TYPE-2 DIABETES PATIENTS IN MALAYSIA IMPACTED BY SUB-OPTIMAL DISEASE MANAGEMENT

Studies on newer classes of drugs for type 2 diabetes patients indicate benefits

not associated with older classes of diabetes drugs

Across the world, the burden of diabetes continues to grow year by year. Today, diabetes affects around 425 million adults, a number expected to rise to an estimated 629 million (1 in 10 adults) by 2045[1]. Asia bears a significant burden, with about 60% of the world’s diabetics living in this continent[2]. Among diabetic patients, 90% of them have type 2 diabetes (T2D) – the preventable type of diabetes, with T2D rates having quadrupled worldwide since 1980[3]. Nearer to home, T2D rates have been consistently on the rise among adults in Malaysia in the past 20 years – from 8.3% in 1996 to 14.9% in 2006, to 20.8% in 2011 and 22.5% in 2015[4].

In Malaysia, it was previously projected that 1 in 5 Malaysian adults would have diabetes by 2020. What is worrying is that this rate was already reached as early as 2014, underlining the seriousness of diabetes prevalence in Malaysia. Although 3.5 million Malaysian adults have diabetes, as many as 53% of diabetic adults are undiagnosed and do not know they have the disease. Meanwhile, the numbers continue to rise, with 4.5 million diabetics projected in Malaysia by 2020[5].

Even as poor diagnosis rates are causing concern, diabetic patients who are already diagnosed also show poor outcomes. Despite 99.5% of diagnosed diabetic patients being treated with medication, as many as 8 out of 10 patients still have uncontrolled diabetes[6]. If we look at global standards like HbA1c levels, which are also used in Malaysia during the care of diabetics, the picture looks bleak. HbA1c levels (which offer a broader picture of blood glucose levels over 2 to 3 months) should be 6.5% or lower in a person with well-controlled diabetes. However, DISCOVER, a recent real world evidence study, has shown that the average HbA1c level in Malaysia is 9.0%, higher than the world average of 8.4% for unmanaged diabetes. DISCOVER – a global, prospective, observational study of patients with T2D who are starting second-line glucose-lowering therapy, saw the participation of 334 patients in Malaysia, who were mainly urban residents (92.9%) and mostly treated by primary care physicians (64.3%). The 9.0% HbA1c level observed surpasses the 8.1% recorded in 2012 by the National Diabetes Registry[7].

The DISCOVER study, which was initiated to plug knowledge gaps on diabetes treatments and outcomes globally, especially in terms of newer classes of glucose-lowering drugs, gathers real world evidence (RWE) on the management of diabetes[8]. The study aims to improve understanding of T2D management and its efficacy, reduce the risk of complications from diabetes and improve quality of life for patients. RWE data, drawn from sources such as pragmatic trials, patient registries, claims databases, electronic medical records and surveys of healthcare professionals and patients, can complement existing data from controlled clinical trials.

“The contribution from a study like DISCOVER that collects real-world evidence is invaluable. In typical controlled clinical studies, the key aim is learning more about how a certain medication works in the human body, so we tend to control for variables in human biology. With a study that focuses on RWE, we can observe how people use a certain medication in an actual everyday clinical setting, which is often influenced by highly localised issues – anything from the medicine supply chain to local cultural attitudes and everything in between. From these insights, we can work more effectively to change patient behaviour,” said Dr Radhakrishna Sothiratnam, National Coordinating Investigator for Malaysia, DISCOVER study. “Through RWE studies, information such as disease burden and unmet medical needs, use of a treatment in representative patient populations and treatment pathways in everyday clinical practice, can be collected,” he said.

Significant lag in treatment of diabetics found

Another key finding of the DISCOVER study is that T2D patients in Malaysia on average experience a 3.3-year lag in treatment, whereby they continue taking first-line medication (medication prescribed when they were first diagnosed) for as long as 3.3 years despite the medication being ineffective in managing their diabetes, before commencing on second-line treatment (the next option if first-line does not work). Accessibility was found to be a key factor in prescribing treatment, with a sulphonylurea (a widely available type of drug accessible to 98.8% of patients) added to metformin (the commonly used first-line medication for diabetics) as a second-line treatment.

Often, diabetic patients, especially those on first-line treatment, do not regularly monitor their HbA1c levels, mistakenly believing that their glucose level is in control, as they are taking the prescribed medication. This lack of monitoring leads to uncontrolled diabetes and treatment lag, when the patient and doctor continue to rely on ineffective treatment. As diabetes is a progressive disease that is irreversible and gets more serious over time, treatment lag will allow the disease to worsen and for complications to develop, a situation that can be prevented with better monitoring. Indeed, the DISCOVER study recorded evidence that diabetic patients in Malaysia had a relatively high rate of potential complications. A quarter of patients had damage to small blood vessels (26.3%) and 1 in 10 had damage to larger blood vessels (9.9%), a relatively high rate, as they were only commencing second-line treatment, although the lag would likely have contributed to this rate.

Small blood vessel (microvascular) damage can lead to blindness, kidney failure, impotence and diabetic foot disorders resulting in amputation, while damage to larger blood vessels (macrovascular) can lead to cardiovascular diseases such as heart attacks, heart failure and strokes[9]. There are research findings that show that good control in diabetes can delay the onset and progression of these complications, underlining the importance of early diagnosis of diabetes, followed by intensive and efficient management of the disease right from the start, to reduce the risk of complications and related diseases that may develop. Overcoming the lag in treatment that has been observed among diabetics is crucial for optimal patient outcomes. Through effective disease management – in terms of effective lifestyle changes and optimal use of medication, the worst effects of diabetes can be delayed as long as possible.

At the same time, with cardiovascular diseases being a health concern among so many Malaysians – for example, ischaemic heart disease was the principal cause of death in 2016, at 13.2% of all deaths, findings from studies that show how specific treatments for diabetes can reduce cardiovascular risks are of importance to Malaysian patients[10].

The impact of innovative new treatments for diabetes

“Diabetes is a serious risk factor, leading to deaths and hospitalisation. As many as 60% of diabetics are found to be dying from cardiovascular diseases[11]. They have up to a four-time higher risk of suffering from heart diseases such as heart failure, heart attack or peripheral vascular disease, while the risk of suffering a stroke is twice as high[12]^,[13]. Diabetics also tend to develop coronary artery disease at a younger age and are more prone to suffering repeated heart attacks. Many patients also may not realise that heart failure has been found to manifest earlier than other types of diabetes-related heart disease such as heart attacks and stroke,” said Dato' Dr Tamil Selvan Muthusamy, Consultant Cardiologist at Cardiac Vascular Sentral Kuala Lumpur (CVSKL).

With diabetes being a risk factor in so many diseases, it is important to manage these risks effectively, such as by choosing the right diabetes medication. One key recent study that looks at how treatment for diabetes can reduce the risk of other diseases where diabetes is a risk factor is CVD-REAL 2, which investigated the positive cardiovascular effects associated with certain drugs for diabetics. CVD-REAL 2, which is also a RWE study, was conducted among more than 400,000 T2D patients in 6 countries across 3 regions (Singapore, Japan, South Korea, Australia, Canada and Israel)[14].

The study examined the impact of newer classes of glucose-lowering medicines, in particular, the effect of sodium-glucose co-transporter-2 inhibitors (SGLT2i) on patients who are newly being prescribed second-line diabetes treatment. SGLT2 inhibitors, which work by preventing the kidneys from reabsorbing glucose back into the blood helps lower blood glucose levels, by causing excess glucose to be removed from the body via urine.

In this study, a majority of participants (74%) did not have a history of cardiovascular disease.

From the study, it was observed that there was a significant risk reduction in the group taking SGLT2i medication compared to other oral glucose-lowering medicines, with 36% lower risk of hospitalisation due to heart failure, 32% lower risk of stroke, 19% lower risk of heart attack and 49% lower risk of death from cardiovascular causes overall. The results suggested that starting diabetics on SGLT2i medication as soon as their first-line treatment requires supplementation or replacement can potentially prevent cardiovascular complications from diabetes.

“With the latest research suggesting positive effects of new diabetes drugs on diseases whereby diabetes is a strong risk factor, it is important to consider these benefits and match them with the patient’s individual risks when choosing a drug to treat their diabetes. It is good to see the research findings that SGLT2i drugs are beneficial across ethnic and racial groups, geographic regions, and even across existing levels of cardiovascular risk. This is especially good for patients starting on second-line treatment already having relatively high levels of complications, due to treatment lag and poor disease control. Also, other demographic factors like higher incidences of stroke among Asian patients mean SGLT2i is a welcome option for Asian diabetics. However, more needs to be done to increase awareness on the benefits of SGLT2i drugs for treating T2D patients, and to improve access to SGLT2i for T2D patients in Malaysia,” said Dr Hew Fen Lee, Consultant Endocrinologist, Ramsay Sime Darby Medical Centre and Puchong Medical Centre.

A call for early awareness

Patient X is among the millions of diabetics in Malaysia. Like many Malaysians, he had no idea that he was diabetic until he went for a medical check-up.

“My condition could perhaps be attributed my lifestyle and my being overweight. I do feel lucky that my condition was detected early and managed well by my doctor. Imagine my shock when I was diagnosed with diabetes, with my blood sugar (HbA1c level) at a score of 11! Today, I want to encourage all Malaysians to take charge of their health and have better awareness of health problems they might have and their overall health risks. Having a disease like diabetes can really impact your quality of life,” said Patient X.

- Dr Radhakrishna Sothiratnam, Principal Investigator, DISCOVER Study & Consultant Physician, Columbia Asia Hospital Seremban

- Dr Anton Kumar Alexander, Associate Medical Director, AstraZeneca Malaysia

- Mr Allen Patino, Country President, AstraZeneca Malaysia

- Dato’ Dr Tamil Selvan Muthusamy, Consultant Cardiologist, Cardiac Vascular Sentral Kuala Lumpur

- Dr Hew Fen Lee, Consultant Endocrinologist, Ramsay Sime Darby Medical Centre

- Ms Sharon SC Chao, Group Brand Manager, AstraZeneca Malaysia

“When you’re at an early stage of diabetes, make sure to keep track of your blood glucose and HbA1c levels, besides taking your medicines as prescribed by the doctor, and manage your lifestyle as advised. It is commonly said that prevention is better than cure, but if it is too late to prevent diabetes, make sure to prevent complications by being the best patient you can, with the best disease control methods and the right medicines,” Patient X concluded.

About DISCOVER

DISCOVER is a global, prospective, observational study of patients with type-2 diabetes (T2D) who are starting second-line glucose-lowering therapy⁸. The study has enrolled over 15,000 patients in 38 countries across six continents, and provides a comprehensive and contemporary picture of treatment patterns and outcomes in patients with T2D worldwide. The DISCOVER study is designed to generate real world evidence (RWE) about people living with T2D worldwide. RWE is key to understanding more about T2D and how it is managed in day-to-day clinical practice, in order to improve disease management. In many regions, data on treatment and outcomes are scarce, especially data on newer classes of glucose-lowering drugs. The DISCOVER study aims to address these knowledge gaps by providing real world observational data on the use of second and later-line glucose-lowering therapies in people with T2D.

The DISCOVER study found that in Malaysia:

·    the average HbA1c level is 9.0%, higher than the world average of 8.4% for unmanaged diabetes, despite the current medical guidelines in Malaysia and globally, which target bringing HbA1c levels to 6.5% or lower.

·   T2D patients in Malaysia on average experience a 3.3-year lag in treatment, whereby they continue taking first-line medication for as long as 3.3 years despite the medication being ineffective in managing their diabetes, before commencing on second-line treatment.

·   a relatively high rate of diabetics in Malaysia were observed to have microvascular (26.3%) and macrovascular (9.9%) damage when they finally commenced second-line treatment following the lag.

About CVD-REAL

CVD-REAL is a multinational, observational cohort study in patients with type 2 diabetes mellitus evaluating the comparative effectiveness of initiating treatment with a sodium-glucose co-transporter-2 (SGLT2) inhibitor versus another glucose-lowering drug. This study will compare the risk of clinically relevant cardiovascular (CV) outcomes (e.g. stroke, myocardial infarction, hospitalization for heart failure and all-cause mortality) in patients who are new users of SGLT2 inhibitors with the risk in those who are new users of other glucose-lowering drugs1.

The CVD-REAL 2 results are consistent with the primary results from CVD-REAL.[15] Of the patients in CVD-REAL 2, some 75% were on dapagliflozin, 9% on empagliflozin, 8% on ipragliflozin (only available in South Korea and Japan), 4% on canagliflozin, 3% on tofogliflozin and 1% on luseogliflozin (both only available in Japan). The data for the study were obtained from anonymised real-world sources including medical records, claims databases and national registries, and were not independently adjudicated or verified against source documents. The meta-analyses were validated by the independent academic statistical group at St. Luke’s Mid America Heart Institute, Kansas City, US. While CVD-REAL was a large study with a robust propensity-matching technique, given its observational nature the possibility of residual, unmeasured confounding factors cannot be definitively excluded.

The CVD-REAL study series is aiming to collect data from approximately 4 million patients overall, from twelve countries across four major world regions.

About AstraZeneca in Cardiovascular, Renal & Metabolic Diseases (CVMD)

Cardiovascular, renal and metabolic diseases together form one of AstraZeneca’s main therapy areas and platforms for future growth. By following the science to understand more clearly the underlying links between the heart, kidney and pancreas, AstraZeneca is investing in a portfolio of medicines to protect organs and improve outcomes by slowing disease progression, reducing risks and tackling co-morbidities. Our ambition is to modify or halt the natural course of CVMDs and even regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and CVMD health for millions of patients worldwide.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide.

For more information, please visit www.astrazeneca.com and follow us on Twitter @AstraZeneca.

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[1] International Diabetes Federation. IDF Diabetes Atlas, 8th ed. Brussels, Belgium: International Diabetes Federation; 2017. Available at http://www.diabetesatlas.org/resources/2017-atlas.html Accessed 5 July 2018.

[2] Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014;103:137–149

[3] World Health Organization. Diabetes. Available at http://www.who.int/mediacentre/factsheets/fs312/en/. Accessed 5 July 2018.

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[6] Ministry of Health Strategic Plan 2016-2020. Available at http://www.moh.gov.my/penerbitan/Pelan%20Strategik%20KKM.pdf. Accessed 5 July 2018.

[7] Feisul MI, Azmi S. (Eds). National Diabetes Registry Report, Volume 1, 2009-2012. Kuala Lumpur; Ministry of Health Malaysia; 2013 Jul.

[8] The Discover Study. Diabetes and Real World Evidence. Available at http://www.discoverdiabetes.com/diabetes-RWE.html. Accessed 9 July 2018.

[9] World Health Organization. About diabetes. Available at http://www.who.int/diabetes/action_online/basics/en/index3.html. Accessed 9 July 2018.

[10] Department of Statistics Malaysia. 31 October 2017. Statistics on Cause of Death, Malaysia. Available at

https://www.dosm.gov.my/v1/index.php?r=column/pdfPrev&id=Y3psYUI2VjU0ZzRhZU1kcVFMMThGUT09. Accessed 9 July 2018.

[11] The Star. 27 August 2017. Diabetes, the killer of hearts. Available at, https://www.star2.com/health/wellness/2017/08/27/diabetes-the-killer-of-hearts/. Accessed 5 July 2018.

[12] Nwaneri C, et al. Mortality in type 2 diabetes mellitus: magnitude of the evidence from a systematic review and meta-analysis. The British Journal of Diabetes & Vascular Disease. 2013;13(4):192-207.

[13] Morrish NJ, et al. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia. 2001;44 Suppl 2:S14-21.

[14] Kosiborod M, Lam CSP, Kohsaka S, et al. Lower Cardiovascular Risk Associated with SGLT2i in More than 400,000 Patients: The CVD-REAL 2 Study. J Am Coll Cardiol. 2018; 71 (23): 2628-2639.

[15] Kosiborod M, et al. Lower risk of heart failure and death in patients initiated on SGLT2 inhibitors versus other glucose-lowering drugs: The CVD-REAL Study. Circulation. 2017; 136: 249-259.