Reducing LDL & improving CV outcomes - systematic review

Silverman MG, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: A systematic review and meta-analysis. JAMA 2016;316:1289-97.

Clinical question: Does reduction of CV outcomes with lipid-lowering therapy correlate with degree of LDL-lowering?

Bottom line:

  • The value of this study is mechanistic; it does not provide clinical guidance. 

  • The analysis demonstrates that CV outcome reduction of proven lipid-lowering drugs is closely associated with degree of LDL-lowering. This supports the lipid hypothesis, i.e. that lipid-lowering drugs which lower CV risk outcomes (statins, bile acid sequestrants, & ezetimibe) do so primarily by lowering LDL.

  • This study does not validate a particular lipid target, nor does it support using interventions with neutral, harmful or conflicting evidence (fibrates, niacin, or CETP inhibitors) to achieve a lipid target.



  • Databases: MEDLINE, Embase
  • Timeframe: 1966 to July 2016
  • Inclusion criteria:
    • Randomized controlled trials (RCTs)
    • Compared (1) LDL-lowering intervention to control/placebo or (2) more vs less intensive statin therapy
    • Reported cardiovascular outcomes including MI
    • Duration of at least 6 months
    • At least 50 events
  • Exclusion criteria: Trial with populations with "significant competing risks", including heart failure & chronic kidney disease
  • Additional measures for comprehensiveness:
    • References lists of identified studies, review and meta-analyses
    • Reviewed abstracts of major cardiovascular meetings held in past 2 years (no mention of which)
    • Contacted content experts

Results of systematic review

  • Included 49 RCTs (n=312,175)
    • Statin (25 trials)
    • Fibrate (9 trials)
    • Diet (4 trials)
    • CETP inhibitor (3 trials)
    • Niacin (3 trials)
    • Bile acid sequestrants (2 trials)
    • PCSK9 inhibitor (2 trials)
    • Ezetimibe (1 trial)
    • Ileal bypass surgery (1 trial)

Results of the meta-analysis

  • Mean follow-up 4.3 years
  • Mean ~absolute reduction in LDL vs placebo in trials
    • PCSK9 inhibitor -1.85 mmol/L
    • Ileal bypass -1.6 mmol/L
    • Bile acid sequestrant -0.90 mmol/L
    • Statin -0.85 mmol/L (all drugs & doses pooled)
    • Diet -0.75 mmol/L
    • Niacin -0.35 mmol/L
    • Ezetimibe -0.3 mmol/L
    • Fibrate -0.25 mmol/L
  • ~23% relative risk reduction (RRR) in major vascular events per 1 mmol/L reduction in LDL with any interventions except CETP inhibitors

Considerations & limitations

  • Generalizability & internal validity
    • Investigators excluded studies that included patients with "significant competing risk", which includes some of the landmark "negative" statin trials (CORONA, GISSI-HF, 4D, etc)
      • Results of this analysis don't apply to the subpopulations of these studies (primarily heart failure & chronic kidney disease)
      • The analysis may overestimate the true relative risk reduction since this exclusion criterion primarily excluded "negative" studies.
    • Numerous differences in populations between trials, including
      • Era (e.g. 1st fibrate/niacin trial conducted in 60s, most statin trials conducted in 1990s-2000s)
      • Primary vs secondary prevention
      • LDL before initiation of study treatment & background CV therapies
  • Results
    • Although interventions produced comparable RRRs in CV outcomes per 1-mmol/L reduction in LDL, actual achievable LDL reduction & therefore realistic CV reductions with each agent are quite different
    • This study evaluated a composite CV outcome, which bundles together outcomes of different severity & importance to patients. Different interventions may have the same effect on a composite CV outcome, but not specific components. For example, statins reduce every type of CV event (death, MI, stroke, revascularization), whereas fibrates only reduce non-fatal MI, but not death or stroke.

HPS2-THRIVE - Niacin for CV prevention

HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-12.

Clinical Question

In patients with cardiovascular disease receiving moderate-intensity statin +/- ezetimibe, does niacin (+ laropiprant) safely reduce cardiovascular events?

Bottom Line

  • In patients with cardiovascular disease already receiving moderate-intensity statin therapy (& half taking ezetimibe) who tolerated niacin for a month, niacin does not reduce cardiovascular events, definitely increases serious adverse events due to numerous causes (NNH 35), and may increase the risk of death (NNH 200) over 4 years.

  • Niacin has no clear role in prevention of cardiovascular disease.


Allocation-concealed "superiority" RCT with all (patients, clinicians, investigators) blinded, low loss-to-follow-up (<1%), analyzed using the intention-to-treat population.

Note 1: All patients subjected to pre-randomization run-in phase where they discontinued previous statin therapy & switched to simvastatin 40 mg/day

  • If total cholesterol >3.50 mmol/L or increased from previous therapy after 4 weeks, added ezetimibe 10 mg/d
  • Once stable on LDL-lowering therapy, all patients given a single daily tablet of niacin extended-release 1 g + laropiprant 20 mg, if tolerated this was doubled x3-6 weeks
  • Patients who tolerated the regimen without clinically-significant adverse effects were randomized to niacin/laropiprant or placebo

Note 2: Randomization performed using minimization algorithm.

Patients and Setting

  • China, Scandinavia, UK, 245 centers
  • April 2007 - July 2010
  • Inclusion criteria:
    1. Men or women 50-80 y/o
    2. History of
      • Cerebrovascular atherosclerotic disease (previous ischemic stroke/TIA, carotid revascularization)
      • MI
      • PAD (intermittent claudication or previous revascularization)
      • Diabetes with above or symptomatic CAD
  • Key exclusion criteria:
    • Receiving LDL-lowering therapy "more intensive" than simvastatin 40 mg + ezetimibe 10 mg
    • <3 months since ACS/MI or stroke
    • Planned revascularization procedure <3 months after randomization
    • SOB at rest for any reason
    • Contraindications to niacin/statin
      • Chronic liver disease, or current ALT >1.5x upper normal limit
      • Serum creatinine >200 mcmol/L
      • Evidence of active inflammatory muscle disease (e.g. dermatomyositis, polymyositis), or CK >3x upper normal limit
    • Concurrent treatment with ezetimibe, fibrate, or potent CYP3A4 inhibitor
  • 51,698 screened -> 42,424 entered run-in phase -> 25,673 randomized (~50% screened)
  • Average patient:
    • 64.9 y/o
    • 17% female
    • Region: Europe 57%, China 43%
    • PMHx
      • Cerebrovascular disease 32%
      • MI 68%
      • PAD 12%
      • Diabetes 32%
    • Lipids (after run-in phase on simvastatin 40 mg +/- ezetimibe 10 mg)
      • Total cholesterol 3.31 mmol/L 
      • HDL 1.14 mmol/L
      • LDL 1.64 mmol/L

Intervention and Control

  • Intervention: Niacin extended-release 2 g + laropiprant 40 mg once daily
    • Average adherence during study: 78%
  • Control: Placeb
    • Average adherence during study: 86%
  • Co-interventions common to both groups: Simvastatin 40 mg +/- ezetimibe 10 mg to achieve total cholesterol <3.50 mmol/L
    • Simvastatin 40 mg: 100%
    • Ezetimibe 10 mg: 47%


  • @ median 3.9 years
  • Niacin improved lipids versus placebo
    • HDL +0.16 mmol/L
    • LDL -0.25 mmol/L
    • Triglycerides -0.37 mmol/L
  • Efficacy: No benefit whatsoever of niacin.
  • Safety: 
    • Significant INCREASE in serious adverse events with niacin (NNH 35), both due to predicted adverse effects of niacin (gastrointestinal issues, new/worsening diabetes), but also adverse effects not yet appreciated to be caused by niacin (serious bleeds & infections)
    • More patients in the niacin group discontinued study due to intolerable side-effects (1/4 patients in the group; NNH 12 versus placebo), despite every patient taking niacin x3-6 weeks in the run-in phase
  • No benefit in any of the 30+ subgroup analyses conducted.

HPS2-THRIVE outcomes

Key Considerations


  • This was a secondary prevention trial of patients with existing atherosclerotic cardiovascular disease (cerebrovascular, coronary or peripheral) also taking simvastatin 40 mg/d (all patients) +/- ezetimibe (~1/2 of patients)
  • Although there were no specific lipid criteria for enrollment, there was also lack of efficacy in the half of patients who had "low HDL [<1.0 mmol/L])
  • Laropiprant is an antagonist of prostaglandin D2 (receptor responsible for niacin flush), designed to improve tolerability of niacin. Despite combining this drug with niacin, tolerability of niacin was abysmal.

Internal validity:

  • This study was "enriched" to demonstrate a benefit with a rigorous run-in phase designed to enroll patients unlikely to discontinue niacin.
    • Despite this, more patients in the niacin group experience serious adverse events & discontinued drug therapy due to intolerability.


  • AIM-HIGH trial (2011) in patients with low HDL also taking moderate-intensity statin: Niacin provided no cardiovascular benefit.

  • In a 2014 meta-analysis, fibrates, niacin & CETP inhibitors (drugs that lower HDL) did not reduce cardiovascular outcomes when added to statins.

  • The Coronary Drug Project trial (1975), which enrolled its first patient in 1966, is the only trial that has demonstrated the cardiovascular benefit of niacin. In a population of men aged 30-64 years with prior MI, niacin reduced the risk of non-fatal MI over ~6 years (NNT 28), with no effect on mortality.

    • This trial is not generalizable to today's practice, being conducted >40 years ago in men with prior MI in an era where aspirin, ACE inhibitors, beta-blockers, statins, and PCI were not yet available/in use.