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FOR HEALTHCARE PROFESSIONALS ONLY

NEWSLETTER

MALAYSIA

MARCH 2016

Updated CPG on T2D management launched


at AFES Congress

he opening ceremony of the 18th ASEAN Federation


of Endocrine Societies (AFES) Congress witnessed
the launch of the revised clinical practice guidelines
(CPG) for the management of type 2 diabetes (T2D)
in Malaysia.

73 percent of total deaths in the country, said Lokman. In


government hospitals, around 30 percent of these deaths
occur in those younger than 55 years old. This indicates
that the nation is losing a big chunk of the economically
productive population, he said.

Launched by Datuk Dr Lokman Hakim Sulaiman, Deputy


Director-General of Health (public health), MOH, the new
CPG has a few changes and additions compared with the
antecedent one. It recommends using HbA1c as a screening
and diagnostic tool for T2D, and provides algorithms for
patients on follow-up plus specific patient profiles. It also
covers additional topics such as unproven therapeutic
modalities, cardiovascular risk estimation, female sexual
dysfunction and mental health issues in diabetes.

Organizing chairperson Professor Nor Azmi Kamaruddin


in his welcome address said that this is the fourth time
Malaysia is hosting the AFES Congress, which takes place
biennially. This year also saw a record high of more than
300 submissions for oral and poster presentations. Nor Azmi
added that the launch of the new edition of CPG was long
overdue as the previous revision was done more than 6 years
ago. Work on the new guideline began back in October 2013,
and I am glad to see the final product more than 2 years
later, he said. The fifth edition of the CPG can be accessed at
http://www.mems.my/file_dir/14963565685527d8749429c.pdf.

The revision of the T2D management guideline is timely


as the incidence of diabetes is on the rise. Changes have
to be incorporated to counter the increasing morbidity
and mortality rates. Additionally, Malaysia is becoming
more affluent and non-communicable diseases (NCDs)
are increasingly prevalent, accounting for an estimated

Also present at the opening ceremony of the congress


were representatives from endocrine societies of six
other AFES member countries, the International Society of
Endocrinology, and the Endocrine Society USA.

Managing CV risk factors in obese T2D

p to 80 percent of patients with T2D are overweight/


obese or have significant amounts of ectopic
fat. This group of individuals is particularly at
increased risk of cardiovascular (CV) disease.

Triglycerides are not directly atherogenic themselves, but


are a useful biomarker of CV disease as they are associated
with atherogenic remnant particles.

It is important to note that these particles are best


indicated by non-fasting triglycerides. This reflects the
increasing trend of not testing fasting lipids that has been
observed lately, said Professor Gary Wittert of the University
of Adelaide, Australia.
In the FIELD* study, the power of serum triglycerides
to predict CV events was attenuated after adjustment for
CONTINUED ON NEXT PAGE

MALAYSIA MARCH 2016


FROM MANAGING CV RISK FACTORS IN OBESE T2D
FRONT PAGE
high-density lipoprotein (HDL) cholesterol. [Diabetes Care
2009;32:493498] This suggested that if HDL cholesterol is
raised, it may not matter as much how the triglycerides are
dealt with. The challenge, however, is that there are no effective
pharmacological means to raise HDL cholesterol levels.
Lowering triglycerides is an effective way to increase
HDL. This can be done using nutritional means by reducing
consumption of refined carbohydrates. With my patients,
this is a non-negotiable measure and I see extremely
effective results from it, shared Wittert. Stopping smoking
and increasing physical activity confer additional benefit
towards this end, he added. Physical activity must consist of
both aerobic exercises and muscle strengthening activities.

(OSA) also effectively reduces BP. When cases of resistant


hypertension or nocturia are observed, physicians must
always consider the presence of OSA.
Wittert also suggests bariatric surgery for extremely obese
T2D patients diagnosed within the last 8 years. Additionally,
he also prescribes omega-3 fatty acid supplements for his
patients. He postulates that studies on this supplement
have not shown benefit due to low doses administered.
He opined that large doses could be given for therapeutic
effects and uses 4 g as the starting dose for his patients.
*FIELD: Fenofibrate Intervention and Event Lowering in Diabetes

In terms of the contribution of glucose towards CV event risk,


a meta-analysis has shown that intensive treatment from the
start gives a better benefit compared with standard glycaemic
control. [Lancet 2009;373:17651772] In elderly patients with risk
of hypoglycaemia and multiple comorbidities, where lowering
of glucose isnt particularly beneficial, it is acceptable to
maintain HbA1c of around 8 percent as long as all the other
risk factors are aggressively controlled.
Pharmacotherapy should be combined with weight
loss, which is achieved by a diet that provides adequate
nutrition ie, the DASH diet to reduce blood pressure (BP) in
hypertensive patients. Treating obstructive sleep apnoea

Moving forward from the TODAY study

he TODAY* study shows that single drug monotherapy


with metformin is relatively ineffective in adolescents
to maintain glycaemic control, says an expert. [N Engl
J Med 2012;366:22472256]

Personalized therapy seems to be the appropriate


approach to take when treating adolescents with T2D, as the
study showed that the combination of metformin with lifestyle
interventions or rosiglitazone gives different outcomes in
different populations. It might be worth evaluating which is
the best combination for individual patients, said Professor
Dr Paul Hofman of the University of Auckland, New Zealand.
The study, which was the largest clinical trial to study
the treatment of youth-onset T2D to date, randomly
assigned youths (10 to 17 years of age) with T2D to one of
three treatment groupsmetformin alone, metformin
and rosiglitazone, or metformin plus an intensive lifestyle
programme.
The study highlighted that T2D in adolescents was
different compared with that in adults. A faster disease
progression rate and treatment failure rate, and higher rates
of complications leading to poor long-term outcomes were
documented in these subjects. Additionally, beta cell function
of the young patients was demonstrated to deteriorate more
quickly compared with adults even with the combination of
metformin and rosiglitazonea combination that is used to
protect beta cell function in adults.
Hofman noted that at the start of the study, about 200
individuals were ineligible for recruitment as they were
type 1 diabetics masked as T2D patients. This indicated the

need to be careful when diagnosing; most obese children


with diabetes probably need antibody testing for accurate
diagnosis.
Physical activity analysis showed that girls do less physical
activity than boys in any age group, whereas among boys,
those with diabetes exercise less compared with obese boys.
This reflects the reduced capacity of T2D patients to perform
physical activity, due to stiff left ventricles resulting in the end
diastolic volume not increasing. Hence, physicians need to be
cautious when recommending exercise to T2D patients.
The current recommendations and guidelines for
management of adolescents with T2D still leave much room
for improvement. Hofman said that he will still be using
metformin or insulin as first-line treatment. There is still no
best approach to diet and exercise. The low-calorie, ketogenic
diet appears to be effective but is unpalatable, resulting in
poor compliance. Bariatric surgery has shown impressive
results in select patients, even leading to sustained resolution
of diabetes. While Hofman was not advocating for its use, he
recommends that it be considered for the right patient.
In summary, he said that the TODAY study highlighted
many issues for which solutions need to be found. The
major issue plaguing proper management of adolescent
T2D patients is compliance. He underscored the need to
be mindful of metabolic imprintingthe children of today
will be the parents of tomorrow. Continuous increase of
adolescent T2D will lead to a direr state of the diabetes
epidemic in the future.
* TODAY: Treatment Options for Type 2 Diabetes in Youth

Sponsored Symposium Highlights

Biosimilars, defined by the European Medicines Agency (EMA) as medicines that are similar to another biological
medicine that has been authorized for use,1 are increasingly accepted worldwide. Besides being more costeffective than the innovator products, biosimilars are similar in quality, safety profile and efficacy to the
innovator products, as they are produced by following a strict pharmacovigilance plan developed by the EMA.1
Biosimilar insulins are one of the classes of biosimilar products available in the market currently. To expand
healthcare professionals knowledge on biosimilar insulins, CCM Pharmaceuticals exclusively invited
Dr Zanariah Hussein and Dr KM Prasanna Kumar to share their experiences in using biosimilar insulins in
managing diabetes at a lunch symposium held during the 18th AFES Congress 2015. The highlights of their
presentations are presented below.

Biosimilar Insulins:
Sharing Clinical Experiences
Dr Zanariah Hussein
Consultant Physician and Endocrinologist
Department of Medicine
Hospital Putrajaya

he global burden of diabetes is immense. The 2015


International Diabetes Federation data showed
that there are currently more than 400 million
people with diabetes around the world.2 Malaysia
has the highest prevalence (ie, 16.6%) among the ASEAN
countries, with an estimated number of 3 million adults
with diabetes to date.2

Insulin and Biosimilar Insulin

Insulin remains the standard of care for diabetes.2 Its


use in the management of diabetes has progressively
increased over the years. In fact, the Malaysian CPG3 also
recommends the use of insulin as early as at diagnosis in
T2D patients with very high glycaemic levels.
With the expiring of several patented insulin products,
there is a growing demand for biosimilar insulins. Studies
showed that biosimilar insulins are currently being used
by about 40% of diabetic patients across 65 countries.4
Biosimilar insulins are the second-generation insulin
products designed to be highly similar to the innovator
products. They have the same amino acid sequence as the
innovator products, but are often made using the later-day
more advanced technology, thus making them more costeffective.
Biosimilar insulins are produced via a series of wellregulated processes that involve cloning of the desired
gene using a suitable host (ie, bacteria or yeast),
followed by fermentation, extraction and purification.
Insugen-R (a biosimilar short-acting human insulin),
Insugen-30/70 (a premixed 30/70 biosimilar human
insulin) and Insugen -N (a biosimilar intermediateacting human insulin), manufactured by Biocon Limited,
are three examples of biosimilar insulins available
currently. These biosimilar insulins are produced using
the yeast Pichia pastoris, which gives higher productivity
than using bacteria.

Clinical Evidence of Biosimilar Human Insulins

Global clinical studies have reported that biosimilar

Dr KM Prasanna Kumar
Former Sr Prof & Head
Department of Endocrinology, Diabetes & Metabolism
MS Ramaiah Medical College & Hospitals
Bangalore

human insulins are generally equally effective, safe, and


well tolerated as compared with the innovator products.4
The bioequivalence between biosimilar short-acting
human insulin and premixed 30/70 biosimilar human
insulin versus the innovator products were proven via
pharmacokinetic (PK)/pharmacodynamic (PD) studies,
while biosimilar intermediate-acting human insulin was
also found to have similar PK profile when compared with
the innovator products.
The European Phase 3 Study was designed to compare
the safety and immunogenicity between biosimilar shortacting plus intermediate-acting human insulins and the
innovator products. A total of 560 patients were enrolled
into this study. Efficacy results at 24 weeks showed that
biosimilar human insulins were non-inferior to the
innovator products in terms of HbA1c reduction. There was
also no difference in the average basal insulin dose when
compared with the innovator products. The safety profiles
(eg, injection site reaction, allergy and hypoglycaemia)
between groups were comparable. Furthermore, the
antibody-binding of biosimilar human insulins was no
different from the innovator productsthe immunogenicity
between groups was comparable. The study concluded
that biosimilar human insulins were non-inferior to their
innovator products in terms of efficacy and safety.
A post-marketing surveillance studythe PRIDE study
was carried out among patients (n=6,164) and doctors
(n=507) to survey their experience with premixed 30/70
biosimilar insulin, biosimilar short-acting human insulin
and biosimilar intermediate-acting human insulin.
Overall, 99% of the investigators opined that all three
types of biosimilar human insulins provided excellent to
fair therapeutic responses, with no significant differences
observed between the biosimilar human insulins and the
innovator products.

The Malaysian Experience on Biosimilar Human Insulins

The ongoing Malaysian Phase 4 Post-marketing


Surveillance Study (protocol number: INSUG-DM-04-G-02)

Sponsored Symposium Highlights

is a 24-week study to assess the safety, tolerability and


efficacy of switching diabetic patients previously treated
with premixed 30/70 human insulin to premixed 30/70
biosimilar human insulin. Analysis on 107 patients who have
been treated for 12 weeks showed that biosimilar human
insulins were well tolerated, and resulted in a reduction
of 0.46% in HbA1c at week 12 (versus HbA1c at baseline)
(Figure 1), thus suggesting their efficacy in HbA1c control.
Out of these 107 patients, about 48% have improved HbA1c,
while 29% have their HbA1c levels unchanged, indicating
that the level of HbA1c control achieved with the biosimilar
human insulin was similar to that of premixed human
insulin. On top of that, analysis on 30 patients who have
completed the 24-week study showed a further reduction
in HbA1c (-0.83% from baseline). No serious drug-related
adverse events have so far been reported. Based on these
preliminary ongoing results that echo what has been
found earlier in the completed large-scale PRIDE study,
Dr Zanariah suggests that biosimilar human insulins may
be used interchangeably with premixed human insulins.
If proper dosages are used, their efficacy is equivalent to
premixed human insulins.
Figure 1: Average HbA1c values for patients who have
been treated with premixed 30/70 biosimilar human
insulin for 12 weeks
9.70
9.60
9.50
9.40
9.30
9.20
9.10
9.00
8.90

12 weeks (107* patients)

Reduction of 0.46%

Figure 2: Biosimilar insulin glargine and innovator


glargine demonstrated similar level of HbA1c control
at the end of 12-week study

Change in HbA1c

10

HbA1c (%)

9
8
7
6
5
4

Baseline

End of 12th week

Biosimilar
insulin
glargine

7.86

7.8

Innovator
glargine

7.76

7.58

Further to the clinically-proven benefits, Dr Prasanna


shared his personal experience in using biosimilar insulin
glargine in his patients. From about 40 patients whom
he has analyzed thus far, he found that biosimilar insulin
glargine showed similar effect on HbA1c control compared
with the innovator glargine. The mean daily insulin
dose used was no different from the innovator glargine.
Biosimilar insulin glargine also did not cause any weight
gain in his patients.

Take-home messages
Baseline HbA1c (%)

Week 12 HbA1c (%)

*1 completed thalassaemic patient was excluded from analysis as


there were no HbA1c readings

Clinical Evidence of Biosimilar Insulin Glargine

The biosimilar insulin glargine (Basalog) is a basal


analogue insulin developed by Biocon Limited using Pichia
pastoris as the host. Although this product has not been
launched in Malaysia, completed PK/PD studies and
ongoing global phase studies have shown that biosimilar
insulin glargine is bioequivalent to the innovator glargine.4
In terms of changes in HbA1c, a multicentre, randomized,
open-label Indian Phase 3 study 5 showed that both
biosimilar insulin glargine and innovator glargine have
similar effects on HbA1c in patients with type 1 diabetes at
the end of 12 weeks (Figure 2). The proportion of patients
who achieved HbA1c below 7% with biosimilar insulin
glargine and innovator glargine were 40.48% and 38.3%,
respectively. Biosimilar insulin glargine and innovator
glargine were equipotent as indicated by the mean daily
insulin dose. In addition, the mean 7-point blood glucose
values and immunogenicity profile between groups were
also comparable.

There are huge unmet medical needs for high-quality


and affordable biosimilars in both developing and
developed countries.
Rigorous physico-chemical and biological characterization
with clinical studies are keys to demonstrate
biosimilarity and quality of biosimilars.
The approval of biosimilar insulins requires strict
regulatory processes. They must demonstrate:

Robust chemistry and manufacturing control data;

Comparable results with innovator products in PK/


PD study; and

0Comparable results with innovator products in Phase


3 study on immunogenicity and efficacy.
Clinical experience in more than 50 countries clearly
established the growing acceptance of biosimilar
insulins as the way forward.
References: 1. European Medicines Agency. Biosimilar medicines. Available at: http://www.
ema.europa.eu/ema/index.jsp?curl=pages/special_topics/document_listing/document_
listing_000318.jsp. Accessed 19 January, 2016. 2. International Diabetes Federation. IDF
Diabetes Atlas, Seventh Edition; 2015. 3. Ministry of Health Malaysia. Clinical Practice
Guidelines: Management of Type 2 Diabetes Mellitus, 4th Edition; 2009. 4. CCM Data on File.
5. Verma M, et al. Int J Diabetes Dev Ctries 2011;31:2631.
Disclaimer: Basalog (manufactured by Biocon Limited) is a biosimilar insulin glargine
marketed in India since year 2009. Basalog has not been registered for use in Malaysia at
the time of writing.

Sponsored as a service to the medical profession by

CCM PHARMACEUTICALS SDN BHD (27754-W)

Lot 2 & 4, Jalan P/7, Section 13, Bangi Industrial Estate,


43650 Bandar Baru Bangi, Selangor Darul Ehsan, Malaysia.
Tel: 603-8924 2188 Fax: 603-8925 7930

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. 2016 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. Enquiries: MIMS Medica Sdn Bhd
(891450-U), Level 3A, Luther Centre, No. 6, Jalan Utara, 46200 Petaling Jaya, Selangor,
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Web site: www.mims.com
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