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Initial Management of Severe Hyperglycemia in Patients with Type 2 Diabetes: an Observational Study

Introduction Current guidelines recommend insulin for patients with type 2 diabetes (T2D) and severe hyperglycemia, but this recommendation lacks sufficient evidence and poses practical challenges. It is unclear whether non-insulin treatments are effective in this setting. The objective of this study was to describe treatment strategies of T2D patients with severe hyperglycemia and identify which initial treatments, interventions, or patient characteristics correlated with successful glucose lowering. Methods This was a retrospective cohort study of 114 patients with T2D and a glycosylated hemoglobin (A1C) ≥12%. Changes in A1C were compared between patients started on non-insulin medications versus insulin-based regimens. Regression analysis was performed to assess predictors of success in achieving A1C ≤9% within 1 year. The main outcomes measures were change in A1C from baseline and predictors of success in achieving A1C ≤9% within 1 year. Results At baseline, 43 patients (37.7%) started one or more non-insulin medications; 71 (62.3%) started insulin. Fifty-eight patients (50.8%) achieved an A1C ≤9%. Predictors of success were newly diagnosed T2D, certified diabetes educator (CDE) visits, and less time to follow-up A1C; insulin therapy was not. Change in A1C was significantly better in the non-insulin cohort compared to the insulin cohort (−4.5% vs. −2.8%, p = 0.001). Newly diagnosed patients were less likely to start insulin therapy (20.8% vs. 73.3%, p < 0.001), less likely to use insulin at any point (29.2% vs 81.1%, p < 0.001), and more likely to achieve an A1C ≤9% compared to patients with established T2D (87.5% vs 41.1%, p < 0.001). Conclusion Insulin therapy was used in roughly two-thirds of patients with severe hyperglycemia, but did not result in better glycemic control compared to non-insulin regimens. Rapid follow-up, more CDE visits, and a new diabetes diagnosis were predictors of successful glucose lowering. Patients with T2D and severe hyperglycemia, particularly those newly diagnosed, may be managed with non-insulin therapy.

hyperglycemia, but did not result in better glycemic control compared to non-insulin regimens. Rapid follow-up, more CDE visits, and a new diabetes diagnosis were predictors of successful glucose lowering. Patients with T2D and severe hyperglycemia, particularly those newly diagnosed, may be managed with noninsulin therapy.

INTRODUCTION
Diabetes affects 25.8 million people (8.3%) in the USA. There were 1.9 million new cases diagnosed in 2010 alone [1]. While the diagnostic threshold for diabetes is an A1C C6.5%, patients can present with severe hyperglycemia with A1C values reaching higher than 14%. Severe hyperglycemia may warrant specific and immediate treatment considerations to prevent acute complications, alleviate symptoms, and preserve beta cell function [2,3].
However, literature regarding the effectiveness of different treatment approaches to manage patients with non-emergent, severe hyperglycemia is limited.
The American Diabetes Association's (ADA) position statement on a patient-centered approach to the management of hyperglycemia in type 2 diabetes recommends that ''if a patient presents with significant hyperglycemic symptoms and/or has dramatically elevated plasma glucose concentrations ([300-350 mg/ dL), or an A1C C10-12%, insulin therapy should be strongly considered from the outset'' [3]. After symptoms are relieved and glucose levels are decreased, oral agents can be added and it may be possible to withdraw insulin, if preferred. This recommendation makes no distinction between newly diagnosed or drug-naïve patients and treated or established patients, and does not provide references or level of evidence. The American Association of Clinical Endocrinologists (AACE) algorithm for glycemic control recommends insulin therapy ± other agents for patients who present with an A1C [9% [4]. The recommendations state that ''for drug naïve patients with A1C levels [9%, it is unlikely that 1, 2, or even 3 agents (other than insulin) will achieve the A1C goal''. The algorithm does, however, suggest that treatment with combination non-insulin agents in drug-naïve patients who do not have symptoms may be sufficient. References or levels of evidence are not provided.
Although consensus statements suggest initiating insulin therapy, this is challenging in real-world practice. Successful insulin initiation requires time, resources, knowledge, proper dose titration, significant patient education and training, self-monitoring of blood glucose, and frequent follow-up [3]. In the primary care setting, many barriers exist, including time restraints, patient resistance, and lack of available resources and trained staff that make it difficult to initiate insulin therapy in a safe and effective manner.
The lack of sufficient evidence and the practical challenges posed by initiating insulin therapy support the need for further evaluation of treatment approaches to severe hyperglycemia in T2D patients. Therefore, the purpose of this study was to (1)  Results of the regression analysis to determine predictors of response are in Table 3. A new diagnosis of diabetes, less days to first A1C follow-up, and more CDE visits were found to be predictors of response, while insulin treatment and number of endocrine clinic visits were not.
Changes in A1C from baseline are in Table 4. The average A1C reduction in the total patient population was 3.5%. The non-insulin-treated cohort had a significantly greater reduction in A1C compared to the insulin-treated cohort  Table 6. No correlation was found between any specific medication regimen and meaningful glucose response.
The current study provides useful insight into real-world use of insulin therapy in this patient population. Overall, insulin use in the responder group was lower than anticipated with only about half initiating insulin-based  This analysis did determine that more visits with a CDE was a predictor of successful Table 5 Comparisons between newly and previously diagnosed subjects    [9,10]. It is highly likely that, in this realworld clinical setting, several patients in the insulin-treated cohort did not have their insulin regimen intensified sufficiently to achieve successful glycemic control. Third, we defined glycemic response as achieving an A1C B9% within the first year. This A1C value does not meet the general target A1C recommended by the ADA, but was determined by the authors, a priori, to constitute a clinically meaningful A1C reduction in this severe hyperglycemia population. Fourth, subjects were regarded as an ''intent to treat'' population. If a patient started therapy with a non-insulin medication within 1 month of baseline, they remained in the non-insulin cohort throughout analysis, regardless of whether they later received insulin medications.

CONCLUSION
The results from this retrospective study show that a new diagnosis of diabetes, more visits with a certified diabetes educator, and fewer days to first follow-up A1C were predictors of success in achieving an A1C B9%, whereas insulin therapy was not. Furthermore, it was observed that insulin therapy did not lead to better A1C reductions or higher odds of achieving an A1C B9% compared to noninsulin regimens, regardless if the patient was newly diagnosed or had an established diagnosis. A new diagnosis of diabetes was a confounding variable. Meaningful glucose reductions were much more likely in newly diagnosed patients than those with established diabetes regardless of the treatment approach. Despite limitations, this study suggests that patients with T2D and severe hyperglycemia, particularly those newly diagnosed, may be able to be managed with non-insulin therapy.
Further randomized prospective studies are warranted to confirm this.