TREATMENT OF DYSLIPIDEMIAS

General Approach to Treatment of Dyslipidemias

Studies of clinical impact of treatment of dyslipidemias

Specific treatments:

Dietary Treatment
Bile Acid Sequestrants
Niacin
HMG-CoA Reductase Inhibitors ("Statins")
Fibric Acid Analogs
Probucol
Cholesterol Absorption Inhibitors
 Hormone Replacement Therapy
Cholesterol-Lowering Margarines
Omega-3 Fatty Acids for Hypertriglyceridemia
Cholesteryl ester transfer protein (CETP) inhibitors
Treatments other than diet, exercise, and medications

IV General approach to treatment per NCEP

  1. Reduce other CAD Risk Factors if possible
  2. Evaluate for secondary causes of dyslipidemia
  3. Base therapy primarily on LDL and other risk factors:
Risk Category LDL target LDL at which to consider meds
(in general, after 3mo trial of lifestyle changes)
CHD and "CHD risk equivalents"
(10y risk of CHD event generally > 20%)
  • < 100
  • < 70 "is a therapeutic option" for most
    pts based on HPS & PROVE- IT per NCEP)
  • Goal of < 70 "reasonable" if CHD + DM
  • > 100 (meds "indicated simultaneously with lifestyle changes")
  • Initiate therapy regardless of LDL level if have CHD + DM
2 or more risk factors < 130 > 130 if 10y risk 10-20% based on Framingham scores, though per NCEP in such pts meds are a "therapeutic option on the basis of clinical judgment" if LDL 100-129 (treating to target of < 100)
> 160 if 10y risk < 10% based on Framingham scores
0-1 risk factor
(10y risk of CHD event generally < 10%)		 < 160 > 190 ("optional in appropriate circumstances" at 160-189)
  1. CHD risk factors recognized by NCEP:
  1. Cigarette smoking
  2. Hypertension
  3. HDL < 40
  4. Family h/o premature CHD (male 1st degree relative < 55yo, female first degree relative < 65yo)
  5. Age > 45yo in men, > 55yo in women
  6. *HDL > 59 = "negative" risk factor; removes one risk factor from total count
  1. "CHD risk equivalents" = conditions that carry a risk for major coronary events equal to that of established CHD (> 20% over 10y)--include
    1. Non-CHD atherosclerotic disease
    2. DM
    3. Multiple risk factors that confer a 10y risk for CHD > 20% (based on the Framingham risk scores--check this for all pts with 2 or more risk factors as above)
      1. Framingham risk scores based on age, tot. chol., HDL, systolic BP, tx for HTN, and cigarette use
  1. If LDL > target, initiate therapeutic lifestyle changes:
    1. Dietary therapy--specifically, limitation of intake of saturated fat & cholesterol
    2. Physical exercise--Raises HDL; maybe some lowering of LDL (Lifestyle Heart Trial), but may have been clouded by concomittant weight loss
    3. Consider increased soluble fiber (10-25g/d) and plant sterols 2g/d if the above doesn't achieve LDL goal
    4. If meds indicated (see above), NCEP recommends first choice be a statin, bile-acid sequestrant, or nicotinic acid. Check fasting lipid panel afte 6wks.
  1. If the "Metabolic Syndrome" is present, priority should be given to addressing its components as a "secondary target of therapy", with:
    1. Weight Control
    2. Physical exercise
    3. Treatment of Hypertension if present
  1. Treatment of Hypertriglyceridemia
  1. Evidence suggests TG level is independently ass'd with CHD risk (see above)
  2. Initial tx--Exercise; if appropriate, glycemic control (if diabetic), weight loss, d/c'ing TG-increasing meds, tobacco cessation, & reduced alcohol intake
  3. Drugs (niacin or fibrate first-line)--Consider (per NCEP) if TG > 200 and "non-HDL" cholesterol (LDL + VLDL) is > (30 + target LDL)
  4. Drugs definitely advisable to prevent pancreatitis if TG > 500 (along with very-low-fat diet and other lifestyle changes as above)
  1. Treatment of low HDL
    1. NCEP does not specify HDL-raising as a specific goal of treatment--"treatment for isolated low HDL is mostly reserved for persons with CHD and CHD risk equivalents."
    2. Low HDL counts as a risk factor and thus influences the recommended thresholds for meds, etc. (see below)
  1. Other notes on treatment
    1. With LDL "well above" 220, drug tx can be started once intensive dietary therapy (Step II diet; see below) has been initiated.
    2. NCEP does not recommend any difference in criteria for using meds in young patients (in contrast to the 1993 NCEP guidelines which were more conservative)
    3. AHA says that don't need to wait to see effect of diet before starting meds in pts with CHD and LDL > 130 (Circ. 95:1683, 1997)
    4. "In older persons (>65 years), clinical judgment is required for how intensively to apply these guidelines; a variety of factors, including concomitant illnesses, general health status, and social issues may influence treatment decisions and may suggest a more conservative approach."
    5. Keep in mind increased risk for malnutrition in the elderly when making dietary recommendations
    6. NCEP Recommends against using tot. chol./HDL ratio as a criterion for tx

V. Dietary treatment

  1. Main goal of dietary tx is to lower LDL, per NCEP
  2. Food components that worsen lipid levels: Saturated fat (should be < 7% tot. calories), "trans" monunsaturated fatty acids, and cholesterol (should be < 200mg/d) (limits per NCEP
  3. Food components that improve lipid levels: unsaturated fat (blocks absorption of cholesterol), soluble fiber (lowers total and LDL cholesterol), calcium (interferes with fat absorption), plant sterols
  4. Controlling obesity can lower LDL and Triglycerides and increase HDL
    1. MRFIT study showed 14mg decrease in LDL with every 10lb decrease in body weight
  1. NCEP III, unlike NCEP II, doesn't specify different levels of dietary modification according to level of lipid abnormalities; recommendations in NCEP III correspond to the more limited "Step 2" diet in the old NCEP II guidelines.
  1. Studies of effectiveness of dietary tx
  1. Supervised fat-restrictive diets (7-20% of total calories) ass'd with 17-37% decreases in LDL (several studies)
  2. Reduced fat intake among free-living subjects (15-21% of total calories) ass'd w/more modest decreases in LDL (9-18%)
  3. JAMA 278:1509, 1997-UW study
  1. 508 "highly motivated" male Boeing employees, avg. age 48yo, with LDL > 75%ile for age were randomized to one of 4 fat-restricted diets x 1y; 444 completed study
  2. Pts divided into "hypercholesterolemic" (TG < 75%ile for age) and "combined hyperlipidemia" (TG > 75%ile for age)
  3. Those w/medical conditions that might alter lipids, e.g. DM & nephrotic sd., and those taking lipid-altering meds, inc. thiazides & beta-blockers, were excluded
  4. Diets designed to contain 30% (#1), 26% (#2), 22% (#3), or 18% (#4) of calories from fat (combined hyperlipidemia pts only randomized to first 3 b/c of small #'s); dropouts didn't vary according to diet assignment
  5. Complaince at 1y was inversely related to degree of prescribed fat restriction
  6. Significant reductions from baseline in both tot. chol. and LDL occurred in all diet groups; sig. more in #2 group c/w #1 group for hypercholesterolemic subjects (10.2% reduction vs. 3.3% reduction in tot. chol.; 5.3% reduction vs. 13.4% reduction in LDL); no sig. diff. between #2 and #3 or #4 groups
  7. HDL levels in hypercholesterolemic subjects were unchanged in #1 and #2 groups and slightly but sig. decreased (by 3-4%) in #3 and #4 groups
  8. TG levels in hypercholesterolemic subjects were unchanged in #1 and #2 groups but increased sig. in #3 and #4 groups (22% and 39%, respectively)
  9. In combined hyperlipidemic subjects, sig. reductions from baseline in tot. chol. and LDL in all diet groups but no sig. diff between the diff. groups; no sig. change in HDL from baseline in any of the diet groups
  1. 46 dyslipidemic adults (mean tot. chol. 257 mg/dL; mean LDL 172 mg/dL) without known CV disease randomized to one of three regimens x 1mo: a) low saturated fat diet; b) low-saturated-fat diet plus lovastatin (20 mg/day); c) special low-saturated-fat diet that was high in plant sterols, soy protein, almonds, and viscous fibers (e.g., oats, barley, eggplant). All diets were vegetarian. LDL decreased by 8% in the control group, by 31% in the statin group, and by 29% in the special-diet group; CRP declines were 10%, 33%, and 28%, respectively (JAMA 290:502, 2003--JW)

VI. Medications for Dyslipidemias--Generally have to continue any meds permanently; chol. rises to pretreatment level when meds are d/c'd (Med. Lett.); see above for NCEP guidelines on when to start meds; recheck lipoprotein analysis 6-8 wks after starting meds and again after another 6wks, using average to determine response

  1. Bile acid sequestrants ("resins")
  1. Lower LDL by 15-30%, raise HDL by 3-5%, raise TG's by 10-50% (though generally not when initial TG levels are normal)
  2. Can cause constipation, bloating, worsening of hemorrhoids; coadministration of psyllium may help with this.
  3. Can interfere with binding of other meds (dig, coumadin, thyroxine, statins, thiazides, beta-blockers), so take other meds > 1h before or > 4h after resins
  4. No monitoring needed; no contraindications; long-term use appears to be safe (not systemically absorbed), though one study showed a nonsig. increase in colorectal tumors and oral/pharyngeal cancers in pts on cholestyramine c/w placebo (Arch. Int. Med 152:1399, 1992)
  5. Can be combined w/HMG-CoA reductase inhibitors (see below)
  6. Cost $40-100/mo in 1996
  7. Doses
  1. Colestipol (Colestid) 5-20g/d (start w/5mg BID)
  2. Cholestyramine (Questran) 4-16g/d (start w/4mg BID)
  3. Colesevelam HCl (Welchol) 1.5-3.75g/d--Unlike others, doesn't interfere w/intestinal absorption of vitamins A, D, E, or K (Med. Lett. 42:103, 2000)
  1. Nicotinic Acid (aka Niacin)-not "nicotinamide" which is different!
  1. Lowers LDL by 5-25%, raises HDL by 15-35%, lower TG's by 20-40%; changes are dose-dependent
  2. Contraindications--can exacerbate all of these
    1. Chronic liver disease (absolute contraindication; the rest are relative)
    2. Gout
    3. DM (relative; ass'd with only a 0.4% increase in HbA1c in a randomized trial in 468 pts with DM and dyslipidemia; 284:1263, 2000--JW)
    4. Cholelithiasis
    5. Peptic ulcer disease
  3. Side effects--reduced with pretreatment with ASA 325mg 30min before dose (no added effect with 650mg; J. Gen. Int. Med 12:591, 1997--AFP)
    1. Hepatitis (reversible), esp. in older sustained-release form
    2. Cutaneous flushing
    3. Nausea & abd. discomfort
    4. Pruritis, urticaria, and hyperpigmentation
    5. Blurred vision
  4. Can be ass'd with hyperuricemia
  5. Can potentiate action of antihypertensives
  6. Monitoring: glucose, uric acid, LFT's at baseline; transaminases Q3mo x 1y and "periodically thereafter" (NCEP report)
  7. Can be used in combination w/statins (but watch out for myopathy), fibric acid analogues, or resins
  8. Dose 1.5-3 g/d, (with immediate release, can start 250mg po QD after meal, can pretreat with ASA to reduce flushing; increase to BID, TID, then increase doses one at a time from 250 to 500)
  1. HMG CoA Reductase inhibitors ("statins")
  1. Lower LDL by 18-55%; raise HDL by 5-15%; lower TGs by 10-30%
  2. Mechanisms of action
    1. Inhibition of HMG CoA reductase, a synthetic enzyme for cholesterol; in addition, may inhibit coagulation cascade and reduce inflammatory markers (JACC 33:1286, 1999--JW)
    2. Inhibition of inflammatory mediators, e.g. lowering of CRP levels--Unclear to what degree this is responsible for reduction in MI incidence
      1. In a re-analysis of data from the AFCAPS/TexCAPS trial, coronary event reduction was found to be significant in pts with high CRP and low LDL but not in pts with low CRP and low LDL (NEJM 344:1959, 2001--JW)
      2. In a study of 3,745 pts with acute coronary syndrome randomized to atorvastatin 80mg/d vs. pravastatin 40mg/d, both LDL and CRP reductions were sig. and independently associated with reductions in cardiovascular events ("PROVE-IT" Trial; NEJM 352:20, 2005--JW)
  1. Most effective if given in the evening
  2. Use in combination with fiber supplements may augment efficacy
    1. In a study in 68 pts with dyslipidemia, all receiving simvastatin 10mg/d, randomized to 15g pysllium (Metamucil)/d vs. placebo x 8wks, the psyllium recipients had sig. greater decreases in LDL (63mg/dL vs. 55mg/dL) (Arch. Int. Med. 165:1161, 2005--JW)
  3. Reduce tot. chol and LDL more than combined HRT in postmenopausal women (Premarin 1.25 + Provera 5mg/d; NEJM 337:595, 1997-JW)
  4. May reduce risk of Macular Degeneration and Cataracts (click links for details)
  5. May reduce risk of Breast Cancer in women
    1. In analysis of data from the WHI, baseline use of hydrophobic statins (simvastatin, lovastatin, and fluvastatin), over mean 6.7y f/u, after controlling for possible confounders, was associated with sig. lower incidence of invasive breast Ca (RR 0.82), though for statins overall, the difference was not significant (J. Nat. Ca. Inst. 98:700, 2006--JW).
    2. In a meta-analysis of 26 randomized studies with at least 1y f/u, there was no sig. diff. in incidence of Ca or death from Ca; including subgroup analysis of hydrophilic vs. lipophilic statins (JAMA 295:74, 2006--JW)
  6. Side effects
    1. Nausea, fatigue, headache, rash, abdominal cramping, and alterations in bowel function
    2. Hepatotoxicity
      1. Elevated transaminases are common (Must monitor LFT's every 6-8 wks for 6-12 mos then 3-4x/yr)
      2. In a study comparing 342 pts with elevated AST or ALT at onset of tx with statins with 1,437 pts with normal baseline transaminases tx'd with statins, and 2,245 with high baseline transaminases not tx'd with statins, mild-to-moderate transaminase increases (< 10-fold above baseline) occurred sig. more often during follow-up among statin recipients with high baseline levels than among statin recipients with normal baseline levels, but the frequency of mild-to-moderate transaminase increases was not higher among statin recipients with high baseline levels than among nonstatin-treated patients with high baseline levels.  Note-No pts had alcohol abuse, Hep B, or Hep C (Gastroent. 126:1287, 2004--JW)
      3. In a retrospective study in a cohort of 25,334 adults who had used a statin, 1.4% had ALT elevations to 3-10x upper limit of normal while on the statin. Among pts with ALT elevations to > 10x normal and no other known cause to explain the ALT elevation (e.g. viral hepatitis), 10 were re-challenged with a statin, the majority did not have recurrent ALT elevation (Am. J. Med. 118:618, 2005--JW)
    3. Myopathy (muscle aches w/CK > 3 x normal; occurs in 0.1%)
      1. Counsel all patients to report severe muscle pains/wekaness or brown urine
      2. Concurrent use of mibefradil, erythromycin or -azole antifungals may increase risk of myopathy
      3. Severe rhabdomyolysis (very rare) occurs more commonly when statins are combined w/ fibric acid analogues, cyclosporine, and "perhaps nicotinic acid" (NCEP report)
      4. Case reports exist of statin-associated myopathy with myalgias and abnormal results on muscle biopsy but normal serum CPK levels (Ann. int. Med. 137:581, 2002--JW)
    4. Peripheral Neuropathy--OR 14.2 in one case-control study which found that greatest risk ass'd with > 2y of statin exposure (Neurol. 58:1333, 2002--JW)
    5. May increase bone density and decrease risk of fx in elderly pts--See under Osteoporosis
    6. May reduce incidence of Diabetes Mellitus
    7. See section on Dementia for data regarding effect of statins
  1. Drug interactions:
    1. May have potential to increase protime in pts on coumadin
    2. Drugs which increase serum levels of lovastatin and simvastatin: "azole" antifungals, macrolide antibiotics, gemfibrozil, nefazodone, and grapefruit juice
  1. Contraindications: pregnancy & breastfeeding, liver disease (relative), renal failure (relative)
  2. Specific meds
  1. Fluvastatin (Lescol) 20-80 mg QD
  2. Lovastatin 10-80 mg/d
  3. Pravastatin (Pravachol) 10-40mg/d
  4. Simvastatin (Zocor) 10-80mg/d
  5. Cerivastatin (Baycol) 0.4-0.8mg/d--REMOVED FROM US MARKET 2001 b/c of rhabdomyolysis incidence
  6. Atorvastatin (Lipitor) 10-80mg QD--90% of reduction in LDL occurs in 1st 2 weeks of tx
  7. Rosuvastatin (Crestor)--May be more potent than Atorvastatin at LDL-lowering and HDL-raising; in Asian patients serum concentrations tend to be higher, though no increased tendency to toxicity in Asians has been reported as of 2004.
  8. Pitavastatin (Livalo)
  1. Comparisons among statin drugs
    1. Atorvastatin 10mg QD produced sig. greater reductions in LDL in head-head comparisons with pravastatin 20QD, lovastatin 20QD, simvastatin 10QD, and niacin 1g TID (Med Letter 39:29, 1997)
    2. Atorvastatin 10-40mg produced sig. greater reductions in LDL and tot. chol. than simvastatin, pravastatin, lovastatin, and fluvastatin. However, no sig. diff between atorvastatin 80/d vs. lovastatin 40/d. TG reductions were greater with atorvastatin 40/d vs. same dose of other meds. No sig. diff. in HDL elevation except that simvastatin 40/d ass'd with sig. greater effect than atorvastatin 40/d. Randomized study of 534 pts over 8wks ("CURVES" Study, Am. J. Cardiol. 81:582, 1998--AFP)
    3. 318 pts with atherosclerosis and LDL > 130mg/dl randomized to atorvastatin, fluvastatin, lovastatin, or simvastatin with dose adjusted to response Q12wks. At 1y, % reaching target levels (< 105mg/dl) were 83% for atorvastatin, 81% for lovastatin, 75% for simvastatin, and 50% for fluvastatin; only the diff. for fluvastatin was sig. (J. Am. Coll. Cardiol. 32:665, 1998--JW)
    4. Simvastatin 80mg/d ass'd with sig. greater HDL increase c/w atorvastatin 40mg/d in a 12wk randomized trial (9.1% vs. 6.8%); summary doesn't mention # of pts (Am. J. Cardiol. .86:221, 2000--AFP)
  1. Fibric acid analogs
  1. Lower LDL by 5-20% (though may raise LDL in pts with high TG!); raise HDL by 10-20%; lower TG's by 20-50%
  2. Mechanism: increase lipoprotein lipase activity and thus clearance of TG's
  3. Side f/x: Constipation, dyspepsia, abd. pain, appendicitis, gallstone formation, myopathy, rhabdomyolysis, anemia, abnormal LFT's
  4. Drug interactions: Can potentiate action of warfarin and oral hypoglycemics; Mixing with HMG CoA reductase inhibitors may cause rhabdomyolysis &/or interfere with absorption of the latter
  5. Must monitor LFT's, CK, CBC Q6-8wks for 6-12mos, then 3-4x/y
  6. Contraindications: liver, GB, or renal disease
  7. Doses
  1. Gemfibrozil 600mg BID (shown to reduce risk of fatal and nonfatal MI's, but total mortality nonsig. increased in a 3.5y f/u study-NCEP report)
  2. Fenofibrate (Tricor, Reliant) 67-201mg PO QD
    1. May reduce LDL more than gemfibrozil (Med. Letter)
    2. Ass'd with hepatic and pancreatic Ca in high doses in rodents
    3. Doesn't interfere w/catabolism of statins and may thus have lower risk for clinical myopathy in pts on statins (Circ 110:227, 2004)
  3. Bezafibrate (not available in US as of 2004)
  4. Clofibrate (ASSOCIATED WITH INCREASED INCIDENCE OF DEATH FROM MALIGNANCY AND GI DISEASE-Lancet 340:1405, 1992-Med. Lett.)
  1. Probucol
  1. Lowers LDL 5-15%; lowers HDL 20-30%; us. no change in TG
  2. Also has some anti-oxidant properties
  3. Can cause diarrhea, abdom. pain, n/v, flatulence; can increase QT interval
  4. Need to check EKG before starting & periodically during therapy
  5. Dose: 500mg BID w/meals
  6. "At present there is no clearly defined role for the use of probucol" (NCEP II Report)
  1. Cholesterol absorption inhibitors
    1. Ezetimibe (Zetia) 10mg QD
      1. Reduces intestinal absorption of dietary & biliary cholesterol
      2. Lowered LDL by 17% and TG by 6% and increased HDL by 1.3% in one study (Am. J. Cardiol. 90:1092, 2002--Med. Lett. 45:17, 2003)
      3. Maximum response usually achieved within 2wks
      4. May cause arthralgias and, if used in conjunction with a statin, increased transaminase levels
      5. Use along with a Simvastatin resulted in sig. greater LDL reduction and HDL elevation (J. Am. Coll. Cardiol. 40:2125, 2002--JW)
  1. Hormone replacement Therapy for postmenopausal women
    1. Reduces LDL and increases HDL
    2. Effect on CHD risk is unclear
    3. "Favorable effects of statin therapy in women in clinical trials make a cholesterol-lowering drug preferable to hormone replacement therapy for CHD risk reduction" (NCEP)
  1. Cholesterol-lowering margarines
    1. Contain plant sterols--similar in chemical structure to cholesterol but different side-chain configuration; decrease intestinal absorption of both dietary and biliary cholesterol, decreasing LDL levels
    2. Benecol--contains hydrogenated sterols derived from pine tree wood pulp, mainly sitostanol
    3. Take Control--contains unsaturated sterols, e.g. from soybean oil, mainly sitosterol
    4. Sitostanol 2g or 3g added to a fixed daily dose of margarine was associated with sig. decrease in average LDL and no sig. change in HDL or triglycerides; no change in placebo group (NEJM 333:1308, 1995--Med. Lett.); appears to have an additive effect when used in combination with an HMG CoA-reductase inhibitor (Med. Lett. 41:56, 1999)
    5. Sitosterol 0.4-1.6g added to a fixed daily dose of margarine was associated with sig. decreases in LDL (6.7-9.9%) with no sig. change in HDL or TG levels (Eur. J. Clin. Nutr. 53:319, 1999--Med. Lett.)
    6. One randomized comparison of sitostanol and plant sterol esters (mostly sitosterol) 3g/d of each c/w a control margarine found no diff. between sitostanol and the plant sterol esters in reduction of LDL c/w control (Eur. J. Clin. Nutr. 52:334, 1998--Med. Letter).
    7. No data on impact on CHD risk or other clinical outcomes as of 1999
    8. No long-term safety data available as of 1999; however, high serum concentrations of plant sterols have been ass'd with premature CHD (Metabolism 40:842, 1991--Med. Lett.)
  2. Cholesteryl ester transfer protein (CETP) inhibitors
    1. CETP is a plasma glycoprotein that transfers cholesterol esters from HDL particles to apolipoprotein B-containing lipoproteins
    2. Torcetrapib, a CEPT inhibitor, has been shown to raise HDL levels

VII. Treatments other than diet, exercise, and medications:

  1. Stress management: results equivocal
  2. Garlic (click link for details)
  3. Tea: In a randomized trial of 240 adults with mild-mod hypercholesterolemia randomized to a  theaflavin-enriched green tea extract 375mg PO QD vs. placebo over 12wks, the tea-extract recipients had sig. lower total cholesterol and LDL levels c/w baseline (-11% and -16% respectively) and no sig. change in HDL or TG; placebo recipients had no sig. change c/w baseline (Arch. Int. Med. 163:1448, 2003--abst)
  4. Surgery: ileal bypass surgery, portocaval shunt
  5. Plasmapheresis and plasma exchange
  6. Liver transplantation
  7. Red yeast rice
    1. Contains monacolin K, an inhibitor of HMG-CoA
    2. In a study in 62 pts who had developed myalgias on statins resolving with discontinuation, randomized to red yeast rice 1.8g vs. placebo QD, at 24wks, mean LDL levels dropped by sig. greater amount in the active treatment group (35 mg/dL vs. 15 mg/dL); no sig. diff. in changes in serum CPK levels between the groups (Ann. Int. Med. 150:830, 2009-JW)