With New LDL Goalposts in FH, Combo Therapy Must Start Early

It’s time to stop futzing about with single LDL-lowering drugs for high- and very-high-risk patients, says lipid expert Kausik Ray.

With New LDL Goalposts in FH, Combo Therapy Must Start Early

MANNHEIM, Germany—Doctors are getting better at treating patients with familial hypercholesterolemia (HF), even shifting LDL levels downwards, but they’re still not doing a good enough job getting them on the lipid-lowering combinations that will be most effective.

Those are the findings from follow-up of patients enrolled in the European Atherosclerosis Society (EAS) Familial Hypercholesterolemia Studies Collaboration (FHSC) registry, which was presented this week as a late-breaking clinical trial at the EAS 2023 Congress.   

“At the population level, we’re not getting our population to goal because we’re not putting enough of our patients onto combination therapy,” said Kausik Ray, MBChB, MD (Imperial College London, England), lead investigator of the FHSC registry. “The mantra has to be to move to combination therapy rather than monotherapy—that starts with the assessment of risk. If you don’t know what the risk is, you don’t know how well you need to treat.”

Overall, slightly less than one-third of these high- and very-high-risk patients were at the target recommended by clinical guidelines, which is more than what was previously seen, but still disappointing, said Ray.

LDL Targets Have Changed

The FHSC registry, known as SANTORINI, is an international collaboration of physicians treating patients in specialized clinics that are included in national, regional, or local FH registries. The FHSC data set consists of 61,612 patients from 56 countries, of whom 42,167 were aged 18 years or older with probable or definite diagnosis of heterozygous FH.

In an analysis published last year in the Lancet, and reported by TCTMD, the FHSC researchers showed that nearly 60% of all FH patients were treated with lipid-lowering medication, and the median LDL-cholesterol level for those on treatment was 4.23 mmol/L (163.57 mg/dL). For those not taking treatment, the median level was 5.43 (210.0 mg/dL).

SANTORINI, said Ray, is the first registry that enrolled FH patients following the update to the European Society of Cardiology (ESC)/EAS guidelines that lowered LDL targets for high- and very-high-risk patients. As of 2019, the target is less than 1.4 mmol/L (55 mg/dL) in addition to at least 50% lowering beyond baseline for both primary and secondary prevention patients at very high risk for ASCVD. For those at high risk, the target is less than 1.8 mmol/L (70 mg/dL) plus 50% lowering, while patients at moderate risk should aim to be below 2.6 mmol/L (100 mg/dL)

“What was different about those guidelines was that the goalposts were changed for three of the risk categories,” said Ray. “For two of those, they’re a lot harder to achieve, namely for high- and very-high-risk patients. What we forgot to tell people is that the guideposts have moved because of the use of combination therapy.”  

The new EAS presentation focuses on 7,210 patients (mean age 65 years; 72.1% male) at high or very high risk for cardiovascular disease with complete data on lipid-lowering therapy and LDL-cholesterol levels at baseline and 1 year.

At baseline, 21.2% of these patients met the guideline-recommended LDL-cholesterol target and had a mean LDL cholesterol of 2.42 mmol/L (93.58 mg/dL). At 1 year, 31.2% of patients were at goal, with a mean LDL cholesterol of 1.98 mmol/L (76.57 mg/dL).

In the high-risk group, there was an increase in the number of patients at goal, up from 24.4% at baseline to 34.2% at 1 year, with corresponding LDL-cholesterol levels decreasing from 2.74 to 2.29 mmol/L (105.96 to 88.55 mg/dL). In the very-high-risk patients, 30.1% were at target at 1 year, which was up from 20.0% at baseline, and LDL levels declined from 2.29 to 1.86 mmol/L (88.55 to 71.93 mg/dL).

“Each group is roughly shifting by 0.4 mmol/L, which is resulting in around an extra 10% of people getting to goal,” said Ray.

In terms of treatment, just 3.0% of patients were not taking any lipid-lowering therapy at 1 year, which was down substantially from baseline where 21.6% weren’t taking any medication. These patients were mostly transitioned to monotherapy, say Ray, noting there was an increase in those taking a single LDL cholesterol-lowering medication from 50.9% at baseline to 55.4% at 1 year.

“That’s mostly statin-based monotherapy, which improved by about 4%,” he said.

There was also an increase in the percentage of patients taking combination therapy, which was up from 27.5% at baseline to 41.7% at 1 year. This was largely the result of more patients taking ezetimibe in addition to statins. There was only a small increase in the use of PCSK9 inhibitors, which increased from 5.6% to 7.8%.

In the high- and very-high-risk groups, similar trends were observed, with large reductions in the number of untreated patients and increases in the use of statins. In the very-high-risk patients, however, the use of combination therapy increased from 29.9% at baseline to 45.3% at 1 year, an increase driven by the use of statins and ezetimibe. In this cohort, use of PCSK9 inhibitors increased from 5.9% to 8.2%.   

Finally, Ray presented data on the treatment patterns of patients who achieved the LDL-cholesterol targets. Overall, 36.6% and 32.0% of high- and very-high-risk patients at goal were taking combination therapy, with more than half of them taking a combination that included a PCSK9 inhibitor. Of the patients who were switched from monotherapy at baseline to combination therapy in follow-up, roughly one-third to half of patients achieved the recommend LDL target.  

While there were signs of improvement in SANTORINI, Ray said physicians should be starting with combination therapy in these high-risk cohorts given the substantial reduction in LDL cholesterol levels that is needed. Given the high LDL-cholesterol levels, they aren’t going to get to start with a single drug.

“As soon as you start using combination therapy, a greater proportion of our patients are going to get to goal,” said Ray.

Possible Hawthorne Effect

In the discussion following the presentation, Stephen Nicholls, MBBS, PhD (Monash University, Melbourne, Australia), who wasn’t involved in the study, questioned whether there might be some “registry bias” with the findings, noting centers enrolled in the FHSC might be more motivated in their treatment of patients.

Ray agreed, adding that SANTORINI could represent the “best-case scenario” when it comes to care of these at-risk patients. There is also the potential Hawthorne effect, with physicians altering prescribing behaviors knowing they are being observed in a study.

“We don’t know for certain that is the case, and we won’t have an answer for that, but there could be some contribution,” said Ray.

Børge Nordestgaard, MD, DMSc (University of Copenhagen, Denmark), who spoke following the presentation, questioned which countries were performing well when it comes to treatment. Ray said they are planning that analysis but noted that baseline data showed some countries did perform better than others when it comes to using combination therapy. The United Kingdom and Ireland, for example, weren’t great, while Spain, Italy, and Portugal were examples of countries where combination use was higher, he said. 

Michael O’Riordan is the Managing Editor for TCTMD. He completed his undergraduate degrees at Queen’s University in Kingston, ON, and…

Read Full Bio
  • Ray KK, Aguilar C, Arca M, et al. Lipid management in patients with high and very high cardiovascular risk: 1-year follow-up data from routine clinical practice in Europe (SANTORINI study). Presented at: EAS 2023. May 24, 2023. Mannheim, Germany.