A systematic review and meta-regression analysis found that statin and nonstatin therapies that act primarily through upregulation of low-density lipoprotein (LDL) receptor expression were associated with similar reductions in LDL cholesterol and relative risks of major vascular events.
The researchers defined major vascular events as a composite of cardiovascular death, acute MI or other acute coronary syndrome, coronary revascularization or stroke. They added that there were five established interventions that act predominantly through upregulation of LDL receptor expression: statins, diet, bile acide sequestrants, ileal bypass and ezetimibe.
Lead researcher Michael G. Silverman, MD, of Brigham and Women’s Hospital and Harvard Medical School, and colleagues published their results online Sept. 27 in JAMA.
The researchers searched the MEDLINE and EMBASE database for randomized trials published between 1966 and July 2016 as well as reference lists and abstracts from major cardiovascular meetings held in the past two years. They identified 49 trials that met their inclusion criteria, which included reporting MIs, lasting at least six months and having at least 50 clinical events.
The studies included 312,000 participants who had 39,645 major vascular events. The mean follow-up period was 4.3 years, the mean LDL cholesterol level was 122.3 mg/dL and the mean age was 62 years old. In addition, 24 percent of participants were women.
For the 25 statin trials, each 38.7 mg/dL reduction in LDL cholesterol was associated with a relative risk of 0.77 for major vascular events. The results were similar in the primary prevention and secondary prevention trials. The absolute reduction in LDL cholesterol accounted for 98 percent of the between-study variability in the reduction of major vascular events, while the percentage reduction in LDL cholesterol accounted for 79 percent.
For the eight trials of nonstatin therapies that act predominantly via upregulation of LDL receptor expression, each 38.7 mg/dL reduction in LDL cholesterol was associated with a relative risk of 0.75 in major vascular events.
The relative risk of the five established interventions that act predominantly through upregulation of LDL receptor expression was within 2 percent of the predicted value from the regression line, according to the researchers.
They added that the observed relative risk of 0.94 for major vascular events for niacin was greater than expected, while the observed relative risk of 0.88 for major vascular events for fibrates was lower than expected. Meanwhile, the observed relative risk of 1.01 for major vascular events for cholesteryl ester transfer protein inhibitors was lower than expected and the estimated relative risk of 0.49 associated with proprotein convertase subtilisin/kexin type 9 inhibitors was lower but not significantly different than the expected relative risk.
The researchers cited a few limitations of the study, including that it did not evaluate patient-level data. They also mentioned that absolute risk reduction in each trial depended on the patient population, the end point and the duration of follow-up. In addition, they had much more data on statins than on the other treatment options.
“The implications of these results deserve careful consideration in light of the strength of the available trial evidence for different types of therapies,” the researchers wrote. “As per current guidelines, when tolerated, statins should be the first-line therapy given the large reductions observed for LDL [cholesterol], the excellent safety profile, the demonstrated clinical benefit, and low cost (now that most are generic). However, the data in the present meta-regression analysis raise the possibility that other interventions, especially those that ultimately act predominantly through upregulation of LDL receptor expression, may provide additional options and may potentially be associated with the same relative clinical benefit per each [38.7 mg/dL] reduction in LDL [cholesterol].”