Journal of the American College of Nutrition, Vol. 17, No. 5, 458-461 (1998)
Published by the American College of Nutrition
Insulin Therapy for a Non-Diabetic Patient with Severe Hypertriglyceridemia
Muhammad A. Jabbar, MD, FACN,
Mohammed I. Zuhri-Yafi, MD and
Jennifer Larrea, RN
Department of Pediatrics, Hurley Medical Center-Michigan State University, Flint, Michigan
Address reprint requests to: Muhammad A. Jabbar, MD, FACN, Department of Pediatrics, Hurley Medical Center, 1 Hurley Plaza, Flint, MI 48502
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ABSTRACT
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Objective: To compare the short and long term effectiveness of fish oil, insulin, and gemfibrozil in a non-diabetic patient with severe hypertriglyceridemia.
Method: An adolescent male with hypertriglyceridemia (triglyceride level 4575 mg/dl) and abdominal pain was treated with the goal of immediate reduction and maintenance of triglyceride (TG) level below 1000 mg/dl. Fish oil, insulin and gemfibrozil were administered sequentially, in separate time blocks, for a duration of 3, 6, and 6 months, respectively.
Results: Fish oil took several weeks to lower TG level, and patient compliance during 3 months of therapy was inadequate. Insulin was effective in immediately lowering the TG level, but was unable to maintain the level below 1000 mg/dl. Gemfibrozil was ineffective in achieving the immediate reduction of TG level; however, it was adequate in maintaining the desired level in the long-term and patient compliance was better than with the fish oil.
Conclusion: In patients with risk of pancreatitis due to severe hypertriglyceridemia, immediate reduction of the triglyceride level is achievable by using a single dose of regular insulin (0.1 unit/kg, subcutaneous) while long-term maintenance therapy can be provided by gemfibrozil.
Key words: hypertriglyceridemia, fish oil, insulin, gemfibrozil
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INTRODUCTION
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In patients with severe hypertriglyceridemia (fasting triglyceride (TG) level greater than 1000 mg/dl), the risks of acute pancreatitis and premature atherosclerosis independently warrant treatment [1–5]. Hence, there is a need for urgency in treatment along with the need for long-term maintenance of TG within an acceptable range in these patients. However, treatment options available for severe hypertriglyceridemia in children and adolescents are limited. Dietary intervention alone is unlikely to achieve the therapeutic goal. Patients treated with fish oil, which lowers very-low-density lipoprotein (VLDL) production, usually become non-compliant due to halitosis and objectionable odor of the fish oil [6]. Gemfibrozil has been useful in adults; however, the long-term effectiveness and side effects in children remain unknown [7].
Insulin has not been used for nondiabetic patients with hypertriglyceridemia. However, insulin is a potent triglyceride-lowering agent as it enhances lipoprotein lipase (LPL) activity in the muscle and the adipose tissue; clinically, insulin therapy corrects hypertriglyceridemia in insulin-dependent diabetic patients.
In this study of an adolescent patient with hypertriglyceridemia, we compared the immediate and long-term effectiveness of fish oil, insulin and gemfibrozil therapy.
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CASE HISTORY
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A 13-year-old white male was referred for evaluation of hypertriglyceridemia. He was otherwise healthy except for the episodes of mild abdominal pain. Physical examination showed weight in the 90th percentile and height in the 75th percentile; body mass index was 22.8. His BP was normal, thyroid was not enlarged and fundus examination revealed no abnormality. There were no eruptive xanthomas nor acanthosis nigricans in the skin. Abdominal examination revealed mild epigastric tenderness, but no organomegaly. Pubertal development was stage II. Laboratory studies showed marked elevation of triglyceride level (4575 mg/dl) with lipemic serum. Cholesterol was 460 mg/dl (Table 1, pretreatment column). Serum amylase and lipase levels were not elevated; C-peptide, insulin, and blood glucose levels were normal. Plasma apolipoprotein CII level was within normal limits, ruling out inherited apoC II deficiency. LPL activity in postheparin plasma was not studied; however, impaired LPL activity (reflected by elevated TG and presence of milky plasma) as well as hepatic overproduction of VLDL (reflected by moderate elevation of cholesterol) appeared to be concomitantly responsible for the hypertriglyceridemia in this patient [8,9].
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TREATMENT PROTOCOL
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Immediate lowering and maintenance of the TG level below 1000 mg/dl was the goal of the treatment protocol. Patient received fish oil, insulin and gemfibrozil in sequential order for 3, 6 and 6 months, respectively. Patient was on a low-fat diet throughout the study period; the carbohydrate composition of the diet was not modified during the study.
Fish Oil
Following the repeat laboratory test, the patient was started on fish oil, which contained eicosapentaneoic acid and docosahexanoic acid in a daily dose of 720 mg and 480 mg, respectively. This treatment was given for 3 months during which the TG level was obtained monthly. Because of poor patient compliance to daily fish oil intake and inadequate lowering of TG level, fish oil protocol was discontinued and insulin protocol was started.
Insulin
Appropriate parental consent was obtained prior to the use of this protocol. The insulin protocol had two phases. In the first phase, a single dose injection of regular insulin (0.1 unit/kg, sub Q) was administered; TG and blood glucose was monitored at baseline, 2 hours and 4 hours after. The patient was monitored in the outpatient clinic for possible hypoglycemia. One week after this regular insulin treatment the second phase was started during which regular insulin (0.1 unit/kg, sub Q) was administered every 2 weeks for 6 months; after each insulin injection, patient remained under parental observation at home for 2 hours for possible hypoglycemia. During this phase, TG level was monitored monthly before the insulin injection.
Gemfibrozil
To provide maintenance therapy without requiring parenteral injection, gemfibrozil was started orally with a dose of 600 mg daily. The dose was later increased to 1200 mg daily and was continued for 6 months; TG level was monitored monthly.
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RESULTS
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Response to Fish Oil
TG level decreased remarkably from pretreatment level of 4575 mg/dl to 708 mg/dl in 2 months. However, the TG level rose to 2127 mg/dl in 3 months (Table 1) and the patient admitted not taking the fish oil due to its unpleasant odor. Serum cholesterol levels showed changes similar to the TG level with initial decline followed by an elevation.
Response to Insulin
Four hours after the insulin injection, triglyceride level decreased significantly (Table 2), thus causing immediate reduction of the risk of acute pancreatitis. Serum cholesterol and HDL showed no significant change. The blood glucose profile showed significant decrease, although the patient remained asymptomatic.
During the second phase of insulin treatment, serum TG level showed a significant decline followed by a rise (lowest level of 565 mg/dl to the highest of 3134 mg/dl) suggesting that the triglyceride-lowering effect of insulin is not sustainable in the long-term. In contrast to TG levels, the serum total cholesterol showed less variation (lowest of 170 to the highest of 282 mg/dl). There was no hypoglycemia during this 6 months of intermittent insulin therapy. Liver function tests and coagulation profile remained normal during this stage.
Response to Gemfibrozil
Serum triglyceride level decreased from 3134 mg/dl to 680 mg/dl after 3 months of treatment, reflecting relatively slow response compared to the insulin therapy; however, the TG levels remained below 1000 mg/dl and showed less fluctuation during the next 3 months. The total cholesterol level showed no change while the HDL level increased significantly.
During the fish oil therapy HDL level ranged between 22 to 37 mg/dl. The immediate effect of insulin on LDL was insignificant (Table 2); during long-term insulin therapy, HDL ranged from 15 to 30 mg/dl. In contrast, the gemfibrozil therapy caused significant elevation of HDL level (Table 3). Abdominal pain subsided in several days and there was no recurrence of the pain or tenderness during the fish oil, insulin or gemfibrozil therapy. Puberty progressed satisfactorily from stage II to stage III over the 12-month period; height increased 6.5 cm during the same interval. The body mass index increased from 22.8 to 25.8 showing a disproportionate increase in weight.
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DISCUSSION
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Data from this patient shows that short acting insulin immediately lowers the TG level in patients with massive hypertriglyceridemia and thus reduces the risk of acute pancreatitis; gemfibrozil is effective in maintaining the target TG level of less than 1000 mg/dl with consequent reduction in the risk of atherosclerosis.
The immediate effect (24 to 48 hours after initiation of therapy) of fish oil or gemfibrozil on TG was not studied for comparison with that of insulin; measurable suppression of hepatic VLDL synthesis was not expected by that time. The effect of gemfibrozil and fish oil on TG level appears to be comparable; however, compliance for long-term use of fish oil is a major concern as noted in our patient. Methods of improving the compliance by use of enteric-coated tablets [10] or modifying the diet to increase fish consumption is of consideration. In contrast to gemfibrozil or fish oil, intermittent insulin therapy failed in maintaining TG level below 1000 mg/dl. It is possible that insulin-induced enhancement of LPL activity is a transient phenomenon that wears off after several weeks of treatment. Furthermore, the need for injection, potential hypoglycemic effect and variation of the TG level during the long-term therapy are factors against long-term insulin therapy. Additional concerns for long-term use of insulin include the adverse effect of hyperinsulinemia on VLDL, LDL, and HDL levels [11].
Indications for treatment of a nondiabetic patient with extreme hypertriglyceridemia have not been clearly defined. Young children and adolescents may be asymptomatic. In symptomatic patients with abdominal pain, the diagnosis of acute pancreatitis may be delayed as the serum amylase and lipase level may not be elevated; this is due to extreme elevation of TG that interferes with the enzyme assay [12]. In addition, it is necessary to exclude other differential diagnoses such as acid peptic disease and gastroesophageal reflux which can further delay the diagnosis of acute pancreatitis. Our patient, who initially presented with abdominal pain but lacked the elevation of pancreatic enzymes, could possibly have the diagnosis of acute pancreatitis that responded to treatment with fish oil. Subsequently, lack of recurrence of abdominal pain or tenderness could be attributed to timely reduction of the TG level. Thus, the intervention of severe hypertriglyceridemia with or without clinical or enzymatic evidence of pancreatitis is indicated.
During treatment with TG-lowering agents, the desired TG level remain to be determined. The level of 2000 mg/dl has been reported to be adequate to avoid pancreatitis; however, the risk of peripheral atherosclerotic disease remain, according to a recent report [3]. In our patient, the desired TG level was set at or below 1000 mg/dl on the basis of a report on patients with hyperlipoproteinemia and pancreatitis [1]. Although this goal was achievable and adequate in preventing pancreatic disease, the risk of premature atherosclerosis remains to be assessed during follow-up. Low HDL level remained an additional risk factor for atherosclerotic disease. Although exercise and weight control is currently recommended, the pharmacologic therapy remains an option for treatment of low HDL level. In the AAP guidelines [13], caution is recommended for those patients receiving gemfibrozil due to the deleterious effect on physical growth. Although the effectiveness and complication of long-term use in children and adolescent need to be assessed from larger study, it appears that gemfibrozil is not only effective in reducing triglyceride but also the effect on physical growth is reassuring.
In patients with severe hypertriglyceridemia, immediate lowering—or "induction"—of the TG level to below 1000 mg/dl is achievable with regular insulin while long-term maintenance therapy can be provided with gemfibrozil.
Received January 1, 1998.
Accepted May 1, 1998.
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ABSTRACT
INTRODUCTION
