Download diabetic hypertension, chronic urticaria and fatty liver disease

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CURRENT TRENDS IN
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DIABETIC HYPERTENSION,
CHRONIC URTICARIA AND
FATTY LIVER DISEASE
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At the Northern Pharmacists Convention cum 48th Malaysian Pharmaceutical Society Seminar 2015 held recently at Bayview
Beach Hotel, Penang, Sanofi invited three distinguished speakers – Dr Khaw Chong Hui, Dr Lo Kang Shang Chit, and
Professor Dr Karl-Josef Gundermann – to speak on the importance of renal protection in managing diabetic hypertension,
the use of antihistamines in managing chronic urticaria (CU), and the role of essential phospholipids (EPL) in fatty liver
diseases, respectively. Below are highlights from their presentations.
RENAL PROTECTION IN THE MANAGEMENT OF DIABETIC HYPERTENSION
D
iabetes mellitus is a highly prevalent disease
worldwide.1 In Malaysia, there are about 2.6 million of
Malaysians suffering from diabetes,1 and at least 95%
of these cases are related to type 2 diabetes mellitus (T2DM).2
Type 2 diabetes mellitus is not a mild disease; it increases the
risks of stroke, cardiovascular (CV) death (eg, heart attack),
non-traumatic lower extremity amputations, blindness and
end-stage renal disease (ESRD) in patients.2
The MicroAlbuminuria Prevalence (MAP) Study3 found
that 39.8% of hypertensive T2DM patients in Asia had
microalbuminuria, suggesting an alarmingly high prevalence
of diabetic nephropathy among Asians. In Malaysia, the
prevalence of microalbuminuria in such patients was as high
as 40%.
MICROALBUMINURIA IS NOT SOLELY A MARKER FOR
KIDNEY FUNCTION
According to Dr Khaw, microalbumiuria is not only a marker for
kidney function, but also serves as a predictor for CV events
such as:
• Ischaemic heart disease – Hypertensive patients without
diabetes and previous CV disease but with higher levels of
microalbuminuria had more ischaemic events compared
with those with normoalbuminuria4;
• Stroke – The risk of stroke increased by eight folds in men
and six to seven folds in women with increasing level of
microalbuminuria5; and
• Coronary heart disease (CHD) and death – Albuminuria,
even at low levels, is associated with increased incidence
of CHD and mortality.6
ANGIOTENSIN RECEPTOR BLOCKERS (ARBs) IN THE
MANAGEMENT OF DIABETIC HYPERTENSION
As explained by Dr Khaw, the CV and renal disorders in T2DM
patients are resulted from the stimulation of AT1 receptor by
16–
14.9
60–
14–
RRR=39%
p=0.08
12–
9.7
10–
8–
6–
5.2
RRR=70%
p<0.001
4–
Irbesartan
n=579
50–
RRR=23%
p=0.006
Amlodipine
n=569
40–
30–
p=NS
20–
0–
Control
(n=201)
150 mg
(n=195)
300 mg
(n=194)
Irbesartan
RRR=20%
p=0.02
Control
n=567
IDNT primary endpoint:
Time to doubling of serum
creatinine, ESRD, or death
10–
2–
0–
Subjects (%)
DIABETES MELLITUS AND ITS RELATION TO DIABETIC
NEPHROPATHY
70–
18–
Subjects with overt
proteinuria (%)
DR KHAW CHONG HUI
Consultant Diabetologist & Endocrinologist
Hospital Pulau Pinang/Visiting Penang
Adventist Hospital, Penang
6
12
18
24 30 36 42
Follow-up (month)
48
54
60
T-T-T = The Treat-to-Target Trial; LAPTOP = Lantus + Amaryl + metformin vs. premixed insulin in Patients with Type-2
diabetes mellitus after failing oral treatment Pathways; LANMET = Lantus plus Metformin; INSIGHT = Implementing New
Strategies with Insulin Glargine for Hyperglycaemia Treatment; APOLLO = A Parallel design comparing an Oral antidiabetic
drug combination therapy with either Lantus once daily or Lispro at mealtime in type 2 diabetic patients failing Oral
treatment; INITIATE = Initiate Insulin by Aggressive Titration and Education
FIGURE 1: Irbesartan reduced the incidence of overt
proteinuria in hypertensive T2DM patients
FIGURE 2: Risk reduction in the progress of diabetic
nephropathy in T2DM patients (combined endpoint):
Irbesartan vs amlodipine vs placebo
high levels of angiotensin II in the activated renin-angiotensin
aldosterone system. This causes vasoconstriction. Angiotensin
receptor blockers are needed to inhibit this stimulation by
displacing angiotensin II from the AT1 receptor to cause
vasodilation and subsequently lower the blood pressure (BP).
and placebo in the 3-year Irbesartan Diabetic Nephropathy
Trial (IDNT) that involved 1,715 T2DM patients with diabetic
nephropathy. Treatment with irbesartan was found to reduce
the time to doubling of serum creatinine and lower the risk of
ESRD (Figure 2).8
IRBESARTAN REDUCES BP AND PROVIDES RENAL
PROTECTION TO HYPERTENSIVE T2DM PATIENTS
Irbesartan is an example of the ARB. Besides resulting
in greater BP reduction as compared with losartan and
valsartan, irbesartan has also demonstrated renoprotective
effects. Irbesartan reduced the incidence of overt proteinuria
in the Irbesartan in Patients with Type 2 Diabetes and
Microalbuminuria Study (IRMA-2) conducted by Parving
et al.7 In this 2-year, double-blind and placebo-controlled study,
590 hypertensive T2DM patients with microalbuminuria but
normal estimated glomerular filtration rate were randomized
to either 150 mg or 300 mg irbesartan daily. A statistically
significant reduction in proteinuria was seen in the 300 mgirbesartan group compared with the placebo group (relative
risk reduction [RRR]=70%; p<0.001). There was also a nonstatistically significant RRR of 39% (p=0.08) in proteinuria in the
150 mg-irbesartan group versus the placebo group (Figure 1).
Irbesartan has also shown greater risk reduction in the
progress of diabetic nephropathy compared with amlodipine
TAKE-HOME MESSAGES:
• Asians are at high risk of diabetic nephropathy. This
makes them vulnerable to kidney damage.
• Microalbuminuria is a predictor for CV events.
• Reducing microalbuminuria using ARBs leads to
reduction in CV events.
• Irbesartan improved clinical outcomes in hypertensive
T2DM patients.
• Irbesartan is more effective in lowering BP compared
with losartan and valsartan.
REFERENCES:
1. Kaur G, et al. BMC Family Practice 2013;14:69. 2. Feisul MI, Azmi S. (Eds).
National Diabetes Registry Report, Volume 1, 2009–2012. Kuala Lumpur:
Ministry of Health Malaysia; 2013 July. 3. Wu AYT, et al. Diabetologia
2005;48:17–26. 4. Jensen JV, et al. Hypertension 2000;35:898–903.
5. Yuyun MF, et al. J Intern Med 2004;255:247–256. 6. Klausen KP,
et al. Hypertension 2005;46:33–37. 7. Parving HH, et al. N Engl J Med
2001;345:870–878. 8. Lewis EJ, et al. N Engl J Med 2001;345:851–860.
ANTIHISTAMINES IN THE MANAGEMENT OF CHRONIC URTICARIA
DR LO KANG SHANG CHIT
Consultant Dermatologist
Island Hospital, Penang
URTICARIA AND CHRONIC URTICARIA
U
rticaria, also known as hives, is defined as superficial
short-lived swellings of the skin due to transient
plasma leakage from the small blood vessels.1 Urticaria
is blanchable, and the lesions may appear white, skin-coloured
or red, and in various sizes and shapes. The wheals are itchy
and usually last for only a few minutes to several hours.2
There are, however, many cases whereby the wheals recur
or last for 6 weeks or longer. In this condition, patients are
known to have chronic urticaria (CU).1,2 Chronic urticaria can
be very distressing and debilitating, as it can cause detrimental
effects on the patient’s daily activities, quality of life and sleep.1
MANAGEMENT OF CHRONIC URTICARIA
According to the 2010 Asian Academy of Dermatology and
Venereology (AADV) Consensus Guidelines,3 management
of CU should ideally begin with the identification and
elimination of the underlying cause(s) and/or trigger factor(s).
Unfortunately, this approach is not applicable in the majority
of patients, although this is the most desirable option. In Dr
Lo Kang’s clinical experience, the cause of CU is unidentified
in at least 95% of the cases. Under these circumstances, the
treatment given should aim at providing symptomatic relief to
the patients.3
GENERAL MEASURES
Generally, patients with CU should avoid non-steroidal antiinflammatory drugs (NSAIDs), codeine, alcohol, angiotensin-
converting-enzyme inhibitors (ACEIs) (in the case of
angioedema), as well as overtiredness and stress, all of which
may potentially trigger CU.3 As for the healthcare providers,
they can advise patients to use cooling antipruritic lotions,
such as calamine or 1% menthol in aqueous cream, to soothe
CU. They should also explain to the patient that the cause of
the condition is unlikely to be found, but the prognosis for
eventual recovery from ordinary urticaria is excellent.4
PHARMACOLOGICAL TREATMENTS
Antihistamines, specifically the non-sedating H1-antihistamines
(nsAH) (eg, fexofenadine), are the mainstay of treatment for
urticaria due to their good safety profile and proven efficacy in
many patients (44–91% of response rate in patients in various
studies).3 The medications should be taken on a regular basis
to obtain consistent results. The nsAH are recommended
as the first-, second-, third- and fourth-line treatment in the
T-T-T = Th
diabetes m
Strategies
drug comb
treatment;
Non-sedating H1-antihistamine (nsAH)
If symptoms persist after 2 weeks
nsAH updosing (up to 4x)
If symptoms persist after 1–4 weeks
Change nsAH or consider adding
leukotriene antagonist
Exacerbation: Systemic steroid (for 3–7 days)
If symptoms persist after 1–4 weeks
Add cyclosporin A, H2-antihistamine,
dapsone, omalizumab
Exacerbation: Systemic steroid (for 3–7 days)
FIGURE 3: Treatment algorithm for CU recommended by
the 2010 AADV Consensus Guidelines
2010 AADV Consensus Guidelines (Figure 3).3 The use of nsAH
in different levels of therapy, either as monotherapy or in
combination with other treatments, is discussed as follows3:
• First-line therapy: Standard dose of nsAH (the newer
generation of nsAH are preferred over the older generation).
• Second-line therapy: Increase the dose of nsAH up to
four times if symptoms persist after 2 weeks, but other
treatment options or combination therapy should also be
tried for best response.
• Third-line therapy: Change to other nsAH, or add a
leukotriene antagonist if symptoms persist after 1 to 4
weeks. Systemic corticosteroids may be added into the
treatment for 3 to 7 days if exacerbation of symptoms
occurs.
• Fourth-line therapy: nsAH can be continued as a
combination with the addition of cyclosporine, non-sedating
H2-antihistamines, dapsone, omalizumab, intravenous
immunoglobulin, or plasmapheresis, if symptoms persist
after a further 1 to 4 weeks. Systemic corticosteroids may
be added into the treatment for 3 to 7 days if exacerbation
of symptoms occurs.
ADDITIONAL TIPS ON USING ANTIHISTAMINES
Apart from the recommendations provided by the 2010
AADV Consensus Guidelines,3 Dr Lo Kang also shared with the
audience some tips on using antihistamines in CU:
• The use of sedating antihistamines as monotherapy is
becoming less common due to concerns on reduced
concentration and performance.
• Response and tolerance to antihistamines may vary among
patients. Therefore, all patients should be offered the
choice of at least two nsAH.
• It is best to avoid all antihistamines in pregnancy,
especially during the first trimester, although none of
the antihistamines has been shown to be teratogenic in
humans.
• Patients should be referred to a dermatologist if they do
not respond to standard doses of antihistamines.
TAKE-HOME MESSAGES:
• Urticaria, often occurs in a very prolonged course, is a
common condition in the community that could lead
to a poor quality of life.
• Antihistamines are the mainstay of therapy for CU; over
50% of patients with CU have shown good response to
this group of medications.
REFERENCES:
1. Tončić RJ, et al. Acta Dermatovenerol Croat 2009;17:305–322. 2. Asthma
and Allergy Foundation of America. Chronic Urticaria (Hives). Available at:
https://www.aafa.org/display.cfm?id=9&sub=23&cont=328. Accessed 10
June, 2015. 3. Chow SKW. Asia Pac Allergy 2012;2:149–160. 4. Grattan
CEH, Humphreys F. Br J Dermatol 2007;157:1116–1123.
EPL: A SUPERIOR COMPOUND TO EFFECTIVELY TREAT FATTY LIVER DISEASES
ESSENTIAL PHOSPHOLIPIDS IN FATTY LIVER DISEASES
Essential phospholipids have been widely used in liver diseases
to repair damaged liver cell membranes.1 Apart from its antioxidative,3 anti-inflammatory,4 anti-apoptotic,5 anti-lipidaemic6
and anti-fibrotic7 effects that had been demonstrated in various
animal models, numerous clinical studies also confirmed that
EPL is beneficial for both non-alcoholic fatty liver diseases
(NAFLD) and alcoholic liver diseases (ALD) in terms of:
• Improving symptoms of fatty liver diseases
Patients with NAFLD treated with 1.8 g of EPL daily for
3 months showed significant reduction in symptom-related
complaints (eg, fatigue, irritability and discomfort in the
right hypochondrium) (Figure 4).8
• Normalizing or reducing transaminase levels
Reduction in transaminase levels by EPL in patients with
ALD was reported by Knüchel9 and Butov et al,10 in which
significantly lower levels of transaminases were observed
in patients after 56 days and 21 days of treatment,
respectively. Butov et al10 also concluded that: “conducted
clinical and experimental study showed the effectiveness of
the use of EPL as hepatoprotector in alcohol-related liver
diseases. The application of EPL reduces the morphological
severity of inflammatory and degenerative changes in the
liver, and improves the clinical picture and laboratory status
of patients”.
• Improving fatty liver in NAFLD due to diabetes
In addition to diet and exercise, combination of EPL with
metformin reduced the incidence of severe and medium
NAFLD in diabetic patients by six cases and 14 cases,
IMPORTANCE OF COMPLIANCE TO DOSAGE AND
TREATMENT DURATION
Compliance to EPL treatment in terms of dosage (optimum
dosage: 0.9 g to 1.8 g) and treatment duration is important to
ensure consistent effectiveness in controlling liver diseases. In
a randomized, double-blind study by Li et al,16 patients with
NAFLD treated with 1.8 g EPL showed reduction in aspartate
transaminase (AST) and alanine transaminase (ALT) after
4 weeks, and the enzyme levels were normalized after 12 weeks
in 88% of the patients. According to Professor Gundermann,
EPL takes a minimum of 4 weeks to become active as it needs
to incorporate itself into the membrane of the hepatocyte.
Therefore, the first significant effect of EPL may only be seen
after 4 weeks of treatment, while further improvements
required a follow-up of up to 24 months.17
Professor Gundermann advised that patients should
continue EPL if there is slight, but steady improvement in their
liver function, or if their NAFLD has not yet completely cured.
However, they may discontinue EPL if no improvement is seen
after 3 months.
GLOBAL EFFICACY AND TOLERABILITY
In the efficacy and tolerability assessments conducted by
Padma et al,18 EPL was rated as good, very good and excellent
by nearly 90% of physicians and patients. In addition, more
than 90% of the physicians and patients also agreed that EPL
is well tolerated.
with EPL
80.0–
40
.0
50.0–
.7
33
.4
40.0–
0
6.
6.
7
7
20
20
.0
.0
26
30.0–
10.0–
66
53
.3
60.0–
.7
n=30
70.0–
20.0–
.7
.7
with EPL
 Post-treatment
86
93
.3
 Pre-treatment
86
90.0–
.3
E
ssential phospholipids (EPL) are highly purified
phospholipids fraction extracted from soybean that
contains about 75% of polyenylphosphatidylcholine
molecules (PPC, a class of EPL).1 The main active ingredient
in PPC is 1,2-dilinoleoylphosphatidylcholine (DLPC), which
is a molecule with two bound linoleic acids that improve
membrane structure and membrane-dependent cellular
functions.1 Essential phospholipids are derived from plant
lecithin, which is generally recognized as safe by the US Food
and Drug Administration (USFDA).2
100.0–
13
WHAT ARE ESSENTIAL PHOSPHOLIPIDS?
respectively. In contrast, the cases of severe and medium
NAFLD in the control group (metformin alone) were
reduced by only two and eight cases, respectively.11
• Inhibiting hepatic fibrosis more effectively than vitamin E
Using FibroTest, Sas et al12 showed that patients with
ALD treated with 1.8 g of EPL daily presented only slight
aggravation in hepatic fibrosis. On the other hand,
significant aggravation in hepatic fibrosis was observed in
patients treated with 0.4 g vitamin E daily.
The effect of EPL on fatty liver diseases had been
reviewed by Hu et al13 in a meta-analysis that involved six
double-blind trials around the world. The investigators
concluded that, in comparison with control, EPL has proven
benefits based on histological studies and its overall clinical
efficacy, in terms of improving clinical symptoms, signs and
biochemical variables. These pharmacological and clinical
data lead to the recommendation of EPL use in fatty liver
diseases by Kuntz and Kuntz14 and the 2010 Guidelines
for the Diagnosis and Management of Alcoholic Liver
Disease.15
% of patient with complaint
PROFESSOR DR
KARL-JOSEF GUNDERMANN
MD Professor and International Expert
Clinical Pharmacology, Gastroenterology,
Hepatology and Phytotherapeutics
University of Szczecin, Poland
Complaint 1
Complaint 1: Asthenia, fatigue
Complaint 2: Sleeping disorder
Complaint 3: Irritability
Complaint 2
Complaint 3
Complaint 4
Complaint 4: Bitter taste in the morning, dry mouth
Complaint 5: Subicteric sclera (jaundice)
Complaint 5
Complaint 6
Complaint 7
Complaint 6: Discomfort in the right hypochondrium
(discomfort under the right shoulder blade)
Complaint 7: Hepatomegaly (enlargement of the liver)
T-T-T = Th
diabetes m
Strategies
drug comb
treatment;
FIGURE 4: Essential phospholipids significantly reduced
patients’ complaint on clinical symptoms
TAKE-HOME MESSAGES:
• Damage to hepatocellular membranes is a common
but treatable process in liver diseases.
• Essential phospholipids contain optimal agents to
prevent and treat these membrane damages.
• Essential phospholipids are evidence-based medicine
for liver diseases.
• Premises for consistent effectiveness of the treatment
are sufficiently high doses of EPL (0.9 g to 1.8 g EPL per
day taken orally)
• First significant effect of EPL was observed after
4 weeks of treatment with further improvement over
24 months.
REFERENCES:
1. Gundermann KJ, et al. Pharmacol Rep 2011;63:643–659. 2. USFDA.
GRAS Notice 0000226; 2007. 3. Aleynik SI, Lieber CS. Alcohol Alcohol
2003;38:208–212. 4. Singh AK, et al. J Med Food 2007;10:526–542.
5. Mi LJ, et al. Alcohol Clin Exp Res 2000;24:207–212. 6. Chirkin AA,
et al. Addiction Biol 1998;3:65–70. 7. Lieber CS, et al Gastroenterology
1994;106:152–159. 8. Kharchenko NV, Korulya IA. Such Gastroenterol
2004;19:46–49 (Ukranian). 9. Knüchel F. Med Welt 1979;30:411–416
(German). 10. Butov MA, et al. Eksp Klin Gastroenterol 2014;(10):28–
32. 11. Sun C, et al. Clin Focus 2008;17:1272–1273. 12. Sas E, et al.
Polyunsaturated Phosphatidylcholine Reduces Insulin Resistance and Hepatic
Fibrosis in Patients with Alcoholic Liver Disease. Results of Randomized
Blinded Prospective Clinical Study. Presented at: 46th European Association
for the Study of the Liver (EASL); March 30–April 3, 2011; Berlin, Germany.
13. Hu G, et al. Chinese Hepatology 2005;(1):5–7. 14. Kuntz E, Kuntz
HD. Therapy of Liver Diseases (Chapter 40). In: Kuntz E, Kuntz HD, eds.
Hepatology – Textbook and Atlas. 3rd ed. Springer Press, Heidelberg 2008:
p896. 15. Li YM, et al. J Dig Dis 2011;12:45–50. 16. Li JH, et al. Infect Dis
Information 2000;13:180–181 (Chinese). 17. Ohbayashi H, et al. J Rural
Med 2007;1:67–73. 18. Padma L, et al. Ind J Clin Pract 2013;23:735–739.
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