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






Rodrigo O. MOREIRA
MD, PhD
Instituto Estadual de Diabetes e Endocrinologia do Rio de Janeiro (IEDE)
Rio de Janeiro – BRAZIL

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

Management beyond borders – a South American perspective


by R. O. Moreira, Brazil



Though insulin resistance and β-cell failure are hallmarks of type 2 diabetes mellitus, the course and treatment of the disease may also be influenced by local and environmental factors. Indeed, there is a growing body of evidence showing that ethnicity may influence diagnosis, the incidence of microvascular and macrovascular complications, the type, and even the response to different medications. Along with ethnicity, socioeconomic status also seems to be an important determinant of diabetic complications. Although these differences have been demonstrated in minorities and subpopulations in the United States, Asia, and Europe, data from South America is scarce. Unfortunately, there is no scientific evidence of good quality comparing data from South America with these communities or even comparing data from different South American populations. Until this information is available, it will remain impossible to define a specific guideline for diabetes treatment in this particular population. In the meantime, local South American diabetes societies should develop guidelines based on the American Diabetes Association and European Association for the Study of Diabetes statements, considering specific characteristics of each country. Defining a global strategy for diabetes diagnosis and management should be seen as an effort to unite specific populations in the fight against this devastating disease.

Medicographia. 2013;35:29-34 (see French abstract on page 34)



Type 2 diabetes mellitus (DM) prevalence is increasing worldwide. In 2011, Danaei et al1 published a very interesting systematic analysis including 370 country-years and 2.7 million participants from health examination surveys and epidemiological studies. Age-standardized prevalence of diabetes was 9.8% (8.6-11.2) in men and 9.2% (8.0-10.5) in women in 2008, leading to an estimated 173 (151-197) million men and 173 (151-197) million women with diabetes. Of those with diabetes, 40% (about 138 million) were from China and India, 10% (about 36 million) from the United States and Russia, and 12% (about 42 million) from Brazil, Pakistan, Indonesia, Japan, and Mexico. In 1980, age-standardized prevalence was 8.3% (6.5-10.4) in adult men and 7.5% (5.8-9.6) in women, yielding 77 (60-97) million men and 76 (58-97) million women with diabetes. Unfortunately, specific data from South America were very scarce. For instance, only one study was included in this analysis from Uruguay, Paraguay, Venezuela, and Argentina. Peru and Colombia contributed with 3 studies, Chile with 2 studies, and Brazil with 6 studies. These results confirmed how little is currently known and how little scientific information is available about type 2 DM in South America.

Also in 2011, the document entitled “Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)”2 was published, replacing the previous ADA/EASD statement from 2008 (“Medical management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy”).3 Despite substantial differences in both documents, the purpose of these two manuscripts was to review the available information on the benefits and risks of glycemic control as well as evidence concerning efficacy and safety of several drug classes used to treat type 2 DM. Review of the medical literature led to the development of specific recommendations for type 2 DM treatment.

The published consensus and/or guidelines by the ADA/EASD is often seen as the official recommendation for diabetes treatment worldwide. However, no specific information was included in those documents regarding an approach to management of type 2 DM in specific populations, particularly South American and African populations. Therefore, one should ask: Do these recommendations also apply to the South American population? Is there enough evidence to suggest that the course or the treatment of type 2 DM should be different in these populations?

Does ethnicity modulate the development of insulin resistance?

Type 2 DM is a disease characterized by insulin resistance (IR) and progressive β-cell failure. IR is defined as an inadequate response by insulin target tissues, such as skeletal muscle, liver and adipose tissue, to the physiological effects of circulating insulin. Ethnicity seems to be one of the IR determinants in specific populations. For instance, higher degrees of IR were seen among African Americans and Latinos in comparison with whites.4 Studies that compared various populations of West African descendants (including African Americans and native Ghanaians) and whites have reported higher degrees of IR among West African descendants.5,6 Interestingly, it seems that alterations in hepatic insulin clearance in African populations may partially explain these findings.5 These studies provide evidence for genetically driven IR as an underlying factor for the ethnic disparities in the prevalence of type 2 DM. Unfortunately, there are no studies comparing South American populations with any other populations worldwide or even within South America.

Does ethnicity influence the development of type 2 DM?

The role of ethnicity in DM development was contested after some results presented by the Diabetes Prevention Program (DPP). The incidence of type 2 DM was found to be similar (–1%) among African Americans, Asian Americans and Pacific Islanders, white Americans, Hispanic Americans, and Native Americans.7 The well-known ethnic disparity in the risk of type 2 DM was surprisingly not evident among the DPP cohort with impaired glucose tolerance (IGT), which was followed for up to four years. The finding of similar transethnic diabetes rates in the DPP suggests that once individuals have progressed from normal glucose tolerance to IGT, the risk of further progression to diabetes is the same across ethnic groups. Thus, it seems that ethnicity and genetic factors may play a role in the progression from a normal to impaired fasting glucose (IFG) state, but not from IFG to type 2 DM.8

Does ethnicity have an impact on the development of diabetes complications?

There is evidence suggesting that ethnicity may be one of the factors related to the development of diabetic complications. However, once again, most of the studies evaluate different populations in the United States and Europe and their results might not be relevant to South America. For instance, the prevalence of diabetic retinopathy in diabetic individuals was 46% higher in African Americans and 84% higher in Mexican Americans compared with non-Hispanic whites. African Americans and Mexican Americans also had higher rates of moderate and severe retinopathy and higher levels of many putative risk factors for retinopathy.9 Similarly, the rates of end-stage renal disease (ESRD) are approximately threefold or higher in African Americans, Latinos, and Native Americans compared with whites.10 The rates of hospitalization for lower extremity ulcers are similar across all ethnic groups, but lower extremity amputation (LEA) rates are two to three times higher in Mexican American and African American patients compared withwhites.11According to Samuel Dagogo-Jack,8 these rather large effects of glycemic control on target organ end points indicate that genetic factors are permissive rather than obligate determinants of risk.





The impact of ethnicity on diabetic complications was also demonstrated by the Kaiser Permanente Medical Care Program.12 Karter et al reported that despite comparable health insurance coverage, ethnic disparities persisted for myocardial infarction (MI), stroke, congestive heart failure (CHF), ESRD, and LEA. Interestingly, patterns of ethnic differences were not consistent across complications and persisted even after adjustment for demographic and socioeconomic factors. For instance, minority populations (Asians and Latinos) had lower incidence of MI, stroke, and CHF. On the other hand, they had a higher incidence of ESRD. The authors concluded that the persistence of ethnic disparities after adjustment suggests a possible genetic origin, the contribution of unmeasured environmental factors, or a combination of these factors. It remains to be determined if the disparities would also be found in the South American population and what impact the environment would have on diabetic complications in a continent characterized by great discrepancies among their countries and populations.

These results have also been contested by other studies. For instance, after adjustment for a well-known risk factor for retinopathy in the NHANES (National Health And Nutrition Examination Survey) III, the black/white disparity was no longer significant.9

Does socioeconomic status affect the development of DM and its complications?

Although significantly different with regard to ethnicity, African American, Latino, and Mexican American populations share a determinant characteristic with South American populations: low socioeconomic status. There is compelling evidence that low socioeconomic status, limitations in access to care, lack of health insurance or underinsurance, and other socioeconomic barriers, all common in South American countries, are important contributors to the increased burden of diabetes and its complications.13,14

In line with these findings, there are results showing that in African American populations, the development of diabetes ketoacidosis has been directly related to the cessation of insulin.15

The most important challenge in determining the particular effect of ethnicity on diabetic complications is how to separate ethnicity from socioeconomic status. A study by Karter et al16 highlights the relevance in making this distinction. Throughout their study, the authors demonstrated that the marked ethnic disparity in LEA rates observed in the general diabetic population is not evident in an ethnically diverse population with uniform health care coverage. Even the low frequency of self-monitoring of blood glucose (SMBG) has socioeconomic underpinnings: with identical health insurance coverage, the frequency of SMBG among African Americans increased to match or exceed that of Asian, Latino, or white patients.

How does socioeconomic status influence DM treatment in South America?

Cost is one factor that must be taken into account when defining a specific treatment for type 2 DM in a specific population. The choice of medications supported by guidelines may be based mainly on efficacy and safety, but this becomes secondary when defining guidelines for South America and Africa. In most countries in Europe and the United States, the government provides either part or all of the treatment for most chronic diseases, whatever medication is used. In South America, there are a limited number of medications available in the public health system (PHS).

For the majority of type 2 DM patients, treatment will be chosen according to the medications available in the PHS. In most South American countries, only metformin and sulfonylureas (mostly chlorpropamide and glibenclamide) are available. For patients who do not tolerate these medications, options are limited to regular insulin and neutral protamine Hagedorn (NPH) insulin. Pioglitazone, dipeptidyl peptidase 4 inhibitors, liraglutide, exenatide, and insulin analogues are available for only a small part of the population who can afford the high costs of these therapies. Importantly, neither the government nor private health insurance reimburse these medications. As a consequence, the development of a specific guideline for our region needs to consider this aspect since it is the major determinant of the kind of treatment most of the population will have access to.

In some countries, or more specifically, in some regions of certain countries, some additional medications may also be available. As an example, there are some regions in Brazil where pioglitazone, dipeptidyl peptidase 4 inhibitors, liraglutide, exenatide, and insulin analogues can be provided to a limited number of type 1 and type 2 DM patients.

The impact of socioeconomic status on glycemic control, however, is still controversial. An analysis of the NHANES III data by Harris et al17 demonstrated that education, income, health insurance coverage, number of physician visits per year, and other variables were not predictive of poor glycemic control in a sample of non-Hispanic whites, non-Hispanic blacks, and Mexican Americans. On the other hand, race/ethnicity was associated with differences in diabetes treatment. A larger proportion of non-Hispanic black men and women were treated with insulin compared with non-Hispanic whites and Mexican Americans.

This finding was complemented by a smaller proportion of non-Hispanic blacks using oral agents, such that the proportions that were treated pharmacologically were similar for each racial or ethnic group. Finally, for those treated with insulin, a higher proportion of non-Hispanic whites used multiple insulin injections compared with non-Hispanic blacks and Mexican Americans.

The impact of ethnicity on the type of diabetes medication used has also been recently demonstrated in the UK population. 18 White patients were less likely to be on intensive diabetes treatment (either “combined oral” or “insulin”) than were South Asian and black African/Caribbean patients, but South Asians were less likely to be on insulin than were whites. Interestingly, glycated hemoglobin (HbA1c) control to 7.5% or less was worse in South Asian and black African/Caribbean patients than in whites despite more intensive treatment in these ethnic groups. In this study, James et al suggested that both socioeconomic status and ethnicity are independently associated with glycemic control.

The lack of association of glycemic control with socioeconomic status was also found in a Michigan community study of whites19 and a South Carolina study of blacks and whites20 in which poor glycemic control was not associated with educational level. These studies reflect the impact of socioeconomic status and ethnicity in the United States and the United Kingdom. Do these results also apply to South America? How would differences in the PHS affect these findings? What would be the most important factor related to diabetes treatment in South America: socioeconomic status or ethnicity?

Should DM treatment in South America be different?

In times of evidence-based medicine and globalization, the development of a specific guideline for South America will only be possible if specific, well-designed controlled trials are available. Unfortunately, this is not the reality. However, it is worth mentioning that most of the large clinical trials currently being carried out have research centers in South America. Therefore, these studies are expected to reflect, partially, the responses to different therapies in the South American population. At this very moment, there is no study that indicates, or even suggests, that the population of South America would respond differently from other populations, even with some of the differences previously mentioned above.

Does South America need a different guideline for the diagnosis and treatment of DM?

Despite the fact that South American populations have characteristics that are completely different from those in Europe and the United States, there are certain aspects that must be taken into consideration when developing specific guidelines for the diagnosis of DM in South America.

_ There are no long-term studies evaluating the course of diabetes in South America. There is no evidence indicating that the incidence of diabetic complications would be significantly influenced by ethnicity in South American populations.

_ There are no specific studies comparing the differences among South American countries with regard to DMor IFG diagnoses. A recent analysis of the ORIGIN (Outcome Reduction with Initial Glargine INtervention) study has shown that the strong correlation found between HbA1c and fasting glucose is affected neither by ethnic nor by geographical factors.21 The strength of the study was the large number of subjects available for the overall and subgroup analyses. These observations were limited by the fact that glucose and HbA1c values were measured locally using a variety of assays worldwide, and that a mathematical approach was used to adjust for differences in each laboratory’s normal range for HbA1c. Thus, laboratory-related variability may have influenced the results. Also, information on the presence of variant hemoglobins or other physiological factors that might affect HbA1c values was not available, and whether such factors may have altered the FPG-HbA1c relationships observed is unknown.


Table I
Table I. Diabetes societies and associations in South America.


_ The development of specific cutoff points for the South American population, especially if different from the ones defined by the United States and Europe, would make it difficult to include these individuals in large clinical trials.

What is the position of the Associación Latinoamericana de Diabetes?

There are many societies and associations for the study of diabetes in South America (Table I). Generally, these societies are responsible for establishing local guidelines for type 2 DM treatment according to specific characteristics of the country. Some of them are affiliated or somehow associated with the local endocrinology societies. Most of the current guidelines for South American countries closely follow the ADA and EASD recommendations with slight differences. All South American diabetes associations are affiliated with the Associación Latinoamericana de Diabetes (ALAD). In 2010, with the approval of all the South American diabetes societies, the ALAD published a guideline22 in an attempt to standardize diabetes treatment in Latin America. Although many of the recommendations are similar to the American and European ones, some specific points are worth mentioning:
_ Metformin is the first option for all type 2 DM patients.
_ If a second medication is needed, options to be considered are sulfonylureas, pioglitazone, acarbose, dipeptidyl peptidase 4 inhibitors, and glucagon-like peptide-1 (GLP-1) analogues. One should note that despite being published in 2010, this guideline sustains that there is no obligatory second medication, and that treatment should be individualized according to the patient profile. Another point that needs mentioning is that the metformin/sulfonylurea combination is the most commonly prescribed treatment for DM in Latin America. The obvious explanation is its lower cost.
_ The SMBG should be carried out according to each patient’s need. Self-monitoring has become more accessible in South America, though cost is still a barrier. In some countries (such as Brazil), there are specific protocols for providing glucose meters to patients, with a varied quantity of test strips, in accordance with the DM classification and medication prescribed.
_ The document claims that there is an insufficient number of specialists for DM treatment in Latin America. Therefore, general practitioners should be capable of carrying out the initial treatment and then, if treatment goals are not achieved in 3 to 6 months, the patient must be referred to a specialist.
_ The document also provides general information for the prescription of diet and physical activity for the diabetic patient.

It is important to point out that references used in the development of this document were the same as those used for the ADA and EASD guidelines. Thus, though considering this to be a specific document for a specific population, it is not based on specific studies within the South American population.

Conclusion

Ethnicity seems to be a relevant risk factor for diabetes and its complications. Unfortunately, there is no scientific evidence of good quality comparing data from South American populations with that from other countries or even comparing data from different populations within South America. Until such information becomes available, making it possible to define specific guidelines for diabetes treatment in this population, local South American diabetes societies should develop guidelines based on the ADA and EASD statements, considering specific characteristics of each country. Defining a global strategy for diabetes diagnosis and management should be seen as an effort to unite specific populations to fight a devastating disease._


References
1. Danaei G, Finucane MM, Lu Y, et al; Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Blood Glucose). National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet. 2011;378 (9785):31-40.
2. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2012;55(6):1577-1596.
3. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2009;52:17-30.
4. Gary TL, Crum RM, Cooper-Patrick L, Ford D, Brancati FL. Depressive symptoms and metabolic control in African Americans with type 2 diabetes. Diabetes Care. 2000;23:23-29.
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6. Osei K, Gaillard T, Schuster DR. Pathogenetic mechanisms of impaired glucose tolerance and type II diabetes in African Americans: the significance of insulin secretion, insulin sensitivity, and glucose effectiveness. Diabetes Care. 1997;20: 396-404.
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8. Dagogo-Jack S. Ethnic disparities in type 2 diabetes: pathophysiology and implications for prevention and management. J Nat Med Assoc. 2003;95:774-789.
9. Harris MI, Klein R, Cowie CC, Rowland M, Byrd-Holt DD. Is the risk of diabetic retinopathy greater in non-Hispanic blacks and Mexican Americans than in non-Hispanic whites with type 2 diabetes? A U.S. population study. Diabetes Care. 1998;21:1230-1235.
10. Rostand SG, Kirk KA, Rutsky EA, Pate BA. Racial differences in the incidence of treatment for end-stage renal disease. N Engl J Med. 1982;306:1276-1279.
11. Lavery LA, Ashry HR, van Houtum W, Pugh JA, Harkless LB, Basu S. Variation in the incidence and proportion of diabetes-related amputations in minorities. Diabetes Care. 1996;19:48-52.
12. Karter AJ, Ferrara A, Liu JY, Moffet HH, Ackerson LM, Selby JV. Ethnic disparities in diabetic complications in an insured population. JAMA. 2002;287(19): 2519-2527.
13. Wisdom K, Fryzek JP, Havstad SL, Anderson RM, Dreiling MC, Tilley BC. Comparison of laboratory test frequency and test results between African Americans and caucasians with diabetes: opportunity for improvement. Findings from a large urban health maintenance organization. Diabetes Care. 1997;20:971- 977.
14. Harris MI. Racial and ethnic differences in health care access and health outcomes for adults with type 2 diabetes. Diabetes Care. 2001;24:454-459.
15. Musey VC, Lee JK, Crawford R, Klatka MA, McAdams D, Phillips LS. Diabetes in urban African Americans. I. Cessation of insulin therapy is the major precipitating cause of diabetic ketoacidosis. Diabetes Care. 1995;18:483-489.
16. Karter AJ, Ferrara A, Liu JY, Moffet HH, Ackerson LM, Selby JV. Ethnic disparities in diabetic complications in an insured population. JAMA. 2002;287:2519- 2527.
17. Harris MI, Eastman RC, Cowie CC, Flegal KM, Eberhardt MS. Racial and ethnic differences in glycemic control of adults with type 2 diabetes. Diabetes Care. 1999;22:403-408.
18. James DG, Baker P, Badrick E, Mathur R, Hull S, Robson J. Ethnic and social disparity in glycaemic control in type 2 diabetes; cohort study in general practice 2004-9. J R Soc Med. 2012;105(7):300-308.
19. Blaum CS, Velez L, Hiss RG, Halter JB. Characteristics related to poor glycemic control in NIDDM patients in community practice. Diabetes Care. 1997;20:7-11.
20. Eberhardt MS, Lackland DT, Wheeler FC, German RR, Teutsch SM. Is race related to glycemic control? An assessment of glycosylated hemoglobin in two South Carolina communities. J Clin Epidemiol. 1994;47:1181-1189.
21. Ramachandran A, Riddle MC, Kabali C, Gerstein HC; ORIGIN Investigators. Relationship between A1C and fasting plasma glucose in dysglycemia or type 2 diabetes: an analysis of baseline data from the ORIGIN trial. Diabetes Care. 2012;35(4):749-753.
22. Associación Latinoamericana de Diabetes. Documento de Posición de ALAD con Aval de Sociedades de Diabetes y Endocrinología Latinoamericanas para el Tratamiento de la Diabetes Tipo 2. http://www.alad-latinoamerica.org/ DOCConsenso/Consenso2010-Doc_Posicion.pdf. Published 2010. Accessed August 31, 2012.


Keywords: ADA; Associación Latinoamericana de Diabetes; EASD; ethnicity; guidelines; socioeconomic status; type 2 diabetes mellitus; South America


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