1
are dyslipidemia, diabetes mellitus, obesity, and hypertension. gastrointestinal fluids, and it is continuously released by a diffu-
In all of these risk factors, an important characteristic abnormal sion-erosion process. This technology has enhanced bioavailabil-
level of plasma lipids is seen. ity as compared to the standard formulation.
Various anti-lipidemic drugs are available. Among these, Other advantages of lidose technology are: (1) a good mass
statins are considered the first line of treatment for cholesterol and drug content uniformity, the volumetric filling of a liquid is
control. Side effects of statins are very well known.3 Hypertrig- not influenced by density of the product; (2) lidose protects the
lyceridemia is a common form of dyslipidemia that is usually cor- active ingredient against oxidation; and (3) capability to use hard
related with cardiovascular diseases, which is generally defined gelatin capsules for: liquid substances, low dosing substances so
by the occurrence of an acute coronary syndrome or the need for as to obtain a uniform blend of sensitive substances, and slightly
a coronary intervention. soluble drugs to obtain dispersion.
Fenofibrates can lower both triglycerides by 40% to 50%, and
serum cholesterol as much as 20% to 25%. Cholesterol reduction OBJECTIVES:
is obtained by lowering low density atherogenic factors such as General Objective:
VLDL and LDL. It is a known fact that the directly proportional To determine the efficacy and safety of fenofibrates particularly
relationship between hypercholesterolemia and atherosclerosis Fenogal (lidose technology) in dyslipidemic patients
existed and has been well established. However, low level of HDL Specific Objective:
is also associated with an increased coronary risk. Considering all 1. To determine the efficacy of Fenogal in decreasing triglycer-
other factors, increased triglyceride level is also associated with ides, total cholesterol, and LDL; and increasing HDL
increased vascular risk.4,5,6 2. To determine the safety of the lidose technology using clini-
Fenogal in lidose technology combines the advantages of a cal parameters, biochemical profile and side effects
capsule and a liquid. When in contact with a physiological me- Significance of the Study:
dium at a temperature of 37oC, it forms a very fine emulsion Fenofibrates are mainly indicated in the treatment of hy-
that coats the gastric mucosa (one dose produces approximately pertriglyceridemia when diet and lifestyle changes are not suf-
50 micro micelles droplets). Lidose enhances bioavailability of ficient. Fibrates are known to lower total cholesterol, LDL, while
active ingredients and it reduces risks of gastrointestinal side increasing HDL when statins are not tolerated.1
effects. Mixed dyslipidemia is a common lipid disorder described
With its IUPAC name of: propan-2-yl 2-[4-(4-chlorobenzoyl) by the presence of an atherogenic lipoprotein phenotype due to
phenoxy]-2-methylpropanoate. abnormalities in various atherogenic and anti-atherogenic lipo-
proteins. Fenofibrates are particularly useful in high residual risk
seen in statin trials which may be due to lipoprotein abnormali-
ties other than LDL. It exerts favorable effects on the atherogen-
ic lipid profile of mixed dyslipidemia and can effectively reduce
cardiovascular disease in patients with mixed dyslipidemia.1
The addition of fenofibrate to statins seems to be beneficial
in patients with acute coronary syndrome. According to Shah et.
al., statins decreased plasma fibrinogen significantly and the ad-
It is a hard capsule with a semi-solid content in which fenofi- dition of fenofibrate further enhanced this reduction of the novel
brate 160mg is homogeneously dispersed within a mixture of lipid risk factor fibrinogen.3
excipients. A hydroxypropylcellulose type of polymer is present
to prevent any formation of fenofibrate crystal when exposed to
2
Methodology:
This was an open labeled study of Fenogal 160mg once scribed using mean and standard deviation. Categorical data
daily involving adult out-patients of cardiologists and internist were presented in frequency and percent distribution. To de-
all over the Philippines who have hypertriglyceridemia, hyper- termine the significance of change in the different outcome
cholesterolemia, or both, from August 2007 to May 2009. Pre- variables, paired t-test was applied to the data. A p-value ≤
vious medications for dyslipidemia (statins, fenofibrates, gemfi- 0.05 was considered significant.
Fenogal. Demographic data of patients were based upon OPD There were 3,000 patients included in this open labeled
charts. Assessment of lipid parameters (total cholesterol, trig- study with a mean age of 52 ± 11.60 years. There were almost
lycerides, LDL, and HDL) and were taken at baseline, week 4, equal number of males (50.6%) and females (49.0%). However,
and week twelve. Blood pressure, heart rate, and biological there were 10 patients with gender not indicated. More than
markers (SGOT, SGPT, alkaline phosphatase, and FBS) were also half (50.2%) of the patients were with both hypercholester-
measured at same interval. olemia and hypertriglyceridemia. Only 12.3% were with hyper-
Continuous data such as age, weight, and height were de- at 50.2% were with both, as shown in Table 1.
The most common medicines taken by patients before LDL likewise significantly decreased from baseline to
entering the study were simvastatin, 19.60% followed by week 4 and week 12. The actual mean decrease at week 4
atorvastatin, 3.47% and Lipanthyl, 2.07%. There were 3 pa- was 17.41 mg/dl with percent change of 8.15% while at week
tients (0.10%) who were already on Fenogal before the study 12 the mean decrease was 29.86 mg/dl with percent change
started, see Appendix A. of 15.91%.
The total cholesterol decreased significantly as early as HDL on the other hand increased significantly after 4
week 4 of therapy with actual change of 28.12 mg/dl and per- weeks and 12 weeks of treatment. The actual mean increase
cent change from baseline of 9.91%. At week 12, the actual was 4.27 mg/dl and percent increase from baseline of 15.64%.
mean decrease was 44.01 mg/dl with percent change from
At week 12, the actual increase was 6.80 mg/dl with percent
baseline of 16.37%.
change from baseline of 23.51%.
3
Triglycerides decreased significantly with actual mean of 60.30 mg/dl from baseline up to week 4 of therapy.
The percent decrease was 20.72%. At week 12, there was 90.61 mg/dl actual decrease and 33.15% change from
baseline. Table 2 shows the details of the effect of the treatment on lipid profile of the patients.
4
Triglyceride
Baseline (n=2532) 234.98 98.11
Week 4 174.68 64.66
Difference:
Actual 60.30 74.34
Percent from baseline 9.91 31.16
p-value 0.000*
Baseline (n=2944) 235.27 97.84
Week 12 144.66 54.99
Difference:
Actual 90.61 86.68
Percent from baseline 33.15 28.86
p-value 0.000*
A statistically significant favorable lipid lowering response based on NCEP-ATP III goals was
achieved as early as 4 weeks of treatment and was sustained up to 12 weeks of treatment, see
table 3.
5
The systolic and diastolic blood pressures of patients decreased significantly from base-
line to week 4 and week 12 of therapy. Heart rate likewise decreased significantly, as
shown in Table 4.
Heart Rate
Baseline (n=2498) 79 9.87
Week 4 78 8.18
Difference 1.53 6.99
p-value 0.000*
Baseline (n=2750) 79 9.57
Week 12 77 8.66
Difference 1.80 8.78
p-value 0.000*
6
There were no significant changes in SGOT and SGPT of patients. Alkaline phosphatase
however showed significant increase in both 4th and 12th week observation periods.
FBS decreased significantly at week 4 and week 12 follow-up. Table 5 shows the results.
7
There were 34 patients who experience adverse events with 1.1% event rate. Most of
the events were gastrointestinal related. Bloatedness was the most common. There
were also elevated laboratory results noted as shown in Table 6.
8
Discussion:
Results of this study revealed that Fenogal (lidose tech- prevalence of dyslipidemia among adult Filipinos >20 years
nology) can significantly decrease triglycerides, LDL, and to- old are as follows: total cholesterol 184.4mg/dL (8.5%), LDL
tal cholesterol, while significantly increasing the HDL. Based 119.4mg/dL (3.7%), HDL 41.1mg/dL (54.2%), and triglycerides
on the ATP III study, fibric acids were able to lower LDL by 118.0mg/dL (20/6%).10 In the present study, it was noted
5-20%, TG by 20-50%, increase HDL by 10-20%.7,8 Comparing a higher mean baseline total cholesterol (232.45mg/dL), LDL
with the present study, similar changes in the lipid profile was (140.47mg/dL), triglycerides (235.98mg/dL) and a somewhat
achieved, namely a decrease in TG by 90.61 mg/dL (33.15%), similar HDL level (49.88mg/dL). This may mean that the pop-
an increase in HDL by 6.80 mg/dL (23.51%), and a decrease in ulation in this study represents a high risk population while
LDL by 29.86 mg/dL (15.91%). In addition we report a total the NNHes study included the normal average adult Filipino.
cholesterol decrease by 44.01 mg/dL (16.37%).
The study affirmed the safety of Fenogal in the treat-
The 3rd Report of the National Cholesterol Education ment of dyslipidemic patients as evidenced by no significant
Program (NCEP) Expert Panel on Detection, Evaluation, and changes in the SGOT and SGPT levels. The adverse event rate
Treatment of High Blood Cholesterol in Adults (Adult Treat- was 1.1% and was mostly gastrointestinal related. Bloated-
ment Panel III) Final Report state that the recommended lev- ness was the most common complaint. This was consistent
els of plasma lipids are as follows: total cholesterol <200mg/ with the NCEP ATP III guidelines which reported that fibrates
dL, HDL ≥40mg/dl, and triglycerides <150mg/dL. For LDL the are generally well tolerated and the most common adverse
goal is based on the risk level: CHD and CHD risk equivalent effects were gastrointestinal.7,8
with a target of <100mg/dL, multiple (>2) risk factors with
a target of <130mg/dL and with 0-1 risk factor with a target Similarly, in a study done by Keating et.al., micronised
of <160mg/dL.7,8 In this study, these targets were achieved fenofibrate was associated with significantly greater im-
as early as 4 weeks of treatment and was sustained up to provements from baseline in TC, LDL-C, HDL-C and TG lev-
12 weeks of treatment with Fenogal. Total cholesterol de- els than placebo in patients with type 2 diabetes mellitus
creased to a mean of 185.83mg/dL and mean triglyceride and metabolic syndrome as well as with significantly less
level was 144.66mg/dL. Average LDL of 109.15mg/dL at 12 progression of coronary atherosclerosis than placebo. It was
weeks was close to the recommended value of <100mg/dL as generally well tolerated in clinical trials, and indicated that
well as mean HDL of 56.26mg/dL at 12 weeks was greater gastrointestinal disorders are the most frequent adverse
than the prescribed value of ≥40mg/dL. events. Elevations in serum transaminase and creatine phos-
phokinase levels have been reported rarely with micronised
Grundy et. al., reported that when LDL lowering drug
fenofibrate.11, 12
therapy is employed in high-risk or moderately high-risk per-
sons, it is advised that intensity of therapy be sufficient to The improvement in the blood pressure, FBS and heart
achieve at least a 30-40% reduction in LDL-C levels.9 In our rate may reflect the patients’ overall change in lifestyle
study, a mean LDL level of 109.15mg/dL corresponding to a brought about by the physicians’ recommendation for such a
15.91% reduction was achieved from baseline up to the 12 change. Likewise such improvements may represent an over-
weeks of study. The results may not have reached the target all progress in the cardiovascular status of the patients as a
of the NCEP guidelines however the mean LDL was close to consequence of the correction of the lipid levels.
the target level of 100mg/dL. In addition, one reason for
not achieving the goal may be that the subjects may rep- A number of trials 13,14,15,16 have been done world-
resent a mixed dyslipidemic population such as in patients wide to determine the effectiveness of fibrates in the preven-
with combined hyperlipidemia wherein only slight changes in tion of cardiovascular disease. These include: Helsinki Heart
LDL cholesterol are observed with fibrates. Furthermore LDL Study, Veterans Affairs High Density Lipoprotein Cholesterol
levels may rise with fibrate therapy in patients with hyper- Intervention Trial (VA-HIT), Bezafibrate Infarct Prevention
triglyceridemia.8 (BIP) trial, and Fenofibrate Intervention and Event Lowering
in Diabetes (FIELD) trial which focused on patients with dia-
According to the National Nutrition and Health Survey betes and dyslipidemia. However, results have indicated a
(NNHeS) study10 in 2003-2004, the average lipid levels and general trend that fibrates can reduce cardiovascular events.
9
Some studies have also suggested that fibrates may have confirm the benefit of cholesterol-lowering therapy in high-
some significant non-cardiac side effects that other drugs do risk patients and support the ATP III treatment goal of LDL-C
not share. Fibrates may also be appropriate for use in pa- <100mg/dL. It supported the inclusion of patients with diabe-
tients at risk of acute pancreatitis due to high triglyceride tes in the high-risk category and confirms the benefits of LDL-
levels. lowering therapy in these patients. It further confirms that
older persons benefit from therapeutic lowering of LDL-C.
Based on the study done by Fiévet et.al.17, statin treat-
One of the major recommendations for modifications is that:
ment substantially reduces cardiovascular morbidity and
in high-risk persons, the recommended LDL-C goal is <100mg/
mortality. Statins lower LDL cholesterol (LDL-C), with limited
dL, but when risk is very high, an LDL-C goal of <70mg/dL is a
effects on other lipid parameters. Fibrates improve athero-
therapeutic option. This therapeutic option extends also to
genic dyslipidemia characterized by high triglyceride and/
patients at very high risk who have a baseline LDL-C <100mg/
or low HDL cholesterol levels and elevated concentrations of
dL. Moreover, when a high-risk patient has high triglycerides
small dense LDL particles, with or without high LDL-C levels.
or low HDL-C, consideration can be given to combining a fi-
Fibrates decrease cardiovascular morbidity, especially in pa-
brate or nicotinic acid with an LDL-lowering drug.7,8
tients with the metabolic syndrome. The purpose of this re-
view is to provide a rationale for the combined use of statins
and fibrates in the management of patients with high resid-
ual cardiovascular risk related to atherogenic dyslipidemia
Conclusion:
The authors conclude that Fenogal (lidose technology)
and persisting after single therapy. Reducing the residual
cardiovascular risk in patients treated with statins requires can be safely and effectively included in the armamentarium
addressing multiple lipid goals. In this context, future thera- of cardiovascular medications. Profiles of patients who had
peutic interventions based on combination therapy, such as experienced rise in alkaline phosphatase needs further inves-
statins and fibrates, appears particularly promising. tigation. Even systolic and diastolic blood pressures, fasting
blood sugar, and heart rate were significantly lowered.
According to Shek et.al.14, practical recommendations
for clinicians who care for patients with refractory mixed
hyperlipidemia are needed. Combination therapy with a sta-
Recommendation:
The authors recommend the use of Fenogal (lidose
tin and fibrates offers significant therapeutic advantage for
the treatment of severe or refractory mixed hyperlipidemia. technology) to be included to optimize medical therapy in
Although such a combination does increase the risk of myo- patients with dyslipidemia.
10
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Appendix A. Previous Medication of Patients for Dyslipidemia
Medications No. %
Afordel 1 0.03
Atorvastatin 104 3.47
Cholestad 5 0.17
Ciprofibrate 1 0.03
Crestor 52 1.73
Ezetemibe 2 0.07
Ezetrol 1 0.03
Fenofibrate 49 1.63
Fenoflex 8 0.27
Fenogal 3 0.10
Fibrafen 5 0.17
Fibrate 3 0.10
Fluvastatin 3 0.10
Forcad 10 0.33
Gemfibrozil 58 1.93
Lescol 6 0.20
Lipanthyl 62 2.07
Lipigem 2 0.07
Lipitor 58 1.93
Lipway 5 0.17
Lopid 18 0.60
Niacin 9 0.30
Nubrex 21 0.70
Omacor 2 0.07
Orlistat 1 0.03
Pravastatin 4 0.13
Reducel 14 0.47
Rosuvastatin 31 1.03
Simvastatin 588 19.60
Vamstat 1 0.03
Vidastat 46 1.53
Vytorin 10 0.33
Ximvast 1 0.03
Zocor 22 0.73
Unrecalled 3 0.10
None indicated 1877 62.56