Free Triglyceride Lowering Study

Free Triglyceride Lowering Study
NO PHYSICIAN OR LABORATORY CHARGES FOR INITIAL VISIT, FOR TREATMENT WITH
LOVAZA 4, 8, AND 12 GRAMS (4 MONTHLY FOLLOW-­UP VISITS), NO CHARGE FOR LOVAZA
TO: Patients with very high triglycerides, greater than 500 mg/dl, despite maximal triglyceride lowering therapy, or greater than
1000 mg/dl without triglyceride lowering therapy.
FROM: Charles J. Glueck MD, Medical Director, Cholesterol Center;; Naila Goldenberg MD, Associate Director, Medical
Center
DATE: 6/2/09
COMMENT: High trigycerides are an independent risk factor for heart attack and stroke, and when 1000 mg/dl or higher, can
cause pancreatitis. Conventional therapy for high triglycerides involves optimal diet, no alcohol, no estrogens, control of
diabetes (when present), fibric acids (Tricor, Trilipix, Fenofibrate), and long chain polyunsaturated omega-­3 fatty acids
(Lovaza). The usual dose of Lovaza is 4 grams per day, but we have data that 8 or 12 grams/day of Lovaza are safe and
effective if conventional triglyceride lowering therapy does not reduce triglycerides to less than 500 mg/dl. We have a newly
available treatment protocol (attached), where we first treat with optimal triglyceride lowering therapy and Lovaza (4
grams/day). If that does not suffice to lower triglycerides to less than 500 mg/dl, then for the next month we would increase the
Lovaza to 8 grams per day (holding other medications stable), and if that did not lower triglycerides to less than 500 mg/dl,
then for the next month we would increase the Lovaza to 12 grams per day. This therapeutic regimen should be safe and
effective.
Inclusion and Exclusion Criteria
Please review the inclusion and exclusion criteria summarized below. If you are interested in participating in this free
program, and meet the inclusion and exclusion criteria (or think you meet the critieria), contact Laura Knoop (513-­585-­7942,
email [email protected]), or Luann Sieve (513-­585-­7951,[email protected]). They will review your current
triglycerides and therapy, and set you up for your first appointment. You would be evaluated at the Cholesterol and
Metabolism Center of the Jewish Hospital, 3200 Burnet Avenue, Cincinnati OH, 45229 (phone 513-­924-­8250, fax 513-­924-­
8273). When you participate in the program you will be seen at each visit by either Dr Charles J. Glueck MD, Dr Naila
Goldenberg, Dr Naseer Khan, or one of their physician associates.
Inclusion Criteria:
1. Primary hypertriglyceridemia with fasting TG levels >1000 mg/dl, and persistence of TG levels > 500 mg/dl despite
maximal TG lowering therapy for 1 month, including Lovaza 4 g/day, fibric acids, and, where indicated, Glucophage for
treatment of hyperinsulinemia.
2. Patients with mild to moderately impaired renal function should be initiated on TRICOR 48 mg and patients with
severe renal impairment should not be given TRICOR.
3. Absence of exclusionary criteria (see below).
Exclusion Criteria
1. Patients with known allergy to fish
2. Hypertriglyceridemia secondary to alcoholism, exogenous estrogens, nephrotic syndrome, hemochromatosis,
glycogen storage disease, uncontrolled diabetes, exogenous corticosteroids, Cushing’s syndrome, uremia).
3. Bleeding gastric or duodenal ulcers, active inflammatory bowel disease.
4. Pregnancy
5. Dementia
6. Patients with bleeding diatheses
7. Patients who are taking concomitant anticoagulants and other medications that affect bleeding time (e.g., warfarin,
aspirin)
8. Patients with abnormal transaminases or any history of liver disease
9. Patients with conditions affecting the skin (e.g. malignancy, vasculitides) that may confound the skin exam.
The Jewish Hosptial Research Council
1. TITLE: Dose related decrease in Triglycerides in patients with Hypertriglyceridemia and treated with Lovaza. FDA IND
105,278
2. DATE OF STUDY SUBMISSION: 11 26 2008, revised 5/21/09, re-­revised 6/01/09
3. PRINCIPAL INVESTIGATORS:
Cholesterol Center Staff:
C.J. Glueck MD, Ping Wang PhD, Naila Goldenberg MD
Jewish Hospital Residents:
Naseer A. Khan MD, Waqas Ahmed MD.
4. PROTOCOL ATTACHED: Yes_____ NO_____
5. INSTITUTIONAL REVIEW COMMITTEE APPROVED: YES _____ PENDING___
6. FINANCIAL STATEMENT ATTACHED: YES___ NO___
7. LENGTH OF STUDY: 12-­16 months
8. SUM REQUESTED: 0 (Personnel Covered Under overall Cholesterol Center Requests)
1. Purpose:
Our aim is to conduct a study to examine dose related decrements in triglycerides (TG) in severely hypertriglyceridemic
patients who are treated with Lovaza at doses of 4, 8, and 12 grams per day. Our hypothesis is that in patients with very high
triglycerides, who do not reach TG levels ≤ 500 mg/dl on maximized triglyceride lowering regimens plus 4 g/day Lovaza, will
respond with further, significant reductions in triglycerides as Lovava is increased to 8 g per day and then to 12 g per day.
The Food and Drug Administration (FDA) approved dose of Lovaza is 4 gm/day. Our previous studies,1 , 2 summarized below,
have shown that in patients receiving optimized triglyceride lowering regimens plus 4 g per day of Lovaza, further elevation of
Lovaza to 8 g, and if necessary, to 12 g has significant efficacy and is safe. We have clinical evidence that there is a linear
decrease in TG with increasing dose of Lovaza.2
2. Significance in relationship to human health:
Omega-­3 fatty acids are a family of poly-­ unsaturated fatty acids. People with certain circulatory problems, such as varicose
veins, benefit from omega-­3 fatty acids. Omega-­3 fatty acids stimulate blood circulation 1 , increases the breakdown of fibrin,
and additionally has been shown to reduce blood pressure 2 . In the GISSI 1 study, Lovaza reduced cardiac events 4 , and in
GISSI 2, reduced mortality from congestive heart failure 4 . Omega-­3 fatty acids may slow progression of loss of renal function
in chronic kidney disease 5 .There is strong scientific evidence that omega 3 fatty acids significantly reduce blood triglyceride
levels while elevating high density lipoprotein cholesterol (HDL) levels. 6 . Fasting and non fasting hypertriglyceredemia have
been associated with atherosclerosis, and coronary heart disease events, even in the absence of hypercholesterolemia 7 .
Severe hypertriglyceridemia (>2000 mg/dl) can also lead to acute hemorrhagic pancreatitis.
Currently, patients having very High TG are treated with Fibric acids (gemfibrozil, Tricor, Antara), and if hyperinsulinemic, with
Glucophage. Lovaza (4g/day) has been shown to be effective and safe in lowering TG levels 8 .
References
1. Leek, K. W., A. D. Blann, et al. (2006). “Effects of omega-­3 polyunsaturated fatty acids on plasma indices of
thrombogenesis and inflammation in patients post-­myocardial infarction. “ Throm Res 118(3): 305-­12.
2. Morris, Martha C. ;; Sacks, Frank;; Rosner, Bernard (August 1993). “Does fish oil lower blood pressure ? A meta-­analysis of
controlled trials”. Circulation 88 (2): 523-­533. American Heart Association. PMID 8339414.
3. Mori, Trevor A.;; Bao, Danny Q.;; Burke, Valerie;; Puddey, Ian B.;; Beilin, Lawerence J. (August 1993). “ Docosahexaenoic acid
but not eicosapentaenoic acid lowers ambulatory blood pressure and heart rate in humans. “ Hypertension 34 (2): 253-­260.
American Heart Association. PMID 10454450
4. Gissi-­Hf, I. (2008). “Effect of n-­3 polyunsaturated fatty acids in patients with chronic heart failure ( The GISSI-­HF trial): a
randomized , double-­blinded, placebo-­controlled trial.” Lancet.
5. Clark, W.F., A. Parbtani, et al. (1993). “Dietary protein restriction versus fish oil supplementation in the chronic remnant
nephron model. “ Clin Nephron 39 (6):295-­304. 6. Vensson, M., J. H. Christensen, et al (2004). “ The effect of n-­3 fatty acids on plasma lipids and lipoproteins and blood
pressure in patients with CRF. “ Am J Kidney Dis 44(1);;77-­83.
7. Yam, D., G. Bott-­Kanner, et al. (2001). “The effct of Omega-­3 fatty acids on risk factors for cardiovascular diseases.”
Harefuah 140(12);; 1156-­8, 1230.
8. Calabresi, L., B. Villa, et al. (2004). “ An omega-­3 polyunsaturated fatty acid concentrate increases plasma high-­density
lipoprotein 2 cholesterol and paraoxonase levels in patients with familial combined hyperlipidemia. “ Metabolism 53 (2 )
:153-­8.
3: Preliminary Studies with high dose omega-­3 fatty acids.
3.1 Glueck et al1-­3 studies:
Our clinical experience has shown that there are, however, many patients with primary hypertriglyceridemia where
conventional treatment with fibric acids, glucophage (for hyperinsulinemia), and 4 g Lovaza fails to normalize triglycerides
(<500 mg/dl).2 There is no published data which indicates that Lovaza 8 or 12 g per day would have therapeutic
effectiveness in further normalizing triglycerides in subjects on maximized triglyceride lowering and Lovaza 4 g per day. We
hypothesize, based on our clinical experience,1 , 2 that increasing Lovaza to 8 and then (if necessary) to 12 g/day would safely
optimize triglycerides in subjects with primary hypertriglyceridemia who failed to normalize their triglycerides on optimal
therapy including Lovaza 4 g/day.
Goldenberg, Glueck et al 2 have treated a large cohort of women with severe hypertriglyceridema with combined fibric acids
and omega-­3 fatty acids up to 12 grams per day. We assessed severe hypertriglyceridemia, hypertriglyceridemic acute
pancreatitis, and failure of triglyceride-­lowering therapy when estrogens were given to 56 women with and without familial
hypertriglyceridemia. The 56 women had been consecutively referred to our center over a 3-­year period because of
triglycerides >400 mg/dl despite diet-­drug treatment and/or a history of hypertriglyceridemic acute pancreatitis (AP). After
study at entry, in 56 women (median age, 52 years), 36 with familial hypertriglyceridemia, to lower triglycerides, estrogens and
SERMs (hormone treatment, HT) were stopped;; a very low fat diet (<15% of calories), gemfibrozil (1.2-­1.5 mg/day),and
omega-­3-­fatty acid (4-­12 g/day) were started, with restudy 2-­4 weeks later. In most cases, the omega-­3 fatty acid dose was
titrated up to 8 to 12 grams per day. Of the 56 women, 24 (43%) were taking hormone therapy (HT) at entry, with median
fasting triglycerides 1270 mg/dl in the HT group and 1087 mg/dl in the no-­HT group. Seventeen women (30%) had a history of
acute pancreatitis (AP), nine of whom (53%) were/had been on HT at the development of AP. Significant positive correlates of
triglycerides at entry in a stepwise regression model were hemoglobin A(1C) (partial r(2)=10.7%, p<0.05) and an interaction
between estrogen use and familial hypertriglyceridemia (partial r(2)=15%, p=0.017). After 2-­4 weeks on therapy, median
triglycerides in the previous-­HT group fell from 1270 to 284 mg/dl (p<0.0001) and in the no-­HT group from 1087 to 326 mg/dl
(p<0.0001). The triglyceride lowering therapy, including dose elevations of omega-­3 fatty acids to 8 to 12 grams per day, was
well tolerated with no clinical side effects beyond rare diarrhea, and serial measurements of complete blood count and
metabolic profile revealed no adverse effects of the combined fibric acids and omega-­3 fatty acids.
In 3 women with severe hypertriglyceridemia, Glueck et al3 used 6,9,and 12 g of omega-­3 fatty acids in conjunction with
gemfibrozil safely and effectively, without side effects.
During pregnancy in women with familial chylomicronemia and previous pancreatitis, where fibric acids cannot be given
safely, Glueck et al 1 lowered triglycerides and prevented pancreatitis with doses of omega-­3 fatty acids up to 32 g/day
throughout the 9 months of pregnancy. The triglyceride lowering therapy was well tolerated with clinical side effects beyond
rare diarrhea, and serial measurements of complete blood count and metabolic profile revealed no adverse effects of the high
dose omega-­3 fatty acids.
COPIES OF GLUECK ET AL1 GOLDENBERG, GLUECK ET AL,2 and Glueck et al3 HAVE BEEN ATTACHED TO THIS
AMENDED SUBMISSION
1. Glueck CJ et al, Nutrition 1996;;12:202-­205
2. Goldenberg NM, Wang, Glueck CJ, Clin Chim Acta 2003;;332:11-­19
3. Glueck CJ et al, J Lab Clin Med 1994;;123:59-­64
Therapy of severe hypertriglyceridemia with fibric acids combined with omega-­3 fatty acids is an established therapeutic
approach with documented safety and efficacy as summarized in the references below. 1-­14
References
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: 332:11-­9.
2. Glueck CJ, Streicher P, Wang P, Sprecher D, Falko JM. Treatment of severe familial hypertriglyceridemia during pregnancy
with very-­low-­fat diet and n-­3 fatty acids. Nutrition;; 1996: 12:202-­5.
3. Arterburn LM, Hall EB, Oken H. Distribution, interconversion, and dose response of n-­3 fatty acids in humans. Am J Clin
Nutr;; 2006: 83:1467S-­1476S.
4. Drexel H, Follath F. [Therapy of hyperlipoproteinemia]. Schweiz Rundsch Med Prax;; 1993: 82:506-­9.
5. Franceschini G, Paoletti R. Pharmacological control of hypertriglyceridemia. Cardiovasc Drugs Ther;; 1993: 7:297-­302.
6. Hachem SB, Mooradian AD. Familial dyslipidaemias: an overview of genetics, pathophysiology and management. Drugs;;
2006: 66:1949-­69.
7. Hexeberg S, Retterstol K. [Hypertriglyceridemia-­-­diagnostics, risk and treatment]. Tidsskr Nor Laegeforen;; 2004: 124:2746-­
9.
8. Malloy MJ, Kane JP. A risk factor for atherosclerosis: triglyceride-­rich lipoproteins. Adv Intern Med;; 2001: 47:111-­36.
9. McKenney JM, Sica D. Role of prescription omega-­3 fatty acids in the treatment of hypertriglyceridemia. Pharmacotherapy;;
2007: 27:715-­28.
10. Pschierer V, Richter WO, Schwandt P. Primary chylomicronemia in patients with severe familial hypertriglyceridemia responds
to long-­term treatment with (n-­3) fatty acids. J Nutr;; 1995: 125:1490-­4.
11. Richter WO, Jacob BG, Ritter MM, Schwandt P. Treatment of primary chylomicronemia due to familial hypertriglyceridemia
by omega-­3 fatty acids. Metabolism;; 1992: 41:1100-­5.
12. Toth PP, Dayspring TD, Pokrywka GS. Drug therapy for hypertriglyceridemia: fibrates and omega-­3 fatty acids. Curr
Atheroscler Rep;; 2009: 11:71-­9.
13. Wierzbicki AS, Mikhailidis DP, Wray R. Drug treatment of combined hyperlipidemia. Am J Cardiovasc Drugs;; 2001: 1:327-­36.
3.2 Other Studies with Omega 3 fatty acids in lowering triglycerides, often
with doses > 4 g per day.:
The Food and Drug Administration (FDA) approved dose of Lovaza is 4 gm/day. We have increasing clinical evidence in
patients already receiving optimized triglyceride lowering regimens (fibric acid, Glucophage, diet, Lovaza 4 g/day) that
increasing Lovaza to 8, and if necessary, to 12 g/day further optimizes triglyceride levels. Unpublished data provided to us by
GSK has shown that there is linear reduction in TG levels who are given higher than 4 gm/day of Lovaza.
DATA ON THE GSK EXTENDED LOVAZA DOSE STUDIES ARE ATTACHED TO THE AMENDED SUBMISSION We summarize below, multiple studies of omega-­3 fatty acids and triglyceride lowering.
3.2 a: The effects of three supplemental doses of fish oil on plasma lipids, lipoproteins, and bleeding times were studied
in ten hypertriglyceridemic patients. Intake of 15, 25, or 40 mL fish oil/d (containing 4.5,7.5, and 12 g n-­3 fatty acids) led to the
decrease in plasma cholesterol concentrations with increasing doses of fish oil and decrease in plasma triglyceride
concentrations. Two higher doses led to increase in low-­density-­lipoprotein cholesterol concentrations. While bleeding times
increased only with the largest dose. 15
3.2. b: Twenty male patients with primary hypertriglyceridemia were treated for 4 weeks with daily supplements (15 g) of
oil, which provided approximately 6 g of polyunsaturated fatty acid (PUFA) either of fish or of vegetable origin. The fish oil
supplement led to a decrease in plasma triglyceride concentrations and increase in high density lipoprotein-­3 (HDL3)
cholesterol concentrations. 16
3.2. c : Forty-­two patients with triglyceride concentrations between 5.65 and 22.60 mmol/l (500 and 2000 mg/dl) were
studied in a prospective, double-­blind, placebo-­controlled trial of Omacor (4 g/day for 4 months). Omacor significantly reduced
triglyceride concentrations, cholesterol , very-­low-­density lipoprotein cholesterol and cholesterol:high density lipoprotein
(HDL) cholesterol ratio. Omacor increased HDL cholesterol and low-­density lipoprotein cholesterol. Omacor was well
tolerated and no patient discontinued medication because of side effects. 17
3.2.d : To evaluate the long-­term efficacy of (n-­3) fatty acids, 2.16 or 4.32 g/d (for 3 mo) and 3.24 g/d (for a further 8 mo
after 1 mo of no treatment) (n-­3) fatty acids were added to the diet of eight patients with primary chylomicronemia. It led to the
decrease in serum triglycerides and VLDL triglycerides. Total cholesterol, HDL and LDL cholesterol as well as lipoprotein (a)
and fibrinogen concentrations were not affected by fish oil treatment. Body weight increased significantly after 11 mo of
treatment with (n-­3) fatty acids11
3.2.e: In 12 patients with primary chylomicronemia due to familial hypertriglyceridemia, the addition of 2.16 g omega-­3
fatty acids over 4 weeks and 4.32 g for 8 weeks resulted in a decrease of serum triglyceride levels. Cholesterol and
triglyceride levels in the chylomicron fraction were reduced concomitantly, the apolipoprotein B-­100/B-­48 ratio increased,
very-­-­low-­density lipoprotein (VLDL) triglycerides, VLDL cholesterol, and total cholesterol levels decreased, and low-­density
lipoprotein (LDL) cholesterol showed a tendency to increase, but this finding did not reach significance. High-­density
lipoprotein (HDL) cholesterol levels remained unchanged, as did the levels of apolipoproteins A-­I, A-­II, and E, and
lipoprotein(a). Apolipoprotein B levels decreased significantly. No clinically relevant side effects occurred, with the exception
of the manifestation of diabetes mellitus in one patient, which could be reversed after discontinuation of treatment12.
3.2.f: Substitution of commercially available omega-­3 for omega-­6 fatty acids improves hypertriglyceridemia but may
worsen other lipoproteins indices and may increase insulin requirements in diabetic hypertriglyceridemic subjects.18
3.2 g: Fish oil concentrate at high doses (9.8 g/d omega-­3 fatty acids) followed by low-­dose maintenance therapy (3.9
g/d) cannot sustain initial large plasma triglyceride reductions. Moreover, the efficacy of the higher dose becomes less
pronounced after the first month of therapy. This reduced efficacy during prolonged therapy, and the lack of beneficial effect
on apolipoprotein and LDL cholesterol levels, may limit the practical benefit of fish oil in the treatment of
hypertriglyceridemia. 19
3.2 h: Very high dose (20 g of n-­3 polyunsaturated fatty acids (PUFA) or 20 g of n-­6 PUFA) of n-­3 PUFA has a
pronounced hypotriglyceridemic effect, which is directly related to the initial plasma level. 20
References
1. Glueck CJ, Streicher P, Wang P, Sprecher D, Falko JM. Treatment of severe familial hypertriglyceridemia during pregnancy
with very-­low-­fat diet and n-­3 fatty acids. Nutrition 1996;;12:202-­5.
2. 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;;332:11-­9.
3. Glueck CJ, Lang J, Hamer T, Tracy T. Severe hypertriglyceridemia and pancreatitis when estrogen replacement therapy is
given to hypertriglyceridemic women. J Lab Clin Med 1994;;123:59-­64.
4. Arterburn LM, Hall EB, Oken H. Distribution, interconversion, and dose response of n-­3 fatty acids in humans. Am J Clin Nutr
2006;;83:1467S-­76S.
5. Drexel H, Follath F. [Therapy of hyperlipoproteinemia]. Schweiz Rundsch Med Prax 1993;;82:506-­9.
6. Franceschini G, Paoletti R. Pharmacological control of hypertriglyceridemia. Cardiovasc Drugs Ther 1993;;7:297-­302.
7. Hachem SB, Mooradian AD. Familial dyslipidaemias: an overview of genetics, pathophysiology and management. Drugs
2006;;66:1949-­69.
8. Hexeberg S, Retterstol K. [Hypertriglyceridemia-­-­diagnostics, risk and treatment]. Tidsskr Nor Laegeforen 2004;;124:2746-­9.
9. Malloy MJ, Kane JP. A risk factor for atherosclerosis: triglyceride-­rich lipoproteins. Adv Intern Med 2001;;47:111-­36.
10. McKenney JM, Sica D. Role of prescription omega-­3 fatty acids in the treatment of hypertriglyceridemia. Pharmacotherapy
2007;;27:715-­28.
11. Pschierer V, Richter WO, Schwandt P. Primary chylomicronemia in patients with severe familial hypertriglyceridemia responds
to long-­term treatment with (n-­3) fatty acids. J Nutr 1995;;125:1490-­4.
12. Richter WO, Jacob BG, Ritter MM, Schwandt P. Treatment of primary chylomicronemia due to familial hypertriglyceridemia
by omega-­3 fatty acids. Metabolism 1992;;41:1100-­5.
13. Toth PP, Dayspring TD, Pokrywka GS. Drug therapy for hypertriglyceridemia: fibrates and omega-­3 fatty acids. Curr
Atheroscler Rep 2009;;11:71-­9.
14. Wierzbicki AS, Mikhailidis DP, Wray R. Drug treatment of combined hyperlipidemia. Am J Cardiovasc Drugs 2001;;1:327-­36.
15. Harris WS, Rothrock DW, Fanning A, et al. Fish oils in hypertriglyceridemia: a dose-­response study. Am J Clin Nutr
1990;;51:399-­406.
16. Sanders TA, Sullivan DR, Reeve J, Thompson GR. Triglyceride-­lowering effect of marine polyunsaturates in patients with
hypertriglyceridemia. Arteriosclerosis 1985;;5:459-­65.
17. Harris WS, Ginsberg HN, Arunakul N, et al. Safety and efficacy of Omacor in severe hypertriglyceridemia. J Cardiovasc Risk
1997;;4:385-­91.
18. Stacpoole PW, Alig J, Ammon L, Crockett SE. Dose-­response effects of dietary marine oil on carbohydrate and lipid
metabolism in normal subjects and patients with hypertriglyceridemia. Metabolism 1989;;38:946-­56.
19. Schectman G, Kaul S, Cherayil GD, Lee M, Kissebah A. Can the hypotriglyceridemic effect of fish oil concentrate be
sustained? Ann Intern Med 1989;;110:346-­52.
20. Svaneborg N, Moller JM, Schmidt EB, Varming K, Lervang HH, Dyerberg J. The acute effects of a single very high dose of n-­
3 fatty acids on plasma lipids and lipoproteins in healthy subjects. Lipids 1994;;29:145-­7.
4: Methods:
4a Subjects:
We will study patients from our Jewish Hospital Cholesterol Center, who were referred to us with primary high TG (TG>1000
mg/dl) and have been treated with Fibric acids, Lovaza 4g, and, in the presence of hyperinsulinemia, Glucophage up to 2.5
g/day, who did not optimize triglyceride levels to < 500 mg/dl. Patients maintaining TG> 500 mg/dl on maximum doses of
Fibric acid, Lovaza (4 g/day) and, in the presence of hyperinsulinemia, Glucophage 2.5 g/day, will subsequently be given high
doses of Lovaza 8g and 12 g per day. During follow-­up:
1. Patients with transaminase elevations greater than 3 times the upper limit of normal, petechiae, bruising, or severe
skin findings should be discontinued from the study drug and appropriate work-­up should be initiated.
2. Patients should be instructed to contact the study site with any evidence of jaundice, severe abdominal pain, bleeding,
or skin findings.
3. Women of child-­bearing potential must use adequate contraception.
The study sequence will be as follows:
Visit 1: Patients must be documented to have primary hypertriglyceridemia (not due to alcoholism, exogenous estrogens,
nephrotic syndrome, hemochromatosis, glycogen storage disease, uncontrolled diabetes, exogenous corticosteroids,
Cushing’s syndrome, uremia). If not already taking Tricor 145 mg/day or gemfibrozil 1.2 g/day, and Lovaza (4g /day) or
Glucophage (in the presence of hyperinsulinemia), these therapies will be instituted, along with dietary instruction, and
restriction of social alcohol intake to zero. Blood will be obtained for measurement of complete blood count, fasting glucose,
HgA1C, insulin, C-­peptide, kidney and liver function tests, T4 and TSH, apoE genotype. Dietary instruction in NIH Type IV or V
diets (as appropriate to each patient) will be initiated. If glucose control is not optimal (HgA1C > 7) further steps will be taken
to optimize diabetes control. Lipid profile will be measured after an overnight fast. Height, weight, and blood pressure will be
recorded. Detailed history and brief physical examination will be carried out.
Visit 2: At visit 2, 1 month after visit 1, adherence to diet will be reviewed. Adherence to Lovaza will be determined by pill
count. Weight and blood pressure will be measured, a brief physical exam will be carried out. After an overnight fast, blood
lipids will be measured. Blood will be obtained for measurement of complete blood count , glucose, renal and liver function,
CBC, insulin and C peptide. If TG remain above 500 mg/dl, Lovaza will be increased to 8 g per day with other components of
the triglyceride lowering regimen held stable. Dermatologic examination will be carried out to look for petechiae or bruising.
Visit 3: At visit 3, 1 month after visit 2. adherence to diet will be reviewed. Adherence to Lovaza will be determined by pill
count. Weight and blood pressure will be measured, a brief physical exam will be carried out. After an overnight fast, blood
lipids will be measured. Blood will be obtained for measurement of complete blood count , glucose, renal and liver function,
CBC, insulin and C peptide. If TG remain above 500 mg/dl, Lovaza will be increased to 12 g per day with other components of
the triglyceride lowering regimen held stable. Dermatologic examination will be carried out to look for petechiae or bruising.
Visit 4: At visit 4, 1 month after visit 3, adherence to diet will be reviewed. Adherence to Lovaza will be determined by pill
count. Weight and blood pressure will be measured, a brief physical exam will be carried out. After an overnight fast, blood
lipids will be measured. Blood will be obtained for measurement of complete blood count , glucose, renal and liver function,
CBC, insulin and C peptide. Dermatologic examination will be carried out to look for petechiae or bruising.
Visits 6, 7 and 8. On subsequent visits 6,7 and 8, each one month apart, we will maintain patients on previous TG lowering
regimen but back off to Lovaza 4 gm/day. Weight and blood pressure will be measured, a brief physical exam will be carried
out. After an overnight fast, blood lipids will be measured. Blood will be obtained for measurement of complete blood count ,
glucose, renal and liver function, CBC, insulin and C peptide.
The protocol does not incorporate a placebo control because it would be unethical not to maximize TG lowering treatment in
patients with severe hypertrigyceridema, due to risk of pancreatitis. At the completion of the stepped intervention with Lovaza
(after 8 and 12 grams), the dose of Lovaza will be reduced to 4 g/day, while other triglyceride lowering medications are
maintained unchanged, and the patients will be followed for 2 more months (once per month) to assess what happens to
triglycerides when the 8 and 12 grams of Lovaza are reduced to 4 grams. Although this is not a placebo control, it is a
practical treatment control to assess effects of 8 and 12 g of Lovaza anteceded and followed by 4 g of Lovaza.
4b. Inclusion Criteria
1. Primary hypertriglyceridemia with fasting TG levels >1000 mg/dl, and persistence of TG levels > 500 mg/dl despite
maximal TG lowering therapy for 1 month, including Lovaza 4 g/day, fibric acids, and, where indicated, Glucophage for
treatment of hyperinsulinemia.
2. Patients with mild to moderately impaired renal function should be initiated on TRICOR 48 mg and patients with
severe renal impairment should not be given TRICOR.
3. Absence of exclusionary criteria (see below).
4c. Exclusion Criteria
1. Patients with known allergy to fish
2. Hypertriglyceridemia secondary to alcoholism, exogenous estrogens, nephrotic syndrome, hemochromatosis,
glycogen storage disease, uncontrolled diabetes, exogenous corticosteroids, Cushing’s syndrome, uremia).
3. Bleeding gastric or duodenal ulcers, active inflammatory bowel disease.
4. Pregnancy
5. Dementia
6. Patients with bleeding diatheses
7. Patients who are taking concomitant anticoagulants and other medications that affect bleeding time (e.g., warfarin,
aspirin)
8. Patients with abnormal transaminases or any history of liver disease
9. Patients with conditions affecting the skin (e.g. malignancy, vasculitides) that may confound the skin exam.
4e. Data Analysis
Each patient will serve as his/her own controls. The major study endpoint will be reduction of TG to < 500 mg/dl.
Paired Wilcoxon tests will be carried out to compare TG levels after 1 month of maximal TG lowering (including Lovaza 4
g/day), against TG levels after 1 month at maximal TG lowering but with Lovaza 8 g/day, against TG levels after 1 month with
maximal TG lowering but with Lovaza 12 g/day. Paired Wilcoxon tests will also be made comparing TG levels reached on the
maximum titrated Lovaza dose (8 or 12 g/day), compared to the 3 months after up-­titration of the Lovaza dose, when all
subjects will be returned to 4 g/day.
Analyses of group changes will be made by analysis of variance with repeated measures, after covariance adjusting for age,
race, gender, and BMI.
Variables to be compared against baseline (maximal TG lowering with Lovaza 4 g/day) will include weight, blood pressure,
the full lipid profile (TG, total cholesterol, LDL cholesterol, HDL cholesterol), CBC and platelet count, fasting blood glucose,
BUN and creatinine, weight, blood pressure.
5. Risks and Benefits:
Risks:
The only potential risk will be discomfort of having blood drawn (total 30 ml). The bloods drawn in the study are the same
which would routinely be drawn clinically in the Cholesterol Center.
It is not anticipated that the increased dose of Lovaza (8 g, 12 g/day) will produce bleeding, but this will be examined at each
sequential patient visit.
Benefits:
All Lovaza during the trial will be free of charge.
No physician charges will be made during the 7 months of the trial.
6. Payment:
There will be no financial remuneration. Parking is free for Cholesterol Center patients
7. Subject Costs:
The tests done are the same as the routine clinical tests done in all Cholesterol Center patients and are covered by third
party payers. There will be no physician fees during the duration of the trial, and all Lovaza for the trial free of charge.
8. Estimated time:
Estimated time to complete study is 12-­16 months.
9. Funding:
The study will be funded by GSK.
Informed Consent Document Revisions
Statement of Informed Consent: Effectiveness and safety of Lovaza 4, 8, and 12 grams per day in optimizing high
triglyceride levels in patients with hypertriglyceridemia despite other optimal therapy.
1. Introduction
Before agreeing to participate in this study, it is important that the following explanation of the proposed procedures be read
and understood. It describes the purpose, procedures, benefits, risks, discomforts and precautions of the study. It also
describes alternatives procedures available and the right to withdraw from the study at any time. It is important to understand
that no guarantee or assurance can be made as to the results. It is also understood that refusal to participate in this study will
not influence standard treatment for the subjects.
2. Objectives
The purpose of this study is to use Lovaza (a pharmaceutical long chain polyunsaturated fatty acid derived from ocean fish) to
prospectively treat high triglycerides (TG) in patients who, despite optimized conventional therapy, do not reach optimal
triglyceride levels (<500 mg/dl). Patients with very high triglycerides, who do not reach optimal levels (<500 mg/dl) on
maximized triglyceride lowering regimens plus 4 g/day Lovaza, will be given higher doses of Lovaza (8 g for 1 month, 12 g for
1 month) to attain optimum TG and high density lipoprotein (HDL) levels.
3. Procedures
We will study patients from our Jewish Hospital Cholesterol Center, who were referred to us with primary high TG (TG>1000
mg/dl) and were conventionally treated with Fibric acids (Tricor, Gemfibrozil), Lovaza 4g, and, in the presence of
hyperinsulinemia, Glucophage up to 2.5 g/day, who did not optimize triglyceride levels to < 500 mg/dl. While maintaining their
antecedent triglyceride-­lowering regimens, these patients will subsequently be 8 g of Lovaza for 1 months, and then 12 g per
day for 1 month. Visit 1:
At study entry, after an overnight fast, blood will be obtained for measurement of complete blood count, fasting glucose,
HgA1C (marker of how well blood sugar was controlled in the last three months), insulin, C-­peptide (precursor of the insulin
molecule), kidney and liver function tests, T4 and TSH (Thyroid function tests), and a genetic test of the inheritance of high
triglycerides (apoE genotype). Dietary instruction as appropriate to each patient will be initiated. If glucose control is not
optimal (HgA1C > 7) further steps will be taken to optimize diabetes control. Lipid profile will be measured after an overnight
fast. Height, weight, and blood pressure will be recorded. Detailed history and brief physical examination will be carried out.
Triglyceride lowering will be initiated with Tricor 145 mg, Lovaza 4 g, and, where necessary, Glucophage (2.55 g/day). A
registered dietitian will instruct in a customized diet. Repeat visit will be scheduled for 1 month.
Patients will be asked to keep a written record of any side effects which they ascribe to the drug treatment program.
Visit 2:
One month after the first visit, adherence to diet will be reviewed. Adherence to Lovaza will be determined by pill count.
Weight and blood pressure will be measured, a brief physical exam will be carried out. After an overnight fast, blood lipids will
be measured. Blood will be also obtained for measurement of complete blood count , glucose, renal and liver function, CBC,
insulin and C peptide. If TG remain above 500 mg/dl, Lovaza will be increased to 8 g per day with other components of the
triglyceride lowering regimen held stable. Repeat visit will be scheduled in 1 month.
Patients will be asked to keep a written record of any side effects which they ascribe to the drug treatment program.
Visit 3:
If TG remain above 500 mg/dl at the third visit, while continuing other drugs and diet unchanged, Lovaza will be increased to
12 g/day. Adherence to Lovaza will be determined by pill count. Weight and blood pressure will be measured, a brief physical
exam will be carried out. After an overnight fast, blood lipids will be measured. Blood will be also obtained for measurement
of complete blood count , glucose, renal and liver function, CBC, insulin and C peptide.
Patients will be asked to keep a written record of any side effects which they ascribe to the drug treatment program.
At any time before the return visit, or any time during the study, if clinical side effects occur, patients should record the side
effects, and call Dr Glueck (513-­924-­8250) and or email Dr Glueck ([email protected]) to review the side effects.
4. Exclusion Criteria 1. Patients with known allergy to fish
2. Hypertriglyceridemia secondary to alcoholism, exogenous estrogens, nephrotic syndrome, hemochromatosis,
glycogen storage disease, uncontrolled diabetes, exogenous corticosteroids, Cushing’s syndrome, uremia).
3. Bleeding gastric or duodenal ulcers, active inflammatory bowel disease.
4. Pregnancy
5. Dementia
6. Patients with bleeding diatheses
7. Patients who are taking concomitant anticoagulants and other medications that affect bleeding time (e.g., warfarin,
aspirin)
8. Patients with abnormal transaminases or any history of liver disease
9. Patients with conditions affecting the skin (e.g. malignancy, vasculitides) that may confound the skin exam.
5. Risks and Precautions
Risks/discomforts may be as follows: I have been told that the study described above may involve the following risks and/or
discomforts and safeguards and/or precautions to avoid them.
1. You are being administered LOVAZA in doses exceeding the recommended dose (recommended dose: 4 grams per
day;; dose in this study: 8-­12 grams per day). There may be risks of the drug at these higher doses, including bleeding,
or risks that are currently unknown. In addition, you will be administered LOVAZA in combination with another
triglyceride-­lowering drug known as a fibrate (fenofibrate or gemfibrozil). The risks of LOVAZA and fibrates in
combination are unknown, but may include bad effects on the liver. You will be monitored for these risks and you
should inform the study site if you have any concerns or changes in your health.
2. There might be discomfort of having blood drawn (total 30 ml). The blood drawn in the study are the same which would
routinely be drawn clinically in the Cholesterol Center.
It is not anticipated that the increased dose of Lovaza (8 g, 12 g/day) will produce bleeding., but this will be examined at each
sequential patient visit.
6. Potential Benefits
Patients unable to maintain optimum TG levels on their previous medications will potentially benefit from the higher doses of
Lovaza, thus decreasing their risk of developing coronary heart disease, pancreatitis and other medical problems related to
high TG.
7. Right of Refusal
Participation in this study is voluntary. If you refuse to participate, there will be no penalty or loss of any benefit to which you
are entitled. If you volunteer to participate in the study, you may withdraw from the study at any time without a penalty or loss of
any benefit to which you are entitled.
8. Confidentiality
Your medical records will be treated as confidential. Only authorized personnel (Dr CJ Glueck) and his designated
Cholesterol Center Research Personnel will have access to the records. It is possible that an authorized person from the
department of Health and Human services, Food and Drug Administration (FDA) or other federal agency will inspect the
records. In all instances except the FDA, your name will remain confidential, as will all laboratory and clinical results. In the
case of a new drug administration the FDA does have aright to know your name and this may be revealed to the proper
authorities from the FDA if requested to do so. With the exception of Dr CJ Glueck and his designated Cholesterol Center
Research Personnel, no one will be permitted to examine your records without your written consent.
Results of your laboratory tests, and results of your evaluation at the cholesterol center will only be released with your written
original signature consent, and will only be released to health care professionals responsible for your care.
9. Costs to the subject There will be no physician, nutrition, or laboratory charges during the 3 month triglyceride lowering trial. All Lovaza during the
trial will be free of charge.
10. Availability of Information
Any question that you may have concerning any aspect of this study or your rights as a subject in the study will be answered
by: Dr CJ Glueck. MD, Phone 513-­924-­8250, Fax 513-­924-­8273, email:[email protected]
The Jewish Hospital of Cincinnati follows a policy of making all the decisions concerning compensation and medical
treatment for injuries occurring during or caused by participation in biomedical or behavioral research on an individual basis.
If believe I have been injured as result of research or have questions about my rights as a research subject, I will contact
Stephen Goldberg, MD, Chairperson, IRB. Phone 513-­686-­5446.