Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-analysis.
The comparative clinical benefit of nonstatin therapies that reduce low-density lipoprotein cholesterol (LDL-C) remains uncertain.



To evaluate the association between lowering LDL-C and relative cardiovascular risk reduction across different statin and nonstatin therapies.



The MEDLINE and EMBASE databases were searched (1966-July 2016). The key inclusion criteria were that the study was a randomized clinical trial and the reported clinical outcomes included myocardial infarction (MI). Studies were excluded if the duration was less than 6 months or had fewer than 50 clinical events. Studies of 9 different types of LDL-C reduction approaches were included.



Two authors independently extracted and entered data into standardized data sheets and data were analyzed using meta-regression.



The relative risk (RR) of major vascular events (a composite of cardiovascular death, acute MI or other acute coronary syndrome, coronary revascularization, or stroke) associated with the absolute reduction in LDL-C level; 5-year rate of major coronary events (coronary death or MI) associated with achieved LDL-C level.



A total of 312 175 participants (mean age, 62 years; 24% women; mean baseline LDL-C level of 3.16 mmol/L [122.3 mg/dL]) from 49 trials with 39 645 major vascular events were included. The RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C level was 0.77 (95% CI, 0.71-0.84; P < .001) for statins and 0.75 (95% CI, 0.66-0.86; P = .002) for established nonstatin interventions that work primarily via upregulation of LDL receptor expression (ie, diet, bile acid sequestrants, ileal bypass, and ezetimibe) (between-group difference, P = .72). For these 5 therapies combined, the RR was 0.77 (95% CI, 0.75-0.79, P < .001) for major vascular events per 1-mmol/L reduction in LDL-C level. For other interventions, the observed RRs vs the expected RRs based on the degree of LDL-C reduction in the trials were 0.94 (95% CI, 0.89-0.99) vs 0.91 (95% CI, 0.90-0.92) for niacin (P = .24); 0.88 (95% CI, 0.83-0.92) vs 0.94 (95% CI, 0.93-0.94) for fibrates (P = .02), which was lower than expected (ie, greater risk reduction); 1.01 (95% CI, 0.94-1.09) vs 0.90 (95% CI, 0.89-0.91) for cholesteryl ester transfer protein inhibitors (P = .002), which was higher than expected (ie, less risk reduction); and 0.49 (95% CI, 0.34-0.71) vs 0.61 (95% CI, 0.58-0.65) for proprotein convertase subtilisin/kexin type 9 inhibitors (P = .25). The achieved absolute LDL-C level was significantly associated with the absolute rate of major coronary events (11 301 events, including coronary death or MI) for primary prevention trials (1.5% lower event rate [95% CI, 0.5%-2.6%] per each 1-mmol/L lower LDL-C level; P = .008) and secondary prevention trials (4.6% lower event rate [95% CI, 2.9%-6.4%] per each 1-mmol/L lower LDL-C level; P < .001).



In this meta-regression analysis, the use of statin and nonstatin therapies that act via upregulation of LDL receptor expression to reduce LDL-C were associated with similar RRs of major vascular events per change in LDL-C. Lower achieved LDL-C levels were associated with lower rates of major coronary events.
TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Michael G
MG
Silverman
Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit, Michigan.
Brian A
BA
Ference
TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Kyungah
K
Im
TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Stephen D
SD
Wiviott
TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Robert P
RP
Giugliano
Center for Human Nutrition, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas.
Scott M
SM
Grundy
TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Eugene
E
Braunwald
TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Marc S
MS
Sabatine
D002318:Cardiovascular Diseases / Q000517:prevention & control*; D008078:Cholesterol, LDL / Q000187:drug effects*; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000517:prevention & control; D009525:Niacin / Q000008:administration & dosage; D011973:Receptors, LDL / Q000187:drug effects / Q000378:metabolism; D040242:Risk Reduction Behavior; D020521:Stroke / Q000517:prevention & control; D015854:Up-Regulation
D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D011973:Receptors, LDL; D009525:Niacin