Treatment Strategies for Dyslipidemia C A S E E X A M P L E S M A - - PDF document

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C A S E E X A M P L E S M A R Y M A L L O Y , M D

Treatment Strategies for Dyslipidemia

Disclosure

I have nothing to disclose

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CASE 1

— 41 year old woman referred because her

lipids did not respond fully to statin Rx. Her initial cholesterol was 285, TG 218, LDL-C 198 , and HDL-C 45. Other health problems included DMII and

• besity, primarily abdominal. Her diet

was moderately high in fat and rapidly absorbed CHO; 2 servings of alcohol 3 times/week; walking 15 min twice/wk.

Case 1, cont.

— On 20 mg atorvastatin, her LDL-C was 153. — Her atorvastatin was increased to 40 mg two

months prior to her visit. Lab results at her visit were:

— TC 215 — TG 205 — LDL-C 130 — HDL-C 44 — HgbA1c 7.9

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Case 1, cont.

— Management of LDL cholesterol:

¡ What should be the LDL-C goal? Why? ¡ If the goal is lower than 130, would you

recommend a higher statin dose or addition of ezetimibe?

¡ Would you let her work on her diet and

exercise before changing her drug treatment? IMPROVE-IT

— >18,000 patients with ACS in 39 countries — Ezetimibe plus simvastatin 40 mg vs simva 40 — LDL-C reduced to a mean of 53.2 vs 69.9 — Modest but significant benefit of the

combination in preventing MI or ischemic stroke; 6.4% lower relative risk of the composite endpoint.

— Patients with diabetes had the most robust

benefit (relative reduction 12%)

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Case 1, cont.

— Why are her triglycerides elevated? — What would you recommend for TG

reduction?

¡ Diet ¡ Exercise ¡ Weight reduction ¡ Fenofibrate? Marine omega 3s? Both? ¡ Control of DM

Non-HDL-C as a Treatment Target

— Considered a co-primary target with LDL-C — Includes all the potentially atherogenic particles:

¡ VLDL and their remnants

¡ LDL ¡ IDL ¡ Lipoprotein (a) ¡ Chylomicron remnants

— When on-Rx values are discordant, non-HDL-C is

more closely aligned with CHD risk than LDL-C

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Case 1, cont.

— Why is her HDL-C low?

¡ Secondary to the TG elevation? ¡ Secondary to her obesity? ¡ Secondary to her lack of sufficient exercise? ¡ Secondary to her DM? ¡ A primary genetic disorder?

— Is it important to direct Rx to this problem?

¡ If so, what are your options?

High Density Lipoprotein-Cholesterol

— In general, goal level is >45 in men; >55 in women — A reduced level of HDL-C is used in risk factor

counting and quantitative ASCVD risk assessment

— High levels are not consistently associated with

protection from ASCVD

— HDL functionality is more important than the level

• f HDL-C

— HDL-C is rarely a treatment target per se — Often addressed by management of other

dyslipidemias

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CASE 2

— 36 year old man with a family history of

premature CAD (father MI at 41). He is a current “light” smoker. Good exercise habits. Diet generally low in saturated and trans fats but eats out 3 to 4 times a week and travels frequently for his job. BMI 23. BP 135/85. He has not accepted his physician’s recommendation to take medicine for his lipids and comes for a second opinion. Case 2, cont.

— PE: Entirely normal — Lab results: ¡ TC 280; TG 180; HDL-C 44; LDL-C 200 ¡ Lp(a) 184 nM/L ¡ Normal levels of ALT, TSH, free T4, FBS; No

proteinuria

¡ Homocysteine 12 micromol/L ¡ LPPLA2 230; hsCRP 13 ¡ Stress ECHO and carotid IMT normal

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Case 2, cont.

— What are his risk factors for CVD? — Do you agree that he should take medication/s? If so,

what?

¡ What should be his LDL-C treatment goal? ¡ His TG goal? ¡ Would you try to reduce his Lp(a)? How? ¡ Should he take ASA?

Lipoprotein (a)

— Increased levels are associated with increased risk

¡ Concentration, size and structure vary greatly among

individuals, probably affecting potential for

• atherogenicity. Levels are chiefly genetically determined.

— No lifestyle interventions affect the level — Level reduced variably by niacin (apo B antisense,

PCSK9 inhibitor, CETP inhibitor, thyroid receptor beta subunit agonists, other)

— Lp(a) is emerging as an important independent risk

factor and should be measured at least once.

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Homocysteine and Lp(a)

— Substantially elevated levels of

homocysteine (probably > 30) interact synergistically with Lp(a)

— Homocysteine liberates the (a) protein

that exerts a strong inhibitory effect on fibrinolysis

CASE 3

— 46 year old woman is noted to have

lipemic serum. She has a history of several episodes of unexplained upper abdominal pain, one with associated nausea, over the past year but is asymptomatic when you see her. General health is otherwise “good”. She gained 10 lbs in the past year. Her mother had the onset of CAD at age 52.

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Case 3, cont.

— BMI 30 — Waist circ. 41; Hip circ. 39 — TC 640; TG 2600 — LDL-C (after ultracentrifugation) 168 — HDL-C 24 — FBS 159; A1c 8.2 — AST 31; ALT 83

Case 3, cont.

— What might be the cause of her abdominal

pain?

— What is her probable lipid diagnosis? — What other diagnoses does she have? — Why is her ALT elevated? — What is her short term risk? — How should she be managed?

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Case 3, Cont.

— In what order would you do the following?

¡ Start a statin ¡ Advise her to eat a low total fat, low

“simple” CHO diet; avoid alcohol; and lose weight

¡ Start metformin? ¡ Advise her to eat zero fat for 72 hours ¡ Start fenofibrate; fish oil?

Case 3, cont.

— Does she need a liver ultrasound? — Should she take natural (includes 4 isomers)

vitamin E?

— If she had abdominal pain at the visit,

hospitalization for acute pancreatitis might be indicated and insulin could be given.

— Plasmapheresis can be used for acute TG

reduction when levels are extremely high

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CASE 4

— 25 year old woman with HeFH has an LDL-

C consistently below 110 mg/dL while taking resuvastatin 40 mg plus ezetimibe. She is seen at 6 month intervals. At her visit today her LDL-C is 180 mg/dL. She feels well and has no new symptoms.

— What do you suspect is the cause of the

increase? Case 4, cont.

— Causes to consider:

¡ Hypothyroidism ¡ Poor compliance with her medications ¡ Early nephrosis ¡ She changed her method of birth control ¡ Her diet now includes more saturated fat ¡ Cholestasis (LpX) (Alk P’tase was normal)

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Birth Control in FH Women

— There is no published data on the use of OCPs in

women with FH yet birth control is essential when a statin is given

— Document baseline lipids before starting a new form

• f birth control

— Mirena (levonorgestrel) IUD has been reported to

increase LDL-cholesterol

— Select a lipid-neutral (combined hormonal) OCP or

vaginal ring

CASE 5

— A 54 year old Asian woman presents with a history of

combined pattern hyperlipidemia and bilateral, less than 50%, external carotid artery stenosis that is

• asymptomatic. Her diet and exercise habits are
• ptimal.

— Pretreatment TC was 278, TG 190, HDL-C 56, LDL-C

• 184. She was given 10 mg of resuvastatin. After 6 wk.

her TC was 119, TG 130, HDL-C 55, LDL-C 38.

— She reports intermittent muscle cramps and aching

in her legs but otherwise feels well. CK is normal. AST is 2X normal.

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Case 5, cont.

— Why is her LDL-C so low? — Does she have myositis secondary to the

statin?

— Does she have liver toxicity secondary to the

statin?

— How will you manage her at this point?

Case 5, cont.

— At each statin dose, LDL-C may be reduced

significantly more in Asians and serum levels of the statin are higher

— Initial statin doses should be lower in

Asians, particularly in women (eg start with no more than 5 mg resuvastatin or 10 mg atorvastatin)

— An abrupt fall in lipid levels could indicate

liver toxicity

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CASE 6

— A 32 year old man presents with an enlarged

liver but is asymptomatic. One of his 2 sisters also has hepatomegaly. His parents are well.

— TC 230; TG 118; LDL-C 176; HDL-C 30 — What relatively rare, previously fatal

disorder, might he have that can now be successfully managed? Lysosomal Acid Lipase Deficiency

— LAL deficiency; CESD; Wolman — Usually presents with an HDL-C <40 for males and <

50 for females; LDL-C > 160; TG may be normal or modestly elevated (i.e. a common lipid phenotype)

— Hepatomegaly; microvesticular steatosis on biopsy;

elevated transaminases; progress to liver failure and sometimes to CVD.

— Statins, resins, and niacin, alone or in combinations

may alter the dyslipidemia but do not affect the root cause of the disease (CE accumulation in the liver)

— Specific treatment now available (recombinant LAL)

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New Agents on the Horizon

— CETP inhibitors increase HDL-C; reduce LDL-C — For HoFH

¡ Mipomersen: antisense that targets RNA for

apoB

¡ Lomitapide: inhibits MTTP (necessary for VLDL

assembly and secretion)

— For other severely elevated levels of LDL-C

¡ Alirocumab: monoclonal antibody to PCSK9

(proprotein convertase subtilisin/kexin type 9)

New Agents on the Horizon

— AMP Kinase Agonists:

¡ Reduces LDL-C and non-HDL-C ¡ Improves insulin sensitivity

— For Triglyceride reduction

¡ Apo C-lll antisense (C-lll suppresses LPL) ¡ DGAT-1 inhibitor (also reduces HgbA1c and

weight)

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Summary

— Setting Rx goals based on risk assessment,

and monitoring LDL-C and non-HDL-C, are important tools in management

— When triglycerides are > 500 mg/dL, they

become the target of therapy

— Don’t forget the “two hit phenomenon”

(genetic predisposition and exacerbation by secondary factors) References

Jacobson TA et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1 – executive summary. J Clin Lipidol. 2014;8:473-488 Watts GF et al. Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation: executive summary. J Atheroscler Thromb. 2014;21:368-374 Jacobson TA. Lipoprotein (a), cardiovascular disease, and contemporary management. Mayo Clin Proc. 2013;88:1294