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Advances in HDL Therapeutics
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Advances in HDL Therapeutics

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John R. Guyton, MD ...

John R. Guyton, MD

1st Annual Duke Preventive Cardiology Symposium
Saturday, April 26, 2014
The overall goal of this activity is to review the latest advancements in the management of lipids in clinical practice, including the new American Heart Association and American College of Cardiology guidelines on lipids announced in November 2013. Topics include learning about evaluation and treatment options in lipids and lipoprotein disorders, as well as focusing on new prevention guidelines, physical activity, nutrition, drug therapies, advanced lipoprotein testing, special patient populations, and new technologies for lifestyle management.

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  • Counterregulatory hormones likely include catecholamine surge, potentially harmful. This might be prevented by giving niacin at mealtime, as it was given in all previous clinical endpoint trials.
  • The effects of macrophages and endothelial cells would be expected to be beneficial, which theoretically could balance the possible harmful effect of antilipolysis in adipocytes.

Transcript

  • 1. Advances in HDL Therapeutics John R. Guyton, M.D. Director, Duke Lipid Clinic Durham, NC
  • 2. Disclosures • Research grants: Merck, Amgen, Regeneron, Sanofi, Amarin, Genzyme/ISIS • Consulting fees: Merck, Regeneron, Sanofi, Amgen, Novella, Novartis
  • 3. Decreased Atherosclerosis in Germany after World War II “Heart infarctions were seldom observed during the years 1945- 1948 in [occupied] West Germany…. The autopsy records of seven Institutes of Pathology showed neither death from heart infarction nor peripheral atherosclerotic arterial occlusion. Advanced forms of atherosclerosis in all arteries were rare between 1945 and 1948 as compared with 1939 and 1955 based on autopsy analyses…” Schettler G. Preventive Medicine 12, 75-83 (1983)
  • 4. GPR109A LIVER MACROPHAGES ADIPOCYTES ENDOTHELIAL CELLS β-Hydroxybutyrate Acetoacetate Fatty acids ( ) GPR109A ? BRAIN GPR109A Regulation of Starvation
  • 5. GPR109A Effects on Macrophages 1. PPARg translocation, transcription of PPARg, CD36 and ABCA1, and ↑cholesterol efflux in monocytoid cells. Rubic et al. Biochem Pharmacol 2004;67:411. 2. Suppression of inflammatory responses in human monocyte-macrophages. Digby et al., ATVB 2012: 32:669.
  • 6. GPR109A-dependent Effects on Atherosclerosis in LDL Receptor-neg Mice 1. ↑ ABCG1 in macrophages. 2. ↑cholesterol efflux in macrophages. 3. ↓ atherosclerosis progression in only in GPR109A- competent mice. 4. Suppression of atherosclerosis in GPR109A-/- irradiated mice by bone marrow from GPR109A+/+ mice, but not bone marrow from GPR109A-/- mice. Lukasova et al, J Clin Invest 2011; 121:1163
  • 7. Pharmaceutical Exploration of GPR109A 1. A wide variety of organic anions bind and activate GPR109A. 2. NA-007 has entered clinical trials.
  • 8. GPR109A LIVER MACROPHAGES ADIPOCYTES ENDOTHELIAL CELLS β-Hydroxybutyrate Acetoacetate Fatty acids ( ) GPR109A ? BRAIN GPR109A Regulation of Starvation
  • 9. Effect of NA-007 on Plasma Nonesterified Fatty Acids 200 mg p.o. 200 mg p.o. 200 mg p.o.
  • 10. Receptor-mediated Effect of NA-007 on Adipocyte Lipolysis and Plasma Nonesterified Fatty Acids (NEFA) 200 mg p.o. 200 mg p.o. 200 mg p.o. Impairment of fuel supply? Counterregulatory hormone response including catecholamines? NA-007 NEFA TIME (minutes)
  • 11. Conclusion: NA-007 should be given at mealtime.
  • 12. O C N Structure of NA-007 O _
  • 13. Niacin – a Paradox 1. Prior clinical trials suggested CV event reduction with niacin, but AIM-HIGH and HPS2-THRIVE did not. 2. AIM-HIGH and HPS2-THRIVE were the first clinical endpoint trials to use bedtime instead of mealtime niacin.
  • 14. Relation of In-Trial Lipoproteins to Cardiovascular Events Placebo + Statin ERN + Statin HR* P HR* P LDL-C 1.39 <0.001 1.01 0.96 HDLC 0.95 0.37 0.99 0.79 NonHDLC 1.30 <0.001 0.98 0.78 TC/HDLC 1.20 0.003 1.04 0.64 * HR, hazard ratio. HR unit is 1 SD of baseline distribution. Adjusted for covariates as listed in AIM-HIGH main paper. Test for heterogeneity of joint effects of HDL-C, LDL-C and LogTG across treatments: p=0.025 Guyton et al. J Am Coll Cardiol 2013; online July 20
  • 15. Bedtime ER niacin changes the relationship between lipoproteins and CV events. 1. Niacin must change – lipoproteins – or events (through nonlipoprotein mechanisms) – or both. 2. It’s very unlikely that niacin will alter LDL enough to make it nonatherogenic. 3. Therefore, it appears that niacin influenced CV events in a nonlipoprotein manner.
  • 16. Coronary Drug Project • 3,908 men aged <65 yrs with history of MI. • 27% decrease in nonfatal MI in niacin group. • Follow-up 9 years after end of trial: 11% lower total mortality in niacin group. 0 5 10 15 20 25 30 35 0 1 2 3 4 5 6 7 Years CumulativeMIs+CVDeaths(%) Niacin Placebo JAMA 1975; 231:360; JACC 1986; 8:1245
  • 17. Stockholm Ischemic Heart Disease Study • 5-year secondary prevention study • Combination treatment with niacin and clofibrate • Total mortality decreased 26% in drug treatment group. • Ischemic heart disease mortality decreased 36%. Acta Med Scand 1988;223:405-418
  • 18. HDL Atherosclerosis Treatment Study (HATS) • 160 pts with measurable CAD by angiography • HDLC <35 and LDLC <145 mg/dl • Randomized to (a) placebo or (b) niacin 2-4 grams daily dose combined with simvastatin 20 mg daily Brown BG, NEJM 2001; 345:1583
  • 19. HDL Atherosclerosis Treatment Study (HATS) • Niacin-statin  ~85% reduction of angiographic progression after 3 years (p < 0.01) • Niacin-statin  70% reduction of cardiovascular events (7 vs. 23 events, p < 0.01, includes revascularization events) Brown BG, NEJM 2001; 345:1583
  • 20. Other Niacin Combination Rx Trials Study Treatments (Total N, follow-up) Clinical Outcomes with Niacin Familial Atherosclerosis Treatment Study (FATS) (Brown et al NEJM 1990) Niacin + colestipol vs. lovastatin + colestipol vs. placebo (146 pts, 2.5 y) Clinical events reduced by 73% (P<0.05) Armed Forces Regression Study (AFREGS) (Whitney et al Ann Intern Med 2005) Niacin, gemfibrozil, and cholestyramine vs. limited use cholestyr- amine (143 pts, 2.5 y) Clinical events reduced by 50% (P<0.05)
  • 21. Both IR and ER Niacin Improve Arterial Wall Morphology • First study to show coronary lesion regression used IR niacin-colestipol combination therapy. • FATS and HATS both showed net regression of coronary lesions by quantitative angiography. • 3 trials have shown reduction of carotid intima- media thickness by U/S with ER niacin added to baseline statin therapy. • 1 trial showed reduction of carotid wall area by MRI with ER niacin added to baseline statin therapy (Lee et al. JACC 2009;54:1787).
  • 22. ARBITER- 6/HALTS: Effect on Carotid Wall Thickness of Adding Extended-Release Niacin vs Ezetimibe to Ongoing Statin Therapy • 363 pts randomized and 208 completed 14-month assessment of CIMT. • Extended-release niacin up to 2000 mg h.s. (avg dose 1715 mg) or ezetimibe 10 mg/d added to background statin rx. • HDLC 42.4  49.9 mg/dl in niacin-treated pts. Taylor AJ, NEJM 2009; 361:2113-22 -0.015 -0.01 -0.005 0 0.005 ChangeinCIMT(mm) 8 mos 14 mos ER-Niacin Ezetimibe P = 0.003
  • 23. Date Wgt Chol TG HDLC LDLC Total HDLC While taking 4/02 163 294 11 93 14.8 no lipid meds, 3 days post-MI Case 82. Treatment of Low HDL Man presented at age 53 in 7/02. He had MI and 4-vessel CABG one month prior to visit. Otherwise in excellent health.
  • 24. Date Wgt Chol TG HDLC LDLC Total HDLC While taking 4/02 163 294 11 93 14.8 no lipid meds, 3 days post-MI 5/02 188 161 230 22 93 7.3 simvastatin 40 mg Case 82. Treatment of Low HDL Man presented at age 53 in 7/02. He had MI and 4-vessel CABG one month prior to visit. Otherwise in excellent health.
  • 25. Date Wgt Chol TG HDLC LDLC Total HDLC While taking 4/02 163 294 11 93 14.8 no lipid meds, 3 days post-MI 5/02 188 161 230 22 93 7.3 simvastatin 40 mg 7/02 190 140 128 39 75 3.6 simva 40, niacin 1500 mg/day, EtOH 0.8 oz Case 82. Treatment of Low HDL Man presented at age 53 in 7/02. He had MI and 4-vessel CABG one month prior to visit. Otherwise in excellent health.
  • 26. Date Wgt Chol TG HDLC LDLC Total HDLC While taking 4/02 163 294 11 93 14.8 no lipid meds, 3 days post-MI 5/02 188 161 230 22 93 7.3 simvastatin 40 mg 7/02 190 140 128 39 75 3.6 simva 40, niacin 1500 mg/day, EtOH 0.8 oz 10/02 194 149 106 50 77 3.0 simva 20, niacin 2500 EtOH 0.8 oz, runs 20 miles/week Case 82. Treatment of Low HDL Man presented at age 53 in 7/02. He had MI and 4-vessel CABG one month prior to visit. Otherwise in excellent health.
  • 27. Date Wgt Chol TG HDLC LDLC Total HDLC While taking 4/02 163 294 11 93 14.8 no lipid meds, 3 days post-MI 5/02 188 161 230 22 93 7.3 simvastatin 40 mg 7/02 190 140 128 39 75 3.6 simva 40, niacin 1500 mg/day, EtOH 0.8 oz 10/02 194 149 106 50 77 3.0 simva 20, niacin 2500 EtOH 0.8 oz, runs 20 miles/week 2/04 196 163 70 51 98 3.2 same regimen Case 82. Treatment of Low HDL Man presented at age 53 in 7/02. He had MI and 4-vessel CABG one month prior to visit. Otherwise in excellent health.
  • 28. Nonpharmacologic Rx for HDL-C Long-term weight loss 20 lbs  5-10% Increased dietary fat 10-20% of cal  4-7% Running 20 miles/week  10-15% Smoking cessation -1.5 ppd  10% Ethanol 1.3 oz (~2.5 drinks)  10-20% Ginsberg, Am J Card 2000; 86:41L Dattilo, Am J Clin Nutr 1992;56:320 Williams, Am J Clin Nutr 1997; 66:1197
  • 29. Pharmacologic Rx for HDL-C Niacin ER 1500 mg 21% Niacin ER 2000 mg 26% Niacin ER/lovastatin 2000/40 30-41% Gemifbrozil 600 mg bid 6-13% Fenofibrate 134-200 mg 11-15% Pioglitazone 45 mg 15% Statins various 2-14% Torcetrapib 120 mg 46-61% Guyton, Arch Int Med 2000; 160:1177 Kashyap, Am J Card 2002; 89:672 Rubins NEJM 1999; 341:410 Fenofibrate prescribing information Goldberg, Diab Care 2005; 28:1547 Brousseau, NEJM 2004; 350:1505
  • 30. Responses of Apolipoprotein A-I Niacin ER 1500 mg 8-9% Niacin ER 2000 mg 11-12% Niacin ER/lovastatin 2000/40 14% Torcetrapib 120 mg 13-16% Ethanol 1.3 oz (~2.5 drinks) 6-13% Guyton, Arch Int Med 2000; 160:1177 Bays, Am J Cardiol 2003; 91:667 Brousseau, NEJM 2004; 350:1505 Camargo, JAMA 1985; 253:2854
  • 31. • ApoA-I infusions led to regression of pre- existing atherosclerosis in rabbits • Reduced initiation and progression of atherosclerosis in transgenic mice and rabbits Apo A-I is Antiatherogenic in Animals
  • 32. ApoA-I Milano/Phospholipid Complexes for Atherosclerosis Regression • 5 infusions of active complexes given weekly to patients (n=35) following acute coronary syndrome, versus saline infusion (n=11 patients). • Primary endpoint: 0.81% reduction from baseline in percent atheroma volume (p=0.02). • Secondary endpoint: 4.2% reduction from baseline in absolute atheroma volume (<0.001). • Placebo subjects had no change in atheroma volume. Active treatment did not differ significantly from placebo. Nissen et al, JAMA 2003; 290:2292
  • 33. RVX-208 • Small molecule promoter of hepatic apoA-I expression. • Increase in capacity of apoB-depleted serum to support cholesterol efflux from macrophages. • Only a minor increase in HDL cholesterol. Tuteja and Rader. Clin Pharmacol Ther April 2014 online pub
  • 34. Anacetrapib and Evacetrapib • These CETP inhibitors have no adverse effects on blood pressure, electrolytes, or aldosterone, as torcetrapib did. • ACCELERATE is determining CV events in evacetrapib vs placebo in 12,000 statin-treated ASCVD subjects. Estimated completion in Jan 2016. • REVEAL is determining CV events in anacetrapib vs placebo in 30,624 statin-treated ASCVD subjects. Estimated completion in Jan 2017. Clinicaltrials.gov
  • 35. • LDL-C and nonHDL-C remain the key targets of lipid-altering strategies. • HDL-C is an important CHD risk factor, but its role as a therapeutic target is uncertain. • Niacin dosed at mealtimes may be beneficial. • There is a short list of new HDL-raising drugs. Summary
  • 36. Is HDL-C Simply a Marker of Increased Cardiovascular Risk? • Smoke • Are sedentary • Are obese • Are insulin resistant or diabetic • Have hypertriglyceridemia • Have chronic inflammatory disorders Low HDL-C levels are commonly found in patients who: