Combination Lipid Therapy
Tailoring, Tinkering or Troubling?
Michael A. Blazing MD
Associate Professor of Medicine
DUMC
Conflicts
• Merck – Advisory Board, IMPROVE IT trial
• Astra Zeneca – Consultant
• Pfizer – Consultant
• Sanofi – Consulta...
Ideal Lipids – The numbers
LDL-C < 100 dL; HDL-C> 50 mg/dL ; Tg < 130 mg/dL
LDL-C – Statin, Niacin, Ezetimibe, Resin
HDL-C...
Available pharmacologic options for
treating dyslipidemia
LDLc HDLc Tg
Statins - 20 - 60% +5 - 15% -10 - 20%
Fibrates -10 ...
Ideal Lipids – Event reduction
Single Therapy
StatinsFibrates
Niacin
Resin
Combination Therapy
NONE
6
ACC/AHA Cholesterol Guidelines
STATIN STATIN and more STATIN
WHY?
Evidence basis for recommendations
7
The unfulfilled (or pending)
promise of adjunctive Rx
• Fibrates – ACCORD
• Niacin – AIM HIGH, HPS II
• Fish oil – pendi...
Triglycerides as an Independent Risk
Factor for Coronary Heart Disease
Independent Risk Factor
• (+) Austin analysis
• (+)...
Fibrates
• Efficacy - 0-10% increase in HDL; 0-10% decrease in
LDL-C and 20-45% reduction in Tg
• Toxicity
– Liver toxicit...
Clinical Studies - Fibrates
Helsinki Heart Study (1986)
• 4081 asymptomatic men; non-HDL cholesterol >
200
– 600 mg Gemfib...
HDL Intervention Trial - (VA HIT)
• Randomized, double-blind trial of gemfibrozil
1200 mg / day vs. matching placebo in 25...
Kaplan-Meier Curves for Primary
Endpoint
0.25
0
Cumulativeendpointrate
0 -------- years ------ 5
P=.006
gemfibrozil
placeb...
Per cent changes in lipids at 1 year
-25
-20
-15
-10
-5
0
5
10
CHOL LDL HDL Trigly
PBO
GEM
P< 0.0001
AHA Scientific Sessio...
14
ACCORD Lipid
Action to Control Cardiovascular Risk in Diabetes
• 5518 patients with DM and H1C > 7.5%
• Age 40-79 with ...
ACCORD – Trial Lipids
ACCORD Study Group. NEJM 4/2010
Base
Feno
EoS
Feno
∆ Base
Placebo
EoS
Placebo
∆ p of ∆
LDL-C
(mg/dL)...
ACCORD – Primary Outcome
ACCORD Study Group. NEJM 4/2010
ACCORD vs Earlier Fibrate Trials
ACCORD Study Group. NEJM 4/2010
Fish Oil and non-HDLc
Lipid changes at 6 weeks with 4 grams of fish oil added to
simvastatin 40mg in patients with persist...
Fish Oil and non-HDLc
Davidson et al Clinial Thearapeautics 2007
4 gm fish oil added to 40mg Simva
Results at 6 weeks
Adjunctive LDL
lowering
Niacin
LDL lowering 10-25%
HDL raising
Very old evidence and
scarce new
CDP
HATS
ARBITER 2
and 3
N...
Clinical Studies -
Coronary Drug Project (1975)
• Compared 8341 men all with previous MI
– 5000 randomized to Clofibrate, ...
Niacin-Statin clinical event reduction
Brown et al NEJM 2001
Vascular Dz.
Age >45 years
Atherogenic
Dyslipidemia
(HDL<40 or
50; TGL>149;
LDL<160)
Simvastatin
Simvastatin +
niaspan
3-5...
HDL-C at Baseline & Follow-upHDL-C at Baseline & Follow-up
*
+25%
+9.8%
Boden, Probstfield AHA Nov 2011
Triglycerides at Baseline and Follow-upTriglycerides at Baseline and Follow-up
-8.1%
-28.6%
Boden, Probstfield AHA Nov 2011
LDL-C at Baseline & Follow-upLDL-C at Baseline & Follow-up
P < 0.001
*
-5%
-12%
Boden, Probstfield AHA Nov 2011
Time (years)Time (years)
Cumulative%withPrimaryOutcomeCumulative%withPrimaryOutcome
00
1010
2020
3030
4040
5050
00 11 22 3...
What happened in AIM HIGH?
LDL management masked any effect?
Niacin could not have had 25% additive effect in patients
wit...
Baseline LIPIDS on statin-based therapy
Mean (SD) baseline
mg/dL mmol/L
Total cholesterol 128 (22) 3.32 (0.57)
Direct-LDL ...
Effect of ERN/LRPT on SERIOUS adverse events
(median follow-up 3.9 years)
Percentage of patients
Excess p value
3.7% <0.00...
Effect of ERN/LRPT on MAJOR VASCULAR EVENTS
0 1 2 3 4
Years of follow-up
0
5
10
15
20
Patientssufferingevents(%)
15.0%
14....
HPS2-THRIVE: SUMMARY
• No significant benefit of ER niacin/laropiprant on the primary
outcome of major vascular events whe...
Adjunctive LDL
lowering
Adsorption inhibitor
LDL lowering 16-18%
CRP lowered
No trial evidence
Adsorption inhibitor
LDL lo...
Sequestrants
• Bind bile acids
– interrupts enterohepatic circulation
– channels cholesterol to bile acids
• upregulates L...
Sequestrants
• Side effects
– constipation (often resolves with fiber)
– drug interactions
• digitalis, thiazides, beta-bl...
Clinical Studies - Cholestyramine study
Lipid Research Clinics Program (LRC)
• Primary prevention study (1984)
– 3800 men
...
38
Addition of ezetimibe to Ongoing Stable
Statin Therapy: Significant Improvements in
LDL-C, TG, and HDL-C
TG = triglycer...
39
Effect of Ezetimibe on hsCRP
Sager et al Am J Cardiol 2003
Ridker PM et al. N Engl J Med 2005;352:20-28.
PROVE IT–TIMI 22
RecurrentMIorCoronaryDeath
(%)
Follow-up (Years)
0.0 0.5 1....
Summary
• Combinations of existing drugs permit one to
tailor therapy to optimize each of the main lipid
parameters
• Tink...
Summary
• Knowing the history of lipid drug therapy – the
benefits and risks with and without statins as a
backbone therap...
Prevention 2014: Combination Lipid Therapies
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Prevention 2014: Combination Lipid Therapies

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Michael A. Blazing, 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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  • Would use the lipids figure by years from the paper and not the delta figure from the earlier version
  • Key Point:
    Addition of ZETIATM (ezetimibe) to ongoing stable statin therapy significantly decreased LDL-C and TG and increased HDL-C.
    Additional Background Information
    Addition of ZETIA to ongoing simvastatin, atorvastatin, or other statin therapy further reduced LDL-C by –26.8%, –25.0%, or –23.5%, respectively, compared with –3.1%, –4.0% and –3.8% for addition of placebo.1
    Addition of ZETIA to ongoing statin therapy also reduced1:
    Total cholesterol by –17.0% vs –2.3% for placebo (P&amp;lt;0.001)
    Apo B by –19.0% vs –3.5% (P&amp;lt;0.001)
    Reference:
    1. Gagné C, Bays HE, Weiss SR, et al, for the Ezetimibe Study Group. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol. 2002;90:1084–1091.
  • Prevention 2014: Combination Lipid Therapies

    1. 1. Combination Lipid Therapy Tailoring, Tinkering or Troubling? Michael A. Blazing MD Associate Professor of Medicine DUMC
    2. 2. Conflicts • Merck – Advisory Board, IMPROVE IT trial • Astra Zeneca – Consultant • Pfizer – Consultant • Sanofi – Consultant
    3. 3. Ideal Lipids – The numbers LDL-C < 100 dL; HDL-C> 50 mg/dL ; Tg < 130 mg/dL LDL-C – Statin, Niacin, Ezetimibe, Resin HDL-C – Niacin, Fibrate, Statin Tg – Fibrate, Niacin Combination therapy of the above agents. Ways to get there – Tailoring and/or Tinkering
    4. 4. Available pharmacologic options for treating dyslipidemia LDLc HDLc Tg Statins - 20 - 60% +5 - 15% -10 - 20% Fibrates -10 - +10% 0 - + 15% -25 - -50% Niacin -5 - -25% +5 - +30% -20 - -40% Binding Resins -5 - -18% 0 - +5% -5 - +15% Absorption inhibitors -5 - -18% 0 - +5% -5 - -15% Fish oil* 0 - +10% + 1- 5% -13 - -30% *Very dependent on baseline Tg
    5. 5. Ideal Lipids – Event reduction Single Therapy StatinsFibrates Niacin Resin Combination Therapy NONE
    6. 6. 6 ACC/AHA Cholesterol Guidelines STATIN STATIN and more STATIN WHY? Evidence basis for recommendations
    7. 7. 7 The unfulfilled (or pending) promise of adjunctive Rx • Fibrates – ACCORD • Niacin – AIM HIGH, HPS II • Fish oil – pending • Absorption inhibitors – Mixed and pending • Investigational – CETP – 2/4 failed 2 ongoing – PCSK9 – Great numbers outcomes pending
    8. 8. Triglycerides as an Independent Risk Factor for Coronary Heart Disease Independent Risk Factor • (+) Austin analysis • (+) Paris Study • (+) Procam • (-) Framingham Relationship to CHD • atherosclerotic remnant particles • association with small, dense LDL, low HDL • Insulin resistance and metabolic syndrome - Grundy
    9. 9. Fibrates • Efficacy - 0-10% increase in HDL; 0-10% decrease in LDL-C and 20-45% reduction in Tg • Toxicity – Liver toxicity – Renal toxicity – Suicide ?? • Consensus – May be effective for low HDL, high Tg cohorts. No benefit in general low HDL population Frick et al N Engl J Med. 1987; Rubins et al NEJM 1999 ;Field Study Investigators Lancet 2005 Bezafibrate Infarction Prevention (BIP) study. Circulation. 2000 ; ACCORD NEJM 2010
    10. 10. Clinical Studies - Fibrates Helsinki Heart Study (1986) • 4081 asymptomatic men; non-HDL cholesterol > 200 – 600 mg Gemfibrozil bid or Placebo – Combined endpoint of MI and cardiac death • Findings • Increase HDL of 10%; decrease in LDL of 10% • 34% reduction in combined endpoint on treatment • Most effective in subgroups with high TG (>200) or LDL/HDL > 5 • No change in total mortality
    11. 11. HDL Intervention Trial - (VA HIT) • Randomized, double-blind trial of gemfibrozil 1200 mg / day vs. matching placebo in 2500 male patients – 40% of patients with CHD have LDL cholesterol < 130 mg/dL and 50% of these individuals have low HDL • Entry criteria – Documented CHD – HDL < 40 mg/dL; LDL < 140 mg/dL • Primary endpoint of Non-fatal MI or CHD Death p=0.006
    12. 12. Kaplan-Meier Curves for Primary Endpoint 0.25 0 Cumulativeendpointrate 0 -------- years ------ 5 P=.006 gemfibrozil placebo AHA Scientific Session, Nov 1998
    13. 13. Per cent changes in lipids at 1 year -25 -20 -15 -10 -5 0 5 10 CHOL LDL HDL Trigly PBO GEM P< 0.0001 AHA Scientific Session, Nov 1998
    14. 14. 14 ACCORD Lipid Action to Control Cardiovascular Risk in Diabetes • 5518 patients with DM and H1C > 7.5% • Age 40-79 with CVD, 55-79 w/o CVD • LDL-C 60 -180 mg/dL; HDL < 55 mg/dL woman or black or < 50 mg/dL all others; and Tg < 750 mg/dL LLT naïve or < 400 mg/dL with LLT • Mean follow-up of 4.7 years ACCORD Study Group. NEJM 4/2010
    15. 15. ACCORD – Trial Lipids ACCORD Study Group. NEJM 4/2010 Base Feno EoS Feno ∆ Base Placebo EoS Placebo ∆ p of ∆ LDL-C (mg/dL) 96 77 -19 97 77 20 0.16 HDL-C (mg/dL) 38 40 +2 38 39 +1 0.01 Tg (mg/dL) 164 122 -42 160 170 -26 0.0001 Base = Baseline EoS = End of Study Feno = Fenofibrate 2765 fenofibrate plus simvastatin (77.3% adherence at EoS) 2753 placebo plus simvastatin (81.3% adherence at EoS) Average dose of simvastatin 22mg
    16. 16. ACCORD – Primary Outcome ACCORD Study Group. NEJM 4/2010
    17. 17. ACCORD vs Earlier Fibrate Trials ACCORD Study Group. NEJM 4/2010
    18. 18. Fish Oil and non-HDLc Lipid changes at 6 weeks with 4 grams of fish oil added to simvastatin 40mg in patients with persistent elevated Tg on Simvastatin Davidson et al Clinial Thearapeautics 2007
    19. 19. Fish Oil and non-HDLc Davidson et al Clinial Thearapeautics 2007 4 gm fish oil added to 40mg Simva Results at 6 weeks
    20. 20. Adjunctive LDL lowering Niacin LDL lowering 10-25% HDL raising Very old evidence and scarce new CDP HATS ARBITER 2 and 3 Niacin LDL lowering 10-25% HDL raising Very old evidence and scarce new CDP HATS ARBITER 2 and 3 Risk in combination with a statin????? Hepatic necrosis Gout Puritis Flushing Sepsis Bleeding Risk in combination with a statin????? Hepatic necrosis Gout Puritis Flushing Sepsis Bleeding Potential Benefit Potential Risks
    21. 21. Clinical Studies - Coronary Drug Project (1975) • Compared 8341 men all with previous MI – 5000 randomized to Clofibrate, Niacin or Placebo – 3300 additional patients randomized to high or low dose estrogen or dextrothyroxine dropped due to side effects • Very modest changes in cholesterol – Clofibrate 6.5%; Niacin 9.9% – Poor adherence rates • Niacin with a 23% reduction in non-fatal MI at 5 years and 11% reduction in mortality at 15 year follow-up Coronary Drug Project Research group JAMA 1975; Canner. JACC 1986
    22. 22. Niacin-Statin clinical event reduction Brown et al NEJM 2001
    23. 23. Vascular Dz. Age >45 years Atherogenic Dyslipidemia (HDL<40 or 50; TGL>149; LDL<160) Simvastatin Simvastatin + niaspan 3-5 yr 3300 patients from 60 sites (U.S. and Canada CV Death NFMI Stroke ACS AIM-HIGH Study Overview LDL-C target <80 mg/dl both groups (may add ezetimibe if needed) Hypothesis -30% event rate with Simva -23% event rate with simva-nia - 50% relative reduction based on ~46% placebo rate 2 year enrollment
    24. 24. HDL-C at Baseline & Follow-upHDL-C at Baseline & Follow-up * +25% +9.8% Boden, Probstfield AHA Nov 2011
    25. 25. Triglycerides at Baseline and Follow-upTriglycerides at Baseline and Follow-up -8.1% -28.6% Boden, Probstfield AHA Nov 2011
    26. 26. LDL-C at Baseline & Follow-upLDL-C at Baseline & Follow-up P < 0.001 * -5% -12% Boden, Probstfield AHA Nov 2011
    27. 27. Time (years)Time (years) Cumulative%withPrimaryOutcomeCumulative%withPrimaryOutcome 00 1010 2020 3030 4040 5050 00 11 22 33 44 MonotherapyMonotherapy Combination TherapyCombination Therapy HR 1.02, 95% CI 0.87, 1,21HR 1.02, 95% CI 0.87, 1,21 Log-rank P value= 0.79Log-rank P value= 0.79 N at riskN at risk MonotherapyMonotherapy Combination TherapyCombination Therapy 16961696 17181718 15811581 16061606 13811381 13661366 910910 903903 436436 428428 Primary OutcomePrimary Outcome 16.2% 16.4% Boden, Probstfield AHA Nov 2011
    28. 28. What happened in AIM HIGH? LDL management masked any effect? Niacin could not have had 25% additive effect in patients with LDL managed to between 40 and 80mg/dL Niacin in placebo effected HDL? Niacin BL 35mg/dl 3yr 42mg/dl +25% P+ 50-200mg N BL 35mg/dl 3yr 38mg/dl +9.8% Wrong population? 80% were metabolic syndrome Baseline Tg 163 AIM HIGH NEJM 2011
    29. 29. Baseline LIPIDS on statin-based therapy Mean (SD) baseline mg/dL mmol/L Total cholesterol 128 (22) 3.32 (0.57) Direct-LDL 63 (17) 1.64 (0.44) HDL 44 (11) 1.14 (0.29) Triglycerides* 125 (74) 1.43 (0.84) *64% fasted for >8 hours
    30. 30. Effect of ERN/LRPT on SERIOUS adverse events (median follow-up 3.9 years) Percentage of patients Excess p value 3.7% <0.0001 1.8% <0.0001 1.4% <0.0001 1.0% <0.0001 0.7% 0.0008 0.4% 0.05 0.7% 0.0002 0.3% 0.0026 ERN/LRPT
    31. 31. Effect of ERN/LRPT on MAJOR VASCULAR EVENTS 0 1 2 3 4 Years of follow-up 0 5 10 15 20 Patientssufferingevents(%) 15.0% 14.5% Placebo ERN/LRPT Logrank P=0.29 Risk ratio 0.96 (95% CI 0.90 – 1.03) Primary outcome: MAJOR VASCULAR EVENTS Non-fatal MI or coronary death; Any non-fatal or fatal stroke (including subarachnoid haemorrhage); or Coronary or non-coronary artery surgery or angioplasty (including amputation)
    32. 32. HPS2-THRIVE: SUMMARY • No significant benefit of ER niacin/laropiprant on the primary outcome of major vascular events when added to effective statin-based LDL-lowering therapy • Significant excesses of serious adverse events (SAEs) due to known and unrecognised side-effects of niacin. Over 4 years, ER niacin/laropiprant caused SAEs in ~30 patients per 1000 • No clear evidence of differences in efficacy or safety in different types of patient (except for an excess of statin- related myopathy in Chinese patients) • Findings are consistent with previous niacin trials. The role of ER niacin for the treatment and prevention of cardiovascular disease needs to be reconsidered
    33. 33. Adjunctive LDL lowering Adsorption inhibitor LDL lowering 16-18% CRP lowered No trial evidence Adsorption inhibitor LDL lowering 16-18% CRP lowered No trial evidence Lack of efficacy reducing intimal thickening in FH patients - ? Event efficacy No increased risk seen in that study but ? cancer risks in SEAS Bile acid binding resins raise Tg esp. if baseline is high Paucity of data Lack of efficacy reducing intimal thickening in FH patients - ? Event efficacy No increased risk seen in that study but ? cancer risks in SEAS Bile acid binding resins raise Tg esp. if baseline is high Paucity of data Potential Benefit Potential Risks Binding resin LDL lowering 16-18% Old trial evidence Binding resin LDL lowering 16-18% Old trial evidence
    34. 34. Sequestrants • Bind bile acids – interrupts enterohepatic circulation – channels cholesterol to bile acids • upregulates LDL receptor • also leads to upregulation of HMG-CoA reductase • Efficacy – LDL decrease of 5-30% – May increase triglycerides
    35. 35. Sequestrants • Side effects – constipation (often resolves with fiber) – drug interactions • digitalis, thiazides, beta-blockers and Coumadin • Compliance - Poor • Dosage - 4-16 grams per day
    36. 36. Clinical Studies - Cholestyramine study Lipid Research Clinics Program (LRC) • Primary prevention study (1984) – 3800 men – Cholesterol > 265 and LDL > 175 • Cholestyramine (24 gms) and diet vs.. Placebo and diet • Findings – 8% fall in cholesterol; 12% fall in LDL – 19% reduction in the incidence of coronary heart disease – No mortality benefit
    37. 37. 38 Addition of ezetimibe to Ongoing Stable Statin Therapy: Significant Improvements in LDL-C, TG, and HDL-C TG = triglyceride. *P<0.001 vs statin + placebo. † P<0.05 vs statin + placebo. Adapted from Gagné C et al. Efficacy and Safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol. 2002;90:1084–1091, with permission from Excerpta Medica Inc. –3%–4% 1% 3%† –14%* –25%* –30% –25% –20% –15% –10% –5% 0% 5% LDL-C TG (median) HDL-C Mean % Change From Treated Baseline Statin + Placebo (n=390) Statin + Ezetimibe 10 mg (n=379)
    38. 38. 39 Effect of Ezetimibe on hsCRP Sager et al Am J Cardiol 2003
    39. 39. Ridker PM et al. N Engl J Med 2005;352:20-28. PROVE IT–TIMI 22 RecurrentMIorCoronaryDeath (%) Follow-up (Years) 0.0 0.5 1.0 1.5 2.0 2.5 LDL ≥70 mg/dl, CRP ≥2 mg/L LDL ≥70 mg/dl, CRP <2 mg/L LDL <70 mg/dl, CRP ≥2 mg/L LDL <70 mg/dl, CRP <2 mg/L LDL <70 mg/dl, CRP <1 mg/L 0.00 0.02 0.04 0.06 0.08 0.10 From lipidsonline.org Trial Evidence Trial cut points – LDL 70mg/dL
    40. 40. Summary • Combinations of existing drugs permit one to tailor therapy to optimize each of the main lipid parameters • Tinkering with the dose or combination of drugs will likely make it possible to achieve most desired lipid levels in most people • The troubling trepidation of tailoring and/or tinkering is a lack of evidence supporting benefit and accumulating evidence of potential harm
    41. 41. Summary • Knowing the history of lipid drug therapy – the benefits and risks with and without statins as a backbone therapy – allows thoughtful theoretically risk reducing combinations to be added to a statin or tried in patients who are intolerant of statin – Fibrates in those with persistently very high Tg – Niacin for intolerant patients or for Tg as above – Fish oil for high Tg or persistently high Tg – Ezetimibe when low LDL-C trumps lack of evidence – Bile acid sequestrates as above • Any decision to use combination therapy needs to montitor for potential adverse effects that have been seen in previous trials

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