The Case for Lower is Better No randomized trial has established the - PowerPoint PPT Presentation

The Case for Lower is Better • No randomized trial has established the optimal target for LDL-C for CVD risk reduction Vs • Biological plausibility – Apo B lipoproteins linked to atherogenesis • Epidemiology data – Mendelian randomization • On Rx LDL-C related to events • CTT meta-analysis – 22% reduction per 1 mmol/L ↓ • Emerging randomized trial data with new meds • Guidelines

CHD Reduction from Earlier LDL-C Lowering: Lifetime low LDL Lifetime lower LDL-C due to genetics resulted in a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life CHD RR Per Sample mmol/L LDL Meta-Analysis OR (95% CI) Size (N) reduction Genetic Studies 312,321 0.46 (0.41-0.51) 54.5 % Statin Trials 169,138 0.76(0.74-0.78) 24% 0.4 0.5 0.6 0.7 0.8 0.9 1 Association between 1mmol/L lower LDL-C and risk of CHD Ferrence BA, et al. J Am Coll Cardiol. 2012;60(25):2631-9.

Proportional effects on MAJOR VASCULAR EVENTS per mmol/L LDL-C reduction, by baseline LDL-C No. of events (% pa) Relative risk (CI) per mmol/L LDL-C reduction Statin/more Control/less More vs less statin < 2.0 704 (17.9%) 795 (20.2%) 0.71 (0.52 - 0.98)  2,<2.5 1189 (18.4%) 1317 (20.8%) 0.77 (0.64 - 0.94)  2.5,<3.0 1065 (20.1%) 1203 (22.2%) 0.81 (0.67 - 0.97)  3,<3.5 517 (20.4%) 633 (25.8%) 0.61 (0.46 - 0.81)  3.5 303 (23.9%) 398 (31.2%) 0.64 (0.47 - 0.86) 3837 (19.4%) 4416 (22.3%) 0.72 (0.66 - 0.78) Total Statin vs control < 2.0 206 (9.0%) 217 (9.7%) 0.87 (0.60 - 1.28)  2,<2.5 339 (7.7%) 412 (9.1%) 0.77 (0.62 - 0.97)  2.5,<3.0 801 (8.2%) 1022 (10.5%) 0.76 (0.67 - 0.86)  3,<3.5 1490 (10.8%) 1821 (13.3%) 0.77 (0.71 - 0.84)  3.5 4205 (12.6%) 5338 (15.9%) 0.80 (0.77 - 0.84) 7136 (11.0%) 8934 (13.8%) 0.79 (0.77 - 0.81) Total All trials < 2.0 910 (14.7%) 1012 (16.4%) 0.78 (0.61 - 0.99)  2,<2.5 1528 (14.0%) 1729 (15.9%) 0.77 (0.67 - 0.89)  2.5,<3.0 1866 (12.4%) 2225 (14.7%) 0.77 (0.70 - 0.85)  3,<3.5 2007 (12.3%) 2454 (15.2%) 0.76 (0.70 - 0.82)  3.5 4508 (13.0%) 5736 (16.5%) 0.80 (0.76 - 0.83) 10973 (13.0%) 13350 (15.8%) 0.78 (0.76 - 0.80) Total 99% or 95% CI 0.5 0.75 1 1.25 1.5 Statin/more better Control/less better

GLAGOV: Objective Objective • To test the hypothesis that LDL-C lowering with a monthly subcutaneous injection of evolocumab 420 mg for 78 weeks will result in a significantly greater change from baseline in percentage atheroma volume (PAV) compared with placebo in subjects taking background statin therapy Design • A 78-week, randomized, double-blind, placebo-controlled, multicenter, phase 3 study. Nicholls SJ, et al. JAMA . [published online ahead of print November 15, 2016]. doi: 10.1001/jama.2016.16951. Puri R, et al. Am Heart J . 2016;176:83-92.

Mean Absolute Change in LDL-C Statin monotherapy Statin + evolocumab 0.2 Mean LDL-C 2.41 mmol/L* LDL-C Absolute Change From Baseline, mmol/L 0 Change from baseline 3.9% – 0.2 – 0.4 – 0.6 – 0.8 – 1.0 – 1.2 Mean LDL-C 0.95 mmol/L* – 1.4 – 1.6 Change from baseline -59.8% – 1.8 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 Study Week No. of patients Placebo 484 446 441 447 441 425 418 Evolocumab 484 456 452 444 449 426 434 Absolute change for evolocumab-statin group: -1.46 (-1.54 to -1.38); P < 0.001 Data shown are Mean (95% CI) *Time-weighted LDL-C; LDL-C = low-density lipoprotein cholesterol Nicholls SJ, et al. JAMA . [published online ahead of print November 15, 2016]. doi: 10.1001/jama.2016.16951. Nissen SE, et al. American Heart Association Scientific Sessions, Nov 12 - 16, 2016, New Orleans, Louisiana. Oral Presentation.

Primary Endpoint: Nominal Change in PAV From Baseline to Week 78 Change in % atheroma volume (%) P = NS* P < 0.001* Difference between groups: -1.0% (-1.8 to -0.64); P < 0.001 Data shown are least-squares mean (95% CI). PAV = Percent Atheroma Volume *Comparison versus baseline Nicholls SJ, et al. JAMA . [published online ahead of print November 15, 2016]. doi: 10.1001/jama.2016.16951.

Category Consider Initiating Target NNT pharmaco-therapy if Primary prevention High FRS (≥20%) LDL-C < 2.0 mmol/L or 35 all > 50% ↓ Intermediate FRS (10- 40 19%) Or LDL- C ≥ 3.5 mmol/L Apo B < 0.8 g/L or Non- HDL ≥ 4.3 Or mmol/L or Apo B ≥ 1.2 g/L non-HDL-C < 2.6 or Men ≥ 50 and mmol/L women ≥ 60 yrs and one additional CVD RF Clinical Statin indicated atherosclerosis* conditions 20 Abdominal aortic aneurysm Diabetes mellitus >40 yrs 15 yrs duration for age >30 yrs (DM 1) Microvascular disease Chronic kidney disease (age ≥ 50 y) eGFR < 60 mL/min/1.73 m 2 or ACR > 3 mg/mmol LDL- C ≥ 5. 0 mmol/L >50% ↓ in LDL -C FRS – modified Framingham Risk Score; ACR – albumin:creatinine ratio; * consider LDL-C < 1.8 mmol/L for subjects with ACS within last 3 months Dyslipidemia Guidelines www.ccs.ca