WHAT IS THE ASSOCIATION BETWEEN HYPERGLYCEMIA AND OUTCOMES?
In 2,471 patients admitted to the hospital with community-acquired pneumonia, McAlister et al10 found that the rates of hospital complications and of death rose with blood glucose levels.
Falguera et al11 found that, in 660 episodes of community-acquired pneumonia, the rates of hospitalization, death, pleural effusion, and concomitant illnesses were all significantly higher in diabetic patients than in nondiabetic patients.
Noordzij et al12 performed a case-control study of 108,593 patients who underwent noncardiac surgery. The odds ratio for perioperative death was 1.19 (95% confidence interval [CI] 1.1–1.3) for every 1-mmol/L increase in the glucose level.
Frisch et al,13 in patients undergoing noncardiac surgery, found that the 30-day rates of death and of in-hospital complications were all higher in patients with diabetes than without diabetes.
Our group3 identified hyperglycemia as an independent marker of in-hospital death in patients with undiagnosed diabetes. The rates of death were 1.7% in those with normoglycemia, 3.0% in those with known diabetes, and 16.0% (P < .01) in those with new hyperglycemia.
The ACE/ADA consensus panel14 set the following glucose targets for patients in the non-ICU setting:
- Pre-meal blood glucose < 140 mg/dL
- Random blood glucose < 180 mg/dL.
On the other hand, hypoglycemia is also associated with adverse outcomes. Therefore, to avoid hypoglycemia, the insulin regimen should be reassessed if blood glucose levels fall below 100 mg/dL. New guidelines will suggest keeping the blood glucose between 100 and 140 mg/dL.
HOW SHOULD WE MANAGE HYPERGLYCEMIA IN THE NON-ICU SETTING?
The ACE/ADA guidelines recommend subcutaneous insulin therapy for most medical-surgical patients with diabetes, reserving intravenous insulin therapy for hyperglycemic crises and uncontrolled hyperglycemia.14
Oral antidiabetic agents are not generally recommended, as we have no data to support their use in the hospital. Another argument against using noninsulin therapies in the hospital is that sulfonylureas, especially glyburide (Diabeta, Micronase) are a major cause of hypoglycemia. Metformin (Glucophage) is contraindicated in decreased renal function, in hemodynamic instability, in surgical patients, and with the use of iodinated contrast dye. Thiazolidinediones are associated with edema and congestive heart failure, and they take up to 12 weeks to lower blood glucose levels. Alpha-glucosidase inhibitors are weak glucose-lowering agents. Also, therapies directed at glucagon-like-protein 1 can cause nausea and have a greater effect on postprandial glucose.14
The two main options for managing hyperglycemia and diabetes in the non-ICU setting are short-acting insulin on a sliding scale and basal-bolus therapy, the latter with either NPH plus regular insulin or long-acting plus rapid-acting insulin analogues.
Basal-bolus vs sliding scale insulin: The RABBIT-2 trial
In the RABBIT 2 trial (Randomized Basal Bolus Versus Sliding Scale Regular Insulin in Patients With Type 2 Diabetes Mellitus),15 our group compared the efficacy and safety of a basal-bolus regimen and a sliding-scale regimen in 130 hospitalized patients with type 2 diabetes treated with diet, with oral hypoglycemic agents, or with both. Oral antidiabetic drugs were discontinued on admission, and patients were randomized to one of the treatment groups.
In the basal-bolus group, the starting total daily dose was 0.4 U/kg/day if the blood glucose level on admission was between 140 and 200 mg/dL, or 0.5 U/kg/day if the glucose level was between 201 and 400 mg/dL. Half of the total daily dose was given as insulin glargine (Lantus) once daily, and the other half was given as insulin glulisine (Apidra) before meals. These doses were adjusted if the patient’s fasting or pre-meal blood glucose levels rose above 140 mg/dL or fell below 70 mg/dL.
The sliding-scale group received regular insulin four times daily (before meals and at bedtime) for glucose levels higher than 140 mg/dL; the higher the level, the more they got.
The basal-bolus regimen was better than sliding-scale regular insulin. At admission, the mean glucose values and hemoglobin A1c values were similar in both groups, but the mean glucose level on therapy was significantly lower in the basal-bolus group than in the sliding-scale group, 166 ± 32 mg/dL vs 193 ± 54 mg/dL, P < .001). About two-thirds of the basal-bolus group achieved a blood glucose target of less than 140 mg/dL, compared with only about one-third of the sliding-scale group. The basal-bolus group received more insulin, a mean of 42 units per day vs 12.5 units per day in the sliding-scale group. Yet the incidence of hypoglycemia was 3% in both groups.
NPH plus regular vs detemir plus aspart: The DEAN trial
Several long-acting insulin analogues are available and have a longer duration of action than NPH. Similarly, several newer rapid-acting analogues act more rapidly than regular insulin. Do these pharmacokinetic advantages matter? And do they justify the higher costs of the newer agents?
In the randomized Insulin Detemir Versus NPH Insulin in Hospitalized Patients With Diabetes (DEAN) trial,16 we compared two regimens: detemir plus aspart in a basal-bolus regimen, and NPH plus regular insulin in two divided doses, two-thirds of the total daily dose in the morning before breakfast and one-third before dinner, both doses in a ratio of two-thirds NPH and one-third regular, mixed in the same syringe. We recruited 130 patients with type 2 diabetes mellitus who were on oral hypoglycemic agents or insulin therapy.
NPH plus regular was just as good as detemir plus aspart in improving glycemic control. Blood glucose levels fell during the first day of therapy and were similar in both groups throughout the trial, as measured before breakfast, lunch, and dinner and at bedtime. The mean total daily insulin dose was not significantly different between treatment groups: 56 ± 45 units in the basal-bolus detemir-aspart group and 45 ± 32 units in the NPH-regular group. However, the basal-bolus group received significantly more short-acting insulin: 27 ± 20 units a day of aspart vs 18 ± 14 units of regular.
Somewhat fewer patients in the NPH-regular group had episodes of hypoglycemia, although the difference between groups was not statistically significant.
In a univariate analysis of the RABBIT-2 and DEAN trials,17 factors that predicted a blood glucose level less than 60 mg/dL were older age, lower body weight, higher serum creatinine level, and previous insulin therapy. Factors that were not predictive were the hemoglobin A1c level and the enrollment blood glucose level. Based on these data, we believe that to reduce the rate of hypoglycemia, lower insulin doses are needed in elderly patients and patients with renal impairment, and that if patients have been taking insulin before they come to the hospital, the dose should be cut back by about 25% while they are hospitalized.