Origins and Evidence Behind New ADA Recommendations for Pediatric A1C

Type 1 diabetes mellitus (T1DM), or insulin-dependent diabetes, is a chronic condition in which the β-cells of the pancreas produce little or no insulin. It is an immune-mediated condition which requires lifelong management with exogenous insulin.

Although the disease is often referred to as “juvenile diabetes,” primarily due to the age of onset, a majority of people with T1DM are adults. In fact, of the estimated 3 million individuals with the disease, less than 200,000 are juveniles.^1,2 This could be explained by the improved survival of individuals with childhood-onset diabetes.³ The American Diabetes Association (ADA) recently released a position statement to better manage T1DM and prevent complications associated with the condition.

ADA Pediatric A1C Recommendation

At the 74th Scientific Sessions of the ADA, held June 13-17, 2014, in San Francisco, the association released a position statement and simultaneously published it online in the journal Diabetes Care. ADA’s first-ever policy statement on T1DM emphasizes changes in how patients and healthcare professionals should address and treat the disease. It also provides care recommendations for all age groups: children, adults, and older patients. The ADA had been working on this position statement for approximately 5 years from the time the decision for separate guidelines for T1DM and type 2 diabetes mellitus (T2DM) was reached.

The first step in the development of the recently announced position statement was creating The American Diabetes Association/Juvenile Diabetes Research Foundation (JDRF) Type 1 Diabetes Sourcebook, which is an evidence-based reference work and consensus report outlining components of care for individuals with T1DM. The position statement itself contains the “practical pearls” from The American Diabetes Association/JDRF Type 1 Diabetes Sourcebook.⁴

One noteworthy change was the recommendation to lower the glycated hemoglobin (A1C) target to less than 7.5% for all T1DM patients under the age of 18 years. Previously, the A1C recommendations for pediatric patients were based on age groups: less than 8.5% for patients 5 years old and younger, less than 8% for those 6 to 12 years of age, and less than 7.5% for those 13 to 18 years of age.

The reasons for the previous less-stringent targets in the younger age groups reflected concerns for the risk of hypoglycemia, which is associated with intensive management in young patients.

Some of the primary concerns were the developmental consequences associated with severe hypoglycemia in growing children.⁵ However, the ADA considered recent and ongoing research, which has dispelled these concerns regarding hypoglycemia and neurocognitive dysfunction.^6,7

Recent evidence demonstrates that detrimental effects in neurocognitive function and the central nervous system are due to elevated blood glucose levels and glycemic variability in pediatric patients with T1DM.⁸ Another reason for the shift toward a universal goal of less than 7.5% for all young patients is the ADA’s recognition that today’s modern treatment and monitoring abilities (eg, insulin analogues, “smart pumps,” and continuous glucose monitoring devices) allow patients to more easily achieve improved glycemic control with fewer hypoglycemic events.⁵ The recommendation of a single A1C goal of less than 7.5% for all pediatric age groups, based on clinical studies and expert opinion, is by no means revolutionary. This recent change by the ADA now aligns its recommendation with that of the International Society of Pediatric and Adolescent Diabetes (ISPAD) and the International Diabetes Federation.^9,10

ADA Adult A1C Recommendation

While the ADA’s recommendations for glycemic control in pediatrics intensified, the recommendations for older T1DM patients were relaxed. The ADA recognized that the older T1DM population has a number of comorbidities and highly variable life expectancy—defined by comorbidity and functional status—as opposed to just age.4 Unlike the pediatric population, who would benefit from interventions such as stringent glycemic control, adult T1DM patients may not benefit, due to already advanced complications or because they don’t survive long enough for the benefits to be realized. Additionally, the strict glycemic control recommended for younger, healthier adults may pose a higher risk of hypoglycemia and treatment burden in the older patients. Therefore, the final glycemic target recommendations for adults with T1DM are: A1C less than 7% for many nonpregnant healthy adults, less than 7.5% for healthy older adults, less than 8% for complex/intermediate older adults, and less than 8.5% for older adults with very complex or poor health.

The age ranges for an “adult” versus an “older adult,” however, are not defined.⁴ For individuals with T1DM, hypoglycemia is the most common acute side effect of insulin therapy and serves as one of the major barriers to optimal glycemic control.¹¹ Despite the overall guidance from the ADA that glycemic control should be approached aggressively, the organization makes it quite clear that it emphasizes individualization when choosing glycemic targets, focusing on the goal of achieving the best possible control—minimizing the risk of severe hyperglycemia and hypoglycemia while maintaining normal growth and development in pediatric patients. The goals for both pediatric and adult patients should be individualized based on duration of diabetes, age/life expectancy, comorbid conditions, known cardiovascular disease or advanced microvascular complications, hypoglycemia unawareness, and individual patient considerations.⁵ All of these need to be factored into the discussion of the stringency of glycemic goals.

The ADA provides guidance on how to successfully monitor blood glucose levels in order to prevent hypoglycemia in T1DM. Self-monitoring of blood glucose (SMBG) allows patients to evaluate their individual responses to their prescribed insulin dosages, and to understand how nutrition and physical activity influence their glucose levels. Overall, frequent SMBG readings allow for insulin dosing adjustments that correlate with lower A1C levels.^12,13 The ADA therefore recommends that patients test their blood glucose prior to—and sometimes after—meals and snacks, at bedtime, before and after exercise, when they suspect low blood glucose, after treating low blood glucose until they are normoglycemic, and prior to critical tasks such as driving.⁴ The position statement points out that this may require patients to perform SMBG more than 10 times daily. In order to ensure the most benefit from SMBG, patients should be routinely educated on appropriate monitoring techniques.

An alternate approach to obtaining accurate blood glucose levels is through continuous glucose monitoring (CGM), which is a real-time measurement of interstitial glucose that parallels plasma glucose. CGM was described as an adjunct to SMBG, with CGM being recommended as a useful tool to reduce A1C levels in adults without increasing hypoglycemia, and as a way to reduce glycemic excursions in children. It is important to note that CGM sensors, which require calibration with SMBG, are not a replacement for self-monitoring.

Also, SMBG is required for making acute treatment decisions, but patients can be alerted to hypo- and hyperglycemic excursions via CGM devices, which have alarms for designated absolute blood glucose levels and also for drastic rates of blood glucose changes.⁴

Discussion of the Landmark Study: DCCT

It is recognized that hyperglycemia is directly related to the incidence of complications, both short- and long-term. For this reason, glycemic control is fundamental to diabetes management. One of the more influential studies focusing on intensive glycemic control—referenced throughout the ADA position statement—was the Diabetes Control and Complications Trial (DCCT). A 10-year study published in 1993, DCCT was a prospective, randomized, and controlled study comparing intensive versus standard glycemic control in patients diagnosed with T1DM. The trial demonstrated that the intensive glycemic control group, which achieved a mean A1C of 7.4%, reduced the incidence of microvascular complications of T1DM compared with standard control, which achieved a mean A1C of 9.1% during the trial period.

Specifically, compared with the control group, intensive glycemic control reduced the risk for retinopathy, neuropathy, and nephropathy by 76%, 60%, and 50%, respectively.¹⁴ Additionally, the DCCT revealed that intensive therapy is not completely positive, being associated with an almost 3-fold increase in cases of severe hypoglycemia. The term was defined as an event with symptoms consistent with hypoglycemia, in which the patient requires the assistance of another person and which is associated with a blood glucose level below 50 mg/dL or with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration.¹⁵ It is worth noting that the DCCT only enrolled pediatric patients between the ages of 13 and 17 years. The lack of evidence in children below 13 years of age was one reason that the ADA has recommended a stratified treatment approach among the different pediatric age groups.⁵

The Follow-up EDIC Study

The DCCT was a landmark study in its own right; however some of the most intriguing data have resulted from its long-term follow-up study—Epidemiology of Diabetes Interventions and Complications (EDIC)—which began in 1994, the year after DCCT ended. The EDIC study, also referenced in the ADA position statement, astonishingly showed persistent microvascular and cardiovascular benefits in subjects who had previously received intensive treatment, even though their glycemic control had deteriorated over time.^16,17 Within 4 years of the DCCT trial ending, the mean A1C of patients, from both the intensive and conventional treatment groups, converged around 8%.16 Nine years into EDIC, there was a 42% decrease in any cardiovascular event and a 57% reduced risk for nonfatal heart attack, stroke, or death from cardiovascular causes when comparing the patients who were originally assigned to the 2 treatment groups.¹⁸ After 18 years, the overall prevalence of diabetes complications was 50% lower among the T1DM patients in the DCCT who were randomly assigned to intensive glucose control compared with those who received conventional treatment, despite the fact that A1C levels are no longer different between the 2 study groups.^19,20

When the patients who were enrolled in the intensive treatment group were compared with those enrolled in the conventional treatment group, the rate of retinopathy was 70% lower at 4 years after the DCCT trial ended, 53% lower at 10 years, and 46% lower at 18 years. Rates of ocular surgery, too, were lower at 18 years in the prior intensive group, with differences of 48% in cataract extraction and 44% in vitrectomy or retinal detachment compared with those patients in the conventional treatment group.¹⁹

Summary

The ADA position statement, which focused solely on the management and treatment paradigm for T1DM, is a significant step forward in disease treatment, as opposed to T2DM, which is often addressed in tandem with T1DM. The statement was intentionally written in an easy-to-understand format, with evidence-based recommendations throughout. According to Lori Laffel, MD, MPH, chief of pediatric, adolescent, and young adult programs at Joslin Diabetes Center, “Previously, guidelines for the care of persons with diabetes didn’t necessarily distinguish between patients with type 1 and type 2 diabetes. Often the guidelines that come out every January from the Diabetes Association are very long. They compile an entire journal. This particular guideline can be digested in a brief reading.”²¹ Laffel is the lead author on these guidelines. Beyond its discussion of glycemic targets, the full statement includes discussions on diagnosis, evaluation and follow-up, comorbidity management, blood glucose monitoring, and issues for special populations.References

1. General diabetes facts. JDRF website. http://jdrf.org/about-jdrf/fact-sheets/general-diabetes-facts/. Accessed August 19, 2014.

2. Pettitt DJ, Talton J, Dabelea D, et al; SEARCH for Diabetes in Youth Study Group. Prevalence of diabetes in U.S. youth in 2009: the SEARCH for Diabetes in Youth study. Diabetes Care. 2014;37:402-408.

3. Scottish Diabetes Research Network Epidemiology Group. Life expectancy in type 1 diabetes: a Scottish Registry Linkage Study. EASD Virtual Meeting website. http://www.easdvirtualmeeting.org/resources/3906. Accessed August 1, 2014.

4. Peters A. How did the new ADA, Type 1 Position Statement get made? [interview]. Interview by Mark Harmel. https://www.youtube.com/watch?v=4CKk9Pe1owY. Published June 21, 2014.

5. Chiang JL, Kirkman MS, Laffel LM, et al. Type 1 diabetes through the life span: a position statement of the American Diabetes Association. Diabetes Care. 2014;37:2034-2054.

6. Cato MA, Mauras N, Ambrosino J, et al; Diabetes Research in Children Network (DirecNet). Cognitive functioning in young children with type 1 diabetes. J Int Neuropsychol Soc. 2014;20: 238-247.

7. Marzelli MJ, Mazaika PK, Barnea-Goraly N, et al; Diabetes Research in Children Network (DirecNet). Neuroanatomical correlates of dysglycemia in young children with type 1 diabetes. Diabetes. 2014;63:343-353.

8. Barnea-Goraly N, Raman M, Mazaika P, et al; Diabetes Research in Children Network (DirecNet). Alterations in white matter structure in young children with type 1 diabetes. Diabetes Care. 2014;37:332-340.

9. Rewers M, Pihoker C, Donaghue K, Hanas R, Swift P, Klingensmith GJ. Assessment and monitoring of glycemic control in children and adolescents with diabetes. Pediatric Diabetes. 2009:10(suppl 12):71-81.

10. The global IDF/ISPAD guideline for diabetes in childhood and adolescence. International Diabetes Federation website. http://www.idf.org/sites/default/files/attachments/ISPAD-LFAC-Pocketbook-final-2.pdf. Published 2013. Accessed August 3, 2014.

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12. Miller KM, Beck RW, Bergenstal RM, et al; T1D Exchange Clinic Network. Evidence of a strong association between frequency of self-monitoring of blood glucose and hemoglobin A1C levels in T1D Exchange clinic registry participants. Diabetes Care. 2013;36:2009-2014.

13. Ziegler R, Heidtmann B, Hilgard D, Hofer S, Rosenbauer J, Holl R; DPV-Wiss-Initiative. Frequency of SMBG correlates with HbA1c and acute complications in children and adolescents with type 1 diabetes. Pediatr Diabetes. 2011;12:11-17.

14. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986.

15. The DCCT Research Group. Epidemiology of severe hypoglycemia in the diabetes control and complications trial. Am J Med. 1991;90:450-459.

16. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research group. Retinopathy and nephropathy in patients with type 1 diabetes 4 years after a trial of intensive therapy. N Engl J Med. 2000;342:381-389.

17. Martin CL, Albers J, Herman WH, et al; DCCT/EDIC Research Group. Neuropathy among the diabetes control and complications trial cohort 8 years after trial completion. Diabetes Care. 2006;29:340-344.

18. DCCT/EDIC Research Group. N Engl J Med. 2005;353:2643-2653.

19. Aiello LP. Diabetic retinopathy and other ocular findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care. 2014;37:17-23.

20. de Boer IH. Kidney disease and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care. 2014;37:24-30.

21. ADA Type 1 Diabetes Position Statement Changes A1C Recommendations for Pediatric Patients [press release]. Boston, MA: Joslin Diabetes Center; July 18, 2014. http://www.joslin.org/news/ADA-position-statement-changes-A1C-recommendations-for-pediatric-patients.html.