There are many ways to lower triglycerides in humans: Which are the most relevant for pancreatitis and for CV risk?

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1 There are many ways to lower triglycerides in humans: Which are the most relevant for pancreatitis and for CV risk? Michael Davidson M.D. FACC, Diplomate of the American Board of Lipidology Professor, Director of Preventive Cardiology The University of Chicago Pritzker School of Medicine

2 Justification for lowering Non-HDL-c to reduce CHD Risk Reduction Assertions Hypertriglyceridemia is correlated with increased CV risk Risk of hypertriglyceridemia is contained within non-hdl-c rather than triglycerides per se TRL-C triglyceride risk lipoprotein cholesterol is an atherogenic component of non-hdl-c Reduced TRL-C is associated with decreased CV events Pharmacologic treatment of high TRL-C has potential to reduce CV risk

3 Non-HDL Cholesterol Triglyceride Rich Lipoproteins Triglyceride Cholesterol All atherogenic lipoproteins HDL LDL IDL VLDL Chylomicron remnant Apo AI Apo B Apo B Apo B Apo B48 Triglyceride Non-HDL Rich Lipoproteins (TRL) TRL-C = Non-HDL-C LDL-C

4 CHD Risk for TG Elevation is Contained within Non-HDL-C and HDL-C Analyses of log e TG were adjusted for HDL-C and non-hdl-c. Analyses of HDL-C were adjusted for non-hdl-c and log e TG. Analyses of non-hdl-c were adjusted for HDL-C and log e TG. Emerging Risk Factors Collaboration. JAMA. 2009;302:

5 When discordant, risk follows non-hdl-c, not LDL-C Discordance Meta-Analysis Risk of Major CV Events during Statin Therapy HRs adjusted for sex, age, smoking, diabetes, systolic BP and trial Boekholdt SM, et al. JAMA. 2012;307:

6 Low High TG Production Large VLDL Remnants slow LPL/HL LPL ApoB ApoB ApoE ApoE ApoC-III ApoC-III Small LDL ApoB ApoC-III Very Smal LDL ApoB ApoC-III Non-HDL-C Remnant Cholesterol LDL-C LPL ApoB ApoE Very Small VLDL Large LDL ApoB Non-HDL-C Remnant Cholesterol LDL-C Cholesterol Triglycerides shdl HDL TG CE TG CETP HL Renal clearance TG HL ApoA5

7 The greater the level of triglycerides the more VLDL-C and less LDL-C within non- HDL-C associated with Increasing CV Risk (VLDL-C) Varbo A, et al. J Am Coll Cardiol. 2013;61:

8 VLDL-C Compared to LDL-C on a Continuous Scale and Hazard Ratios of Ischemic Heart Disease (VLDL-C) Copenhagen Heart Study; Varbo A, et al. Clin Chem. 2015;61:

9 Lipoprotein Cholesterol Levels and IHD Copenhagen Studies (n = 73,513): Risk of Ischemic Heart Disease By Lipoprotein Cholesterol Levels Varbo et al. JACC 2013;61:

10 Lipoprotein Genotypes and IHD Copenhagen Studies: Causal vs Observational Risk Estimates HRs for 1 mmol/l or a 1 ratio unit increase or decrease in plasma lipoprotein levels Varbo et al. JACC 2013;61:

11 VLDL-C is causal for atherosclerosis greater than LDL-C: Each VLDL particle carries 5-20X more cholesterol than LDL with unregulated uptake by macrophages VLDL VLDL Adapted from Nordestgaard BG, Varbo A. Lancet. 2014;384:

12 Cumulative incidence curves for risk of coronary heart disease (CHD) by small dense lowdensity lipoprotein-cholesterol (sdldl-c) and large buoyant LDL-C (lbldl-c) quartiles, adjusted for age, race, and sex. Hoogeveen R C et al. Arterioscler Thromb Vasc Biol. 2014;34: Copyright American Heart Association, Inc. All rights reserved.

13 Adjusted hazard ratios (HRs) for incident coronary heart disease by small dense low-density lipoprotein-cholesterol (sdldl-c) quartiles stratified by LDL-C risk categories, adjusted for age, sex, and race, smoking, body mass index, hypertension, diabetes mellitus, diabetes mellitus medications, and log high-sensitivity C-reactive protein. Hoogeveen R C et al. Arterioscler Thromb Vasc Biol. 2014;34: Copyright American Heart Association, Inc. All rights reserved.

14 Cumulative incidence of cardiovascular events in subgroups with low-density lipoproteincholesterol (LDL-C) <100 mg/dl (<25th percentile) and small dense LDL-C (sdldl-c) <27.8 mg/dl (<25th percentile), from proportional hazards models adjusted for age, sex, and race. Hoogeveen R C et al. Arterioscler Thromb Vasc Biol. 2014;34: Copyright American Heart Association, Inc. All rights reserved.

15 Fibrates, EPA, Niacin CV Outcome Trials Larger Risk Reductions in Hypertriglyceridemia Trial (drug) HHS (gemfibrozil) BIP (bezafibrate) VA-HIT (gemfibrozil) FIELD (fenofibrate) ACCORD (fenofibrate) JELIS (ethyl-epa) AIM-HIGH (niacin) Entire cohort HR (95% CI) Subgroup Subgroup HR (95% CI) 0.66 (0.47, 0.92) TG 184 mg/dl BMI >27.5 kg/m (0.15, 0.58) 0.91 (NR) TG 200 mg/dl 0.60 (NR) 0.78 (0.65, 0.93) TG 151 mg/dl 0.73 (0.58, 0.93) 0.89 (0.75, 1.05) TG 204 mg/dl HDL-C <42 mg/dl 0.92 (0.79, 1.08) TG 204 mg/dl HDL-C 34 mg/dl 0.81 (0.69, 0.95) TG >150 mg/dl HDL-C <40 mg/dl 1.02 (0.87, 1.21) TG >198 mg/dl HDL-C <33 mg/dl 0.73 (0.58, 0.91) 0.69 (NR) 0.47 (0.23, 0.98) 0.74 (0.50, 1.09) Maki et al. J Clin Lipidol. 2012;6:413. Guyton et al. JACC 2013;62:1580.

16 Relationship Between Change in VLDL-C with Fibrates (Estimated from TG Responses) and CV Outcomes Change in VLDL-C (mg/dl) HR (95% CI) HHS (1987) (0.47, 0.92) SIHD (1988) (NR) VA-HIT (1999) (0.65, 0.93) BIP (2000) (NR) FIELD (2005) (0.75, 1.05) ACCORD (2010) (0.79, 1.08) Abbreviations: ACCORD = Action to Control Cardiovascular Risk in Diabetes; BIP = Bezafibrate Infarction Prevention; FIELD = Fenofibrate Intervention and Event Lowering in Diabetes; HHS = Helsinki Heart Study; NR = not reported; SIHD = Scandinavian Ischaemic Heart Disease Secondary Prevention Study (Carlson and Rosenhamer); VA-HIT = Veterans Affairs HDL Intervention Trial Calculated from: Nordestgaard BG, Varbo A. Lancet. 2014;384: Maki KC, et al. J Clin Lipidol. 2012;6: Carlson LA, Rosenhamer G. Acta Med Scand. 1988;223:

17 Meta-regression Demonstrates that VLDL-C Lowering is Highly Correlated with a Reduction in the Hazard Ratio for a Major CV Event Each 8.9 mg/dl reduction in VLDL-C (equivalent to 0.5 mmol/l for TG) in the fibrate outcome trials is associated with a reduction of 26% in the hazard for a CV event 1.0 Y = *X ; r = -0.93, P = Y = *X ; r = -0.93, P = HR for CV Events BIP ACCORD FIELD VA-HIT SIHD HHS VLDL-C Reduction (mg/dl) Calculated from: Nordestgaard BG, Varbo A. Lancet. 2014;384: Maki KC, et al. J Clin Lipidol. 2012;6: SIHD is Carlson LA, Rosenhamer G. Acta Med Scand. 1988;223:

18 In ACCORD MACE Risk was Reduced 31% in Patients with TG 204 mg/dl and HDL 34 mg/dl Pre-specified subgroup analysis (baseline TG levels 204 mg/dl + HDL-C 34 mg/dl) suggested favorable risk reduction for MACE with fenofibrate (HR 0.69; 95%CI ; p=0.032 within subgroup, p=0.06 for interaction). Adapted from ACCORD Study Group, NEJM 2010; 362:1563.

19 VLDL-C and LDL-C Changes in ACCORD in Subgroups with Dyslipidemia vs. Others 8.6 mg/dl reduction in VLDL-C is associated with a reduction of 31% in the hazard for a CV event Change in VLDL-C with Fenofibrate (mg/dl) High TG/Low HDL-C Others Change in LDL-C with Fenofibrate (mg/dl) High TG/Low HDL-C Others Fenofibrate Placebo Difference High TG was defined as TG 204 mg/dl and low HDL-C was defined as HDL-C 34 mg/dl. High TG/Low HDL-C subgroup: fenofibrate n = 316 and placebo n = 287 Others: fenofibrate n = 1465 and placebo n = 1495

20 Fenofibric Acid + High-Dose Statin Does Not Provide Incremental Non- HDL-C Reduction Fillippatos TD. Cardiovasc Drugs Ther. 2012;26:

21 FIRST Trial: Fenofibric Acid plus statin vs statin monotherapy; Rate of Change in CIMT by Baseline Lipids Within Group Difference Between Group Difference Trilipix + atorva Placebo + atorva Baseline Lipids (mg/dl) by Rate of change Rate of change tertiles n (mm/yr) n (mm/yr) Interaction P value LDL-C Trilipix Better Placebo Better >75 and > HDL-C >36 and > Triglycerides >169 and > non-hdl-c >106 and > Between Group Difference in Rate of Change in Posterior wall IMT (mm/year) Table 14.2_ ; 14.2_ ;14.2_ Davidson et ATVB

22 LDL Particle Number Significantly Increased in Patients on Statins in Combination with Fenofibric Acid 22

23 Fenofibrate Significantly Increases PCSK9, Which Correlates with LDL- C Increase Trout JS, et al. J Lipid Res. 2010;51:

24 Atherogenic Dyslipidemia Study: Absolute and Percentage Changes in Laboratory Parameters and Blood Pressure From Baseline Until Follow-Up Visit 24

25 AIM-HIGH Subgroup Data for Elevated TG/Low HDL-C Targeted Therapy Consistent with the Pattern of 7 Other Trials *TG 198 mg/dl and HDL-C < 33 mg/dl In a subgroup of patients (n=522;15.3% of trial population) in the highest TG tertile ( 198 mg/dl) and lowest HDL-C tertile (<33 mg/dl), there was suggestion of a 26% reduction in risk with niacin ER, compared with placebo, added on to statin treatment, but this did not reach nominal statistical significance (HR 0.74; 95% CI ; p=0.07). In an even smaller group of patients (n= % of population) with mixed dyslipidemia (TG > 200 mg/dl and HDL-C < 32 mg/dl), the treatment effect in the niacin group was larger (HR 0.64, p = 0.032). Adapted from Guyton, Slee, JACC, Volume 62, Issue 17, 22 October 2013

26 AIM-HIGH: Relationship of CV events to baseline and in-trial lipoprotein variables ERN = extended-release niacin LLT = LDL-C lowering therapy Guyton JR, et al. J Am Coll Cardiol. 2013;62:

27 AIM-HIGH and HPS-2 Results Should Be Interpreted with Caution AIM-HIGH Atherogenic lipoproteins correlated positively with CV events in the control group but niacin might have caused harm The top tertile for baseline (on-statin) non-hdl-c in HPS2- THRIVE had values >=97 mg/dl, a very low value

28 LS Mean change from baseline (%) Comparison of lipid changes with omega-3 FFA 2g dose containing both EPA and DHA to a pure ethyl ester EPA 4g dose in patients with severe hypertriglyceridemia Median change from baseline (%) EVOLVE MARINE 30 OM-3 FFA 2 g olive oil 30 Icosapent ethyl 4 g mineral oil ,5 2, ** 16 * NR -10 * -4-8 ** ,7 *** -3,5-4, ** ,5 ** -27 *** ,6 *** TG Non-HDL-C HDL-C VLDL-C LDL-C LDL-C/ApoB TG Non-HDL-C HDL-C VLDL-C LDL-C LDL-C/ApoB N=399 N=229 *p 0.05, **p <0.05* < 0.01, <0.01** **p < <0.001*** *

29 EPA and DHA modify the composition of VLDL particles differently in patients with severe HTG Severe HTG Severe HTG Treated with EPA Severe HTG Treated with EPA + DHA ApoC-II ApoC-III ApoC-II ApoC-III ApoC-II ApoE ApoE ApoE Decreased TG composition Decreased ApoC-III improves lipolysis

30 ApoC-III reduction may help explain the differences between EPA and DHA on lipoprotein changes EPA DHA Triglycerides Non-HDL-C VLDL-C LDL-C LDL Size HDL Adapted: Vrablik et al. Physiological Research (2009); von Schacky, Vascular Health and Risk Management (2006)

31 The Effects of 10 lbs of weight loss

32 STRENGTH (EPA+DHA) vs. REDUCE-IT (EPA only): STRENGTH Targets Patients Most Likely to Benefit from Non-HDL-C Reduction Clinical factors STRENGTH REDUCE-IT Number of patients ~13,000 ~8,000 Inclusion criteria TG 200 mg/dl, <500 mg/dl HDL-C <40 mg/dl (men) HDL-C <45 mg/dl (women) 4 weeks on statin Established CVD or at high risk for development of CVD TG 200 mg/dl, <500 mg/dl (started with TG 150 mg/dl) 4 weeks on statin Established CVD or at high risk for development of CVD Primary endpoint MACE MACE Dosing regimen 4 g/d 4 g/d Placebo Corn oil Mineral oil

33 Risk Reduction with Fenofibrate (ACCORD) or Niacin (AIM-HIGH) Added to Statin Therapy in Subjects with High TG and Low HDL-C Active Events Placebo Events Relative Risk Reduction Median Follow-up Placebo Event Rate/y ACCORD 12.4% 17.3% 28.3% 4.7 y 3.7% AIM-HIGH 17.0% 22.4% 24.1% 3.0 y 7.5% In 1,000,000 people with high TG and low HDL-C, a 26% risk reduction would prevent the following numbers of events each year with annual event rates of 3.7% and 7.5%, respectively: 1,000,000 x x (1 0.26) = 27,306 events prevented 1,000,000 x x (1 0.26) = 55,278 events prevented Midpoint of the above estimates is 41,292 events prevented

34 Conclusions New epidemiological and interventional data show a relationship between VLDL-C and CVD risk (stronger than LDL-C), supporting the use of non-hdl-c as an approvable surrogate. Triglyceride lowering also improves causal factors for CHD such as remnant cholesterol and small dense LDL-c Fibrate and niacin appear to have CV benefits in the patients with high TG/Low HDL-c but may cause harm in other dyslipidemic subgroups Patients with elevated TGs paired with low HDL-C, on optimal statin therapy, are still at very high CV risk. STRENGTH, targeting this high risk population with omega-3 therapy, is not expected to complete until 2020.