Call for Tighter LDL Targets for Highest Risk Patients

Becky McCall

November 15, 2021

LONDON - Tighter low-density lipoprotein (LDL) targets, should be the aim in very high-risk patients, using a combination of therapies in a new era of ‘ones not twos’ (in terms of mmol/L), according to experts in lipid and cardiovascular risk management

"We underestimate residual cardiovascular risk in people living with type 2 diabetes, and despite aggressive management of blood pressure, lipids and glycaemia, still there’s an appreciable number of patients with type 2 diabetes who die with cardiovascular disease," said GP Kevin Fernando, from North Berwick Health Centre, near Edinburgh, speaking at the 2021 Diabetes Professional Care conference.

"Tighter LDL targets are needed as we are now in an era of ‘ones’ for highest risk patients," added Dr Fernando, who is also Scottish lead of the Primary Care Diabetes Society. "Address residual cardiovascular risk with cardioprotective diabetes therapies and with more aggressive management of lipids as well."

The panel discussion addressed issues around lipid-lowering dilemmas in different patient scenarios using a case-based approach, as might be presented in primary care and with the multi-disciplinary team.

Dr Fernando was joined by Victoria Ruszala, MFRPSII, Specialist Pharmacist, Cardiology and Diabetes, North Bristol NHS Trust, and Hannah Beba, Consultant Pharmacist, Leeds Clinical Commissioning Group (CCG).

"In our area, LDL is all everyone is talking about," said Ms Ruszala. "They’ve adopted the European guidelines because they are more up to date. Drugs are based around LDL not non-HDL. Now we know the outcome, benefits are based on LDL."

Ms Beba explained that some localities in her area do not even report LDL levels. "Non-HDL is useful because we look at it by lining up all the bad guys, so we account for all the risk, having taken out the good guy. It makes sense to account for everything that might contribute to cardiovascular risk."

However, she added that she has reported LDL. "I do think the European guidelines are really helpful because they separate out high and very high risk. It’s important that we narrow down the very high risk and we do need to be thinking about this in practice – especially in the lipid clinic - and aim for LDL under 1.4 [mmol/L]."

Until recently, the evidence base has been dominated by cardiometabolic, renal, and blood pressure drugs, whereas various lipid-lowering agents have been largely neglected, "probably because we’ve only really had statins until recently," said Dr Fernando.  Now, a number of agents are available including proprotein convertase subtilisin kexin 9 (PCSK9) drugs and, notably, inclisiran, approved by NICE in September this year to be administered in primary care settings as a twice-yearly injection.

"Like blood pressure and diabetes, where we take an early combination approach, we’re going to see a shift in primary and secondary care towards early combination lipid-lowering therapies," he said.

He added that primary care physicians were being asked to achieve ever tighter LDL-cholesterol targets, and that statins alone would not satisfy that requirement: this is where multiple lipid-lowering therapies would be needed.

European Society of Cardiology (ESC) targets for lipid lowering

Current ESC targets established in the 2019 ESC/EAS Guidelines for the management of dyslipidaemias give four risk categories: very high risk, high risk, moderate risk and low risk. Dr Fernando said for the very high risk patients, clinicians should strive for an LDL target of less than 1.4 mmol/l and an over 50% reduction from baseline.

Typical very high risk patients might include, for example, those with cardiovascular disease, or living with type 2 diabetes, or type 1 diabetes with end organ damage such as left ventricular damage, or multiple cardiovascular risk factors such as chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73m2) or hypertension or long duration diabetes (>10 years).

The LDL target depends on a patient’s individual cardiovascular risk. "There is robust evidence that the lower the LDL, the better," he said. "I look less and less at total cholesterol but focus on the LDL, which has the atherogenic aspects," said Dr Fernando. "Even the moderate risk patients should lower their LDL more than before," he added. The moderate risk target for LDL is 2.6 mmol/l.

Dr Fernando tends increasingly to follow to the ESC guidelines because they are more evidence based, he says. "I think NICE [National Institute for Health and Care Excellence] is outdated. This is where we need to look at guidelines as handrails not train tracks."

"Often patients are started on a statin and that’s it, but in very high-risk patients, we need to start a statin along with a number of new tools in the toolbox."

Familial hypercholesterolemia more common than many think

Dr Fernando turned to familial hypercholesterolemia, which is more common than often thought and found in about 1 in 250 people. Effectively, a typical practice of around 8000 patients would expect to have 30-40 patients with familial hypercholesterolemia, he said.

"We know these people have a high risk of cardiovascular disease, but if we identify and manage them then they can have a normal life expectancy as someone without familial hypercholesterolemia," he said.

NICE suggests systematic screening of records for people with total cholesterol over 7.5 mmol/l. "This would prompt consideration of familial hypercholesterolemia," said Dr Fernando, depending on age, and especially if there’s a family history of cardiovascular disease. A patient with a total cholesterol over 9 mmol/l should be referred for specialist assessment.

He also explained that the Simon Broome criteria, which are UK based and suggested by NICE, can be used to identify definite or possible familial hypercholesterolemia. "Ultimately, I would need to refer to my genetic specialist colleagues, for genetic screening."

Ms Beba explained how a patient with suspected familial hypercholesterolemia would be investigated. "We’d normally take a very detailed family history with the patient, run the bloods including lipoprotein A and other proteins that provide a genetic signal and are key to the overall picture. Genetic testing would be consented to and done, and once there’s a confirmed diagnosis a genetic nurse then traces other cases related to that index case in the family tree. We then contact anyone else we think is eligible for genetic testing."

A growing toolbox of lipid-lowering agents

Knowing which tools to use for which patient is the question. Dr Fernando highlighted a couple of newer agents. Icosapent ethyl (Vascepa), a highly purified omega-3 oil product, was found to reduce cardiovascular risk in people with elevated triglyceride levels. "This is yet another new tool in the toolbox for us to consider, which might not suit everybody, but it will some. It’s already approved by the FDA in the US and is en route to doing so in the UK."

Inclisiran was approved by NICE for people with high cholesterol and a history of cardiovascular events. It has a novel mechanism of action that clears cholesterol from the liver using RNA interference technology.  "Inclisarin has been endorsed by the NHS although it doesn’t have any outcome data yet," Dr Fernando said. "After the rosiglitazone [antidiabetic drug] debacle a few years ago, it was mandatory for new diabetes drugs to prove their safety and efficacy, but inclirasan just gets in. Something doesn’t fit to me."

Asked by Medscape UK how he approaches a patient with very high cardiovascular risk, Fernando said: "One size does not fit all and we need to use our clinical judgement, and we need to generalise trial results to everyday patients."

He said he uses statins for everyone but says acetamide is underused in primary care despite it having been around for many years. "Increasingly I’m seeing patients being discharged from hospital on statins and acetamide. As a minimum I would say a statin and acetamide."

Finally, he emphasised that despite the expanding armamentarium of drugs available, good lifestyle advice is all-important. "For all our patients, the single thing they can all do to reduce the cardiovascular risk is to stop smoking. If someone is a smoker I would forget all these drugs and just focus on stopping the smoking, that is the single best thing you can do.

"Remember there’s no such thing as a sudden heart attack - it takes years of preparation," he concluded.

COI: Dr Fernando has declared previous speaker honoraria from all current manufacturers of SGLT2 inhibitors. Ms Beba and Ruszala have not declared any relevant conflicts of interest.

A case-based approach to common lipid lowering dilemmas in primary care and the wider MDT.

Presented Thursday 11 November, 2021 at the Diabetes Professional Care meeting 2021.

No abstract

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