Discussion

Clinical practice guidelines advise against pursuit of low glycemic targets, and caution with use of insulin and sulfonylureas, among patients with complex and very complex health status,1 3–5 16–18 as doing so exposes patients to risk of hypoglycemia without yielding meaningful improvements in health outcomes.30–34 Yet, in a contemporary cohort of 194 157 US adults with type 2 diabetes, we found that older patients and patients with multiple and/or advanced comorbidities frequently achieved very low HbA_1c levels using insulin and, to a lesser degree, sulfonylureas. Indeed, patients least likely to benefit from intensive glycemic control and most likely to experience hypoglycemia with insulin therapy (ie, older and multimorbid adults) were most likely to achieve low HbA_1c levels and to be treated with insulin to achieve them. In contrast, patients who are likely to benefit from, and less likely to be harmed by, intensive control (ie, younger and healthier adults) more often had high HbA_1c levels and were less frequently treated with insulin despite suboptimal glycemic control. The impact of cumulative multimorbidity on insulin use was strongest with diabetes-concordant comorbidities (eg, CKD, cardiovascular disease, retinopathy, and so on), but was still apparent with advanced comorbidities (eg, dementia, ESRD, cancer) and discordant comorbidities (eg, cirrhosis, COPD, depression, and so on), suggesting that the perception of shared treatment goals and potential for disease comanagement may prompt more intensive glucose-lowering strategies that rely on insulin.

The AGS,16 ADA,1 17 and VA/DoD3 clinical practice guidelines have identified a number of comorbid health conditions that contribute to clinical complexity, predispose patients to undesired effects of intensive glucose-lowering therapy (including increased risk of hypoglycemia), make it difficult to manage diabetes, and/or signal underlying frailty or diminished life expectancy. Yet, in our patient population, mean HbA_1c levels were lower among patients with comorbidities compared with patients without, especially if the comorbidities were unrelated to diabetes or were advanced: 7.4% with no comorbidities, 7.3% with only concordant comorbidities, 7.1% with only discordant comorbidities (decreasing further as the number of discordant comorbidities increased), and 7.0% with advanced comorbidities. Higher HbA_1c levels observed among patients with concordant comorbidities may reflect guideline-recommended relaxation of glycemic targets in these patients, greater difficulty managing diabetes in the setting of existing complications, or longer diabetes duration. This association may also reflect greater risk of having diabetes complications in the setting of poor glycemic control. Low HbA_1c levels among patients with discordant and advanced comorbidities are concerning, and suggest an opportunity to de-escalate therapy in the presence of multimorbidity. Importantly, these HbA_1c levels reflect HbA_1c levels achieved by the patient, not necessarily HbA_1c levels pursued by the clinician. Examination of whether clinicians subsequently deintensified or intensified therapy in response to potentially excessive or inadequate treatment, respectively, was beyond the scope of this study.

The odds of insulin use were increased fivefold, independent of HbA_1c level, among patients with ≥3 concordant comorbidities compared with patients with none. Patients with concordant comorbidities were also 24% less likely to be treated with a sulfonylurea, suggesting that clinicians may preferentially rely on insulin in this population. This may reflect longer diabetes duration and greater insulin deficiency. Moreover, some diabetes-concordant conditions, most notably CKD, may necessitate use of insulin or sulfonylureas when other medications are inadequate or contraindicated. However, this does not justify the observed attainment of very low HbA_1c levels using these drugs. Indeed, nearly 13% of patients who have an advanced comorbidity and achieved HbA_1c ≤5.6% or 5.7%–6.4% were treated with insulin, and nearly 18% were treated with a sulfonylurea. We saw similar, high rates of insulin and sulfonylurea use at low HbA_1c levels among patients with concordant-only, discordant, and both concordant and discordant comorbidities, though there were relatively few patients in our cohort (2.7%) who had only discordant comorbidities. For patients with concordant comorbidities, attainment of low HbA_1c may reflect the clinician’s and/or patient’s desire to slow the progression of existing diabetes complications and/or prevent the onset of others. In addition, patients with diabetes-concordant comorbidities may be more likely to see their healthcare providers for diabetes management, resulting in greater focus on diabetes and higher intensity of treatment. Yet, such encounters also present an opportunity to re-evaluate current care, engage in shared decision-making, and deintensify therapy if the current level of glycemic control is not aligned with evidence or goals of care.

We also examined glycemic management among younger and healthier adults in the context of emerging concerns about increased rates of diabetes-related complications and hyperglycemic emergencies in the younger age groups.15 35 36 Our findings confirmed the presence of a risk/treatment paradox, with overall worse glycemic control and low rates of insulin therapy despite elevated HbA_1c levels among younger patients and patients with few comorbidities. Just 46.3% of patients 18–44 years old achieved HbA_1c ≤6.9%, compared with 62.5% of patients 75 years and older. Conversely, 23.1% of patients 18–44 years old had HbA_1c ≥9.0%, compared with just 5.6% of people ≥75 years old. ADA guidelines recommend insulin therapy when HbA_1c levels exceed 10%.18 Yet, even with HbA_1c ≥10%, only half of patients 18–44 years old were treated with insulin, compared with 61% of those ≥65 years old. Analogously, only 37% of patients without any of the examined comorbidities and HbA_1c ≥10% were treated with insulin, compared with more than 70% of patients with multiple comorbidities. While diabetes management is complex at any age, some of the challenges that young people face may be unique and need to be considered. For instance, younger people with commercial and employer-sponsored insurance are more likely to have high deductible health plans, limited coverage, and/or higher out-of-pocket costs than older adults with Medicare Advantage plans. Younger people may have less contact with healthcare providers and fewer opportunities to intensity treatment. They also have to balance the needs of their diabetes with other responsibilities, such as education, employment, and family. While we considered cumulative clinical complexity in our analyses, we could not capture the intangible work of living with diabetes and the overall burden of disease that people with diabetes face.37

AGS, as part of the American Board of Internal Medicine Choosing Wisely initiative, advised against using medications other than metformin to achieve HbA_1c <7.5% in most older adults.38 Similarly, NICE used a higher HbA_1c threshold to recommend starting medications associated with heightened hypoglycemia risk.4 In contemporary clinical practice, however, older patients were frequently treated with sulfonylureas and insulin at low HbA_1c levels. Sulfonylureas were used by 18%, 19%, and 28% of patients ≥75 years old whose HbA_1c levels were ≤5.6%, 5.7%–6.4%, and 6.5%–6.9%, respectively. Similarly, insulin was used by 7%, 6%, and 13%, respectively. Overall, increasing age was independently associated with greater odds of sulfonylurea use and decreasing odds of insulin use, suggesting that clinicians may be more hesitant to treat older adults with insulin but not with sulfonylureas. Finally, the proportions of older and clinically complex patients treated with insulin/sulfonylurea to achieve low HbA_1c targets were comparable to earlier studies,7–9 12 despite the increasing availability of medications posing a lower risk of hypoglycemia (DPP-4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors) and with additional cardiovascular and renal benefits (GLP-1 receptor agonists, SGLT2 inhibitors)18 than insulin and sulfonylurea. This is consistent with recent findings that older patients and patients with CKD, heart failure, and cardiovascular disease are all less likely to be prescribed SGLT2 inhibitors than younger and healthier people, despite their benefit in these contexts.39 Our study therefore reinforces the age and comorbidity-driven risk/treatment paradox in glucose-lowering therapy.

Our work builds on prior studies of glycemic overtreatment, which heretofore focused primarily on select comorbidities (most often, CKD or dementia)6 9 10 or older adults,7–12 by expanding analysis to wide ranges of age and multimorbidity. This is important, as treatment regimens and goals need to consider the patient’s overall health status, clinical complexity, and disease burden, not a few select comorbidities or chronological age. Similarly, a study by McAlister and colleagues found a similar risk/treatment paradox in glucose and blood pressure management among patients with diabetes (not restricted to type 2) in UK primary care practices between 2003 and 2015 as a function of frailty.13 However, our findings also need to be considered in the context of the study’s limitations. Some health conditions are not reliably captured in claims data, including dementia, incontinence, and falls. Claims also cannot capture disease severity, frailty, symptom burden, or life expectancy. Cases resulting in billed visits and thereby identified in claims are likely to be more severe or sufficiently bothersome to seek medical care, making individualized diabetes management especially important in this context. The prevalence of these conditions is likely much higher than suggested by our study. HbA_1c levels may not reliably reflect average glycemia, particularly in patients with anemia of chronic disease, uremia, or cirrhosis.40 Medication capture may also not be complete, and some patients without fills may be treated with medications obtained through low-cost generic drug programs (these would be metformin, sulfonylurea, and human insulin)41 or those obtained as samples. However, because our objective was to identify potentially inappropriate use of sulfonylurea/insulin drugs, missing medication data is likely to underestimate the prevalence of potential overtreatment.

The study population was comprised of commercially insured and Medicare Advantage beneficiaries with prescription drug coverage, and both glycemic control and glucose-lowering treatment regimens likely differ among patients with no or public health coverage who may be more likely to use lower cost medications such as human insulin and sulfonylurea. Similarly, the study cohort is older than the general US population, with 62.5% of patients aged 65 years and older. As such, the prevalence of comorbidities and multimorbidity may be higher in our study than in the general population. Finally, claims data cannot inform us about the patients’ individualized treatment targets, goals and preferences for care, day-to-day blood glucose levels, and conversations that took place between patients and their clinicians all of which can impact treatment decisions.

Nevertheless, our study suggests ample opportunity for treatment deintensification among older patients and patients with advanced and/or multiple comorbidities, which may lower their risk of hypoglycemia. At the same time, younger and healthier adults would benefit from continued focus on improving access to diabetes care and better control of hyperglycemia. Population health management efforts and policy solutions, implemented through performance measurement,42 43 can support individualized diabetes care and align it with scientific evidence and clinical practice guidelines.17 Most importantly, clinicians should continue to engage their patients in shared and informed decision-making, weighing the risks and benefits of glucose-lowering treatment regimens in the specific context of each patient, carefully considering the patient’s comorbidity burden, age, and goals and preferences for care.