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Case Study: Hypertriglyceridemia in a Woman With Insulin Resistance

	Presentation

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B.L. is a 24-year-old woman with a history of dermatomyositis diagnosed at age 3. She received treatment with cyclophosphamide (Cytoxan), metho-trexate, and prednisone until she was 11 years old with successful remission.

When she was 16 years old, she presented with lipoatrophic facial features, hirsutism, amenorrhea, and acanthosis nigricans in the axillary and groin areas. She was lean and muscular but not virilized. An oral glucose tolerance test showed fasting glucose of 159 mg/dl and insulin of 538 µu/ml (normal <10 µu/ml) and 2-h glucose of 300 mg/dl, which is diagnostic of diabetes and suggestive of insulin resistance. Her insulin receptor antibody titers were checked twice and were negative on both occasions. TSH was normal. Testosterone was 1.6 mg/ml (normal 0.10–0.90 mg/ml). Serum cholesterol was 315 mg/dl, and triglycerides were 2,748 mg/dl.

Her mother and maternal grandmother had type 2 diabetes, and her father had dyslipidemia.

B.L. was diagnosed as having type A syndrome of insulin resistance and treated with leuprolide (Lupron), 7.5 mg intramuscularly each month, and advised to follow a low-fat (20%) diet. A year later, her testosterone levels had normalized to 0.17 ng/ml with suppressed gonadotropin levels. Triglyceride and total cholesterol levels had fallen to 2,117 mg/dl and 216 mg/dl, respectively. Her HbA_1c concentration was 6.5%.

Given concern for future osteopenia with the use of a GnRH antagonist and the patient’s desire to promote female secondary sexual characteristics, she was started on conjugated equine estrogen (Premarin) at 0.3 mg every other day. The importance of following the low-fat diet was reinforced.

Over the next several months, triglyceride levels continued to be elevated, while HDL cholesterol was 20 mg/dl. She was started on gemfibrozil (Lopid) 600 mg twice a day, with lowering of triglyceride levels from 1,800 mg/dl to 772 mg/dl. A year later, leuprolide and conjugated equine estrogen were discontinued, and the patient was started on norgestrel/ethinyl estradiol (LoOvral 1/201/20).

Six months later, B.L. presented to the emergency room with sudden onset of right upper quadrant abdominal pain, nausea, and vomiting. Laboratory studies revealed a triglyceride level of 4,638 mg/dl, total cholesterol of 734 mg/dl, white blood count of 20,000, and amylase of 130 mg/dl. She was diagnosed as having pancreatitis and treated accordingly.

	Questions

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1. What are potential contributing factors to B.L.’s hypertriglyceridemia?
   
2. What treatment strategies could be employed to lower her triglycerides?
   

	Commentary

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Hypertriglyceridemia is the most common lipid abnormality in type 2 diabetes. Insulin resistance and insulin deficiency result in decreased lipoprotein lipase (LPL) activity, leading to slower breakdown of very-low-density lipoproteins (VLDLs) and chylomicrons. Increased hepatic production of triglycerides also occurs.

Most patients with well-controlled type 2 diabetes have normal triglyceride levels. Persistent hypertriglyceridemia or severe elevations in triglycerides usually indicate an underlying familial hyperlipoproteinemic disorder or the presence of secondary causes for the high triglyceride levels.

At diagnosis, B.L. was not taking any drugs known to cause hypertriglyceridemia, such as alcohol, thiazides, ß-blockers, bile acid sequestrants, oral estrogens, retinoids, or steroids. It is likely that she had a familial disorder.

Lifestyle changes are usually implemented as the initial management for elevated triglyceride levels. These changes include adopting a diet that limits saturated fats, losing weight, getting regular physical activity, ceasing cigarette smoking, and avoiding alcohol or consuming it only in moderation. B.L. was able to control her triglyceride levels with a low-fat diet and gemfibrozil while on a very low dose of the conjugated equine estrogen. Because she was taking oral contraceptives when she developed pancreatitis, it is possible that the oral contraceptives contributed to the severe elevations in her triglyceride level. Oral estrogens raise triglycerides by increasing VLDL secretion rates, and her norgestrel/ethinyl estradiol has a higher estrogen potency than the conjugated equine estrogen she was taking. Oral contraceptives were discontinued.

Both hyperglycemia and insulin resistance contribute to hypertriglyceridemia and low HDL cholesterol levels. Efforts should be made to correct hyperglycemia. Studies of pharmacological agents that directly improve insulin resistance, such as the thiazolidinediones, have focused on their lipid-altering potential. These drugs are known to exert a hypotriglyceridemic action via peroxisome proliferator-activated receptor (PPAR)-mediated induction of LPL expression in adipose tissue. Troglitazone (Rezulin) and pioglitazone (Actos) have been shown to decrease triglyceride levels, and all of the drugs in this class appear to increase HDL levels. An increase in LDL levels has been reported, but changes in the size of the LDL cholesterol particles may make the cholesterol less susceptible to oxidation.

B.L. was initially treated with troglitazone for her insulin resistance syndrome. Before treatment, her HbA_1c was 5.8%, total cholesterol was 249 mg/dl, triglycerides were 1,563 mg/dl, and HDL was 17 mg/dl. With troglitazone, B.L.’s insulin levels fell, but her triglyceride levels remained high. When troglitazone was withdrawn from the market, she was switched to pioglitazone.

For triglycerides that remain 400 mg/dl (and LDL <130 mg/dl), fibrates such as gemfibrozil and fenofibrate (Tricor) are the drugs of first choice. These medications activate PPARs, which are nuclear transcription factors that upregulate LPL transcription and downregulate the LPL inhibitor apolipoprotein C3. Gemfibrozil 600 mg twice daily was prescribed, lowering the triglyceride levels substantially although not to <400 mg/dl.

Because their mechanisms of action are different, fibrates and nicotinic acid may be used in combination and should be considered in patients with severe hypertriglyceridemia or high risk for pancreatitis. Niacin works primarily by inhibiting adipose tissue lipases, thus reducing the substrate for hepatic lipoprotein synthesis. While relatively contraindicated in patients who have diabetes, in whom it may worsen hyperglycemia, there are few data to support such a recommendation. Niacin may worsen hyperglycemia by increasing insulin resistance, but it may still be used with caution to treat hyperlipidemia in diabetic patients. Results of the Arterial Disease Multiple Intervention Trial (ADMIT) showed unchanged HbA_1c levels among participants with diabetes treated with niacin for up to 48 weeks, although glucose levels were modestly increased in participants with and without diabetes.

When B.L.’s triglyceride levels were fluctuating between 682 and 5,764 mg/dl, niacin was added to gemfibrozil and troglitazone. She continued to have HbA_1c levels 7%. Her triglyceride levels decreased to 317 mg/dl. Unfortunately, B.L. developed hives, and niacin was discontinued.

Combining statins (HMG-CoA reductase inhibitors) with fibrates or nicotinic acid is usually safe and effective but requires judicious use and careful monitoring because severe myopathy and rhabdomyolysis have been reported in 1% of patients on such combination therapy. Statins act by preventing cholesterol synthesis and lower triglycerides by inhibiting the assembly and secretion of VLDL. B.L.’s history of dermatomyositis was a concern, but after discontinuing niacin, her triglyceride levels increased to >1,000 mg/dl. She was then started on atorvastatin (Lipitor), 20 mg daily.

For resistant hypertriglyceridemia inadequately controlled by diet and drugs, fish oil supplements (-3 fatty acids) may also play a role. Interest in -3 fatty acids started in the 1970s with studies on Greenland Eskimos whose diets were high in fat, cholesterol, and -3 fatty acids but who had low rates of coronary artery disease. The -3 fatty acids in fish oil reduce hepatic synthesis of triglyceride and VLDL and shorten the turnover of VLDL in plasma. The triglyceride response is dose-dependent with a decrease of 30% at a daily dose of 3 g and up to 50% at 9 g. No change in total or HDL cholesterol has been reported, but LDL may increase by 7%.

B.L.’s triglycerides were in the 1,000s while on gemfibrozil and atorvastatin. She was then started on fish oil supplements (500 mg eicosapentaenoic acid [EPA] and 300 mg docosahexaenoic acid [DHA]) with meals. Her triglyceride level decreased from 1,000 to 700 mg/dl.

Most recently, while on pioglitazone, 30 mg daily, gemfibrozil, 600 mg twice daily, atorvastatin, 40 mg daily, and EPA/DHA three times a day with meals, her total cholesterol was 174 mg/dl, triglyceride levels were 329 mg/dl, HDL was 25 mg/dl, and LDL was 83 mg/dl.

	Clinical Pearls

Top Presentation Questions Commentary Clinical Pearls Suggested Readings

 

• Persistent hypertriglyceridemia in well-controlled diabetes warrants review of modifiable risk factors. Abrupt and massive elevation in triglycerides to >2,000 mg/dl can precipitate pancreatitis.
  
• Diet and improved glycemic control can often ameliorate moderate hypertriglyceridemia.
  
• Fibrates and nicotinic acid are potent triglyceride-lowering medications that may be needed to effectively manage severe hypertriglyceridemia. Used with caution, they can help in the management of hypertriglyceridemia in diabetic patients.
  
• Fish oil is an option to lower triglyceride levels in resistant hypertriglyceridemia inadequately controlled by diet and medications.
  

	Suggested Readings

Top Presentation Questions Commentary Clinical Pearls Suggested Readings

 
American Diabetes Association: Management of dyslipidemia in adults with diabetes (Position Statement). Diabetes Care 24 (Suppl. 1):S58–S61, 2001

Ballantyne CM, Grundy SM, Oberman A, Kreisberg RA, Havel RJ, Frost PH, Haffner SA: Hyperlipidemia: diagnostic and therapeutic perspectives. J Clin Endocrinol Metab 85:2089–2112, 2000[Full Text]

Connor WE, DeFrancesco CA, Connor SL: -3 fatty acids from fish oil: effects on plasma lipoproteins and hypertriglyceridemic patients. Ann NY Acad Sci 683:16–34, 1993[Medline]

Elam MB, Hunninghake DB, Davis KB, Garg R, Johnson C, Egan D, Kostis JB, Sheps DS, Brinton EA. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: a randomized trial. Arterial Disease Multiple Intervention Trial. JAMA 284:1263–1270, 2000[Medline]

Harris WS: Nonpharmacologic treatment of hypertriglyceridemia: focus on fish oils. Clin Cardiol 22 (Suppl. II):II-40–II-43, 1999

Miller M: Current perspectives on the management of hypertriglyceridemia. Am Heart J 140:232–240, 2000[Medline]

	Footnotes

 
Liza L. Ilag, MD, is a lecturer and research fellow in the Division of Endocrinology and Metabolism at the University of Michigan in Ann Arbor.

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