would require lowering the LDL-C to 0.75 mmol/L,” explained Baigent. “If we want a good reduction in risk, we have to maximize the LDL reduction in our patients.”

Pharmacological strategies to lower LDL-C

In very high-risk patients with recent myocardial infarction (MI) or angina, aggressive treatment with the highest tolerated statin dose – with the option to add ezetimibe if the goal is not achieved – is recommended. For patients at very high risk, including those with FH (with ASCVD or another major risk factor), who are not achieving their target despite being on a statin-ezetimibe combination, adding a PCSK9⁺ inhibitor is advised. “This is big change from the previous guidelines,” added taskforce co-chair Dr François Mach from the Geneva University Hospital in Geneva, Switzerland.

“The vast majority of patients can get to the 1.4 mmol/L level with the combination of high-dose statin and ezetimibe … this is a cheap and safe combination. The use of PCSK9 inhibitors may be restricted to a very small proportion of patients at the highest risk for ASCVD,” added Baigent.

Statins are the first drug of choice to reduce CVD risk in individuals with hypertriglyceridaemia (triglyceride 200 mg/dL or >2.3 mmol/L). Similarly, a PCSK9 inhibitor is advised in very high-risk FH patients  and those with ACS if targets are not reached with the maximal tolerated dose of statin plus ezetimibe. Intake of eicosapentaenoic acid (EPA) is advised on top of statins in patients with elevated triglycerides.

“Based on the REDUCE-IT trial, it is reasonable to use high-dose EPA [icosapent ethyl] in high-risk patients with triglyceride levels between 1.5 and 5.6 mmol/L (135-499 mg/dL) despite statin therapy,” Baigent shared.

The authors said the benefits of statins far outweigh their risk, but these medications should not be used by pregnant women or premenopausal women who may become pregnant. In patients >75 years, statins may be considered based on the risk level, baseline LDL, health status, and potential interaction with other drugs.

Another important update to the 2019 guidance is the removal of the distinction between primary and secondary prevention. “Data show that the benefits of statins do not differ between primary and secondary prevention, rather, it is the level of risk that is important,” Baigent said. “So now, the recommendations are similar for a similar level of risk, regardless of whether a patient has had a previous event. Risk though is calculated the same way in both settings.”

Take-aways for clinicians

Statin intolerance is frequently encountered by practitioners and may be difficult to manage. However, “true statin intolerance is rare as demonstrated in previous placebo-controlled randomized trials,” said the guideline authors. “Statin therapy (ie, changing the statin or reducing the dose) is possible in most patients. So, the message to clinicians is – try to keep patients on statins in the vast majority of cases.”

CVD risk stratification

The guideline recommends the use of coronary artery calcium (CAC) imaging with CT to aid treatment decisions for patients at moderate risk of ASCVD, particularly when LDL-C is not reached with lifestyle intervention alone and there are doubts on whether LDL-C-lowering treatment is required. “Patients with very low calcium risk are at a very low CVD risk,” Mach said.

“Assessment of arterial (carotid or femoral) plaque burden on ultrasonography may also be informative,” said the authors. “ApoB analysis may be a better measure of exposure to atherosclerotic lipoproteins and hence, may be particularly useful for risk assessment in individuals where measurement of LDL-C underestimates this burden, such as those with high triglycerides, diabetes, obesity, or in those with very low LDL-C.”

A one-off measurement of lipoprotein (a) [Lp(a)] may also help to identify those with very high inherited Lp(a) levels who may have a substantial lifetime risk of ASCVD. “This helps to further risk stratify patients at high risk, those with a family history of premature CVD, and determine treatment strategies in those whose estimated risk is on the border of risk categories,” they added.

The right approach

“The ‘lower is better’ message and the recommended LDL targets, I think, is the right approach and that coincided with what I believe to be right,” commented Dr Steve Nissen from the Cleveland Clinic in Cleveland, Ohio, US, who is unaffiliated with the guideline.

Dr Deepak Bhatt from the Brigham and Women's Hospital, Boston, Massachusetts, US, added that the guidelines validate approaches to risk-stratify patients and personalize therapies. “And that’s a big conceptual change.”

Diabetes-CVD guideline signals paradigm shift

The guideline on diabetes, prediabetes, and CVD, done in collaboration with the European Association for the Study of Diabetes (EASD), elevates SGLT2 inhibitors and GLP-1 receptor agonists to first-line therapy in patients with diabetes who have CVD or are at high or very high CVD risk.

The results of several CVOTs with newer glucose-lowering agents have shown very positive results in terms of CV events (non-fatal MI, non-fatal stroke, and CV death). “These results have really changed the paradigm on how cardiologists have to approach patients with diabetes,” said Professor Francesco Cosentino, ESC chairperson of the guidelines task force from the Karolinska Institute and Karolinska University Hospital in Stockholm, Sweden.

As such, empagliflozin, canagliflozin, dapagliflozin, liraglutide, semaglutide, or dulaglutide are recommended in treatment-naïve patients with T2D and established CVD or with high or very high CV risk. Metformin is now relegated as first-line therapy in T2D patients who are overweight without established CVD and with moderate CV risk. Patients already on metformin who develop CVD should have an SGLT2 inhibitor or GLP-1 receptor agonist added to their treatment.

“After years of dominance, metformin has been slightly pushed out of the limelight to patients who don’t have CVD and who are drug-naïve,” said Professor Peter J. Grant, EASD chairperson of the guidelines task force from the University of Leeds, UK. 

CV risk reclassified

Another major change pertains to CV risk classification. “The duration of diabetes together with the presence of comorbidities and other risk factors is driving the type of CV risk of our patients,” said Cosentino.“We’ve reclassified CV risk so that we no longer talk about primary and secondary prevention but really talk about degrees of risk [ie, moderate-, high-, and very high-risk],” added Grant.

Patients with moderate risk are young with <10 years with diabetes, those with high risk have had diabetes for ≥10 years plus have ≥1 additional risk factor but no target organ damage, and those with very high risk have diabetes and established CVD or target organ damage/≥3 risk factors/>20 years with diabetes.

“This type of classification is impacting all of our new recommendations and it is anticipated that it may provide proper diagnostic and therapeutic approaches to patient care,” Cosentino added.

For example, the management of dyslipidaemia – LDL-C targets and recommended reductions – in diabetes patients is built around these new classifications, said Grant. While statins remain the first-choice lipid-lowering agent, a PCSK9 inhibitor is now recommended in patients with very high CV risk with persistent high LDL-C despite maximum statin plus ezetimibe or with statin intolerance.

With regard to antiplatelet therapy, aspirin is not recommended as primary prevention in patients with moderate CV risk. However, aspirin at a dose of 75–100 mg/day for primary prevention can be considered for diabetes patients with high or very high CV risk who do not have contraindications.

Lifestyle is key         

Lifestyle modification is recommended for patients with prediabetes to delay or prevent progression into diabetes as well as counselling against alcohol consumption.

“There has been a long-standing view that moderate alcohol intake has beneficial effects on the prevalence of CVD,” said Grant. “Two high-profile analyses have reported this is not the case and that alcohol consumption does not appear to be beneficial. On the basis of these new findings we changed our recommendations.”

Hypertension and kidney disease

Lifestyle changes are also recommended to manage hypertension in patients with diabetes or prediabetes. In terms of medical management, RAAS blockers are preferred over beta-blockers or diuretics in patients with prediabetes. Recommended initial treatment is a RAAS blocker combined with a calcium channel blocker or thiazide/thiazide-like diuretic. Blood pressure (BP) targets should be individualized, with different targets in older patients and those with high cerebrovascular risk or diabetic kidney disease. 

In patients with kidney disease (eGFR 30 to <90 mL/min/1.73m²), SGLT2 inhibitors are preferred, as well as the GLP-1 receptor agonists liraglutide and semaglutide, said Grant.

Significance of the guidelines

“The emphasis of these guidelines is to provide state of the art information on how to prevent and manage the effects of diabetes on the heart and vasculature, with a focus on new data that has emerged since the 2013 document,” said Cosentino.

Other recommendations include continuous self-monitoring of blood glucose and BP levels, medical management of peripheral vascular disease, arrhythmias, and heart failure, and coronary revascularization, all of which can be viewed at https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehz486/5556890.

Chronic coronary syndromes

The new guideline on chronic coronary syndromes recognizes that stable coronary artery disease (CAD) can be a dynamic condition and that noise and air pollution can increase the risk of heart attack and stroke. “Hence, policies and regulations are needed to minimize both,” said Dr Juhani Knuuti, chairperson of the guidelines task force and director of the Turku PET Centre, Finland. The guidance also recommends cognitive behavioural therapy and cardiac rehabilitation and puts emphasis on lifestyle modification (smoking cessation, diet, exercise).

Pulmonary embolism

The guideline on pulmonary embolism (PE), produced in collaboration with the European Respiratory Society, does not change much from the 2014 iteration but focuses more on precise recommendations for diagnosis and risk stratification. It advises clinicians to first consider symptoms and blood test before moving to CT or ultrasound, if necessary.

“The aim is to get to the diagnosis as reliably and quickly as possible, in order to start lifesaving therapy and prevent other clots from reaching the lungs,” said Dr Guy Meyer, co-chairperson of the guidelines task force and respiratory medicine physician, Hôpital Européen Georges-Pompidou, Paris. Anticoagulants are recommended for patients with confirmed acute PE whereas thrombolytic drugs, catheter-based procedures, or surgery, if a patient with acute PE is in shock.

Supraventricular tachycardia

The guideline on supraventricular tachycardia (SVT) recommends antiarrhythmic drugs for acute episodes but not for long-term therapy. Catheter ablation is now recommended more strongly than before and is the preferred treatment for SVT over antiarrhythmic drugs in pregnant women.