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Association Between Age and LDL-C Response to Statins
Quick Takes
- Initiation of treatment with a low- to moderate-intensity statin was associated with a greater reduction in LDL-C levels among older patients than among younger patients.
- This association between age and statin response was found whether the statin was prescribed for primary prevention, for secondary prevention, or among patients with diabetes.
- The cohort study is hypothesis generating for a study to assess whether utilizing low- to moderate-intensity statins when initiating statins in persons aged ≥75 years may reduce incident myalgia and diabetes with no reduction in clinical benefit.
Study Questions:
Is there an association between age and reduction in low-density lipoprotein cholesterol (LDL-C) based on age?
Methods:
A nationwide register-based cohort study was conducted in Denmark from 2008 to 2018 in 82,958 patients. Statins were limited to simvastatin single dose range of 10, 20, and 40 mg/day (all considered low to moderate intensity) and atorvastatin 10, 20, 40, and 80 mg/day (10 and 20 mg considered low intensity and 40 and 80 mg high intensity). LDL-C response was defined as percentage reduction in pre-statin LDL-C level, and percentage reduction differences according to age and simvastatin or atorvastatin dose based on a longitudinal model for LDL-C. Pre-statin LDL-C was ascertained in the 12 weeks before initiation, and the level during statin use was ascertained between 4 and 24 weeks after initiation.
The primary study outcome was LDL-C percentage reduction, calculated as [pre-statin LDL-C – LDL-C during statin use] / pre-statin LDL-C] with results expressed as per 5-year age group beginning at <50 years and increasing by 5 years to ≥75 years, by a restricted cubic spline at the 5th, 35th, 65th, and 95th percentiles, and by age trend per 25 years for initiators aged 75 years versus 50 years.
Results:
Among the 82,958 statin initiators, 10,388 (13%) were aged ≥75 years. With low- to moderate-intensity statins, those aged ≥75 years had greater mean LDL-C percentage reductions than those younger than 50 years—e.g., 39.0% versus 33.8% for simvastatin, 20 mg; and 44.2% versus 40.2% for atorvastatin, 20 mg. The adjusted percent reduction differences for initiators aged 75 years compared with initiators aged 50 years was 2.62 percentage points. This association was consistent for primary prevention (2.54 percentage points) and secondary prevention (2.32 percentage points) but smaller for initiators of high-intensity statins (atorvastatin, 40 mg: 1.36 percentage points; atorvastatin, 80 mg: –0.58 percentage point).
Conclusions:
Low- to moderate-intensity statins were associated with a greater reduction in LDL-C levels in older persons than younger persons and may be more appealing as initial treatment in older adults who are at increased risk for adverse events.
Perspective:
Inter-individual variability in the LDL-C response to statin treatment is large, and age affects the magnitude of LDL-C reduction. There are several potential reasons. Older adults had higher plasma concentrations of statins with the same dose than young adults in pharmacokinetic studies, which has several published explanations including statin pharmacokinetics in older persons. The bioavailability of statins may be higher in older adults due to greater drug absorption; age-related changes in hepatic function may lead to increased statin exposure—for example, decreased activity of the cytochrome P450 3A4 enzyme that metabolizes simvastatin and atorvastatin; and renal function declines with age, which may also affect statin concentrations.
The reduction in cardiovascular events in clinical trials with various LDL-C lowering drugs is fairly consistent; each 40 mg/dL reduction in LDL-C reduces atherosclerotic cardiovascular disease by about 20%, largely irrespective of age, sex, baseline LDL-C, or previous vascular disease, and of vascular and all-cause mortality. But those trials have not been designed for and under-represent the elderly. Nevertheless, the ability to begin with lower doses of statins in the elderly provides important safety value, particularly since the dose and LDL-C lowering effect of statins correlates with myopathy, which correlates with compliance and long-term risk of developing diabetes (perhaps less important in those >75 years of age). In a population study followed for up to 15 years, those who take statins have a 38% greater risk of developing type 2 diabetes compared with those who are not on statins. Risk increased among people who were overweight or obese and had an impaired glucose balance. That the percent reduction differences were small and negative in the atorvastatin 80 mg dose may be explained by the minimal decrease in LDL-C between the 40 mg and 80 mg dosing in clinical trials (about 7%).
Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Geriatric Cardiology, Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Statins
Keywords: Aged, 80 and over, Atorvastatin, Cholesterol, LDL, Diabetes Mellitus, Type 2, Dyslipidemias, Geriatrics, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypolipoproteinemias, Myalgia, Myocardial Ischemia, Primary Prevention, Risk, Secondary Prevention, Simvastatin
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