Age No Barrier to Lipid Lowering Benefit

Older people with elevated LDL cholesterol shouldn’t necessarily be treated less intensively than younger patients in either primary or secondary prevention of atherosclerotic cardiovascular disease (ASCVD), two studies suggested.

One study showed that in the general Danish population, people ages 70 to 100 had the greatest absolute risk of MI and ASCVD but benefited the most from statins for primary prevention compared to younger people.

Separately, a meta-analysis showed that individuals age 75 or older had risk of major vascular events reduced at least as much with LDL-lowering therapies as younger patients. Both reports were published in The Lancet.

Still, a note of caution on the controversial use of statins and other lipid-reducing agents in older people was sounded by Frederick Raal, MB BCh, PhD, and Farzahna Mohamed, MB BCh, both of University of the Witwatersrand in Johannesburg, South Africa.

“Older patients have a high burden of risk factors for ASCVD. Pill burden and polypharmacy with multiple medications being prescribed for hypertension, diabetes, and hypercholesterolaemia, as well as other comorbidities such as osteoarthritis, is a concern,” they wrote in an accompanying commentary.

“Physician judgment and shared decision making, taking into account functional status, independence, and quality of life, are therefore important for deciding on the need for lipid-lowering treatment in older patients for both primary and secondary prevention of cardiovascular disease and one needs to carefully consider whether the benefit will outweigh the risk,” the editorialists urged.

Moreover, there has been no randomized trial of lipid lowering specifically enrolling these older patients. The much-anticipated STAREE trial in a primary prevention cohort ages 70 and older is not expected to be completed before 2023.

Progressive Increase in ASCVD Risk With Age

In people who lived to 70-100 years without developing ASCVD or diabetes, high LDL cholesterol was still linked to subsequent MI and ASCVD events, reported Martin Bødtker Mortensen, PhD, and Børge Grønne Nordestgaard, MD, both of Copenhagen University Hospital in Denmark.

Every 1.0 mmol/L increase in LDL cholesterol was associated with greater risk of MI (HR 1.34, 95% CI 1.27-1.41) and ASCVD (HR 1.16, 95% CI 1.12-1.21) over a mean 7.7 years of follow-up in the overall population and across all age groups in the Copenhagen General Population Study (CGPS).

Yet older people had greater absolute risk. For example, individuals age 80-100 years had 2.5 more events per 1,000 person-years with every 1.0 mmol/L increase in LDL cholesterol, whereas people age 20-49 years had just 0.6 more MIs per 1,000 person-years.

“This finding supports the idea of cumulative burden of LDL cholesterol over a person’s lifetime and progressive increase in risk for MI and ASCVD with age. Thus, high LDL cholesterol in apparently healthy people older than 70 years is not a benign finding because it is associated with a substantially higher risk of developing MI and ASCVD,” Mortensen and Nordestgaard wrote.

Notably, they found that the number needed to treat (NNT) with a moderate-intensity statin for 5 years to prevent one MI or ASCVD event was just 80 in people ages 70-100 years but increased with younger age to 769 for those ages 20-49 years.

“Although no randomised controlled trial of statin therapy in primary prevention has specifically enrolled participants older than 75 years, available randomised controlled trial evidence has not indicated an upper age threshold beyond which statin therapy does not reduce risk,” the researchers wrote.

Overall, the study’s findings were novel and differ from reports from cohorts enrolled decades ago, the investigators said. Over the years, life expectancy has increased in many countries and older people have become healthier, with disease onset later in life, they said.

“These favourable changes could account for why elevated LDL cholesterol is associated with increased risk of MI and ASCVD in individuals aged 70–100 years in contemporary, but not in historic, populations,” they suggested.

Mortensen and Nordestgaard studied CGPS participants who did not have ASCVD or diabetes at baseline and who were not taking statins. Patients had been randomly selected to reflect the Danish general population.

In total, there were 91,131 people enrolled from 2003 to 2015. Those in the 80-100 age range accounted for 3% of the cohort, and those ages 70-79 another 12%.

Study authors cautioned that the results may not be generalizable, given the inclusion of only white Europeans.

Benefits of Lipid Lowering Regardless of Age

LDL cholesterol-lowering therapies reduced cardiovascular risk for people age 75 or older, according to a meta-analysis of statin, ezetimibe (Zetia), and PCSK9 inhibitor trials, largely in secondary prevention.

Every 1 mmol/L reduction in LDL cholesterol was associated with a 26% reduction in risk of major vascular events in these patients (RR 0.74, 95% CI 0.61-0.89). Moreover, each component of the primary outcome was in line with a significant benefit of LDL reduction:

• Cardiovascular death (RR 0.85, 95% CI 0.74-0.98)
• MI (RR 0.80, 95% CI 0.71-0.90)
• Stroke (RR 0.73, 95% CI 0.61-0.87)
• Coronary revascularization (RR 0.80, 95% CI 0.66-0.96)

The extent of risk reduction didn’t differ significantly by age. Among older patients, the achieved risk reduction was similar between statin and non-statin treatment (P=0.64 for interaction), reported Marc Sabatine, MD, MPH, of Brigham and Women’s Hospital and Harvard Medical School, and colleagues.

Study authors are slated to present their meta-analysis at this year’s virtual American Heart Association meeting. Included were 244,090 patients from 29 randomized trials published from 2015 to 2020.

“These results should strengthen guideline recommendations for the use of lipid-lowering therapies, including non-statin treatment, in older patients,” Sabatine and colleagues said. They noted that American cholesterol guidelines give only a class IIa recommendation for statins in secondary ASCVD prevention in people 75 or older, and there is no guidance on the addition of a non-statin.

“In addition to showing that lipid-lowering therapies reduce mortality and morbidity in older patients, we also found no offsetting safety concerns,” the group added, acknowledging that their safety data had been limited to non-statin treatment studies.

The meta-analysis added five individual trials to a prior meta-analysis of 24 trials by the Cholesterol Treatment Trialists’ Collaboration. Of the total study participants, 8.8% were 75 years or older.

Investigators cautioned that the trials they had selected differed in outcome definitions and study duration (median follow-up ranged from 2.2 years to 6.0 years). Another limitation was that older patients participating in trials may not be representative of their age group.

“The trials that were assessed in this meta-analysis were predominantly secondary prevention studies; therefore, whether lipid-lowering therapy should be initiated for primary prevention in people aged 75 years or older is unclear,” Raal and Mohamed added.

“When to start lipid-lowering therapy and the duration of therapy are probably more important than whether to start lipid-lowering therapy, particularly for the primary prevention of cardiovascular disease in older patients, for whom further evidence is required,” they said.