Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: A systematic review and meta-analysis

Michael G. Silverman, Brian A. Ference, Kyungah Im, Stephen D. Wiviott, Robert P. Giugliano, Scott M Grundy, Eugene Braunwald, Marc S. Sabatine

Research output: Contribution to journalArticle

304 Citations (Scopus)

Abstract

IMPORTANCE The comparative clinical benefit of nonstatin therapies that reduce low-density lipoprotein cholesterol (LDL-C) remains uncertain. OBJECTIVE To evaluate the association between lowering LDL-C and relative cardiovascular risk reduction across different statin and nonstatin therapies. DATA SOURCES AND STUDY SELECTION The MEDLINE and EMBASE databaseswere searched (1966-July 2016). The key inclusion criteria were that the study was a randomized clinical trial and the reported clinical outcomes includedmyocardial 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. DATA EXTRACTION AND SYNTHESIS Two authors independently extracted and entered data into standardized data sheets and data were analyzed usingmeta-regression. MAIN OUTCOMES AND MEASURES 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. RESULTS A total of 312 175 participants (mean age, 62 years; 24%women; mean baseline LDL-C level of 3.16 mmol/L [122.3mg/dL]) from 49 trials with 39 645 major vascular eventswere 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 thatwork 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 RRwas 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 trialswere 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), whichwas 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), whichwas 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 levelwas 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). CONCLUSIONS AND RELEVANCE 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.

Original languageEnglish (US)
Pages (from-to)1289-1297
Number of pages9
JournalJAMA - Journal of the American Medical Association
Volume316
Issue number12
DOIs
StatePublished - Sep 27 2016

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Risk Reduction Behavior
LDL Cholesterol
Meta-Analysis
Blood Vessels
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Therapeutics
LDL Receptors
Up-Regulation
Cholesterol Ester Transfer Proteins
Fibric Acids
Niacin
Information Storage and Retrieval
Primary Prevention
Acute Coronary Syndrome
Secondary Prevention
Bile Acids and Salts
MEDLINE
Infarction
Randomized Controlled Trials
Stroke

ASJC Scopus subject areas

  • Medicine(all)

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Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions : A systematic review and meta-analysis. / Silverman, Michael G.; Ference, Brian A.; Im, Kyungah; Wiviott, Stephen D.; Giugliano, Robert P.; Grundy, Scott M; Braunwald, Eugene; Sabatine, Marc S.

In: JAMA - Journal of the American Medical Association, Vol. 316, No. 12, 27.09.2016, p. 1289-1297.

Research output: Contribution to journalArticle

Silverman, Michael G. ; Ference, Brian A. ; Im, Kyungah ; Wiviott, Stephen D. ; Giugliano, Robert P. ; Grundy, Scott M ; Braunwald, Eugene ; Sabatine, Marc S. / Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions : A systematic review and meta-analysis. In: JAMA - Journal of the American Medical Association. 2016 ; Vol. 316, No. 12. pp. 1289-1297.
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abstract = "IMPORTANCE The comparative clinical benefit of nonstatin therapies that reduce low-density lipoprotein cholesterol (LDL-C) remains uncertain. OBJECTIVE To evaluate the association between lowering LDL-C and relative cardiovascular risk reduction across different statin and nonstatin therapies. DATA SOURCES AND STUDY SELECTION The MEDLINE and EMBASE databaseswere searched (1966-July 2016). The key inclusion criteria were that the study was a randomized clinical trial and the reported clinical outcomes includedmyocardial 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. DATA EXTRACTION AND SYNTHESIS Two authors independently extracted and entered data into standardized data sheets and data were analyzed usingmeta-regression. MAIN OUTCOMES AND MEASURES 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. RESULTS A total of 312 175 participants (mean age, 62 years; 24{\%}women; mean baseline LDL-C level of 3.16 mmol/L [122.3mg/dL]) from 49 trials with 39 645 major vascular eventswere 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 thatwork 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 RRwas 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 trialswere 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), whichwas 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), whichwas 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 levelwas 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). CONCLUSIONS AND RELEVANCE 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.",
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T1 - Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions

T2 - A systematic review and meta-analysis

AU - Silverman, Michael G.

AU - Ference, Brian A.

AU - Im, Kyungah

AU - Wiviott, Stephen D.

AU - Giugliano, Robert P.

AU - Grundy, Scott M

AU - Braunwald, Eugene

AU - Sabatine, Marc S.

PY - 2016/9/27

Y1 - 2016/9/27

N2 - IMPORTANCE The comparative clinical benefit of nonstatin therapies that reduce low-density lipoprotein cholesterol (LDL-C) remains uncertain. OBJECTIVE To evaluate the association between lowering LDL-C and relative cardiovascular risk reduction across different statin and nonstatin therapies. DATA SOURCES AND STUDY SELECTION The MEDLINE and EMBASE databaseswere searched (1966-July 2016). The key inclusion criteria were that the study was a randomized clinical trial and the reported clinical outcomes includedmyocardial 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. DATA EXTRACTION AND SYNTHESIS Two authors independently extracted and entered data into standardized data sheets and data were analyzed usingmeta-regression. MAIN OUTCOMES AND MEASURES 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. RESULTS A total of 312 175 participants (mean age, 62 years; 24%women; mean baseline LDL-C level of 3.16 mmol/L [122.3mg/dL]) from 49 trials with 39 645 major vascular eventswere 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 thatwork 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 RRwas 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 trialswere 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), whichwas 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), whichwas 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 levelwas 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). CONCLUSIONS AND RELEVANCE 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.

AB - IMPORTANCE The comparative clinical benefit of nonstatin therapies that reduce low-density lipoprotein cholesterol (LDL-C) remains uncertain. OBJECTIVE To evaluate the association between lowering LDL-C and relative cardiovascular risk reduction across different statin and nonstatin therapies. DATA SOURCES AND STUDY SELECTION The MEDLINE and EMBASE databaseswere searched (1966-July 2016). The key inclusion criteria were that the study was a randomized clinical trial and the reported clinical outcomes includedmyocardial 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. DATA EXTRACTION AND SYNTHESIS Two authors independently extracted and entered data into standardized data sheets and data were analyzed usingmeta-regression. MAIN OUTCOMES AND MEASURES 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. RESULTS A total of 312 175 participants (mean age, 62 years; 24%women; mean baseline LDL-C level of 3.16 mmol/L [122.3mg/dL]) from 49 trials with 39 645 major vascular eventswere 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 thatwork 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 RRwas 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 trialswere 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), whichwas 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), whichwas 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 levelwas 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). CONCLUSIONS AND RELEVANCE 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.

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