Atherosclerosis is the most common pathophysiologic process leading to cardiovascular disease (CVD). In 2016, an estimated 15 123 deaths in mainland Portugal were attributable to ischemic heart disease, ischemic cerebrovascular disease, or peripheral arterial disease, which corresponded to 14.3% of overall mortality. In the same year, disability-adjusted life years attributable to atherosclerosis totaled 260 943, of which 75% were due to premature death (196 438 years of life lost) and 25% due to disability (64 505 years lived with disability).1

Plasma lipid abnormalities by themselves may be responsible for as many as 50% of myocardial infarctions and 25% of strokes. Lowering low-density lipoprotein cholesterol (LDL-C), the primary driver of atherogenesis, reduces the risk of major vascular events. Statins, ezetimibe, and PCSK9 inhibitors have biologically equivalent effects on the risk of vascular events per unit change in LDL-C. The clinical benefit of these interventions depends on the absolute magnitude of the achieved LDL-C reduction and the total duration of treatment. In short, lower is better, and so is longer.2

Pharmacologic lowering of LDL-C is safe. The risk of serious muscle injury, including rhabdomyolysis, is <0.1%, and the risk of serious hepatotoxicity is about 0.001%. Newly diagnosed diabetes occurs at a rate of about 0.2% per year of treatment, and there is no convincing evidence for a causal relationship between statins and cancer, cataracts, cognitive dysfunction, peripheral neuropathy, erectile dysfunction, or tendonitis.3

LDL-C lowering is also cost-effective, even more so with the advent of generic pricing. Accordingly, it has been suggested that eligibility for preventive statin therapy should be expanded to younger individuals and that treating patients at borderline risk regardless of LDL-C level would likely be highly cost-effective.4,5

Over the past decade, several observational studies have reported the LDL-C levels of patients receiving lipid-lowering therapy in Portugal (Table 1). These reports indicate that LDL-C levels are above the recommended goals in most patients eligible for pharmacologic LDL-C lowering, and the rates of LDL-C control have not improved over time. An additional reason for concern is the significant number of patients eligible for LDL-C lowering therapy who are not receiving any treatment.

In this issue of the Journal, Meireles-Brandão et al. report the results of the ISTO study, which provides further evidence on the control of LDL-C in primary prevention patients living in Portugal.12 ISTO is a retrospective study of 516 patients managed at a CVD risk outpatient clinic in a university hospital. Study patients had at least two CVD risk factors and were followed for at least two years between 1995 and 2015. At baseline, 75.0% of patients were overweight or obese, 71.9% were not regularly physically active, 63.8% had a history of hypertension, 30.6% had diabetes, and 13.0% were current smokers. Moderate-intensity statin therapy was prescribed for 91.5% of patients at baseline and intended to be maintained throughout follow-up. At a median follow-up of 11 years, median LDL-C levels had improved significantly, from 172 mg/dl at baseline to 92 mg/dl at last follow-up. This change was associated with significant reductions in both median carotid intima-media thickness and CVD risk at last follow-up. Nevertheless, since most patients had high CVD risk at baseline (according to the Framingham risk score or the ASCVD risk estimator) and considering the wide range of LDL-C levels at last follow-up, from 37 mg/dl to 211 mg/dl, it seems reasonable to conclude that most patients had not achieved currently recommended LDL-C goals at last follow-up.

The findings of the ISTO study, like previous studies performed in Portugal, are not surprising. Most of the patients receiving lipid-lowering therapy in these studies were on moderate-intensity statin therapy and very few were taking ezetimibe. Taking a statin is certainly not enough to prevent avoidable atherosclerotic CVD. Optimal lowering of LDL-C is not achieved in most patients initiated on statin monotherapy, and these patients will experience significantly increased risk of future CVD, whether or not established CVD is present at baseline.13,14

Now is the time to step out of the comfort zone, to fight treatment inertia and realize the full potential of the benefits of LDL-C reduction in patients at high or very high CVD risk, by combining statin therapy with ezetimibe and/or other LDL-C lowering therapies such as bempedoic acid and PCSK9 inhibitors as needed to achieve the recommended LDL-C goal.

“Great things never came from comfort zones.” (Neil Strauss)