In this study, two-thirds of eligible patients initiating statin treatment had a change in their HDL-C level, and the degree of change was similar to that observed in randomised clinical trials . A paradoxical decrease in HDL-C of >0.1 mmol/L was associated with a 56 % increase in major adverse cardiovascular events compared with unchanged HDL-C levels. The results were consistent across subgroups based on age, gender, presence of diabetes, primary and secondary prevention. No association between increased HDL-C levels and risk of major adverse cardiovascular events could be observed.
Results from a recent meta-analysis did not demonstrate an association between statin treatment, HDL-C change, and CVD risk . Our patients had a relatively high untreated HDL-C level (1.48 mmol/L), in line with observations of untreated HDL-C levels in other Scandinavian studies, but in contrast with the recent publications [11, 21–23]. We observed a greater reduction in HDL-C (−0.27 mmol/L) compared with the meta-analysis (−0.13 mmol/L), and the relatively small HDL-C reduction in the meta-analysis might not have been sufficient to detect CVD risk associations. Furthermore, our findings are supported by a recent study which shows that a paradoxical decrease in plasma HDL-C levels after statin therapy is an important risk factor predicting long-term adverse cardiac events in patients with acute myocardial infarction .
Low single point measurements of HDL-C levels in patients receiving statin treatment have been reported to be associated with increased CVD risk, irrespective of the low LDL-C levels achieved . We have shown that patients with a relatively high HDL-C (mean 1.48 mmol/L) newly initiated on cholesterol-modifying treatment (statin) and who experienced a consecutive HDL-C reduction have an increased cardiovascular risk, independently of baseline LDL-C and LDL-C change on statin treatment. Our findings are in line with previous observational data where a threshold for increased cardiovascular risk for HDL-C values below 1.3–4 mmol/L was observed . Since the untreated HDL-C is relatively high in our material, this is the likely explanation for why we do not observe a reduced cardiovascular risk with increased HDL-C values. A major decrease in HDL-C level, independent of the size of the LDL-C reduction, might cause a shift in cholesterol transport. Indeed, the one-third of patients initiated on statin therapy who had a paradoxical reduction in HDL-C level  may have a suboptimal balance of cholesterol in/out transport to/from the inner arterial wall. Other important cardiovascular risk-lowering properties of HDL-C include antioxidant, anti-apoptotic, anti-inflammatory, antithrombotic, and anti-proteolytic properties, which account for the direct protective action on endothelial cells . The decrease in HDL-C might consequently negatively impact these protective actions. However, we believe that reduction of HDL-C per se is associated with increased cardiovascular risk and not necessarily a statin-specific effect. Thus, we would highlight the importance of non-pharmacological efforts that will prevent HDL-C reductions, such as avoiding weight gain and/or maintaining physical activity levels.
The endpoint was a composite of hospitalisation with a primary diagnose of myocardial infarction, unstable angina pectoris, or ischaemic stroke, or cardiovascular death. An analysis of the separate endpoint components showed that risk of ischaemic stroke was statistically significant. The risks of coronary events and cardiovascular death were not significant, although the trends showed indication of similar directions/patterns. This finding might be somewhat surprising, as a predominant effect of statin treatment on coronary disease would be expected. However, as more patients in Sweden die outside hospital owing to coronary disease than owing to stroke, and a proportion of fatal coronary events occur in the out-of-hospital setting, stroke events were more likely to be a classified event in our study because more of these patients survived to hospitals [25, 26]. Similar results were observed when comparing outcome of separate analysis of cardiovascular death with all-cause death. Interestingly, the recent study which showed that a paradoxical decrease in plasma HDL-C levels after statin therapy initiation also had results driven by significantly higher incidence of stroke in the decreased HDL-C group .
Eighteen percent of patients initiated on statin treatment during the observation period were included in the study. The main reason for exclusion was lack of laboratory data, as only laboratory measurements from primary care were available. This favoured the inclusion of patients with regular healthcare controls (hypertension, diabetes, atrial fibrillation) in primary care. A considerable proportion of secondary prevention patients with initiation of statin treatment in hospital did not have a pre-treatment HDL-C measurement available to us and were therefore not included (Table S1).
The exclusion of a significant proportion of patients might call into question the generalisability of the results. However, we found consistent results in all subgroup analyses, with a numerically higher risk of reaching the composite endpoint with decreased HDL-C levels for all subgroups (older vs. younger patients, men vs. women, primary vs. secondary prevention patients, and presence of diabetes). However, among secondary preventive patients, a smaller numerical difference in cardiovascular risk between unchanged and decreased HDL-C groups was observed. Secondary prevention, for patients recently experiencing a myocardial infarction or a stroke, might potentially a have an initial increased thrombotic risk, which is more critical than the long-term effect caused by the atherosclerosis process. Altogether, this indicates that the study findings might be valid for a broad statin-treated population.
A further potential limitation regarding generalisability is the fact that the absolute majority of patients in Sweden are treated with relatively low doses of simvastatin. The frequent use of low-dose simvastatin might be the result of a stringent reimbursement regime, only allowing the use of high-potency statins in patients who do not reach treatment goals or in individuals who do not tolerate simvastatin. The effect on HDL-C change achieved by statins in general is reported to be independent of the reduction in LDL-C .
The present study is observational and unmeasured confounders may have influenced our results. Patients with malignancy or history of alcoholism were not included in the study. Changes in body weight, smoking pattern, or physical activity might influence levels of HDL-C, the latter two of which are not systematically recorded in primary care records. Since smoking previously was reported to be associated with generally low HDL-C levels, it is likely that smokers would be in the unchanged group or increase group due to the regression to the mean effect in our study [10, 27]. Furthermore, if the increase in HDL-C was due to cessation of smoking, a decrease in HDL-C should be found more frequently in smokers. In Sweden, not only is the overall smoking practice low (<15 %) but the likelihood of patients starting smoking during initiation of statin therapy can also be considered to be low. Furthermore, the effect of smoking cessation programmes in primary care is modest [28, 29]. The inverse correlation between physical activity and HDL-C change is low and can therefore be considered to be of minor importance . We did not observe a marked percentage increase in body mass index in patients with a reduction in HDL-C, when compared with patients with unchanged HDL-C levels.
Low compliance to statin treatment could potentially be a possible explanation for our findings. However, patients were only included in the analyses while on statin treatment, and only if the reported LDL-C reduction was >0.5 mmol/L. The risk of the results being due to low compliance and/or statin response can therefore also be considered to be low.
The statin prescription pattern might be a source of confounding by indication. We found that patients with high cardiovascular risk in general had a lower untreated LDL-C, and vice versa. This correlation between LDL levels and CVD risk has been reported previously in a real-life clinical setting . However, we found no correlation between LDL-C change and HDL-C change, as also supported by a previous report . A prescription bias based on low HDL-C levels might also be a source of explanation for our findings. As low HDL-C is not a reason for initiation of statin treatment in Sweden, though, it is not likely that HDL-C should be affected by confounding by indication. Furthermore, we observed a mean difference of 1.1 mg of simvastatin between the decrease and unchanged groups after propensity score matching. We do not think this minimal difference in dosing had any impact on the results.
Laboratory data were only available from primary care records. Biological and analytical variation of HDL-C values may be a potential source of misclassification into the different HDL-C change groups. However, we observed similar associations with baseline cholesterol parts [HDL-C, plasma triglycerides (TG), and LDL-C] on HDL-C change pattern in our study compared to those reported in randomized clinical trials . Thus, in our study, patients with high HDL-C had higher likelihood of HDL-C reduction and patients with low HDL-C and higher associated cardiovascular risk at baseline would more likely be identified for the HDL-C decrease group. In Sweden, HDL-C samples are generally analysed at regional central laboratories, all of which have participated in national quality and standardisation programmes since the end of the 1980s . The analytical variation for HDL-C in the Swedish external quality assurance programme is between 3 % and 4 % (at the level of 1.68 mmol/L) , while the biological variation of HDL-C is approximately 7 %. Patients in our study had to have a decrease in HDL-C of >0.1 mmol/L, and the average HDL-C decrease was 0.27 mmol/L. Our conservative estimations of the HDL-C variation support the notion that the magnitude of the observed HDL-C decrease was sufficient.
The present study also has several important strengths. First, the composite endpoint has been validated previously in Swedish studies . Second, only statin-naïve patients were included in order to increase the likelihood of analysing the actual treatment effect on HDL-C levels. The observed HDL-C change pattern is similar to that observed in randomised clinical trials . Third, our analyses carefully matched the patients for numerous cardiovascular diagnoses, risk factors, including baseline LDL-C, and LDL-C change on treatment, thus increasing the likelihood of similar baseline risk. Finally, using Swedish national health registers the follow-up was performed with basically no loss of events.