Exploring health disparities in a clinical trial setting
Health disparities in diabetes care arise from many causes. A new study in a recent issue of Diabetologia uses the ACCORD trial to explore the influence of racial, ethnic and economic factors in achieving diabetes targets, such as HbA1c, thereby shedding light on health disparities. Dr Susan Aldridge reports.
The outpatient management of diabetes is focused on achieving HbA1c, blood pressure and cholesterol (the ABCs) targets in order to avoid microvascular and macrovascular complications. Disparities have been widely reported in the usual care for type 2 diabetes, with higher rates of incidence and complications and lower rates of treatment target achievement and novel therapies among racial and ethnic minorities and socioeconomically disadvantaged individuals.
Although disparities in clinical trial enrolment do occur, disparities should, in theory, be mitigated once people are actually in a trial. Medications are provided free of charge and participants have access to healthcare professionals who are dedicated to ensuring they receive optimal care and adhere to the trial protocols.
However, it’s not known whether other factors that contribute to disparities in health outcomes, such as socioeconomic status, environmental injustice and exposure to systemic or personal racism, lead to persistent disparities in outcomes, even within the favourable setting of a clinical trial. Therefore, evaluating disparities within a clinical trial could act as an experimental model in which access to medication and healthcare are more equal than in the real world. This would reduce access-related disparities in outcomes and allow the evaluation of the role of the other social determinants of health, as described above.
Furthermore, clinical trials can be useful in looking at the limits of clinical care. Those who enrol tend to be younger, healthier and more health conscious than the general population. And the care they receive in the trial may well be better than in the real world, with frequent visits, proactive follow-up, use of clinical guidelines and easier access to clinicians. So the outcomes of at least some clinical trials can be viewed as a treatment ceiling – the upper limit on outcomes as a result of being in the best clinical setting.
The ACCORD trial
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial can be used as a model for optimal care, as described above. ACCORD was a large multicentre trial that enrolled participants from 2001 to 2005 and assessed the effect of intensive vs standard ABC targets in adults with type 2 diabetes. All participants were assigned to either intensive (HbA1c < 42 mmol/mol) or standard (HbA1c 53.0-62.8 mmol/mol) glycaemic targets. Slightly less than half were also assigned to intensive (systolic blood pressure < 120 mmHg) or regular (systolic blood pressure < 140 mmHg) blood pressure targets. The remainder were assigned to the use of fenofibrate or placebo in addition to background statin therapy, with a target of ≥ 25% reduction in triglyceride levels.
In terms of treatment burden imposed by these targets, HbA1c was regarded as high, blood pressure as medium and triglyceride lowering as low. Evidence-based treatment algorithms and medications were provided, with researchers encouraged to use any treatment they wanted to achieve the ABC targets.
Because ACCORD enrolled a diverse population with type 2 diabetes, provided frequent visits with clinical research teams and compared treatment targets rather than different medications, it provides a good model for studying both disparities and the limits of achievable glycaemic and blood pressure controls.
In a new study, Sara J Cromer from Massachusetts General Hospital and colleagues elsewhere report on an analysis of ACCORD where they tested for achievements in ABC targets by race, ethnicity and educational attainment. They hypothesised that disparities would persist even within the clinical trial setting and would be greatest for the high treatment burden of glycaemic control and least for the low treatment burden of triglyceride control. They also looked at the inability of many participants to achieve their ABC targets even within a clinical trial and at the factors that may hinder this achievement.
The authors worked with 10,244 ACCORD participants, of whom 62.4% reported White ethnicity versus 19%, 7.2% and 11.4% reporting Black, Hispanic and Other ethnicity, respectively. The categories for educational attainment were: college degree, less than high school diploma, high school diploma and some college education, reported by 26%, 14.8%, 26.4% and 32.8%, respectively.
Achievement of ABC targets by race and ethnicity
One year from the start of the ACCORD trial, 52% of White participants compared with 39%, 43% and 48% of Black, Hispanic and Other ethnicities achieved their glycaemic target. Similar disparities existed in both the intensive and control arms. In adjusted analyses, allowing for confounding factors, Black, Hispanic and Other ethnicities were associated with lower odds of achieving their glycaemic targets compared with those of White ethnicity.
When it came to systolic blood pressure, 69% of those of White ethnicity, compared with 61%, 69% and 70% of those of Black, Hispanic and Other ethnicity, respectively, achieved their targets, whether intensive or standard. In adjusted analyses, only Black ethnicity was associated with lower rates of target achievement compared with those of White ethnicity.
Finally, 46% of White participants achieved triglyceride reduction of ≥ 25%, compared with 50%, 50% and 54% among Black, Hispanic and Other ethnicity participants. Adjusted analyses showed that rates of achieving this target were higher among Black and Other participants compared with White participants.
Other findings
For all three ABC targets, there were no differences with respect to educational achievement. As a safety measure, the researchers also looked at rates of severe hypoglycaemia, which were highest at 12.3% among Black participants compared with Hispanic, Other and White ethnicity, at 5.1%, 7.4% and 7.4%, respectively. And adjusted analyses showed that having less than a high school diploma or having a high school diploma were associated with a higher level of severe hypoglycaemia compared with having a college degree.
Shedding light on health disparities
These findings have important implications for clinical practice as they show that health disparities persist even in a highly supportive clinical setting like a clinical trial. The findings also reveal, overall, a low rate of goal achievement regardless of race, ethnicity or educational achievement. This highlights the limits of clinical management even in a resource-rich setting.
Various degrees of disparities have already been described in other type 2 diabetes trials, particularly in those involving lifestyle intervention, such as the Diabetes Prevention Program, Look AHEAD and REAL HEALTH-Diabetes. ACCORD provided a unique opportunity to look at the impact of racial and ethnic differences and socioeconomic status with three different interventions varying as to treatment burden within the same population and care model.
The racial and ethnic disparities were largest for the highest burden glycaemic intervention, which involved self-monitoring and self-titration, but small or even non-existent for blood pressure intervention, which only involved monitoring by a clinician and occasional medication titration, as well as the triglyceride intervention, which only involved adherence to a single medication.
It is important that ACCORD was not a trial of a specific treatment but of treatment target achievement. The use of a range of treatments is what also happens in real-world clinical care, except that medications are provided for free, along with intensive support and proactive follow-up, which may not always be available from participants’ usual healthcare provider.
So the disparities seen in this study do not reflect lack of access to medications, healthcare or support. There may have been differences in participant behaviours within the trial, such as adherence to the protocol, but the findings don’t support this. However, it could be that social determinants of health associated with race and ethnicity, like socioeconomic status, environmental differences and exposure to racism, contributed to differences in ability to meet targets. These would include differences in health literacy and diabetes education, and perhaps the absence of culturally tailored education within ACCORD. And educational attainment did not seem to influence the achievement of targets, suggesting that socioeconomic status alone is not the primary contributor to the racial and ethnic disparities observed.
Race and ethnicity are social constructs that are linked to many adverse circumstances that are hard to measure, which may have contributed to the outcomes of this study. Finally, although a protocol was being followed in this study, it is possible that intensification of therapy in order to meet ABC targets might have differed by race and ethnicity because of unconscious bias. There was also the finding that there was a modest influence of insulin dose and non-insulin medication use on the link between race and ethnicity and glycaemic-goal achievement.
It was also notable that despite intensive interventions and physician-led strategies not following a specific treatment regimen, a significant proportion of all participants were unable to meet their treatment targets, particularly glycaemic targets. The rates seen in this study were similar to those seen in recent studies based in the general population. Recognition of these limits of clinical care in the ACCORD trial can perhaps inform clinical goals in the real-world setting where fewer resources are available.
In conclusion, ACCORD participants of Black, Hispanic and Other ethnicities were less likely to achieve their glycaemic targets than White participants, while Black participants were less likely to achieve blood pressure targets. However, Black, Hispanic and Other ethnic participants were more likely to achieve their triglyceride targets. Disparities persisted after adjusting for baseline characteristics, diabetes duration and control, and educational attainment. So disparities exist even within clinical trials and maybe they depend upon treatment burden and other factors needing further investigation. The barriers to achieving treatment targets may, therefore, be greater for some populations, even in clinical trials and especially in real-world clinical settings. Clearly the underlying reasons for health disparities require further research.
To read this paper, go to: Cromer SJ, Thaweethaai T, Wexlert DJ. Racial/ethnic and socioeconomic disparities in achievement of treatment goals within a clinical trial: a secondary analysis of the ACCORD trial. Diabetologia 16 September 2023. https//doi.org/10.1007/s00125-023005997-2
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Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.