TRIGLYCERIDES, LOW HDL CHOLESTEROL, CORONARY HEART DISEASE, STROKE, AND PANCREATITIS: DIAGNOSIS AND THERAPY.

CJ Glueck MD, James E. Lang MD, Marzieh Salehi MD, Pawel Szczykutowicz MD, Cholesterol Center, Jewish Hospital (01/25/05)

If you have questions about diagnosis and therapy of high triglycerides, low HDL cholesterol, or other lipid and coagulation disorders, contact us by email at glueckch@healthall.com. We can also be reached by fax (513-585-7950), or in the afternoons between 2 and 4 pm by phone (513-585-7800).

Our mailing address is Cholestrol Center, Jewish Hospital, Alliance Business Center, 3200 Burnet Ave, Cincinnati Ohio, 45229.

Phone: 513-585-7800 Fax: 513-585-7950
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web: http://www.jewishhospitalcincinnati.com/glueck/cholesterol.html

1. Background, Population Studies:

A. HDL Cholesterol:

There is considerable evidence that low levels of high-density cholesterol (HDL-C) are a contributory factor in the development of atherosclerosis and coronary heart disease (CHD). Low HDL-C is one of the most common lipid disorders in patients with premature coronary artery disease. In the Framingham study, for example, low HDL-C values were associated with increases in risk for CHD of approximately 70% in men and of more than 100% in women. Epidemiological studies such as the Prospective Cardiovascular Munster (PROCAM) study and the Framingham Offspring Study demonstrated that low HDL-C is an independent predictor of risk after controlling for the presence of other CHD factors. More recently, the Atherosclerosis Risk in Communities (ARIC) study has shown that HDL-C is a significant independent predictor of CHD risk. In this study, 12,339 middle-aged individuals without CHD were followed for CHD events for 10 years, with a total of 725 events being observed during follow-up. HDL-C, LDL-C and lipoprotein (a) were independent predictors in both sexes, and the triglyceride level was an independent predictor in women. The median values of HDL-C in the lowest risk (highest concentration) were 62 mg/dl in men and 81 mg/dl in women.

There are a variety of genetic causes of low HDL-C as described below. In addition, patients with hypertriglyceridemia usually have lower HDL cholesterol. Progesterone, b Beta blockers, poorly controlled diabetes, uremia, zinc, anabolic steroids, and male sex hormones (testosterone, androstenedione) lower HDL cholesterol levels.

B. Triglycerides:

Triglycerides are predominantly carried in the blood stream by very low density lipoproteins (VLDL). There is, however, considerable heterogeneity of triglyceride-rich particles. Triglyceride-rich particles derived from dietary fat, chylomicrons, are not themselves associated with CHD, but, when very high (>1,000 mg/dl) can cause pancreatitis. However, these chylomicron particles are gradually reduced in size by lipoprotein lipase to intermediate density lipoproteins (IDL) which are atherogenic. Similarly, VLDL from the liver is reduced in size by lipoprotein lipase, producing atherogenic IDL. VLDL predicts progression of coronary artery disease and CHD events. Because of the close relationship of high triglycerides with low HDL cholesterol, triglycerides have not uniformly been shown to be independent risk factors for CHD and ischemic stroke. However, in a meta-analysis of 14 population-based studies, triglycerides were an independent risk factor for CHD independent of HDL cholesterol (Arteriosclerosis 1991;11:2-14). In a meta-analysis of 17 population-based studies, elevated triglycerides were associated with a 30% increase in CHD risk in men and a 75% increase in women ( J Cardiovasc Risk 1996;3:213-219). Triglycerides are a major, independent risk factor for CHD in women (ages 50-69 years) in 14 year followup in the Framingham Heart Study ( Am J Cardiol 1992;70:3-9).

From studies listed below, hypertriglyceridemia has been increasingly recognized as a risk factor for CHD.

1. Montreal Heart Study (Circulation 1993;88:2762-2770): VLDL cholesterol, but not LDL cholesterol predicted progression of coronary artery disease and CHD events.
2. Boston Heart Study (Circulation 1997;96:2520-2525): CHD risk factors in 340 cases with heart attack and 340 matched community controls. Significant association of elevated triglycerides with CHD, which remained significant after adjustment for HDL cholesterol. Fasting triglycerides were a significant independent risk factor, particularly when HDL cholesterol levels were also considered.
3. Honolulu Heart Study (Circulation 1995;93:1430-1436): CHD risk was elevated in subjects with low HDL cholesterol and high triglyceride levels when total cholesterol was borderline high or high, independent of other CHD risk factors.
4. Prospective Munster Study (Am J Cardiol 1996:77:1179-1184): Of >4000 subjects studied prospectively, 5% of the subjects with triglyceride >200 mg/dl and LDL cholesterol/HDL cholesterol ratio >5.0 had 25% of CHD events.
5. Copenhagen Male Study (Circulation 1998;97:1029-1036): In 8 year followup of middle aged and elderly men, there was a gradient of CHD risk which accompanied increasing triglycerides, even when adjusting for HDL cholesterol.

2. Targets for optimal triglycerides and HDL cholesterol levels

According to the American Heart Association, triglyceride levels of less than 150 mg/dL are normal; levels from 150-199 are borderline high; levels from 200 mg/dL to 499 mg/dL are high; levels of 500 mg/dL or above are very high. In general, we do not treat triglyceride between 150 and 200mg/dL with medications.

In the average man, HDL cholesterol levels range from 40 to 50 mg/dL. In the average woman, they range from 50 to 60 mg/dL. The National Cholesterol Education Program Adult Treatment Panel III (ATPIII) guidelines for lipid-lowing therapy established an HDL-C below 40 mg/dl as a major positive risk factor ( increasing the categorical definition of low HDL-C from 35 mg/dl to the current level) and established HDL-C levels of 60 mg/dl or more as a negative risk factor, i.e., protective.

3. Causes of High Triglycerides:

1. Genetic. About 1/500 people have an inherited tendency towards high plasma triglycerides. These inherited hypertriglyceridemias are autosomal dominant traits, so that when high triglycerides are diagnosed and acquired causes are ruled out (as below), then all first degree family members (parents, siblings, children) should be checked. Triglycerides are predominantly transported by very low density lipoproteins (VLDL) and by larger, predominantly diet-derived particles, chylomicrons. The majority of people with inherited high triglycerides have triglycerides carried predominantly by VLDL, and usually have triglycerides <750 mg/dl. When people with inherited high triglycerides have both high VLDL and chylomicron triglycerides, then the triglyceride levels are often >1,000.
   
   Lipoprotein lipase (LPL) deficiency is a rare autosomal recessive disorder characterized by markedly elevated plasma triglycerides. Normally, triglycerides in chylomicrons are hydrolyzed by LPL, and the genetic absence of LPL results in marked hyperchylomicronemia. LPL deficiency is associated with recurrent episodes of acute pancreatitis, which can be life-threatening and can also lead to chronic pancreatic insufficiency.

2. Acquired. The six most common causes of acquired high triglycerides are excessive alcohol intake, exogenous estrogens or estrogen agonists, poorly controlled diabetes, beta blocker drugs, corticosteroids, and uremia. Very often when triglycerides are >1,000 mg/dl, these very high levels reflect an acquired cause for high triglycerides superimposed on a genetic cause. Less common causes of acquired high triglycerides include kidney failure, nephrotic syndrome, albuminuria, hypothyroidism, many liver diseases, hemochromatosis, hyperparathyroidism, and glycogen storage disease.

4. Interventions to lower triglyceride levels:

1. Triglyceride >1,000 mg/dl: Dangerous, high risk of pancreatitis, venous and arterial blood clots, acute heart attack and stroke. Requires immediate intervention with fat-free diet (<5% of calories as fat), alcohol-free diet, medications (Lopid 1.5 g/day or Fenofibrate 145 mg/day), omega-3 fatty acids (8-12 g/day), and control of secondary factors (alcohol, exogenous estrogens, estrogen agonists, corticosteroids, etc).

2. Triglyceride 750-1,000 mg/dl. Dangerous, requires immediate intervention with low fat diet (<20% of calories as fat), alcohol-free diet, medications (Lopid 1.2 g/day or Fenofibrate 145 mg/day), omega-3 fatty acids (4-8 g/day), and control of secondary factors (alcohol, exogenous estrogens, estrogen agonists, corticosteroids, etc).

3. Triglyceride 500-750 mg/dl. Requires intervention with low fat diet <25% of calories), alcohol-free diet, medications (Lopid 1.2 g/day or Fenofibrate 145 mg/day), omega-3 fatty acids (4-6 g/day), and control of secondary factors (alcohol, exogenous estrogens, estrogen agonists, corticosteroids, etc).

4. Triglyceride 250-500 mg/dl. Requires intervention with diet and, if values do not fall below 250 mg/dl on diet alone, medications (Lopid 1.2 g/day or Fenofibrate 145 mg/day or, particularly if LDL cholesterol is >130 mg/dl, Lipitor 10-40 mg/day, or Zocor 10-40 mg/day), omega-3 fatty acids (2-4 g/day), and control of secondary factors (alcohol, exogenous estrogens, estrogen agonists, corticosteroids, etc).
   
   General Comment: Weight loss, avoidance of alcohol, and tight control of diabetes (fasting blood sugar <130, HgAIC <7.1) are very important in control of high plasma triglycerides, in addition to other therapies noted above.

Are estrogens or SERMS (Evista, Tamoxifen) contraindicated in some women?

Severe hypertriglyceridemia and pancreatitis with estrogen induced hypertriglyceridemia when exogenous estrogens or pregnancy are superimposed on pre-existing familial hypertriglyceridemia.

In our experience, by far the most common cause of acquired high triglycerides in women is Hormone Replacement Therapy (HRT), Evista, Tamoxifen, or estrogen-containing oral contraceptives. HRT and oral contraceptives ARE CONTRAINDICATED in women with familial hypertriglyceridemia, and should be discontinued in any woman with triglycerides > 250 mg/day.

I: Yes! Most women with triglycerides >300 mg/dl should never take exogenous estrogens or SERMS.

1. When fasting plasma triglycerides are >500 mg/dl (absolutely contraindicated).
2. When fasting plasma triglycerides are >250 mg/dl (relatively contraindicated).

WHY?

Exogenous estrogens or SERMS, when superimposed on familial (inherited) hypertriglyceridemia (high fasting plasma triglycerides) increase the production of triglycerides from the liver and decrease the clearance of triglycerides from the blood. Subsequently, triglycerides often rise above 1000 mg/dl leading to pancreatitis, heart attack, and stroke.

 

II: Yes! All women heterozgyous for the mutant Factor V Leiden gene or for the prothrombin gene should never take exogenous estrogens or SERMS.

WHY?

Without exogenous estrogens, the risk of venous thrombosis in women heterozgyous for V Leiden or the Prothrombin gene mutations is 8-fold that of the geneal population. When estrogens, and (probably) SERMS are given to V Leiden or Prothromin gene heterozygotes, the risk of venous thrombosis rises to 40 times that of the general population and the risk of arterial thrombosis rises to twice that of the general population.

References:

Triglycerides and estrogens

1. Goldenberg NM, Wang P, Glueck CJ. An observational study of severe hypertriglyceridemia, hypertriglyceridemic acute pancreatitis, and failure of triglyceride-lowering therapy when estrogens are given to women with and without familial hypertriglyceridemia. Clin Chim Acta. 2003 Jun;332(1-2):11-9.
2. Glueck CJ, Lang J, Tracy T, Oakes N, Speirs J. Severe hypertriglyceridemia and pancreatitis when estrogen replacement therapy is given to hypertriglyceridemic women. J Lab Clin Med 1994;123:59-64.
3. Stone NJ. Estrogen-induced pancreatitis: a caveat worth remembering. J Lab Clin Med 1994;123:18-19
4. Glueck CJ, Streicher P, Wang P, Sprecher D, Falko JM. Treatment of severe familial hypertriglyceridemia during pregnancy with very low fat diet and omega-3 fatty acids. Nutrition 1996; 12: 203-205.
5. Glueck CJ, Lang JE. Lipoprotein Metabolism in the Elderly. The Merck Manual of Geriatrics, Abrams WB, Beers MH, Berkow RB, eds. Merck and Co, Rahway, NJ, 1995, pp 1023-1052.
6. Glueck CJ, Christopher C, Mishkel MA, et al: Pancreatitis, familial hypertriglyceridemia and pregnancy. Am J Obstet Gynecol 1980;136:755-761.
7. Glueck CJ, Scheel D, Fishback J, et al: Estrogen-induced pancreatitis in patients with previously covert familial type V hyperlipoproteinemia. Metabolism 1972;21:657-666.
8. Zorrilla E, Hulse M, Hernandez A, Gershberg H. Severe endogenous hypertriglyceridemia during treatment with estrogen and oral contraceptives. J Clin Endocrinol Metab 1968;28:1793-1796.
9. Davidoff F, Tishler S, Rosoff C. Marked hyperlipemia and pancreatitis associated with oral contraceptive therapy. NEJM 1973;289:552-555.
10. Hoogerbrugge N. Hypertriglyceridemia following oestrogen use. Ned Tijdschr Geneeskd 1997;141:1225-1227 (Dutch)
11. Stone NJ. Secondary causes of hyperlipidemia. Med Clin North Am 1994;78:117-141.
12. Parker WA. Estrogen-induced pancreatitis. Clin Pharm 1983;2:75-79.
13. Editorial. Pancreatitis from oral contraceptives. Br Med J 1973;4:688-689
14. Brunzell JD et al. The interaction of familial and secondary causes of hypertriglyceridemia: role in pancreatitis. Trans Assoc Am Physicians 1973;86:245-254.

Estrogen increases risk of venous thrombosis and osteonecrosis in women heterozygous for the mutant Factor V Leiden gene.

1. Gomes MP, Deitcher SR. Risk of venous thromboembolic disease associated with hormonal contraceptives and hormone replacement therapy: a clinical review. Arch Intern Med. 2004 Oct 11;164(18):1965-76.
2. Smith NL, Heckbert SR, Lemaitre RN, Reiner AP, Lumley T, Weiss NS, Larson EB, Rosendaal FR, Psaty BM. Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis. JAMA. 2004 Oct 6;292(13):1581-7.
3. De Stefano V, Rossi E, Leone G. Inherited thrombophilia, pregnancy, and oral contraceptive use: clinical implications. Semin Vasc Med. 2003 Feb;3(1):47-60.
4. Glueck CJ et al. Heterozygosity for the Leiden mutation of the factor V gene, a common pathoetiology for osteonecrosis of the jaw. J Lab Clin Med 1997;130:540-543.
5. Glueck CJ, McMahon RE, Bouquot JE, Triplett D. Exogenous estrogen therapy may exacerbate thrombophilia, impair bone healing, and contribute to development of chronic facial pain. Cranio, The Journal of Craniomandibular Practice 1998;16:143-153.
6. Levesque H et al. Estrogen therapy and venous thromboembolic disease. Reve Med Interne 1997;18 (suppl 6): 620S-625S.
7. Weitz IC et al. Tamoxifen-associated venous thrombosis and activated protein C resistance due to factor V Leiden. Cancer 1997;79:2024-2027.
8. Hennekens CM et al. Sensitivity to activated protein C; influence of oral contraceptives and sex. Thromb Haemost 1996;73:402-404.
9. Caine YG, Bauer KA, Barzegar S, et al. Coagulation activation following estrogen administration to postmenopausal women. Thrombosis and Haemostasis 1992;68:392-395.
10. Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Annals of Int Med 1997;127:895-903.

5. Causes of low HDL cholesterol:

1. Genetic. About 1/500 people have an inherited tendency towards isolated low HDL cholesterol, usually with normal total cholesterol, triglycerides, and LDL cholesterol. The inherited low HDL is mostly transmitted as an autosomal dominant trait, so that when low HDL cholesterol is diagnosed and acquired causes are ruled out (as below), then all first degree family members (parents, siblings, children) should be checked.
   
   Tangier disease is a rare genetic disorder associated with markedly reduced HDL cholesterol levels (less than 5 mg/dl), accumulation of cholesterol in macrophages and related cells, neuropathy, and premature atherosclerosis. It is caused by mutations in the ATP-binding cassette protein 1 (ABC1), a cellular protein that promotes nascent HDL and lipid-poor apoA-I.
   
   ApoA-I is the major protein in HDL. A genetic deficiency of apoA-I results in markedly reduced HDL and seems, at least in some kindreds, to increase the risk for coronary artery disease.
   
2. Acquired. Patients with hypertriglyceridemia usually have lower HDL cholesterol and a higher risk of heart attack and stroke. Beta blockers, poorly controlled diabetes, uremia, anabolic steroids, corticosteroids, male sex hormones (testosterone), excessive zinc intake, and severe physical inactivity lower HDL cholesterol levels.

6. Interventions to raise HDL cholesterol levels

1. Cessation of smoking, weight loss, tight control of diabetes (fasting blood glucose <130 mg/dl, HbA1C <7.1%), increased aerobic exercise (usually requires 5 sessions/week, 30 minutes/session). If possible, cessation of beta blockers is central in attempts to raise HDL-C

2. Gemfibrozil 1.2 g/day, or bezafibrate 0.4g/ day, or micronized Fenofibrate 145 mg/day, or NiaSpan 1.5 g/day. However, a greater increase in HDL-C was seen with bezafibrate (18%) than with gemfibrozil (6%) in the BIP trial.

3. If HDL cholesterol levels cannot be elevated, then vigorous lowering of LDL cholesterol with statin drugs (as recently shown in the Afcaps/Texcaps study), by improving the ratio of total cholesterol/HDL cholesterol, will reduce CHD events. Rosuvastatin is a new statin that has been found to raise HDL-C significantly more than other statins.

7. Controlled clinical trials

1. Helsinki Heart Study (Circulation 1992;85:37-45):
   Primary prevention (patients had no previous CHD). Five year randomized, double-blind, placebo-controlled study in 4081 middle aged men. Total CHD endpoints fell by 34% in the Gemfibrozil treatment group compared to placebo (p<.05). In patients with HDL cholesterol < 35 mg/dl, there was a 62% reduction in CHD. Gemfibrozil (Lopid, 1.2 g/day) reduced CHD in patients with triglyceride >200 mg/dl (2.3 mmol/L) and a LDL cholesterol/HDL cholesterol ratio >5. The change in HDL cholesterol alone was a significant, independent variable for reduction of CHD events (p<.01). Gemfibrozil reduced triglyerides 62%, and increased HDL cholesterol 25%. Gemfibrozil's effect on CHD events was most pronounced in those with low initial HDL cholesterol (<42 mg/dl).

2. Bezafibrate Coronary Atherosclerosis Intervention Trial (Lancet 1996;347:849-853):
   Secondary prevention in 92 young (<45 years old) survivors of myocardial infarction. Randomized to Bezafibrate or placebo, followed for 5 years. In treated group, there was a 26% reduction in VLDL triglyceride, a 9% increase in HDLC; LDL cholesterol was not changed. Bezafibrate slowed progression of coronary artery stenosis (blockage) and reduced CHD events by 72%.

3. Lipid Coronary Angiography Trial (LOCAT) (Circulation 1997;96:2137-2143):
   Studies done in 372 patients, randomized to Gemfibrozil or placebo, with 2 angiograms separated by 32 months. Patients with LDL cholesterol >174 mg/dl, triglycerides > 354, or HDL cholesterol >43 mg/dl were excluded, so that the study was done in a low HDL, mildly hypertriglyceridemic population. Coronary artery disease progression was reduced in native vessels and in grafts. Compared to placebo, VLDL triglycerides fell 40% and HDL cholesterol rose 15%. The treatment benefit in LOCAT was related to reduced VLDL, alterations in size and characteristics of LDL, and increased HDL.

4. VA-Hit Study. N Engl J Med 1999;341:410-418:

   1. Double blind trial, 2,531 men with CHD, HDL cholesterol < 40 mg/dl, LDL cholesterol < 140 mg/dl, and triglycerides < 300 mg/dl.

   2. Treatment: Lopid 1.2 g/day vs placebo; duration 5 years.

   3. Outcomes: HDL cholesterol rose 6% in Lopid group, total cholesterol and triglyceride fell 4% and 31%. Significant differences persisted over the 5 year period.

   4. Outcomes: Risk of nonfatal MI or CHD death was 22% lowr in men on Lopid than placebo. When stroke was added, risk reduction was 24%.

   5. No increase in rate of cancer events.

5. Diabetes Atherosclerosis Intervention Study (DAIS) Lancet 2001;357:905-910

1. 3 yr, angiographic, double-blind, placebo controlled
2. Treatment: Fenofibrate (Tricor) 200 mg/day vs placebo
3. Patients: 418 subjects with Type II diabetes
4. Outcomes: On Fenofibrate, 40% reduction in arterial atherosclerosis and 23% fewer deaths and cardiac event.
   
   General: Fibrates lower triglyceride-rich lipoproteins, and increase HDL cholesterol, while reducing levels of dense LDL. There is usually an increase in lipolysis of triglyceride-rich lipoproteins and reduction of hepatic triglyceride production. Third generation fibrates like Fenofibrate also may moderately lower fibrinogen. It is not clear whether Fibrates increase homocysteine levels in serum. Homocysteine should be checked before beginning Fibrate therapy, and 3 months later.