Data of 738 patients (74%) were available for the 1‑year follow-up visit: 178 patients did not re-sign informed consent, 16 had died, in 38 the cholesterol level had not been measured after 1 year and 29 patients were lost to follow-up. At baseline, i.e. during hospitalisation for myocardial infarction, before protocol initiation, the mean age was 66 (± 9) years, 78% were men, 45% had diabetes mellitus (Tab. 1) and 23% did not use LLT (Tab. 2). Median duration from baseline to the 1‑year follow-up was 384 days (364–435). Among patients who did and those who did not participate in the 1‑year follow-up analysis, there were no significant differences in age, sex and medical history. However, for those who participated, LDL‑C target attainment during the initial study period was higher (90% vs 76%, p < 0.001) and median (95% confidence interval) LDL‑C levels were lower (1.5 [1.45–1.5] vs 1.6 [1.51–1.62], p < 0.001). The better LDL‑C outcomes among participants were observed concurrently with more intensive LLT, including more frequent use of PCSK9i (5% vs 1.5%, p = 0.02) and a higher prevalence of HIST + ezetimibe combination therapy (25% vs 16%, p = 0.007). Of the available 738 patients, 31 (4%) did not adhere to the specified protocol during the treatment phase of the PENELOPE study. Therefore, the per-protocol cohort included 707 patients, representing 71% of the initial PENELOPE cohort (Fig. S1, Electronic Supplementary Material).

At the end of the intervention phase of the protocol-led LDL-C-lowering strategy, in the 738 patients participating in the 1‑year follow-up, the target LDL‑C level (≤ 1.8 mmol/l) was achieved in 86% (intention-to-treat) and 90% of patients (per-protocol) who were treated solely with oral medication. When including those receiving a PCSK9i this increased to 91 and 95% respectively. The median LDL‑C at the end of the intervention phase was 1.5 (1.2–1.7) mmol/l (Figs. 1 and 2).

The cumulative effect of adding or adjusting lipid-lowering medication and 1‑year follow-up. The cumulative effect is the percentage of patients treated with lipid-lowering medication who reach the target level (LDL-C ≤ 1.8 mmol/l) in the previous and the corresponding steps. The denominator is 738 patients for the intention-to-treat cohort (all patients with 1‑year follow-up) and 707 for the per-protocol cohort. (HIST high-intensity statin, LDL‑C low-density lipoprotein cholesterol, PCSK9i proprotein convertase subtilisin/kexin type 9 inhibitor)

Median low-density lipoprotein cholesterol (LDL‑C) over time. The median LDL‑C at baseline, end of PENELOPE treatment phase (study period) and 1‑year follow-up (1 year) in the intention-to-treat population (n = 738)

After 1 year, in 471 of 738 patients (64%) LDL‑C was still ≤ 1.8 mmol/l. The distribution of LDL‑C at baseline and after 1‑year follow-up is demonstrated in Fig. 3. The median LDL‑C level after 1 year was 1.6 (1.3–2.0) mmol/l (Fig. 2).

Low-density lipoprotein cholesterol (LDL‑C) distribution at baseline, end of study period and 1‑year follow-up. The LDL‑C distribution at baseline, end of PENELOPE treatment phase and 1‑year follow-up in the intention-to-treat cohort (n = 738, all patients at 1‑year follow-up)

After 1 year, statin monotherapy was being used by 430 patients (58%), statin + ezetimibe by 221 patients (30%), PCSK9i + ezetimibe (whether in combination with a statin or not) by 48 patients (7%), and ezetimibe monotherapy by only 9 patients (1%). In the main treatment groups, an LDL‑C level ≤ 1.8 mmol/l was maintained in 270 patients (63%) with a median LDL‑C of 1.7 (1.4–2.0) mmol/l, 156 patients (71%) with a median LDL‑C of 1.6 (1.3–1.9) mmol/l and 39 patients (81%) with a median LDL‑C of 1.0 (0.9–1.3) mmol/l, respectively.

Patient-reported therapy adherence was 94%. Thirty patients (4%) were not using LLT; nevertheless, 16 of these patients (53%) reported positive therapy adherence. Patient-reported therapy adherence was seen in 409 (95%) patients on statin monotherapy, in 213 (96%) patients on statin + ezetimibe and in 45 (92%) patients on PCSK9i + ezetimibe (+ statin). The specified treatment groups are demonstrated in Tab. 2.

Between the end of protocol and 1‑year follow-up, a total of 164 patients (22%) were switched to a different LLT regimen. The main reasons for these changes were myalgia (in 65 patients) and LDL‑C levels (in 47 patients). Specified changes are demonstrated in Fig. S2 (Electronic Supplementary Material). Sex, age, medical history and oral versus PCSK9i therapy were not related to target attainment (Fig. S3, Electronic Supplementary Material).

In the per-protocol cohort, 463 of 707 patients (66%) met LDL‑C target levels after 1 year, with a median LDL‑C level of 1.6 (1.3–2.0) mmol/l and a patient-reported therapy adherence rate of 94%.

Within the 1‑year follow-up period, 71 patients (9%) experienced a serious cardiovascular event, one or a combination of: cardiovascular death (n = 10), myocardial infarction (n = 26), unstable angina pectoris (n = 14), in-stent thrombosis (n = 9), revascularisation (n = 19), cerebrovascular accident/transient ischaemic attack (n = 5), hospitalisation for heart failure (n = 13), graft failure after coronary artery bypass graft surgery (n = 3) and resuscitated cardiac arrest (n = 2). In 41 patients a non-fatal, non-cardiovascular adverse event occurred, and 4 patients died of a non-cardiovascular cause.

Of the 634 patients without a history of statin intolerance, 65 (10%) developed muscle complaints between the end of the study period and 1‑year follow-up, causing 27 patients (4%) to cease statin therapy, of whom 16 (3%) did not maintain their target LDL‑C level. Six patients (3%) ceased ezetimibe due to side effects between the end of the study period and 1‑year follow-up.