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FOR HEALTHCARE PROFESSIONALS ONLY

NEWSLETTER
NEWSLETTER
FOR HEALTHCARE PROFESSIONALS ONLY NEWSLETTER MALAYSIA • MARCH 2016 Updated CPG on T2D management launched at

MALAYSIA MARCH 2016

Updated CPG on T2D management launched at AFES Congress

2016 Updated CPG on T2D management launched at AFES Congress T he opening ceremony of the

T he opening ceremony of the 18 th 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.

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 HbA 1c 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.

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

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.

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.

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.

Society of Endocrinology, and the Endocrine Society USA. Managing CV risk factors in obese T2D U

Managing CV risk factors in obese T2D

U 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

► FROM “MANAGING CV RISK FACTORS IN OBESE T2D” FRONT PAGE high-density lipoprotein (HDL) cholesterol.

FROM “MANAGING CV RISK FACTORS IN OBESE T2D” FRONT PAGE

high-density lipoprotein (HDL) cholesterol. [Diabetes Care 2009;32:493–498] 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.

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;373:1765–1772] In elderly patients with risk of hypoglycaemia and multiple comorbidities, where lowering of glucose isn’t particularly beneficial, it is acceptable to maintain HbA 1c 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

MALAYSIA • MARCH 2016

(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.

effects and uses 4 g as the starting dose for his patients. *FIELD: Fenofibrate Intervention and

*FIELD: Fenofibrate Intervention and Event Lowering in Diabetes

Fenofibrate Intervention and Event Lowering in Diabetes Moving forward from the TODAY study T he TODAY*

Moving forward from the TODAY study

T 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;366:2247–2256]

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 groups—metformin 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 rosiglitazone—a 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 imprinting—the 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.

will lead to a direr state of the diabetes epidemic in the future. * TODAY: Treatment

* 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 cost- effective 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 18 th 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 Dr KM Prasanna

Dr Zanariah Hussein Consultant Physician and Endocrinologist Department of Medicine Hospital Putrajaya

Endocrinologist Department of Medicine Hospital Putrajaya Dr KM Prasanna Kumar Former Sr Prof & Head Department

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

T 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 CPG 3 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 cost- effective.

Biosimilar insulins are produced via a series of well- regulated 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 intermediate- acting 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

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 short- acting 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 HbA 1c 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 studywas 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)

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 HbA 1c at week 12 (versus HbA 1c at baseline) (Figure 1), thus suggesting their efficacy in HbA 1c control. Out of these 107 patients, about 48% have improved HbA 1c , while 29% have their HbA 1c levels unchanged, indicating that the level of HbA 1c 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 HbA 1c (-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 HbA 1c values for patients who have been treated with premixed 30/70 biosimilar human insulin for 12 weeks

9.70

 

12 weeks (107* patients)

   

9.60

   

9.50

Reduction of 0.46%

9.40

9.40  
 

9.30

9.20

     

9.10

9.00

8.90

         

Baseline HbA 1c (%)

Week 12 HbA 1c (%)

*1 completed thalassaemic patient was excluded from analysis as there were no HbA1c readings

Clinical Evidence of Biosimilar Insulin Glargine

® ) 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

The biosimilar insulin glargine (Basalog

In terms of changes in HbA 1c , a multicentre, randomized, open-label Indian Phase 3 study 5 showed that both biosimilar insulin glargine and innovator glargine have similar effects on HbA 1c in patients with type 1 diabetes at the end of 12 weeks (Figure 2). The proportion of patients who achieved HbA 1c 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.

Sponsored Symposium Highlights

Figure 2: Biosimilar insulin glargine and innovator glargine demonstrated similar level of HbA 1c control
Figure 2: Biosimilar insulin glargine and innovator
glargine demonstrated similar level of HbA 1c control
at the end of 12-week study
Change in HbA 1c
10
9
8
7
6
5
4
Baseline
End of 12 th week
Biosimilar
insulin
7.86
7.8
glargine
Innovator
7.76
7.58
glargine
HbA 1c (%)

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 HbA 1c 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

There are huge unmet medical needs for high-quality and affordable biosimilars in both developing and developed countries.

Rigorousphysico-chemicalandbiologicalcharacterization 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, 4 th Edition; 2009. 4. CCM Data on File. 5. Verma M, et al. Int J Diabetes Dev Ctries 2011;31:26–31.

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

writing. Sponsored as a service to the medical profession by CCM PHARMACEUTICALS SDN BHD (27754-W) Lot

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.

Fax: 603-8925 7930

Tel: 603-8924 2188

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