- Email: [email protected]
A pilot study in the efficacy and safety of gemfibrozil in a pediatric population
Journal of Clinical Lipidology (2008) 2, 106 –111
A pilot study in the efficacy and safety of gemfibrozil in a pediatric population Courtney M. Smalley, AB,* Stanley J. Goldberg, MD Department of Pediatrics, University of Arizona College of Medicine, 1501 North Campbell Avenue, PO Box 245073, Tucson, AZ 85724-5073, USA KEYWORDS: Children; Cholesterol-lowering drugs; Gemfibrozil; Lipoproteins; Metabolic syndrome; Prevention
BACKGROUND: Gemfibrozil reduces plasma triglycerides and raises high-density lipoprotein cholesterol (HDL-C) in adults and also reduces the incidence of cardiovascular endpoints in adults. Its efficacy in improving lipid abnormalities has not been evaluated in children. OBJECTIVE: Our purpose was to investigate whether gemfibrozil would lower triglycerides and raise HDL-C with minimal adverse effects in a pediatric population with metabolic syndrome. METHODS: We conducted a retrospective study of 47 pediatric patients with metabolic syndrome who started gemfibrozil treatment, 1200 mg/day because of failure or lack of interest in therapeutic lifestyle changes. Eligibility required patients to be younger than 21 years of age, and have pretreatment and on-treatment fasting lipid profiles. Data recorded included age at start of treatment, blood pressure, body mass index, waist circumference, percent body fat, total plasma cholesterol, HDL, low-density lipoprotein, triglycerides, alanine aminotransferase, and aspartate aminotransferase. Treatment duration was elapsed time between starting gemfibrozil and the last clinic visit. RESULTS: Average age of the study cohort was 14 years and mean duration on medication was 249 days. Those patients who had pretreatment and on-treatment plasma lipid data (33 of 47) were included in an analysis for efficacy. All 47 patients were monitored for safety. Mean triglycerides decreased by 57%: 426 (standard error of mean ⫽ 33.6) to 184 mg/dL (standard error of mean ⫽ 19) (P ⬍ 0.0001). Mean HDL increased by 20%: 35 to 42 mg/dL (P ⬍ 0.001). Body composition changes were insignificant, indicating that the lipid changes can be attributed to gemfibrozil. Two of forty-seven patients reported muscle pain from the drug, one of whom was considered to have had a possible adverse effect from the medication as indicated by muscle pain. CONCLUSION: Gemfibrozil significantly lowers triglycerides and raises HDL with reasonable safety in a pediatric population with metabolic syndrome. © 2008 National Lipid Association. All rights reserved.
Statins,1– 4 niacin,5–7 and fibric acids,8 –12 have been proven in adult populations to reduce risk for coronary heart disease,13 and cholesterol absorption inhibitors,14 –16 have been shown to reduce low-density lipoprotein (LDL) in adult populations. Pediatric populations with dyslipidemia * Corresponding author. E-mail address: [email protected] Submitted January 13, 2008. Accepted for publication February 13, 2008.
present different problems and issues than adult populations because the time to an event is usually decades away. Nonetheless, arterial damage secondary to cardiac risk factors does occur in children and teenagers.17 Although some lipid-lowering medications, primarily statins, have been studied in children and teenagers with familial hyperlipidemia,18,19 very little attention has been focused on pharmaceutical treatment of pediatric patients with substantially elevated triglycerides or low high-density lipoprotein (HDL).
1933-2874/$ -see front matter © 2008 National Lipid Association. All rights reserved. doi:10.1016/j.jacl.2008.02.003
Smalley and Goldberg
Safety of gemfibrozil in a pediatric population
A threefold increase in obese children has been documented in the United States during the past 30 years, and many of these children have elevated fasting and postprandial triglycerides, decreased HDL, and increases in total serum cholesterol and non-HDL cholesterol (HDL-C).20,21 Elevated triglyceride levels and low HDL are two of the five criteria for metabolic syndrome.22 Patients with increased triglycerides also form smaller and denser LDL and HDL than those with normal triglycerides.23,24 Clearly, therapeutic lifestyle change (TLC) is the best treatment for these patients, but some children and teenagers fail TLC or lack interest in beginning a program of TLC. Medications used to treat increased triglycerides and decreased HDL-C levels include fibric acids, niacin, and statins. Statins have limited capability to decrease substantially elevated triglycerides and to substantially increase HDL-C, and niacin can be difficult to use in a pediatric population, due to flushing.4 However, an early gemfibrozil trial, the Helsinki Heart Study, showed in an adult population that this fibric acid substantially decreased triglycerides (43%) and increased HDL-C (10%) with minimal side effects.8 This type of change in triglycerides and HDL-C was confirmed in the Veteran Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) trial, in which triglycerides decreased by 31% and HDL-C increased by 6% at 1 year.10 It has also been proven that fibric acids, which are peroxisome proliferative activated receptor-␣ agonists, can inhibit vascular wall inflammation and reduce cardiovascular events.25 Although these adult studies and their results are of interest, only two small studies have been completed in children. A pediatric study of seven patients examined the efficacy and safety of gemfibrozil for lowering triglycerides.26 A slightly larger group of 14 patients with familial hypercholesterolemia were evaluated on a different fibric acid, bezafibrate. This study did find benefit, reporting a 23% decrease in triglycerides and a slight increase in HDL-C.27 The safety and low cost as well as the growing problem of hypertriglyceridemia in children make fibrates worthy of evaluation in the pediatric population. Adverse effects of gemfibrozil as monotherapy in the large adult trials were uncommon.8 –11 The major reported adverse effects in these studies were abdominal pain or discomfort, but myalgia and, less commonly, myositis or rarely myolysis, constitute other safety issues. Gemfibrozil is usually found on tier 1 of managed-care formularies, so low total cost and lower copays are required of patients. The hypothesis of the present study was that gemfibrozil will lower triglycerides and raise HDL-C in a pediatric population with hypertriglyceridemia and insulin resistance syndrome with minimal side effects.
Methods The cohort in this study acquired in a retrospective fashion from all patients seen in the lipid clinic over a
107
period of 5 years that were placed on gemfibrozil as treatment for hypertriglyceridemia. Inclusion in the study required (1) referral to our lipid clinic between August 2001 and June 2006; (2) age of younger than 21 years at the start of treatment; (3) failure or disinterest in a TLC program; (4) fasting triglyceride of at least 250 mg/dL; and (5) treatment with gemfibrozil. All consecutive patients meeting these criteria were included. Those patients who were treated with combination therapy including statins, niacin, bile acid sequestrants, or other fibric acids were then excluded. The dose of gemfibrozil was 600 mg twice daily except in one young child who was prescribed 300 mg twice daily. All treated patients were also advised of recommended lifestyle changes at each visit.24 Although this was a retrospective study, criteria for starting gemfibrozil remained consistent for the study duration. The protocol and informed consent document were approved by the Institutional Review Board at the University of Arizona. Data collected during pretreatment and on-treatment included age in years, height (cm), weight (kg), and body mass index measurements (calculated as weight [kg] divided by height [m2]). Blood pressure was measured in the right arm with the patient sitting. Waist circumference was measured as the abdominal circumference at the crest of the ileum. Body fat was measured by calipers according to the method of Durnin and Womersley.28 Percent body fat from caliper measurements was determined from tables by age and gender. Total cholesterol, HDL, LDL, and triglycerides were recorded in all patients. LDL was computed from the Friedewald equation if the triglyceride level was ⬍400 mg/dL.29 Alanine aminotransferase and aspartate aminotransferase were reported only in patients with pretreatment and on-treatment values. Duration of treatment was recorded as elapsed time between the start of gemfibrozil pretreatment to the last clinic visit date. Other medications taken in addition to gemfibrozil were recorded. Each patient was also evaluated for metabolic syndrome by the pediatric guidelines set forth by Third National Health and Nutrition Examination Survey, which requires that the patient meet three or more criteria.21 Fasting glucose was not obtained pretreatment in all patients (particularly early in the study), so only four of five metabolic syndrome criteria were evaluated. All patients were checked for hypothyroidism and diabetes, but not necessarily at visit 1 because laboratory results were used from referring physician at visit 1. No patients in the inclusion group had hypothyroidism or diabetes. Proteinuria was only checked if serum albumin was low. Blood urea nitrogen and creatinine were checked initially and all were within normal limits. Data were evaluated by a paired t-test using each patient as their own control. LDL measurements for the paired t-test included only patients whose pretreatment triglyceride value was ⬍400 mg/dL.
108 Table 1
Journal of Clinical Lipidology, Vol 2, No 2, April 2008 Statistics for the gemfibrozil intervention group Pretreatment (value ⫾ SEM)
Triglycerides (mg/dL) HDL (mg/dL) Total cholesterol (mg/dL) LDL (mg/dL) ALT AST BMI % Body fat Ab circ (inches) Systolic BP (mmHg) Diastolic BP (mmHg)
426 35 207 100 55.2 37.6 31.2 33.7 39.7 117 69
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
33.3 1.3 8.6 5.1 9.2 4.9 0.8 1.0 0.9 1.7 1.4
On-treatment (value ⫾ SEM) 184 42 178 106 30.5 26.6 31.0 32.9 40.6 116 70
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
18 1.8 4.6 4.9 3.9 2.0 0.9 1.1 1.1 1.6 1.0
% Change
P value
⫺57 20 ⫺14 6 ⫺44 ⫺29 ⫺0.6 ⫺2.4 2.3 ⫺0.9 1.4
⬍0.0001 ⬍0.0001 0.007 0.169 0.002 0.022 0.94 0.54 0.43 0.71 0.51
Ab circ, abdominal circumference; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; BP, blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SEM, standard error of mean.
Results Under the inclusion criteria, the study population consisted of 47 patients started on gemfibrozil. Thirty-three patients had two sets of lipid data, including pretreatment and on-treatment results with gemfibrozil and will be referred to as the intervention group. Within this intervention group, three patients took the medication irregularly, one patient stopped the morning dose because of a self-diagnosed adverse effect, one patient was prescribed 600 mg/day because of young age, and one patient’s dose was lowered to 600 mg/day because the triglycerides dropped to 50 mg/dL from ⬎300 mg/dL. Fourteen patients did not qualify because of lack of on-treatment data, but served to assess adverse effects of the medication. Within this disqualified group, nine patients had no adverse effects, four patients could not be contacted, as they had moved without forwarding address, and one patient self-terminated the medication because of a self-perceived adverse effect. Possible adverse reactions were recorded in two patients. One patient from the intervention group had pain in the midback region about 30 minutes after taking the medication in the morning, but never experienced pain with the evening dose and continued the evening dose. One patient from the disqualified group complained of muscle pain that disappeared after discontinuation of the medication. The latter patient was considered to have had true adverse effect from the gemfibrozil, even though he was not evaluated by a physician. Mean duration on medication in the intervention group was 249 days and mean age was 14 years. Thirty of thirtythree patients in the intervention group met three or four of the four pediatric criteria for metabolic syndrome, with increased fasting glucose (criterion 5) not included. Mean number of criteria for metabolic syndrome for the intervention population was 3.25 of 4. For the intervention group, mean triglyceride levels decreased significantly by 56.8%
from pretreatment to on-treatment: 426 mg/dL (standard error of mean [SEM] ⫽ 33.6) to 184 mg/dL (SEM ⫽ 19) (P ⬍ 0.0001) (Table 1, Fig. 1). Mean HDL increased significantly by 20% from 35 mg/dL (SEM ⫽ 1.4) to 42 mg/dL (SEM ⫽ 1.6) (P ⫽ 0.00003) (Table 1, Fig. 1). Total cholesterol levels decreased by 14% from 207 mg/dL (SEM ⫽ 9.4) to 178 mg/dL (SEM ⫽ 4.8), (P ⬍ 0.007). Mean LDL rose insignificantly from 100 mg/dL (SEM ⫽ 5.4) to 106 mg/dL (SEM ⫽ 5.3). The Friedewald equation does not permit estimation of LDL when triglycerides are ⬎400 mg/dL. Patients with initial triglycerides ⬎400 mg/dL were eliminated from the LDL paired t-test. Additionally, for the 23 of 33 patients who had pretreatment and on-treatment liver function tests, mean alanine aminotransferase, and aspartate aminotransferase liver enzymes decreased from 55 to 30 mg/dL and 38 to 27 mg/dL, respectively (P ⫽ 0.002, P ⫽ 0.02). Mean abdominal circumference increased insignificantly from 39.7 to 40.6 inches (P ⫽ 0.43), mean percent body fat remained constant at 33% (P ⫽ 0.42), and mean body mass index decreased insignificantly from 31.2 to 31.0 (P ⫽ 0.94). Systolic and diastolic blood pressure did not change. Other medications used by the intervention population had no known lipid effects, except for five patients who were also prescribed fish oil to lower triglycerides. To separate the effects of gemfibrozil from those of fish oil, the five patients on fish oil were removed and the remainder of the intervention population was reexamined. In this new calculation, there was no difference in percent change of mean triglycerides at 57% and a slight reduction in percent change of mean HDL from 20% to 19% (P ⬍ 0.001 and P ⬍ 0.001, respectively).
Discussion The most important finding of this study was that gemfibrozil reduced mean triglycerides 56.8% and increased
Smalley and Goldberg
Safety of gemfibrozil in a pediatric population
109
Individual % Change in Triglycerides and HDL
Figure 1 Individual data for each patient showing the percent change in triglycerides (black bar) and high-density lipoprotein (HDL) (gray bar). Mean triglycerides pretreatment were 426 mg/dL (standard error of mean [SEM] ⫽ 33.6) and decreased on treatment to 184 mg/dL (SEM ⫽ 19) (P ⬍ 0.0001). Mean HDL increased significantly between pretreatment mean of 35 mg/dL (SEM ⫽ 1.4) and the on-treatment mean of 42 mg/dL (SEM ⫽ 1.6) (P ⫽ 0.00003).
HDL 20% in a pediatric population with metabolic syndrome. Gemfibrozil treatment was accompanied by a low level of adverse effects. This study comprises the largest gemfibrozil intervention in a pediatric population. A Turkish study enrolling 12 children with persistent nephrotic syndrome is the only prior gemfibrozil study performed in a pediatric population.26 Seven were treated with gemfibrozil and five received placebo. This study reported a 53% reduction of triglycerides at month 4, with no significant changes in HDL. No adverse effects were reported in that study.26 The major differences between that and the present study were (1) our population was larger and without proteinuria, (2) HDL increased significantly in our study, and (3) we report one patient with a possible adverse effect. In the present study, decreased triglycerides and increased HDL were independent of body composition, as demonstrated by insignificant changes in mean percent body fat, body mass index, and abdominal circumference. In adult populations, several clinical trials have demonstrated decreased mean triglycerides and an increased mean HDL resulting from gemfibrozil treatment. Data from the
Helsinki Heart Study showed a 43% decrease in triglycerides and a 10% increase in HDL levels [8], whereas VAHIT reported a 31% decrease in mean triglycerides and a 6% increase in mean HDL compared to the placebo group.10 Both trials demonstrated a significant reduction in the occurrence of major cardiac endpoints in middle-aged men with gemfibrozil treatment (Helsinki, 34%; VA-HIT, 22%). The beneficial effect occurred mainly in the subgroup, with more elevated triglycerides and low HDL-C. The Lopid Coronary Angiography Trial, which studied men whose main lipid abnormality was low HDL, demonstrated through angiographic measurements that gemfibrozil slowed the progression of coronary atherosclerosis.11 This group of children had quite elevated triglycerides, with a mean pretreatment fasting level of 426 mg/mL. Gemfibrozil produced a 57% reduction, which was impressive. However, the long-term benefit of lowering elevated triglycerides in children and adolescents remains unknown, except for prevention of pancreatitis. Values of fasting triglyceride levels ⬎500 mg/dL are considered sufficiently high to place patients at risk and should be treated to prevent
110 pancreatitis, because with illness or dietary indiscretion, values can rise to much higher levels. Patient safety is of considerable importance when using any pharmaceutical product. In this study, we could only judge short-term adverse effects. Use of gemfibrozil resulted in muscle pain reported by one patient from the disqualified group. This patient terminated the medication and indicated that the muscle pain stopped, but did not contact the physician at the time of stopping medication. One patient in the intervention group complained of back pain after the morning dose, but no pain occurred after the evening dose and he continued taking the medication in the evening only. This patient was not considered to have a true adverse reaction. The other commonly known adverse effect associated with the drug is abdominal discomfort or pain, but none of our pediatric patients reported these symptoms. Forty-one of forty-seven patients were known not have adverse events, but we had no information for four patients who could not be contacted. Long-term safety of gemfibrozil was not established by this study. This issue is important because medication started in childhood might be required for decades. Limitations of this study include (1) limited treatment population size; (2) 14 patients failed to have follow-up laboratory values; (3) 2 o f 47 patients reported a potentially adverse event, of which one patient discontinued the medication immediately upon experiencing muscle pain; (4) no placebo-treated group was included, but each patient served as his own control; (5) it remains unclear whether the criteria utilized to start treatment with gemfibrozil were optimal. Future investigations are necessary to determine whether a triglyceride ⬎250 mg/dL should be changed to a different value in a pediatric population; and lastly, (6) although the criteria for starting and following patients on gemfibrozil remained constant throughout the period of analysis, this was a retrospective study.
Conclusion The major implication of this study is that gemfibrozil significantly lowers triglycerides and raises HDL with reasonable safety in a pediatric population. However, this study did not establish criteria for initiating gemfibrozil therapy in a pediatric population.
Acknowledgments Financial support received from Medical Student Research Program, PHS grant number: Type: 2, Activity: T35, ID Serial No. Hl07479-23, Grant NIH T35 HL07979, National Institutes of Health, Bethesda, MD.
Journal of Clinical Lipidology, Vol 2, No 2, April 2008
References 1. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):7–22. 2. Scandinavian Simvastatin Survival Study Writing Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389. 3. 4S Group and the AFCAPS/TexCAPS Research Group. The metabolic syndrome and risk of major coronary events in the Scandinavian Simvastatin Survival Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Am J Cardiol. 2004;93:136 –141. 4. LaRosa JC, He J, Vuppurturi S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA. 1999; 282:2340 –2346. 5. Morgan JM, Capuzzi DM, Guyton JR. A new extended-release niacin (Niaspan): efficacy, tolerability, and safety in hypercholesterolemic patients. Am J Cardiol. 1998;82(12A):29U–34U. 6. Guyton JR, Blazing MA, Hagar J, et al. Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Niaspan-Gemfibrozil Study Group. Arch Intern Med. 2000;160:1177–1184. 7. Matthan NR, Giovanni A, Schaefer EJ, Brown BG, Lichtenstein AH. Impact of simvastatin, niacin, and/or antioxidants on cholesterol metabolism in CAD patients with low HDL. J Lipid Res. 2003;44:800 – 806. 8. Frick MH. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237–1245. 9. Multiple Risk Factor Intervention Trial. Risk factor changes and mortality results. Multiple Risk Factor Intervention Trial Research Group. JAMA. 1982;248:1465–1477. 10. Rubins HB. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341:410 – 418. 11. Frick MH. Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Circulation. 1997;96: 2137–2143. 12. Rossner S, Oro L. Fenofibrate therapy of hyperlipoproteinaemia: a dose-response study and a comparison with clofibrate. Atherosclerosis. 1981;38:273–282. 13. Bhatnagar D. Lipid-lowering drugs in the management of hyperlipidaemia. Pharmacol Ther. 1998;79:205–230. 14. Sudhop T, Lütjohann D, Kodal A, et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation. 2002;106: 1943–1948. 15. For the Ezetimibe Study Group, Dujovne CA, Ettinger MP, et al. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, in ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol. 2002;90:1092–1097. 16. For the Ezetimibe Study Group, Knopp RH, Gitter H, et al. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J. 2003;24: 729 –741. 17. McMahan CA, McGill HC, Gidding SS, et al. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) research group. PDAY risk score predicts advanced coronary artery atherosclerosis in middle-aged persons as well as youth. Atherosclerosis. 2007; 190:370 –377.
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Safety of gemfibrozil in a pediatric population
18. de Jongh S, Lilien MR, op’t Roodt J, Stroes ES, Bakker HD, Kastelein JJ. Early statin therapy restores endothelial function in children with familial hypercholesterolemia. J Am Coll Cardiol. 2002;40:2117–2121. 19. Wiegman A, Hutten BA, de Groot E, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA. 2004;292:331–337. 20. Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 19992004. JAMA. 2006;295:1549 –1555. 21. de Ferranti SD, Gauvreau K, Ludwig DS, Neufeld EJ, Newburger JW, Rifai N. Prevalence of the metabolic syndrome in American adolescents: findings from the Third National Health and Nutrition Examination Survey. Circulation. 2004;110:2494 –2497. 22. Moreno LA, Pineda I, Rodriguez G, Fleta J, Sarría A, Bueno M. Waist circumference for the screening of the metabolic syndrome in children. Acta Paediatr. 2002;91:1307–1312. 23. Stampfer MJ, Krauss RM, Ma J, Blanche PJ, Holl LG, Hennekens CH. A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. JAMA. 1996;276: 882– 888.
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24. McNamara JR, Jenner JL, Li Z, Wilson PW, Schaefer EJ. Change in LDL particle size is associated with change in plasma triglyceride concentration. Arterioscler Thromb. 1992;12:1284 –1290. 25. Tai ES, Collins D, Robins SJ, et al. The L162V polymorphism at the peroxisome proliferator activated receptor alpha locus modulates the risk of cardiovascular events associated with insulin resistance and diabetes mellitus: the Veterans Affairs HDL Intervention Trial (VAHIT). Atherosclerosis. 2006;187:153–160. 26. Buyukcelik M, Anarat A, Bayazit AK, et al. The effects of gemfibrozil on hyperlipidemia in children with persistent nephrotic syndrome. Turk J Pediatr. 2002;44:40 – 44. 27. Wheeler KA, West RJ, Lloyd JK, Barley J. Double blind trial of bezafibrate in familial hypercholesterolaemia. Arch Dis Child. 1985; 60:34 –37. 28. Durnin JVGA, Wormersley J. Body fat assessed from total body density and its estimation from skinfold thickness: measurements on 481 men and women aged 16 to 72 years. Br J Nutr. 1974;32:77–97. 29. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499 –502.
A pilot study in the efficacy and safety of gemfibrozil in a pediatric population Courtney M. Smalley, AB,* Stanley J. Goldberg, MD Department of Pediatrics, University of Arizona College of Medicine, 1501 North Campbell Avenue, PO Box 245073, Tucson, AZ 85724-5073, USA KEYWORDS: Children; Cholesterol-lowering drugs; Gemfibrozil; Lipoproteins; Metabolic syndrome; Prevention
BACKGROUND: Gemfibrozil reduces plasma triglycerides and raises high-density lipoprotein cholesterol (HDL-C) in adults and also reduces the incidence of cardiovascular endpoints in adults. Its efficacy in improving lipid abnormalities has not been evaluated in children. OBJECTIVE: Our purpose was to investigate whether gemfibrozil would lower triglycerides and raise HDL-C with minimal adverse effects in a pediatric population with metabolic syndrome. METHODS: We conducted a retrospective study of 47 pediatric patients with metabolic syndrome who started gemfibrozil treatment, 1200 mg/day because of failure or lack of interest in therapeutic lifestyle changes. Eligibility required patients to be younger than 21 years of age, and have pretreatment and on-treatment fasting lipid profiles. Data recorded included age at start of treatment, blood pressure, body mass index, waist circumference, percent body fat, total plasma cholesterol, HDL, low-density lipoprotein, triglycerides, alanine aminotransferase, and aspartate aminotransferase. Treatment duration was elapsed time between starting gemfibrozil and the last clinic visit. RESULTS: Average age of the study cohort was 14 years and mean duration on medication was 249 days. Those patients who had pretreatment and on-treatment plasma lipid data (33 of 47) were included in an analysis for efficacy. All 47 patients were monitored for safety. Mean triglycerides decreased by 57%: 426 (standard error of mean ⫽ 33.6) to 184 mg/dL (standard error of mean ⫽ 19) (P ⬍ 0.0001). Mean HDL increased by 20%: 35 to 42 mg/dL (P ⬍ 0.001). Body composition changes were insignificant, indicating that the lipid changes can be attributed to gemfibrozil. Two of forty-seven patients reported muscle pain from the drug, one of whom was considered to have had a possible adverse effect from the medication as indicated by muscle pain. CONCLUSION: Gemfibrozil significantly lowers triglycerides and raises HDL with reasonable safety in a pediatric population with metabolic syndrome. © 2008 National Lipid Association. All rights reserved.
Statins,1– 4 niacin,5–7 and fibric acids,8 –12 have been proven in adult populations to reduce risk for coronary heart disease,13 and cholesterol absorption inhibitors,14 –16 have been shown to reduce low-density lipoprotein (LDL) in adult populations. Pediatric populations with dyslipidemia * Corresponding author. E-mail address: [email protected] Submitted January 13, 2008. Accepted for publication February 13, 2008.
present different problems and issues than adult populations because the time to an event is usually decades away. Nonetheless, arterial damage secondary to cardiac risk factors does occur in children and teenagers.17 Although some lipid-lowering medications, primarily statins, have been studied in children and teenagers with familial hyperlipidemia,18,19 very little attention has been focused on pharmaceutical treatment of pediatric patients with substantially elevated triglycerides or low high-density lipoprotein (HDL).
1933-2874/$ -see front matter © 2008 National Lipid Association. All rights reserved. doi:10.1016/j.jacl.2008.02.003
Smalley and Goldberg
Safety of gemfibrozil in a pediatric population
A threefold increase in obese children has been documented in the United States during the past 30 years, and many of these children have elevated fasting and postprandial triglycerides, decreased HDL, and increases in total serum cholesterol and non-HDL cholesterol (HDL-C).20,21 Elevated triglyceride levels and low HDL are two of the five criteria for metabolic syndrome.22 Patients with increased triglycerides also form smaller and denser LDL and HDL than those with normal triglycerides.23,24 Clearly, therapeutic lifestyle change (TLC) is the best treatment for these patients, but some children and teenagers fail TLC or lack interest in beginning a program of TLC. Medications used to treat increased triglycerides and decreased HDL-C levels include fibric acids, niacin, and statins. Statins have limited capability to decrease substantially elevated triglycerides and to substantially increase HDL-C, and niacin can be difficult to use in a pediatric population, due to flushing.4 However, an early gemfibrozil trial, the Helsinki Heart Study, showed in an adult population that this fibric acid substantially decreased triglycerides (43%) and increased HDL-C (10%) with minimal side effects.8 This type of change in triglycerides and HDL-C was confirmed in the Veteran Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) trial, in which triglycerides decreased by 31% and HDL-C increased by 6% at 1 year.10 It has also been proven that fibric acids, which are peroxisome proliferative activated receptor-␣ agonists, can inhibit vascular wall inflammation and reduce cardiovascular events.25 Although these adult studies and their results are of interest, only two small studies have been completed in children. A pediatric study of seven patients examined the efficacy and safety of gemfibrozil for lowering triglycerides.26 A slightly larger group of 14 patients with familial hypercholesterolemia were evaluated on a different fibric acid, bezafibrate. This study did find benefit, reporting a 23% decrease in triglycerides and a slight increase in HDL-C.27 The safety and low cost as well as the growing problem of hypertriglyceridemia in children make fibrates worthy of evaluation in the pediatric population. Adverse effects of gemfibrozil as monotherapy in the large adult trials were uncommon.8 –11 The major reported adverse effects in these studies were abdominal pain or discomfort, but myalgia and, less commonly, myositis or rarely myolysis, constitute other safety issues. Gemfibrozil is usually found on tier 1 of managed-care formularies, so low total cost and lower copays are required of patients. The hypothesis of the present study was that gemfibrozil will lower triglycerides and raise HDL-C in a pediatric population with hypertriglyceridemia and insulin resistance syndrome with minimal side effects.
Methods The cohort in this study acquired in a retrospective fashion from all patients seen in the lipid clinic over a
107
period of 5 years that were placed on gemfibrozil as treatment for hypertriglyceridemia. Inclusion in the study required (1) referral to our lipid clinic between August 2001 and June 2006; (2) age of younger than 21 years at the start of treatment; (3) failure or disinterest in a TLC program; (4) fasting triglyceride of at least 250 mg/dL; and (5) treatment with gemfibrozil. All consecutive patients meeting these criteria were included. Those patients who were treated with combination therapy including statins, niacin, bile acid sequestrants, or other fibric acids were then excluded. The dose of gemfibrozil was 600 mg twice daily except in one young child who was prescribed 300 mg twice daily. All treated patients were also advised of recommended lifestyle changes at each visit.24 Although this was a retrospective study, criteria for starting gemfibrozil remained consistent for the study duration. The protocol and informed consent document were approved by the Institutional Review Board at the University of Arizona. Data collected during pretreatment and on-treatment included age in years, height (cm), weight (kg), and body mass index measurements (calculated as weight [kg] divided by height [m2]). Blood pressure was measured in the right arm with the patient sitting. Waist circumference was measured as the abdominal circumference at the crest of the ileum. Body fat was measured by calipers according to the method of Durnin and Womersley.28 Percent body fat from caliper measurements was determined from tables by age and gender. Total cholesterol, HDL, LDL, and triglycerides were recorded in all patients. LDL was computed from the Friedewald equation if the triglyceride level was ⬍400 mg/dL.29 Alanine aminotransferase and aspartate aminotransferase were reported only in patients with pretreatment and on-treatment values. Duration of treatment was recorded as elapsed time between the start of gemfibrozil pretreatment to the last clinic visit date. Other medications taken in addition to gemfibrozil were recorded. Each patient was also evaluated for metabolic syndrome by the pediatric guidelines set forth by Third National Health and Nutrition Examination Survey, which requires that the patient meet three or more criteria.21 Fasting glucose was not obtained pretreatment in all patients (particularly early in the study), so only four of five metabolic syndrome criteria were evaluated. All patients were checked for hypothyroidism and diabetes, but not necessarily at visit 1 because laboratory results were used from referring physician at visit 1. No patients in the inclusion group had hypothyroidism or diabetes. Proteinuria was only checked if serum albumin was low. Blood urea nitrogen and creatinine were checked initially and all were within normal limits. Data were evaluated by a paired t-test using each patient as their own control. LDL measurements for the paired t-test included only patients whose pretreatment triglyceride value was ⬍400 mg/dL.
108 Table 1
Journal of Clinical Lipidology, Vol 2, No 2, April 2008 Statistics for the gemfibrozil intervention group Pretreatment (value ⫾ SEM)
Triglycerides (mg/dL) HDL (mg/dL) Total cholesterol (mg/dL) LDL (mg/dL) ALT AST BMI % Body fat Ab circ (inches) Systolic BP (mmHg) Diastolic BP (mmHg)
426 35 207 100 55.2 37.6 31.2 33.7 39.7 117 69
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
33.3 1.3 8.6 5.1 9.2 4.9 0.8 1.0 0.9 1.7 1.4
On-treatment (value ⫾ SEM) 184 42 178 106 30.5 26.6 31.0 32.9 40.6 116 70
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
18 1.8 4.6 4.9 3.9 2.0 0.9 1.1 1.1 1.6 1.0
% Change
P value
⫺57 20 ⫺14 6 ⫺44 ⫺29 ⫺0.6 ⫺2.4 2.3 ⫺0.9 1.4
⬍0.0001 ⬍0.0001 0.007 0.169 0.002 0.022 0.94 0.54 0.43 0.71 0.51
Ab circ, abdominal circumference; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; BP, blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SEM, standard error of mean.
Results Under the inclusion criteria, the study population consisted of 47 patients started on gemfibrozil. Thirty-three patients had two sets of lipid data, including pretreatment and on-treatment results with gemfibrozil and will be referred to as the intervention group. Within this intervention group, three patients took the medication irregularly, one patient stopped the morning dose because of a self-diagnosed adverse effect, one patient was prescribed 600 mg/day because of young age, and one patient’s dose was lowered to 600 mg/day because the triglycerides dropped to 50 mg/dL from ⬎300 mg/dL. Fourteen patients did not qualify because of lack of on-treatment data, but served to assess adverse effects of the medication. Within this disqualified group, nine patients had no adverse effects, four patients could not be contacted, as they had moved without forwarding address, and one patient self-terminated the medication because of a self-perceived adverse effect. Possible adverse reactions were recorded in two patients. One patient from the intervention group had pain in the midback region about 30 minutes after taking the medication in the morning, but never experienced pain with the evening dose and continued the evening dose. One patient from the disqualified group complained of muscle pain that disappeared after discontinuation of the medication. The latter patient was considered to have had true adverse effect from the gemfibrozil, even though he was not evaluated by a physician. Mean duration on medication in the intervention group was 249 days and mean age was 14 years. Thirty of thirtythree patients in the intervention group met three or four of the four pediatric criteria for metabolic syndrome, with increased fasting glucose (criterion 5) not included. Mean number of criteria for metabolic syndrome for the intervention population was 3.25 of 4. For the intervention group, mean triglyceride levels decreased significantly by 56.8%
from pretreatment to on-treatment: 426 mg/dL (standard error of mean [SEM] ⫽ 33.6) to 184 mg/dL (SEM ⫽ 19) (P ⬍ 0.0001) (Table 1, Fig. 1). Mean HDL increased significantly by 20% from 35 mg/dL (SEM ⫽ 1.4) to 42 mg/dL (SEM ⫽ 1.6) (P ⫽ 0.00003) (Table 1, Fig. 1). Total cholesterol levels decreased by 14% from 207 mg/dL (SEM ⫽ 9.4) to 178 mg/dL (SEM ⫽ 4.8), (P ⬍ 0.007). Mean LDL rose insignificantly from 100 mg/dL (SEM ⫽ 5.4) to 106 mg/dL (SEM ⫽ 5.3). The Friedewald equation does not permit estimation of LDL when triglycerides are ⬎400 mg/dL. Patients with initial triglycerides ⬎400 mg/dL were eliminated from the LDL paired t-test. Additionally, for the 23 of 33 patients who had pretreatment and on-treatment liver function tests, mean alanine aminotransferase, and aspartate aminotransferase liver enzymes decreased from 55 to 30 mg/dL and 38 to 27 mg/dL, respectively (P ⫽ 0.002, P ⫽ 0.02). Mean abdominal circumference increased insignificantly from 39.7 to 40.6 inches (P ⫽ 0.43), mean percent body fat remained constant at 33% (P ⫽ 0.42), and mean body mass index decreased insignificantly from 31.2 to 31.0 (P ⫽ 0.94). Systolic and diastolic blood pressure did not change. Other medications used by the intervention population had no known lipid effects, except for five patients who were also prescribed fish oil to lower triglycerides. To separate the effects of gemfibrozil from those of fish oil, the five patients on fish oil were removed and the remainder of the intervention population was reexamined. In this new calculation, there was no difference in percent change of mean triglycerides at 57% and a slight reduction in percent change of mean HDL from 20% to 19% (P ⬍ 0.001 and P ⬍ 0.001, respectively).
Discussion The most important finding of this study was that gemfibrozil reduced mean triglycerides 56.8% and increased
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Safety of gemfibrozil in a pediatric population
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Individual % Change in Triglycerides and HDL
Figure 1 Individual data for each patient showing the percent change in triglycerides (black bar) and high-density lipoprotein (HDL) (gray bar). Mean triglycerides pretreatment were 426 mg/dL (standard error of mean [SEM] ⫽ 33.6) and decreased on treatment to 184 mg/dL (SEM ⫽ 19) (P ⬍ 0.0001). Mean HDL increased significantly between pretreatment mean of 35 mg/dL (SEM ⫽ 1.4) and the on-treatment mean of 42 mg/dL (SEM ⫽ 1.6) (P ⫽ 0.00003).
HDL 20% in a pediatric population with metabolic syndrome. Gemfibrozil treatment was accompanied by a low level of adverse effects. This study comprises the largest gemfibrozil intervention in a pediatric population. A Turkish study enrolling 12 children with persistent nephrotic syndrome is the only prior gemfibrozil study performed in a pediatric population.26 Seven were treated with gemfibrozil and five received placebo. This study reported a 53% reduction of triglycerides at month 4, with no significant changes in HDL. No adverse effects were reported in that study.26 The major differences between that and the present study were (1) our population was larger and without proteinuria, (2) HDL increased significantly in our study, and (3) we report one patient with a possible adverse effect. In the present study, decreased triglycerides and increased HDL were independent of body composition, as demonstrated by insignificant changes in mean percent body fat, body mass index, and abdominal circumference. In adult populations, several clinical trials have demonstrated decreased mean triglycerides and an increased mean HDL resulting from gemfibrozil treatment. Data from the
Helsinki Heart Study showed a 43% decrease in triglycerides and a 10% increase in HDL levels [8], whereas VAHIT reported a 31% decrease in mean triglycerides and a 6% increase in mean HDL compared to the placebo group.10 Both trials demonstrated a significant reduction in the occurrence of major cardiac endpoints in middle-aged men with gemfibrozil treatment (Helsinki, 34%; VA-HIT, 22%). The beneficial effect occurred mainly in the subgroup, with more elevated triglycerides and low HDL-C. The Lopid Coronary Angiography Trial, which studied men whose main lipid abnormality was low HDL, demonstrated through angiographic measurements that gemfibrozil slowed the progression of coronary atherosclerosis.11 This group of children had quite elevated triglycerides, with a mean pretreatment fasting level of 426 mg/mL. Gemfibrozil produced a 57% reduction, which was impressive. However, the long-term benefit of lowering elevated triglycerides in children and adolescents remains unknown, except for prevention of pancreatitis. Values of fasting triglyceride levels ⬎500 mg/dL are considered sufficiently high to place patients at risk and should be treated to prevent
110 pancreatitis, because with illness or dietary indiscretion, values can rise to much higher levels. Patient safety is of considerable importance when using any pharmaceutical product. In this study, we could only judge short-term adverse effects. Use of gemfibrozil resulted in muscle pain reported by one patient from the disqualified group. This patient terminated the medication and indicated that the muscle pain stopped, but did not contact the physician at the time of stopping medication. One patient in the intervention group complained of back pain after the morning dose, but no pain occurred after the evening dose and he continued taking the medication in the evening only. This patient was not considered to have a true adverse reaction. The other commonly known adverse effect associated with the drug is abdominal discomfort or pain, but none of our pediatric patients reported these symptoms. Forty-one of forty-seven patients were known not have adverse events, but we had no information for four patients who could not be contacted. Long-term safety of gemfibrozil was not established by this study. This issue is important because medication started in childhood might be required for decades. Limitations of this study include (1) limited treatment population size; (2) 14 patients failed to have follow-up laboratory values; (3) 2 o f 47 patients reported a potentially adverse event, of which one patient discontinued the medication immediately upon experiencing muscle pain; (4) no placebo-treated group was included, but each patient served as his own control; (5) it remains unclear whether the criteria utilized to start treatment with gemfibrozil were optimal. Future investigations are necessary to determine whether a triglyceride ⬎250 mg/dL should be changed to a different value in a pediatric population; and lastly, (6) although the criteria for starting and following patients on gemfibrozil remained constant throughout the period of analysis, this was a retrospective study.
Conclusion The major implication of this study is that gemfibrozil significantly lowers triglycerides and raises HDL with reasonable safety in a pediatric population. However, this study did not establish criteria for initiating gemfibrozil therapy in a pediatric population.
Acknowledgments Financial support received from Medical Student Research Program, PHS grant number: Type: 2, Activity: T35, ID Serial No. Hl07479-23, Grant NIH T35 HL07979, National Institutes of Health, Bethesda, MD.
Journal of Clinical Lipidology, Vol 2, No 2, April 2008
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