Should there be evidence-based management for all ethnic groups of diabetics or not?






Siew Pheng CHAN
MBBS (Malaya)
FRCP (Edinburgh)
Consultant Endocrinologist Sime Darby Medical Centre
Subang Jaya, and Honorary Consultant Endocrinologist
University of Malaya Medical
Centre, Kuala Lumpur – MALAYSIA

Should there be evidence-based management for all ethnic groups of diabetics or not?

Management beyond borders – an Asian perspective


by S. P. Chan, Malaysia



Asia is the “hotspot” for type 2 diabetes mellitus (T2DM)—all recent epidemiological studies continue to show rapid increases in prevalence occurring over a shorter time frame compared with other regions, with China and India having the largest number of people with diabetes. Apart from large numbers of people affected, it is also well-known that diabetes in Asia occurs in younger age groups and at a lower body mass index (termed the “metabolically obese” phenotype). With the younger age at onset, duration of disease is therefore longer, with higher risk of developing complications. Understanding which key pathophysiological abnormalities play major roles in triggering the development of T2DM will help clinicians make decisions on appropriate therapeutic agents. The important role of loss of β-cell mass and β-cell secretory dysfunction in the Asian diabetic individual makes the class of sulfonylureas (SUs) a clear choice either after metformin monotherapy failure or as first-line therapy in patients who are either intolerant of metformin or for whom metformin is contraindicated. The most recent guidelines (International Diabetes Federation 2011 and American Diabetes Association/ European Association for the Study of Diabetes 2012) for the management of diabetes/hyperglycemia have continued to affirm the position of SUs. Gliclazide MR, as the agent used in ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), can therefore lay claim to having outcome data to support its clinical utility. The ADVANCE study includes a sizeable Asian cohort and as such, results and lessons learned can be directly applicable to the Asian T2DM patient.

Medicographia. 2013;35:21-28 (see French abstract on page 28)



Type 2 diabetes mellitus (T2DM), is known to cause premature death, largely via a two- to fourfold increase in macrovascular complications, in particular, cardiovascular mortality. The earlier the age of diabetes onset, the more years of life lost. Type 2 diabetes in Asians, as reported by the Asia-Pacific Cohort Studies Collaboration, is associated with similarly increased cardiovascular complications (Figure 1, page 22)1 as those reported from T2DM studies in white subjects.2,3,4

In an interim analysis of the UKPDS (United Kingdom Prospective Diabetes Study), an assessment of effect of ethnicity on incident fatal/nonfatal myocardial infarction (median follow-up 8.7 years) showed that despite having the lowest incidence of hypertension and current smoking, and being younger than their white and black counterparts, Asian Indian patients had a similar cardiovascular risk to whites.5


Figure 1
Figure 1. Sex-, study-, and age-adjusted hazard ratios (log scale) for deaths from major cardiovascular diseases and all causes (diabetic
vs nondiabetic), by age group.

Abbreviations: CI, confidence interval; homog, homogeneity.
After reference 1: Woodward et al. Diabetes Care. 2003;26:360-366. © 2003, American Diabetes Association.



In addition to the clinical consequences of T2DM, the unfortunate fact is that Asia has the highest burden of people with T2DM. Some of the world’s most populous countries are in Asia, including China, India, and Indonesia. Apart from sheer population sizes, the prevalence of T2DM in Asia has risen over a much shorter time, occurring in a younger age group (approximately 10-15 years younger than in whites) and in people with a lower body mass index (BMI).6





In the Asia-Pacific Cohort Studies Collaboration report,1 based on data from more than 93 000 people from China, Japan, Singapore, and Taiwan, Asian diabetic subjects had a lower mean BMI of 23.9 kg/m2, compared with nondiabetic subjects with a mean BMI of 22.1 kg/m2 (Table I). This is in contrast to the higher BMIs noted in white T2DM subjects.

In Shaw’s review7 of current global estimates of T2DM burden, 5 of the top 10 countries for numbers of people aged 20-79 years with diabetes are from the Asia-Pacific region (Table II).

These estimates are based on current prevalence rates of diabetes. The prevalence is increasing rapidly in many of these developing countries, driven by socioeconomic advancement, greater urbanization, as well as nutritional transition to over nutrition and sedentary lifestyle. A clear relationship between wealth of a country and burden of diabetes has been noted: as the average per capita consumption increases, a corresponding increase in diabetes prevalence is seen.

The majority of the projected increase is expected to come from developing countries such as those from the Asia-Pacific region. From 2010 to 2030, the numbers of diabetic people are projected to increase by 72% in South Asia and 47% in the Western Pacific region as opposed to 20% and 42% for Europe and North America, respectively (Table II).7 This may prove to be a gross underestimate, given recent published prevalence data from Malaysia, Indonesia, and China.

Indonesia is expected to have the greatest absolute increase in adults with T2DM, rising from 3.4 million in 2010 to 16.5 million in 2030. Pramono et al,8 in a recent epidemiological study conducted in 2007, noted that 4.1% of the total 5.6% of the population found to have diabetes were undiagnosed. In addition, the main predictive factors for diabetes were age, visceral obesity, hypertension, and smoking.

Malaysia is already experiencing an epidemic of diabetes, with 11.6% of the population above the age of 18 years found to have diabetes in the 3rd National Health and Morbidity Survey conducted in 2006.9 Much of this has been driven by the associated increasing trend in obesity/overweight, of 33.6% and 19.5%, respectively. In the most recently released 4th National Health and Morbidity Survey conducted in 2011, the prevalence of diabetes has jumped to 20% (Ministry of Health Malaysia report, 2012).


Table I
Table I. Mean values of baseline variables – Asia.

Abbreviations: BMI, body mass index; CI, confidence interval.
Adapted from reference 1: Woodward et al. Diabetes Care. 2003;26:360-366. © 2003, American Diabetes
Association.



Table II
Table II. Top 10 countries for numbers of people aged 20-79 years with diabetes in
2010 and 2030.

Abbreviation: No, number.
Adapted from reference 7: Shaw et al. Diab Res Clin Pract. 2010;87:4-14. © 2007, Elsevier Ireland Ltd.



For China, in a survey conducted from 2007-2008,10 the age standardized prevalence of total diabetes was 9.7%, accounting for 92.4 million adults with diabetes. This number alone is higher than that projected in Shaw’s7 estimate of 62.6 million in 2030.

Asia is, therefore, the “hotspot” for diabetes and will remain so in the near future. The resultant economic burden of therapy for controlling glycemia as well as management of diabetic complications will be a strain on governmental funds as many of these are developing countries with limited financial resources. Understanding pathophysiology – Asian T2DM

Recognition of the major underlying pathophysiological processes that determine T2DM occurrence in the Asian individual will help clinicians make appropriate therapeutic decisions.

_ Role of β-cell secretory dysfunction
-Cell secretory dysfunction is thought to play a bigger role in the pathogenesis of T2DM in the Asian population than in whites. In whites, β-cell mass in patients with T2DM has been shown to be reduced by 40%-60% in human autopsy studies.11-14

Similar to Butler’s cadaveric study,15 Yoon et al16 reported that β-cell volume was reduced to less than 50% in pancreatectomy specimens of nonobese Korean T2DM subjects, compared with that of BMI-matched normal controls. In this elegant study, β-cell volume correlated significantly with BMI: the clinical implication being that the lower the BMI, the greater the loss in β-cell mass. In addition, β-cell mass was observed to be increased, with a resultant higher α/βratio than in controls. These findings support the role of selective β-cell loss in the pathogenesis of T2DM.

Clinical observations and experimental data support a close interrelationship between reduction in β-cell mass and β-cell dysfunction. Human donors who underwent a 50% pancreatectomy eventually developed diabetes.17 Loss of β-cell mass was noted to be associated with increased β-cell apoptosis, while new islet formation rates and β-cell replication were noted to remain normal.15

In addition, data from Japanese populations18,19 found that impaired early-phase insulin secretion, assessed by the insulinogenic index during the oral glucose tolerance test, was the initial abnormality in the development of glucose intolerance (Figure 2 A and B). When progressing from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT), there was a 50% loss of β-cell secretory function. There was a further loss of up to 80% of β-cell function once frank DM ensued. In contrast, when progressing from NGT to IGT and subsequently to DM, insulin resistance increased by only approximately 2-fold. These findings confirmed the earlier study by Matsumoto et al.20


Figure 2
Figure 2. (A) Comparison of insulin secretion index in the basal
state across the range of glucose tolerance. Insulin secretion decreases
with increasing glucose intolerance. (B) Early-phase insulin
secretion decreases remarkably with increasing glucose intolerance.
*Significant differences assessed by analysis of variance.

Abbreviations: DM, diabetes mellitus; HOMA, homeostatic model assessment;
IGT, impaired glucose tolerance; NGT, normal glucose tolerance.
After reference 18: Fukushima et al. Metabolism. 2004;53:831-835. © 2004, Elsevier Inc.



In a longitudinal study by Chen et al19 in Japanese American, migrant, nondiabetic men, impairment of early-phase insulin secretion, as assessed by insulin secretion at 30 minutes after an oral glucose load, was present at baseline, prior to the onset of diabetes. At baseline, there was no significant difference in intra-abdominal fat and fasting insulin between those who remained normal glucose tolerant and those who progressed to diabetes. After 5 years, after the superimposition of increased visceral adiposity, these subjects subsequently developed diabetes. Very similar findings have been reported in Korean T2DM.21

These data clearly show the clinical relevance and importance of lower basal and impaired early-phase insulin secretion in the pathogenesis of Asian T2DM. Therapeutic agents that address β-cell dysfunction would be expected to play a major role in achieving glycemic control in these individuals.

_ Role of insulin resistance
In general, the Asian T2DM individual has a lower mean BMI (23-25 kg/m2), as shown in Table I.1 Asian populations have more visceral fat for any given BMI.22-25 Deurenberg-Yap et al reviewed this in a multiethnic population in Singapore and concluded that the equivalent BMI cutoff for obesity in Asians is 3 kg/m2 less than that for whites, ie, 27 kg/m2.26 In fact, the “metabolically obese” phenotype among individuals of normal weight is a common phenomenon found in Asians, notably Asian Indians.25,27-32 This phenotype, characterized by a higher degree of abdominal obesity despite a normal BMI, a higher proportion of body fat, and increased insulin resistance compared with whites, renders these populations more highly susceptible to development of diabetes.25,30-32 Raji et al,33 in a study of a group of healthy Asian Indians compared with age- and BMI-matched whites, found that Asian Indians had significantly more total abdominal fat and visceral fat (assessed by computed tomography scan), had typical metabolic dyslipidemia with low levels of high-density lipoprotein cholesterol, had elevated triglycerides, and were profoundly insulin resistant, as assessed by the euglycemic hyperinsulinemic clamp, compared with their white counterparts. Notably, the mean BMI of these healthy Asian Indians was 23 kg/m2.

In the UKPDS, 10% of the entire cohort was of Asian Indian origin. These Asian Indian patients were significantly younger, included more men, and had a lower mean BMI than the white and Afro-Caribbean patients (P<0.001). The Asian Indian cohort was the most insulin resistant, when compared with the white and Afro-Caribbean cohorts.5

Optimizing glucose management of the Asian T2DM subject – choice of therapeutic agent

It is important to consider the contribution of impaired insulin secretion and insulin resistance to the development of diabetes as these have therapeutic significance. All current guidelines (including those from the International Diabetes Federation in 2011 and those from the American Diabetes Association/ European Association for the Study of Diabetes in 201234) continue to include sulfonylureas (SUs) as a possible add-on therapy following failure of metformin monotherapy or as a first line agent in patients who are intolerant to metformin or where metformin is contraindicated. Metformin will continue to be an important therapeutic agent as the Asian T2DM subject has a greater percentage of visceral fat and lower muscle mass, for any given BMI. Insulin resistance has also been shown to occur at lower BMI levels. Use as first-line is recommended in most guidelines (irrespective of BMI), including those from many Asian countries.


Figure 3
Figure 3.
Cumulative incidence of major complications and all-cause mortality in the ADVANCE study, by region.

Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation.
Adapted from reference 37: Clarke et al. PloS Med. 2010; 7(2):e1000236. © 2010, Clarke et al.



However, in many Asian T2DMsubjects, SUs would be an appropriate choice of therapeutic agent, as they address the major β-cell secretory dysfunction. When deciding which SU to choose, consideration of the individual drugs’ pharmacokinetics and pharmacodynamics would aid in decision making. The differences in metabolism of the various SUs are likely to affect their efficacy. Cytochrome P450 (CYP) 2C9 and CYP2C19 are responsible for the metabolism of over 20% of clinical therapeutic drugs. CYP2C9 genetic polymorphism is known to be responsible for the metabolism of oral SUs, eg, glibenclamide and glimepiride. The metabolites of both glibenclamide and glimepiride are metabolically active and have persistent hypoglycemic potential.

In contrast, CYP2C19 genetic polymorphism appears to play an important role in the pharmacokinetics of gliclazide modified release (MR). For example, the area under the curve for gliclazide is significantly higher by 3.4-fold (95% confidence interval [CI], 2.5-4.7; P<0.01) in CYP2C19 poor metabolizer (PM) subjects compared with subjects with other genetic polymorphisms. 35 The half-life (t1/2) is also prolonged from 15.1 to 44.5 h (P<0.01). Similar increases in serum levels of gliclazide were found in the multiple-dose study. In addition, there is a greater prevalence (20%) of CYP2C19 PMs in Asian populations than in whites and Africans (5%). This can account for the greater antihyperglycemic response to gliclazide therapy in some Asian diabetic subjects. This will also explain the greater variability of response to gliclazide MR therapy in Asian subjects.

Lessons from ADVANCE

Lessons learned from the mega outcome trial, the ADVANCE study (Action in Diabetes and Vascular disease: PreterAx and DiamicroNMR Controlled Evaluation), are relevant for the Asian T2DM individual. This is because approximately 40% of the ADVANCE study subjects were from Asia, namely from China, India, Malaysia, and the Philippines.

ADVANCE used gliclazide MR as the active therapeutic agent in the intensive arm. Subjects randomized to the standard arm were allowed to be treated with other SUs. The objective was to achieve glycemic control with an HbA1c target of 6.5% in the intensive arm. This was successfully achieved, and it is important to note that it was achieved without weight increase and with only a low risk of severe hypoglycemia.36 Of the 91% on gliclazide MR in the intensive arm, 70% were taking gliclazide MR 120 mg daily, with 74% on metformin, 17% on thiazolidinediones, 19% on acarbose, and 40% on insulin.

Results reported by Clarke et al37 (2010) show that Asian T2DM subjects in the ADVANCE study suffer from significantly more cerebrovascular events and nephropathy events compared with other ethnic groups (Figure 3).37

Increased risk of renal disease and a requirement for renal replacement therapy have been previously noted as particular problems in Asian diabetic subjects. Karter et al,38 in the longitudinal observational study in the Kaiser Permanente Medical Care Program from 1995-1998, noted that there are clear ethnic disparities in diabetic complications, with Asian, Latino, and black diabetic subjects having higher levels of end-stage renal disease than their white counterparts (Figure 4A).38


Figure 4
Figure 4. (A) Ethnic disparities in diabetic complications – Kaiser
Permanente (1995-1998). (B) End-stage renal disease patients
with diabetes, 2003.

Adapted from (A) reference 38: Karter et al. JAMA. 2002;287:2519-2527.
© 2002, American Medical Association; and (B) reference 6: Yoon et al. Lancet.
2006;368:1681-1688. © 2006, Elsevier Limited.



Figure 5
Figure 5. ADVANCE – Effects of glucose control strategy on renal outcomes.

Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation; CI, confidence interval.
Based on data from reference 36: ADVANCE Collaborative Group. New Engl J Med. 2008;358:2560-2572.



Yoon et al6 also noted that diabetes was the primary cause behind the large proportion of patients with end-stage renal disease on dialysis in many Asian countries, including Malaysia, Korea, Pakistan, Taiwan, and the Philippines (Figure 4B).6 These data confirm the global trend of diabetes as the main cause of end-stage renal failure requiring renal replacement therapy. Therefore, given the higher predilection for developing renal complications noted in Asian T2DM subjects, the improved renal outcomes found in the ADVANCE study take on greater significance.

In ADVANCE, achievement of the HbA1c target of 6.5% provided microvascular benefits, specifically, a 21% reduction in renal events (P=0.006), 9% reduction in microalbuminuria (P=0.018), and 30% reduction in macroalbuminuria (P<0.001) (Figure 5).36 Improvement in the urinary albumin-creatinine ratio observed at the end of the ADVANCE study was found to correlate with lower risk of cardiovascular death.39 In the context of the Asian T2DM subject, the prevention of albuminuria progression and subsequent renal failure would be expected to translate to lower morbidity and hopefully, eventual reduction in cardiovascular mortality.

ADVANCE-ON (the ADVANCE posttrial ObservatioNal study), the observational follow-up phase of ADVANCE is currently ongoing and is expected to provide further important answers about potential cardiovascular benefits after successful glucose control.

Conclusion

The Asian T2DM patient will dominate the diabetes landscape in the foreseeable future, with epidemic proportions of people with diabetes onset at a younger age, with the “metabolically obese” phenotype. With the expectation of increased life spans as a result of improved health care, these people will live longer with the disease. Diabetic complications, both microvascular and macrovascular, have been observed in the Asian diabetic to a similar extent to that reported in whites. Unfortunately, cerebrovascular and renal complications have been noted more frequently in Asians. The societal costs of managing these will place a burden on the individual. In addition, the potential adverse economic impact will likely overwhelm most governmental budgets.

Affordable therapeutic agents with proven efficacy and outcome studies to back their utility will be the important factors determining how clinicians make appropriate decisions in the challenging task of choosing antihyperglycemic agents. Recent updates on glycemic goals do not back down from our management strategy—which was always to individualize targets— but rather reaffirm it. The lower the better should still be the goal, the only precaution being that this should be done without causing hypoglycemia. _


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Keywords: ADVANCE; Asian diabetes; body mass index; insulin secretory dysfunction; renal complications; type 2 diabetes mellitus