Can Innovative Technologies Overcome HbA1c Disparity for African-American Youth with Type 1 Diabetes?

Abstract

Achieving normal or near-normal glycemic control as reflected by HbA1c levels in patients with type 1 diabetes (T1D) is important for preventing the development and progression of chronic complications. Despite delineation and dissemination of HbA1c management targets and advances in insulin pharmacology, insulin delivery systems, and glucose monitoring, the majority of children with T1D do not achieve HbA1c goals. In particular, African Americans are more likely not to reach HbA1c goals and have persistently higher HbA1c than Non-Hispanic Whites. Availability of pumps and other technology has not eliminated the disparity in HbA1c. Multiple factors play a role in the persisting racial disparity in HbA1c outcome. The carefully designed application and deployment of new technology to help the patient/family and facilitate the supportive role of the diabetes management team may be able to overcome racial disparity in glycemic outcome and improve patient quality of life.

Racial Disparity in Type 1 Diabetes Outcomes

Type 1 Diabetes (T1D) is one of the most prevalent chronic diseases of childhood in the United States.¹ Epidemiologic studies indicate that its incidence has been increasing, especially among ethnic minority children.^2-4 Poor glycemic control of T1D leads to the development of serious acute and chronic complications with heightened morbidity and mortality.^5-7 It has been demonstrated that onset of T1D during childhood and pre-puberty contributes to the cumulative burden of abnormal metabolic exposure leading to the development and progression of complications.^8,9 Therefore, maintaining MBG as close to normal and as soon as possible can prevent micro- and macrovascular complications.^7,10-12

Clinical management optimizing glycemic control must not be delayed, because patients with chronically poor glycemic control have continued higher risk for complications long after they improve their HbA1c.^13,14 Therefore, rather than waiting for adulthood to improve glycemic control, pediatric patients with T1D should achieve and maintain optimal glycemic control in childhood in order to have the best chance of averting acute and chronic complications.^12,15,16 Despite this clinical imperative, standard management approaches have been unable to achieve optimal glycemic control in the majority of African American/Non-Hispanic Black (NHB) youth with T1D, nor bring HbA1c of NHB patients into parity with that of Non-Hispanic White (NHW) patients.^17-26 Chronically higher HbA1c in NHB youth with T1D are associated with higher acute and chronic morbidity and mortality compared to NHW patients.^27-31

Continued failure of current modes of therapy to achieve optimal control or even glycemic levels comparable to those in NHW patients potentially will lead to persistently higher occurrence of “preventable” complications among NHB patients as they age.^11,12 In addition to the attendant preventable suffering, decreased productivity, and reduced quality of life and life expectancy for those NHB patients, there will be the added burden of unnecessary health expenditures for mitigation of avoidable complications.³²

Over the years there have been many studies highlighting multiple obstacles to the management of diabetes associated with higher HbA1c levels in disadvantaged minority populations. This paper will consider whether the application of emerging new technologies for diabetes treatment could overcome a number of specific obstacles to optimal management and mitigate long-standing disparities in HbA1c outcome.

Obstacles to Achieving Optimal Control with Type 1 Diabetes

Type 1 diabetes is a challenging disorder for youth and their families to manage successfully.^33,34 Achievement of normal or near-normal blood glucose levels throughout the day requires frequent repeated monitoring of blood glucose levels, assessment of the glycemic content of meals ingested, attention to the adjustment of insulin to cover glycemic changes from meals, and response to and control of out-of-range glucose levels. There is also need for surveillance and control of glucose levels during the hours of sleep. As the attention needed to attain optimal glucose control is a 24/7 effort, patients and their family often develop “diabetes distress” and burnout from the continuous daily struggle to manage the disease.^35-37 The currently recommended HbA1c goal may be beyond the ability of most patients/families to achieve with available management techniques.^33,34,38 In particular, pediatric NHB patients have HbA1c levels persistently higher than those of NHW or Hispanic ethnicity when matched for type of insulin delivery used and age.^22,23 Racial disparity in HbA1c continues as adolescents mature into young adults.³⁹

Biologic Factors

A portion of the disparity in HbA1c between NHB and NHW patients may be due to biologic factors. Many studies including children and adults have shown that HbA1c overestimates MBG in many NHB patients.^21,40,41 Thus, at any given level of MBG, NHBs on average have higher HbA1c than NHWs. This difference in HbA1c has been reported to be between 0.3 and 0.8 (HbA1c%) depending on the population studied and assay methods used.^21,41,42 The concentrations of the biochemical precursor to clinically measured HbA1c, labile HbA1c, has also been found to be higher in NHB vs NHW youth, suggesting differences in the internal RBC environment as a possible underlying cause of this phenomenon.⁴³ Factors influencing HbA1c concentration such as variation in RBC indices and iron content do not appear to underlie MBG-independent racial disparity in HbA1c.^44,45 Some investigators have suggested differences in intracellular glucose, red cell longevity, and deglycating enzymes as possible mechanisms.^46-48 However, the mechanism(s) leading to higher HbA1c in NHB individuals at similar MBG levels remains unclear.

Higher HbA1c in NHB vs NHW patients at the same MBG suggests that standard glucose-lowering therapies would likely not eliminate this component of racial difference in HbA1c. And treatment to an HbA1c target without the recognition that HbA1c overestimates concurrent MBG may put NHB patients at greater risk for iatrogenic hypoglycemia then NHW patients.^49,50 There is circumstantial evidence for this occurring: some studies have reported a higher occurrence of hypoglycemia in NHB patients with T1D, despite their having higher HbA1cs than NHW patients.²³ Fear of hypoglycemia may be another factor preventing some families from wanting or trying to achieve target HbA1c.^51-54 If higher HbA1c in NHB vs NHW despite similar MBG contributes to the greater occurrence of chronic complications of diabetes, then novel therapies targeting its mechanism will need to be developed.

Data are available suggesting that predictors of long-term poor HbA1c outcome are already present at diagnosis and in the first few years post-diagnosis in NHB youth.^25,55 These factors include lower residual β-cell function with less likelihood of entering the “honeymoon” phase, along with higher frequencies of severe hypoglycemia and subsequent DKA events.^25,55 If lower residual insulin secretion is more prevalent in NHB youth post-diagnosis, it may be another predictor for the lack of success of current management approaches to achieve “treat to HbA1c target” objective.

Management Factors

The DCCT was a landmark study demonstrating that intensive insulin therapy that lowered and maintained HbA1c in the normal/near-normal range prevented the development and progression of microvascular diabetes complications.^7,10 The lessons of the DCCT eventually led to the evolution and adoption of lower HbA1c target goals for clinical management.¹²

The DCCT enrolled 1441 participants at 29 clinical sites. That gave the study team at each site on average about 50 patients who had been carefully selected for the trial. In practice, study staff devoted more time and attention to the 25 or so patients randomized to the Intensive care arm in order to help them attain the glycemic target. Given that ~96% of DCCT participants were White, and adolescents comprised between 9% and 19% of the various study arms,^7,10 the DCCT was distinctly unrepresentative of minority pediatric populations. The resources in staff time; ready access to nutrition, behavior, medical, and nursing support; and medical supplies available to each patient in the Intensive arm of the DCCT were much more favorable to management adherence and glycemic outcome success than typical management resources available to minority patients in current real-world diabetes clinic settings.

NHB patients typically have fewer diabetes clinic visits than NHW patients.^17,19 Pediatric diabetes management teams often do not have sufficient staff and time to contact vulnerable patients who miss appointments and address their management needs outside of formal clinic hours.⁵⁶ In addition to limitations in staff and resources available in pediatric diabetes clinics, there are other management and behavioral factors that have been associated with the persistent disparity in HbA1c outcome.^57,58 NHB patients are much less likely to have access to insulin pumps^23,59 or continuous glucose monitoring devices.²⁴ However, racial disparity in pump access/use alone does not fully explain HbA1c disparity, as NHB patients have higher HbA1cs than NHW patients even when matched for insulin delivery system used and age.²³ Thus factors other than access to pumps play a role in higher HbA1c.

NHB patients are disproportionately disadvantaged compared to NHW patients, with lower levels of educational attainment, lower income levels, and less family stability. Many patients and their families also live in neighborhoods with high levels of social/environmental stress.^23,60,61 Socioeconomic challenges and the need to care for other family members may distract the primary caretaker from providing regular supervision and supportive management of their child with diabetes.^5,62,63 This may contribute to NWB patients and their families having higher level of diabetes distress and associated higher HbA1c.³⁷

Social and economic disadvantage is associated with less access and use of advanced technology and higher HbA1c.⁶⁴ NHB patients have less contact with the diabetes management team and receive less outside support of the treatment plan than do NHW patients another obstacle to achieving treatment goals.^24,65,66 Disadvantaged patients/families may be unable to use complex technology to its full capability or discontinue its use after a short period of time. Furthermore, there may also be bias on the part of providers against prescribing specific technologies to minority and disadvantaged families.⁶⁷

Diabetes management professional staff often are of different ethnicity and socioeconomic status than the NHB patients they serve. Thus, the management team may not be fully aware, sensitive and able to clearly address the special management challenges these patients and families.^59,65,68,69 Perceptions of racism on the part of the families may further deter adherence to management.⁷⁰

Can Technology Be Used to Overcome Racial Disparity in HbA1c Outcomes?

As noted earlier, over the last few decades, young NHBs have had persistently higher HbA1cs than their NHW counterparts.^17-26 There are numerous challenges confronting NHB patients/families and their diabetes support teams that militate against achievement of HbA1c levels in parity with NHWs.^{23,39,58,60,63,71} Merely having access to current technologies such as pumps does not seem to bring HbA1cs of NHB patients into parity with NHW patients.^23,72

Now is the time to reconsider our approach to managing T1D and to design programs to overcome the racial disparity in outcomes. Furthermore, in order to achieve and maintain HbA1c goals, patients and their families must be able to trust, accept and continue using the new techniques and approaches for the long term.⁷³

Enhanced time and attention both during and outside of clinic are important in improving HbA1c outcomes, even in highly motivated patients.^7,10,74 Therefore, in addition to increased access to sophisticated insulin delivery and glucose sensor systems, patients and their families should also receive enhanced support necessary to overcome special barriers to management and assist with long-term acceptance and utilization.^75,76 Frequent contact with the family in their home could be accomplished with video conferencing apps.^75,77-79 Video conferencing use was infrequent in pediatric diabetology but quickly burgeoned during the COVID-19 emergency in the spring of 2020 and has become more widely used and accepted by patients and practitioners.^80,81 Challenges of billing and reimbursement previously limiting telehealth use were quickly addressed.⁸² Video conferencing and messaging would facilitate members of the diabetes team to communicate frequently about diabetes management issues with patients and families.⁷⁵ Video sessions would reduce the time and inconvenience entailed by physical clinic visits. When combined with facilitated data transfer for review of pump and sensor information, as well as details on meals consumed and patient growth, these video visits would enhance efficient diabetes management and problem solving. The extra contact would help support families in continuing adherence with the management plan. Automated analysis of streaming patient data could proactively identify patients needing more contact outside of scheduled virtual sessions and traditional clinic visits.⁸³ These enhanced virtual contacts will be most beneficial when designed to be culturally sensitive and in alignment with the needs, skills, capabilities, and time availability of high-risk patients and families. This technology may be able to more effectively direct staff attention to the needs of vulnerable patients/families to optimize their glycemic control.

Biological factors such as the tendency for HbA1c to overestimate MBG for NHB patients could also be mitigated by technology. For example, MBG data from continuous glucose monitoring, periodically paired with HbA1c measurements, would give an individualized metric of the MBG/HbA1c relationship in a form such as the Hemoglobin Glycation Index (HGI) or Glucose Management Indicator.^84,85 These indices would guide individual assessment of HbA1c to better reflect the actual relationship with MBG. Recognition of a patient’s actual MBG in relationship to HbA1c may help prevent iatrogenic hypoglycemia.⁵⁰ Further research is needed to determine whether higher HbA1c in NHB patients at similar MBG levels to NHW patients increases eventual risk for diabetes complications, as suggested from assessments in other populations.⁸⁶ Alternatively it may be an artifact that will be no longer be of importance once continuous glucose monitoring data are widely available for most patients.

Advances in insulin delivery systems, glucose monitoring, and control algorithms have brought the dream of an artificial pancreas closer to reality. Currently available systems are referred to as advanced “hybrid” closed loop (AHCL) pumps because they still need user input regarding meal carbohydrate content to properly calculate mealtime insulin boluses. The ultimate goal remains a completely closed loop system, a true artificial pancreas, that would eliminate the need for any user input and function completely automatically to maintain blood glucose levels throughout the day within physiologic range.⁸⁷

Current AHCL devices, although they are not yet fully independent of user input, could still facilitate achievement of better glycemic control⁸⁸ by overcoming many obstacles and inconveniences of diabetes care. AHCL pumps are able to anticipate hypoglycemia and stop insulin infusion prior to the occurrence of biochemical hypoglycemia, restoring the insulin infusion once it is safe to do so based on the trend of glucose levels. Patients and their families who resist optimizing glucose with older insulin delivery methods due to fear of hypoglycemia may be willing to trust an AHCL pump that would automatically shut off insulin infusion before occurrence of actual biochemical hypoglycemia.

The AHCL pump can increase basal rates and initiate small additional boluses of insulin to prevent the occurrence of hyperglycemia. At mealtime, the insulin bolus is calculated based on the carbohydrates to be consumed, and built-in continuous glucose sensor data from the device is used to calculate any additional insulin corrections if needed. Sensor glucose data also permits assessment of the subsequent effectiveness of calculated mealtime insulin boluses and improves insulin delivery. Real-time sensor data eliminates the need for the patient to frequently obtain capillary glucose sticks before and after meals and during sleep. This technology would further help overcome inconvenience, drudgery and numeracy issues that occur when patients must perform capillary glucoses, calculate insulin needed to cover meal carbohydrates, and correct for out-of-range premeal glucose levels. The AHCL pump should be able to compensate for biologic factors such as lower residual insulin secretion. Such an insulin delivery system would make management of T1D much easier and safer than older technologies, especially those where the patient and family had to make all management decisions on insulin dosing based on separately obtained glucose data, whether from a continuous glucose sensor or capillary blood glucoses. Eliminating many repetitive and unpleasant tasks needed to control glucose levels may increase the acceptability and enhance the likelihood of long-term continued use of the technology for successful glucose control.

Ideally we foresee that a combination of technologies would be put in place. In addition to a “state of the art” AHCL pump, the patient and family would have more frequent contact with a diabetes team member from the convenience of home using video conferencing and messaging apps. Video meetings would be used to troubleshoot issues with the AHCL pump and address carbohydrate counting, sick days, exercise, and other issues. Automatic streaming and review of the patient’s sensor and pump data would permit early identification of management problems and the development of solutions by the diabetes team to be implemented at video conferences and in standard clinic visits. Enhanced support by the team would encourage families in continued use of the technologies and adherence with the management plan.

We have begun a feasibility trial (NCT04614623) to test whether access to combined application of these technologies for diabetes management can bring about parity in HbA1c between NHB and NHW youth with T1D, and whether this technological approach will be trusted, accepted, and successfully used by families over the long term.