Glycemic Control in Medical Inpatients with Type 2 Diabetes Mellitus Receiving Sliding Scale Insulin Regimens versus Routine Diabetes Medications: A Multicenter Randomized Controlled Trial

INTRODUCTION

Diabetes mellitus (DM) is a common comorbid condition in hospitalized patients. Traditionally, patients with type 2 DM are converted from their routine diabetes medications to a sliding scale insulin (SSI) regimen or receive the SSI in addition to their routine diabetes medications during hospitalization.^1,2 The SSI regimen consists of short-acting insulin 4 to 6 times a day, based on regularly obtained capillary blood glucose measurements. In the face of metabolic stressors, other acute medical conditions, and varying diet and activity levels, the SSI is used in belief that this regimen is better able to maintain tight glycemic control and avoid glycemic events (ie, hypoglycemia and hyperglycemia). It is not clear how this practice began, but it has become a popular method of glucose control usually learned during residency training.¹ For example, in a study of medical inpatients, physicians prescribed an SSI regimen for 61% of patients with type 2 DM who were admitted to the hospital for reasons other than metabolic control.³

There are several problems associated with the use of the SSI regimen, however.^1,4–,⁹ The regimen typically results in an increase in the number of insulin injections received, and insulin is given retrospectively for high blood glucose values and not given during euglycemia or before anticipated hyperglycemia attributable to concurrent or planned meals. Patients are often awakened during the night for blood glucose monitoring and insulin therapy, which may increase the incidence of nocturnal hypoglycemia. In addition, there is no standard SSI regimen, and dosages vary widely between patients, providers, and institutions.

Furthermore, some evidence suggests that SSI regimens carry additional risk of glycemic events instead of protecting against them. In both retrospective and nonrandomized studies, not only have SSI regimens been associated with an increase in hyperglycemia and hypoglycemia, but they have also been associated with an increased length of stay for hospitalized diabetic patients.^3,7,10,11 Additionally, there is no evidence to suggest any short- or long-term benefit from tight glycemic control during hospitalization for most comorbid medical conditions. Although hyperglycemia has theoretical effects on granulocyte adhesion, chemotaxis, phagocytosis, etc, and has demonstrable effects on glycosuria and dehydration, these effects have not been studied in prospective clinical trials to demonstrate adverse consequences.¹² While tight glycemic control with insulin and glucose infusions has been associated with reductions in mortality in patients with acute myocardial infarction and reductions in morbidity and mortality in critically ill patients in the intensive care unit setting, there is no known benefit from tight glycemic control during hospitalization for many other illnesses.^13,14

Given all this, the use of the SSI regimen has come under increased scrutiny in the management of medical inpatients with type 2 DM. Considering the frequency of use of SSI regimens in patients with type 2 DM and comorbid conditions and the type and results of published studies examining their effect on glycemic control, we conducted a prospective, randomized controlled trial to evaluate the addition of the SSI regimen to routine diabetes medications in terms of its effects on glycemic events and length of hospitalization in patients with type 2 DM hospitalized for other comorbid illnesses.

METHODS

RESULTS

A total of 153 patients were enrolled in the study between June 2000 and October 2001 (Figure 1⇓). The clinical and demographic characteristics of the treatment groups were similar at randomization (Table 2⇓). The primary reasons for hospitalization included cardiovascular disease (44.1%), infection (10.3%), pulmonary disease (8.4%) and neurological disease (7.6%). Of the patients who had admission diagnoses of cardiovascular disease, 19 had chest pain, 14 had congestive heart failure, 4 had atrial fibrillation, and 1 had pulmonary hypertension. Although patients with acute myocardial infarction (AMI) were excluded from enrollment, patients with chest pain were allowed to enroll in the study until cardiac enzymes clarified the diagnosis, because of the high clinical frequency of noncardiac causes for chest pain. There were no differences in admission diagnoses between the groups. Admission and discharge diagnosis matched in 78.7% and 68.0% of patients in the intervention and control groups, respectively (P = .14).

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Figure 1.

Flow diagram of multicenter trial comparing the sliding scale insulin regimen versus routine diabetes medications.

Many patients were receiving combination therapy (ie, oral sulfonylurea and intermediate acting insulin, etc) for glucose control (43.8%), and 5.3% had diet-controlled diabetes (Table 2⇑). Oral sulfonylurea agents were the most commonly used antidiabetic agents (54.9%), and significantly more patients in the control group were receiving intermediate acting insulin (50.0% control group, 33.3% intervention group, P = 0.04). The use of corticosteroids during hospitalization was not different between the groups (20.0% intervention group, 14.1% control group, P = 0.33). As Figure 1⇑ indicates, 8 patients were withdrawn from the study (4 in each group) for the following reasons:

• Exclusion criteria met after enrollment (n = 3)

• Development of hyperglycemia greater than 400 mg/dL (22.2 mmol/L) (n = 2)

• Development of hypoglycemia less than 50 mg/dL (2.8 mmol/L) (n = 1)

• Length of stay less than 24 hours (n = 1)

• Patient’s request (n = 1)

DISCUSSION

This study demonstrates no benefit from the addition of the SSI regimen to routine diabetes medications in patients with type 2 DM hospitalized for other comorbid conditions. Patients experienced a similar rate of hyperglycemia and hypoglycemia and length of stay regardless of treatment assignment.

These results differ from the nonrandomized study in patients with type 2 DM hospitalized for comorbid conditions and treated with an SSI regimen.¹¹ In the report by Queale and colleagues, 76% of 171 patients were placed on a SSI regimen during hospitalization. When used alone, the SSI regimen was associated with a threefold increase in risk of hyperglycemic events when compared to no standing regimen. Hypoglycemic events occurred in 23% of the 171 patients studied, and 40% experienced hyperglycemic events. Since this study was nonrandomized, there is the potential bias that patients with more unstable diabetes were assigned to the SSI regimen and differed from those who continued their routine medications. Our study suggests that when patients are randomly allocated to treatment regimens to avoid assignment bias, there are no differences between the 2 treatment regimens evaluated.

The results of this study suggest that either the addition of the SSI regimen or the use of routine diabetes medications alone are equally acceptable treatment strategies for managing diabetes in a patient hospitalized for another illness. Clinicians should consider patient preferences in their selection and consider any cost differential in making their treatment decision. Because SSI regimens require multiple insulin injections during the day that place increased demand on nursing personnel, this approach may be more expensive while not providing any benefit over routine diabetes medications. Physicians should consider the additional nursing time demands and cost implications before routinely ordering SSI coverage for their patients.

In addition to finding no difference in primary outcomes between the addition of an SSI to routine medications and routine medications alone in this study, we also identified 3 risk factors associated with glycemic events. Patients who were using intermediate acting insulin at the time of admission were nearly 3 times as likely to have glycemic events during their hospitalization. It is doubtful that the use of intermediate acting insulin led to poorer glycemic control in this group, but rather that the use of intermediate acting insulin was a marker for poorer glycemic control. In addition, patients receiving corticosteroids and those with elevated blood glucose values greater than 250 mg/dL (13.9 mmol/L) on admission were also about 7 times more likely to have glycemic events, regardless of the treatment assignment. Consequently, the presence of these risk factors in a diabetic patient admitted for another medical problem should alert the physician that poor glycemic control is likely and might prompt closer monitoring in an effort to avoid complications.

This study is limited in the fact that the population was chosen from a convenience sample, rather than from consecutive patients hospitalized and meeting study inclusion criteria. It is possible that a subset of patients who may have received benefit or been harmed by the use of the SSI regimen were not enrolled in the study. Physicians were not blinded to treatment assignment and were allowed to adjust the regular diabetes regimen during hospitalization in response to patient factors (ie, blood glucose values, new contraindications, side effects, cost, etc). Although these were not specifically monitored during the study, it is possible that medications were changed differently among the 2 treatment groups, and this may have affected the study outcomes. However, this was allowed during the study in order to simulate routine care. Finally, blood glucose control was not assessed in the study (ie, daily blood glucose values), so it is possible that 1 group may have had better blood glucose control during hospitalization. However, there is a lack of evidence to support the benefit of short-term glucose control in diabetic patients with the comorbid conditions enrolled in this study.

Also, it is important to note that this study focused only on patients with type 2 DM. Other studies in patients with type 1 DM and DKA found that the use of the SSI alone resulted in higher blood glucose values and prolonged the duration of hospitalization when compared with regimens including long-acting insulin.^7,10 Because our study excluded patients with type 1 DM, the results of our study should not be generalized to these patients. Physicians should also be reminded that patients who were unable to take food or medications by mouth were excluded from the study. Therefore, our results should not be applied to this patient population where the SSI regimen is routinely used. Our results should not be applied to patients with type 2 DM who are critically ill, as these patients were excluded. In addition, our study used a specific SSI regimen, and results may have been different if a more or less aggressive regimen were used.

The use of the SSI regimen in combination with routine diabetes medications does not influence the rate of hyperglycemia or hypoglycemia or change the length of stay in patients with type 2 DM hospitalized for other conditions. Patients receiving intermediate acting insulin as part of their routine diabetes medication regimen, those with elevated blood glucose values upon admission, and those given corticosteroids during hospitalization may be more likely to have glycemic events. Other measures (ie, use of long-acting insulin and other antidiabetic agents) may be effective in minimizing hyperglycemia and hypoglycemia during hospitalization in patients with type 2 DM and other comorbid conditions.