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. 2021 Jul 18;26:e00248. doi: 10.1016/j.plabm.2021.e00248

Table 2.

Clinical Trials and Meta-analysis demonstrating significant Primary and Secondary Prevention of CVD Events.

Drug Class Clinical Trials Participants Intervention (versus placebo) Main Outcomes*
PPARγ agonist PRO-ACTIVE 5238 T2DM Pioglitazone titrated 15 mg–45 mg od (+baseline medications) Pioglitazone group vs. placebo:
  • •

    had at least one event in 1° composite endpoint: HR 0.90, 95% CI 0.80–1.02.

  • •

    reached 2° endpoint (composite of all-cause mortality, non-fatal MI, and stroke): HR 0.84, 0.72–0.98 [91].
SGLT2 inhibitors EMPA-REG 7020 T2DM Empagliflozin 10 mg or 25 mg od + standard therapy Empagliflozin group vs. placebo:
  • •

    occurrence of 1° outcome: HR 0.86, 95% CI 0.74–0.99

  • •

    occurrence of 2° outcome: HR 0.89, 95% CI, 0.78–1.01

  • •

    death from CV causes: HR 0.62, 95% CI 0.49–0.77; 38% RR reduction.

  • •

    hospitalisation for heart failure: 35% RR reduction.

  • •

    death from any cause: 32% RR reduction [93].
GIT lipase inhibitor XENDOS 3305 non-DM BMI >30 kg/m2 Orlistat 120 mg tid + lifestyle changes Orlistat + lifestyle changes vs. placebo:
  • •

    Progression to T2DM: HR 0.627, 95% CI 0.455–0.863; 37.3% RR reduction [95].
Statins CTT Met-analysis 18,686 (1466 T1DM 17,220 T2DM) 14 randomised CT Statins vs. placebo ((RR per mmol/L LDL reduction):
In T2DM:
  • •

    all-cause mortality: RR 0.91, 99% CI 0.82–1.01

  • •

    reduction in CHD mortality: RR 0.88, 99% CI 0.75–1.03

  • •

    reduction in vascular mortality: RR 0.87, 99% CI 0.76-1.00

  • •

    incidence of major vascular event: RR 0.79, 99% CI 0.72–0.86

  • •

    incidence of major coronary event: RR 0.78, 99% CI 0.69–0.87

  • •

    incidence of coronary revascularisation: RR 0.75, 99% CI 0.64–0.88

  • •

    incidence of stroke: RR 0.79, 99% CI 0.67–0.93

  • In T1DM:

  • •

    reduction in major vascular events: RR 0.79, 99% CI 0.62–1.01 [98].
Ezetimibe IMPROVE-IT 18,144 (27% T2DM) Simvastatin 40 mg + Ezetimibe 10 mg od Simvastatin–Ezetimibe group vs. Simvastatin group:
  • •

    occurrence of 1° end point (composite of CV death, non-fatal MI, unstable angina requiring rehospitalisation, coronary revascularisation or non-fatal stroke): HR 0.936; 95% CI 0.89–0.99 [113].
Fibrates Meta-analysis 36,489 10 randomised CT (2 trials in T2DM only) Fibrate group vs. placebo:
  • •

    occurrence of non-fatal MI: OR 0.78, CI 0.78–0.86

  • •

    ↓TC 8% and ↓ TG by 30%

  • •

    ↑ HDL by 9% [121].
Meta-analysis 45,058 18 randomised CT (6 trials in T2DM only) Fibrate group vs. placebo:
  • •

    MACE: 10% RR reduction, 95% CI 0-18

  • •

    coronary events: 13% RR reduction, 95% CI 7-19

  • •

    risk of albuminuria progression: 14% RR reduction, 95% CI 2–25 [122].
Omega-3 fatty acid JELIS 18,645 (16% DM) Pravastatin 10 mg or Simvastatin 5 mg od + EPA 600 mg tid Impaired glucose metabolism group had a significantly higher CAD HR compared to normoglycaemic group:
  • •

    non-EPA group: HR 1.71, 95% CI 1.37–2.13

  • •

    EPA group: HR 1.63, 95% CI 1.27–2.09 [130].
REDUCE-IT 8179 (59% DM) Baseline statin + EPA 4 g od Icosapent ethyl group vs. placebo:
  • •

    occurrence of 1° end point: HR 0.75, 95% CI 0.68–0.83

  • •

    occurrence of 2° end point: HR 0.74, 95% CI 0.65–0.83 [131].
PCSK9 inhibitors Meta-analysis 46,833 (PCSK9 inhibitors) & 42,770 (comparator) (21.5% T2DM) 38 randomised CT on PCSK9 inhibitors vs placebo/any comparator PCSK-9 inhibitors vs. placebo or any comparator:
  • •
    incidence of MACE:
    • -
      Diabetics: OR 0.82, 95% CI 0.74–0.91
    • -
      Non-diabetics: OR 0.73, 95% CI 0.64–0.84 [137].
Review of studies 60,997 24 randomised CT on Alirocumab (18) & Evolocumab (6) Alirocumab vs. placebo (high-certainty evidence) - decreased the risk of:
  • •

    CVD events: ARD -2%; OR 0.87, 95% CI 0.80–0.94

  • •

    mortality: ARD -1%; OR 0.83, 95% CI 0.72–0.96

  • •

    MI: ARD -2%; OR 0.86, 95% CI 0.79–0.94;

  • •

    any stroke: ARD 0%; OR 0.73, 95% CI 0.58–0

  • Alirocumab vs. ezetimibe & statins (low-certainty evidence) - decreased the risk of:

  • •

    CVD events: ARD 1%; OR 1.37, 95% CI 0.65–2.87

  • •

    mortality: ARD -1%; OR 0.51, 95% CI 0.18–1.40

  • •

    MI: ARD 1%; OR 1.45, 95% CI 0.64–3.28

  • •

    any stroke: ARD < 1%; OR 0.85, 95% CI 0.13–5.61

Evolocumab vs. placebo (high-certainty evidence) - decreased the risk of:
  • •

    CVD events: ARD -2%; OR 0.84, 95% CI 0.78–0.91

  • •

    mortality: ARD < 1%; OR 1.04, 95% CI 0.91–1.19

  • •

    MI: ARD -1%; OR 0.72, 95% CI 0.64–0.82

  • •

    any stroke: ARD < −1%; OR 0.79, 95% CI 0.65–0.94

  • Evolocumab vs. ezetimibe & statins (low-certainty evidence) - decreased the risk of:

  • •

    CVD events: ARD < −1%; OR 0.66, 95% CI 0.14–3.04

  • •

    mortality: ARD < 1%; OR 0.43, 95% CI 0.14–1.30

  • •

    MI: ARD < 1%; OR 0.66, 95% CI 0.23–1.85

  • •

    any stroke: insufficient data [138].

*all results have significant p-value.

Abbreviations: ARD, absolute risk difference; BMI, body mass index; CV, cardiovascular; CVD, cardiovascular disease; CT, clinical trial; CI, confidence interval; CAD, coronary artery disease; ↓, decrease; DM, diabetes mellitus; EPA, eicosapentaenoic acid; GIT, gastrointestinal; HR, hazard ratio; HDL, high density lipoprotein cholesterol; ↑, increase; LDL, low density lipoprotein cholesterol; od, daily; MACE, major cardiovascular event; MI, myocardial infarction; OR, odds ratio; PPARγ, peroxisome proliferator-activated receptor gamma; 1°, primary; PCSK9, proprotein convertase subtilisin/kexin 9; RR, relative risk; 2°, secondary; SGLT2, sodium-glucose cotransporter 2; tid, three times daily; TC, total cholesterol; TG, triglyceride; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; vs, versus.