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ore dS ym po siu CURRENT TRENDS IN ts Sp on s DIABETIC HYPERTENSION, CHRONIC URTICARIA AND FATTY LIVER DISEASE m h lig gh i H 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. sanofi-aventis (Malaysia) Sdn Bhd (334110-P) Unit TB-18-1, Level 18, Tower B, Plaza 33, No.1, Jalan Kemajuan, Seksyen 13, 46200 Petaling Jaya, Selangor Darul Ehsan, Malaysia. Tel: 603-7651 0800 Fax: 603-7651 0801/0802 Editorial development by MIMS Medica. The opinions expressed in this publication are not necessarily those of the editor, publisher or sponsor. Any liability or obligation for loss or damage howsoever arising is hereby disclaimed. ©2015 MIMS Medica. All rights reserved. No part of this publication may be reproduced by any process in any language without the written permission of the publisher. 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