Conclusions
In an observational analysis of a large global cohort of patients with type 2 diabetes, we found that a quarter of older participants had an HbA1c level of <7.0% (53.0 mmol/mol) at baseline and approximately half of participants had an HbA1c level of <7.0% (53.0 mmol/mol) during follow-up. The overall increase in the proportion of patients receiving inappropriately intensive treatment could be explained, in part, by the fact that all DISCOVER participants were initiating second-line glucose-lowering therapy (defined as add-on or switching), which may result in a decrease in the overall mean HbA1c level between baseline and 6 months. Thereafter, the proportion of participants for whom therapy was inappropriately tight remained high, possibly because some physicians failed to recognize inappropriate intensification and adapt treatment accordingly.
The proportion of patients who were overly intensively treated varied across countries in all income brackets. A novel finding was that patients in high-income countries were more likely to have intensive glycemic control, potentially reflecting stricter treatment regimens, with a greater emphasis placed on glucose monitoring and achieving glycemic targets, and better access to healthcare. The increased prevalence of baseline vascular complications in patients from high-income countries, compared with patients from lower-middle-income countries seen in a previous analysis of DISCOVER data,11 may also play a part in driving the high rate of inappropriately intensively treated diabetes, with a focus on ensuring that these patients achieve good glycemic control to minimize their risk of diabetes-related vascular complications. Intensive glycemic control and the presence of comorbidities that require medical treatment may place some patients at an increased risk of polypharmacy, with low HbA1c levels only achieved, in some cases, through the use of multiple glucose-lowering medications. In the USA, 57% of women and 59% of men reported using more than five different medications on a weekly basis, with older adults with type 2 diabetes at high risk of polypharmacy.13 Similarly, in Italy, 51.7% of older individuals (aged ≥65 years) with type 2 diabetes were reported to have polypharmacy, with comorbidities and diabetes-related complications shown to be associated with increased risk of polypharmacy.24
At each time point, approximately one-third of overly intensively controlled patients received a glucose-lowering treatment associated with a high risk of hypoglycemia. However, patients in lower-middle-income and upper-middle-income countries were more likely to use medications with a high risk of hypoglycemia. This may be indicative of the limited availability and affordability of alternative glucose-lowering therapies, such as DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors, in middle-income countries.25–27 As such, there seems to be a substantial global opportunity for quality improvement by adopting a personalized treatment approach to decrease the risk of hypoglycemia in older patients with type 2 diabetes.
Our findings are in line with a previous study in the USA in which half of the participants with type 2 diabetes who were aged ≥75 years were prescribed therapies associated with a high risk of hypoglycemia, despite having an HbA1c level of <7.0% (53.0 mmol/mol).15 18 A similar study in the UK found that 35.7% of people with type 2 diabetes aged ≥70 years were prescribed either insulin or a sulfonylurea; of these individuals, one-third had an HbA1c level of <7.0% (53.0 mmol/mol).16 Finally, the Guideline Adherence to Enhance Care (GUIDANCE) study of people aged >65 years with type 2 diabetes in eight European countries found that 44.7% of patients were prescribed either insulin or a sulfonylurea despite having an HbA1c level of <7.0% (53.0 mmol/mol).17 In addition, these studies were all conducted in either Europe or the USA and are therefore not representative of a global population. Our study extends these previous findings to a global cohort of patients from countries with varied income levels.
Our results, in combination with those of previous studies, indicate that many older patients are still potentially being inappropriately tightly controlled.15–17 These individuals may thus be at an increased risk of polypharmacy, with adherence to stringent glycemic targets requiring treatment with multiple glucose-lowering medications.13 The addition of multiple glucose-lowering medications to the treatment regimen of older individuals is associated with an increased risk of drug–drug interactions and other adverse events.28 The use of glucose-lowering medications that are associated with hypoglycemia in a substantial proportion of these patients is of particular concern. Data from previous studies have shown severe hypoglycemia to be a common cause of hospitalization among older individuals with type 2 diabetes, with the proportion of individuals hospitalized for hypoglycemia exceeding that of hyperglycemia.29 30 Given the association between inappropriately intensive treatment and risk of hypoglycemia, there may be a need for some physicians to consider treatment regimen simplification (discontinuation of at least one glucose-lowering agent or a reduction in dosage) in some older patients, as per the current ADA guidelines.1 The benefits and risks of different combinations of glucose-lowering therapies, in combination with medications for associated comorbidities, must be weighed and discussed with the individual and/or caregiver.13 Primary healthcare practitioners may also benefit from education on how to recognize and manage potentially inappropriate treatment intensifications in older patients. Too tightly controlled glycemia may also result from, at least in part, variables we were unable to measure, such as physician preference and experience, medication costs and availability, and number of physician visits. However, without studying the long-term effects of inappropriate treatment intensification on patient outcomes, our data do not support treatment de-intensification in these patients.
The primary strengths of the DISCOVER study program are both the large number of patients enrolled and the range of treatment sites and countries included, some of which have rarely been studied before. Data collection with a standardized eCRF allowed for the comparison of results between countries and regions. The observational nature of DISCOVER provided an ideal setting to investigate global treatment patterns, with minimal external influence and all treatment decisions made by the physician, as in routine clinical practice. However, our results must be interpreted with several limitations in mind. Although DISCOVER sites were selected to optimize diversity in each country, it is unclear if our findings truly reflect the quality of care within each country or can be generalized outside of the countries and regions included in the study. Participation in DISCOVER may have caused some healthcare practitioners to make different treatment decisions than they would if the data were not being recorded. Given that participants enrolled in DISCOVER were all initiating second-line glucose-lowering therapy, our findings may also not be representative of the entire type 2 diabetes population and may overestimate the proportion of older individuals who are inappropriately strictly managed. Given their involvement in DISCOVER, participating physicians and sites may also be more focused on quality of care than others. This may have resulted in an over-representation of more advanced treatment centers. In line with the observational nature of the study, there was no requirement to record all study variables and a complete data set was not available for all patients. Although these analyses highlight a subset of patients whose treatments are inappropriately intensive, associations between intensive glycemic control and potential adverse effects related to severe hypoglycemia could not be assessed due to the limited follow-up time. Of note, only a small number of participants experienced major hypoglycemic events during the first 12 months after baseline (no participants among those receiving inappropriate treatment intensification at baseline but no high-risk medication and three participants among those receiving inappropriate treatment intensification at baseline and high-risk medications; data not shown). Finally, our definition of an inappropriately intensive glucose-lowering treatment in this older population was based on an HbA1c level of <7.0%, in line with ADA guidelines, which recommend an HbA1c level of <7.5% in older patients. However, lower HbA1c targets may be appropriate for some of these patients. For example, patients early in the disease process, who are otherwise healthy without comorbidities, may benefit from initial tight glycemic control to reduce the risk of microvascular complications and may have been misclassified as being inappropriately tightly controlled.1
To conclude, in a global cohort of patients with type 2 diabetes initiating second-line glucose-lowering therapy, we found that 23.5% of older patients treated in routine clinical practice are potentially receiving an inappropriately intensive treatment, leaving them at an increased risk of polypharmacy and possible downstream complications, such as severe hypoglycemia. This proportion of patients increased to more than 50% during follow-up, with substantial variation between regions. Overall, up to one-third of these patients, or more in lower-middle-income and upper-middle-income countries, received treatment with high-risk glucose-lowering medication, potentially leaving them at an even greater risk of hypoglycemia. This highlights the inequality of type 2 diabetes care across the globe and also the need for a more personalized approach to treatment of type 2 diabetes in older patients, with a greater consideration of the benefit to risk ratio of intensive glycemic control. Future analyses could provide information on outcomes associated with inappropriate treatment intensifications and the possible benefits and harms of complex treatment regimens and treatment with high-risk medications and could complement results from interventional studies.