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Chapter 1

The Evolution of Glycemic Control in the Hospital Setting

Etie Moghissi, MD, FACE,¹ and Silvio Inzucchi, MD²

¹Associate Clinical Professor, Department of Medicine, University of California Los Angeles, Los Angeles, CA. ²Professor of Medicine Section of Endocrinology, Yale School of Medicine, New Haven, CT.

DOI: 10.2337/9781580406086.01

Introduction

Patients with diabetes are hospitalized three times more frequently than those without diabetes, and hyperglycemia in the hospital setting is associated with increased mortality, morbidity, longer hospital stays, and cost. Yet at the turn of the twenty-first century, few appreciated the risk of acute hyperglycemia among hospitalized patients. There were no clinical practice guidelines or recommended glycemic targets for inpatients, and every hospital relied on sliding-scale insulin therapy to manage hyperglycemia.

Early observational studies and the seminal 2001 randomized clinical trial of intensive insulin therapy in critically ill patients¹ paved the way for diabetes organizations to issue calls for tight glycemic control in the critically ill patients.^2–4 Investigations published after these initial recommendations, however, called into question the benefit of maintaining near-normal glycemic control in the critically ill and raised concerns regarding the prevalence of incremental hypoglycemia associated with such an approach.^5–8 Notably, the Normoglycemia in Intensive Care Evaluation Using Glucose Algorithm Regulation (NICE-SUGAR) study actually showed that a 14% increased risk of death accompanied dramatically increased rates of severe hypoglycemia in patients whose glucose was controlled to the euglycemic range,⁹ the latter confirmed by meta-analysis of multiple studies involving the critically ill.⁸ These findings prompted the American Association of Clinical Endocrinologists (AACE)/American Diabetes Association (ADA) consensus group to evaluate all related published studies and update their recommendations for glycemic targets in hospitalized patients,¹⁰ with the goal of recommending reasonable, achievable, and safe glycemic targets. The consensus group chose a target of 140–180 mg/dL for critically ill patients based on the best available evidence. The group’s primary concern was maintaining patient safety, especially the avoidance of hypoglycemia. The panel recommended insulin as the treatment of choice for the majority of hospitalized patients. Continuous intravenous (IV) insulin infusion was recommended for those patients in the intensive care unit (ICU), and scheduled insulin in the form of basal, nutritional, and supplemental injections was preferred for the noncritically ill (Table 1.1). Echoing these recommendations, in 2012 The Endocrine Society issued an updated guidance focused on noncritically ill patients,¹¹ with similar recommendations as the AACE/ADA consensus group. Both groups emphasize that clinical judgment, individualized regimens tailored to each patient, and ongoing assessment of clinical status must be incorporated into day-to-day decisions regarding the management of hyperglycemia.^10,11

Table 1.1—Summary of ADA/AACE Recommendations for Management of Hyperglycemia among Hospitalized Patients

	Critically ill	Noncritically ill
Blood glucose target	• 140 to 180 mg/dL(7.8 to 10.0 mmol/L)	• Premeal: <140 mg/dL (<7.8 mmol/L)* • Random: <180 mg/dL (<10.0 mmol/L)*
Preferred treatment regimen	• Intravenous insulin infusion of regular insulin • Use validated insulin infusion protocol • Frequently monitor blood glucose to minimize hypoglycemia	• Scheduled subcutaneous administration of insulin, with basal, nutritional, and correction components • Prolonged therapy with sliding-scale insulin as the sole regimen is discouraged • Noninsulin antihyperglycemic agents are not appropriate for most hospitalized patients who require therapy for hyperglycemia

*Provided these targets can be safely achieved. More stringent targets may be appropriate in stable patients with previous tight glycemic control; less stringent targets may be appropriate in terminally ill patients or those with severe comorbidities.

Stress Hyperglycemia

Approximately one-third of hospital inpatients experience hyperglycemia, with up to a third of these individuals having no previous history of diabetes.^12–14 Although a substantial portion of these patients likely have prediabetes or undiagnosed diabetes, acute injury and illness clearly can lead to glucose elevations in those with previously normal glucose tolerance. This stress hyperglycemia results from a complex interplay between inflammatory cytokines, catecholamines, the oxidative stress resulting from gluco- and lipotoxicity, and activation of the hypothalamic-pituitary-adrenal axis, all resulting in insulin resistance and insufficient pancreatic insulin secretion. Treatments commonly used among inpatients, such as glucocorticoids, enteral and parenteral nutrition, and vasopressors also may lead to or exacerbate glucose elevations.¹⁵ Regardless of the cause, however, hyperglycemia, particularly when severe, must be treated to reduce adverse outcomes, including dehydration, electrolyte disturbance, infectious complications, and poor wound healing.

Hyperglycemia and Adverse Hospital Outcomes

Epidemiologic studies began to establish a clear link between increasing blood glucose levels and hospital mortality in the late 1990s and early 2000s. In a 1999 publication from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study, the risk of death among 620 patients with diabetes admitted for acute myocardial infarction (MI) rose by 8% with each 18 mg/dL increase in admission blood glucose (relative risk [RR] 1.08, 95% confidence interval [CI] 1.05–1.11; P < 0.001).¹⁶ A 2003 retrospective review of data from ICU patients revealed that the mortality rate approximately doubled among patients with a mean glucose value during hospitalization between 160 and 199 mg/dL and roughly tripled among patients with mean glucose between 200 and 299 mg/dL. Above 300 mg/dL, the rate of death was approximately fourfold higher.¹⁷ In a large retrospective study of more than 250,000 admissions to 173 hospitals published in 2009, the risk of death nearly doubled for patients with blood glucose 146–199 mg/dL during hospitalization (odds ratio [OR] 1.31; 95% CI 1.26–1.36), independent of severity of illness. The odds of death, adjusted for illness severity, more than doubled at 200–299 mg/dL (OR 1.82; 95% CI 1.74–1.90), and almost tripled for glucose values >300 mg/dL (OR 2.85; 95% CI 2.58–3.14).¹⁸ Other observational and controlled studies have unequivocally supported the association between hyperglycemia and inpatient mortality risk.^14,19–21 In addition, patients with hyperglycemia are more likely to have prolonged hospital stays, infections, and greater degrees of disability after hospital discharge.^14,21–23 Data from outside the ICU further establish the association of hyperglycemia with adverse outcomes. For example, in a study of 2,471 patients with community acquired pneumonia, blood glucose levels >200 mg/dL during hospitalization were associated with higher rates of mortality and in-hospital complications than blood glucose levels <200 mg/dL.²⁴

Patients at greatest risk for adverse hospital outcomes may be those without a previous history of diabetes, which emphasizes the importance of treating inpatient hyperglycemia regardless of the cause. A retrospective review of medical records of more than 2,000 critically ill patients showed significant increases in mortality among patients with new hyperglycemia, that is, those without previously diagnosed diabetes. The mortality rate was about eight times higher among patients with hyperglycemia as those with normal glucose levels (P < 0.01) and about five times higher than patients with diagnosed diabetes (P < 0.01).¹⁴ In the aforementioned retrospective study of 250,000 admissions, the odds of mortality were significantly higher for patients with no previous history of diabetes than for those with diagnosed diabetes (P < 0.01). Compared with normoglycemic patients, those without diagnosed diabetes had a 35% increased risk of death if their glucose was 111–145 mg/dL (OR 1.35; 95% CI 1.30–1.41). Successively increasing glucose ranges were associated with a doubled, tripled, and quadrupled mortality risk (146–199 mg/dL: OR 2.14, 95% CI 2.04–2.24; 200–299 mg/dL: OR 2.91, 95% CI 2.71–3.11; >300 mg/dL: OR 4.04, 95% CI 3.44–4.75).¹⁸ Observational studies such as these can only be considered hypothesis generating. Indeed, because the degree of illness will be associated with the level of stress hyperglycemia, studies such as these are particularly prone to influence by unmeasured confounders. It is only through randomized clinical trials that one may know whether glucose control actually improves the risk of adverse outcomes in hospitalized patients with hyperglycemia.

Effects of Glycemic Control on Inpatient Outcomes

Both retrospective and prospective controlled studies have brought us to our current understanding of optimal glucose control for both critically ill and noncritically ill patients. In the DIGAMI study, 1-year mortality significantly decreased by 29% (P = 0.027) in patients with diabetes randomly assigned to insulin-glucose infusion for the first 24 h after acute MI compared with patients given standard therapy of the time, in which insulin was given during the first 24 h only if it was deemed clinically necessary.²⁵ Other early controlled trials comparing tight glucose control to standard treatment approaches also demonstrated significant reductions in mortality and morbidity among both ICU and noncritical inpatient populations. In an often-cited 2001 prospective, randomized clinical trial involving 1,548 surgical ICU patients in Belgium, intensive insulin therapy to maintain glycemia between 80 and 110 mg/dL significantly reduced mortality risk by 32% (P < 0.04) compared with standard treatment of the time, in which insulin was given only when patients’ blood glucose exceeded 215 mg/dL, with the goal of maintaining blood glucose values of 180-200 mg/dL. In addition, intensive insulin therapy also significantly reduced the duration of ICU stays and ventilatory support, need for dialysis, and episodes of septicemia.¹ These results were supported by a retrospective analysis of ICU patients who had undergone coronary artery bypass grafting (CABG). The investigators compared hospital records from two time periods during which different glucose control approaches had been used. During the earlier period, subcutaneous (SQ) insulin had resulted in a mean glucose value of 213 mg/dL among CABG patients, whereas a later protocol using insulin infusion resulted in a mean glucose value of 177 mg/dL. Insulin infusion reduced the risk of death by 57% (OR 0.43; P = 0.001).¹⁹

Further investigations, however, were not able to confirm the benefit of near normalization of glucose and raised concerns regarding the risk of hypoglycemia with this approach. In 2003, the same Belgian investigators published results from a second clinical trial, showing that tight glucose control did not significantly reduce mortality in the medical (as opposed to surgical) ICU, except among patients whose ICU stays exceeded 5 days.²⁶ Subsequently, the NICE-SUGAR study highlighted the dangers of hypoglycemia that accompany tight glucose control. This international investigation compared 90-day mortality in a cohort of 6,104 patients who were admitted to medical and surgical ICUs at 42 different hospitals where they were assigned randomly to glycemic targets of 81–108 mg/dL and 144–180 mg/dL. Rates of severe hypoglycemia were ~15 times greater among intensively treated patients (OR 14.7, 95% CI 9.0–25.9; P < 0.001), and mortality was 14% higher in the same group compared with patients whose glucose was less intensively controlled (P = 0.02).⁹ A meta-analysis of 26 randomized controlled trials involving 13,567 ICU patients (including the NICE-SUGAR cohort) supported the NICE-SUGAR finding that the risk of hypoglycemia is too great to justify near-normal glucose values, especially in medical ICU patients. In the pooled analysis of studies reporting hypoglycemia, the relative risk of hypoglycemia was 6.0 (95% CI 4.5–8.0) for intensive insulin therapy compared with conventional glucose control. Meanwhile, the overall relative risk of death was 0.93 (95% CI 0.83–1.04).⁸ As a result of these findings, recommendations for target glucose levels were relaxed from the euglycemic range to the values shown in Table 1.1.

Protocols for Glucose Management

A major goal of treating hyperglycemia in the hospital is patient safety, because overtreatment and undertreatment of hyperglycemia represents major quality concerns. Well-defined, validated protocols for the management of hyperglycemia will include provisions for glucose monitoring and the treatment of hypoglycemia as well as guidance on matching insulin administration to blood glucose levels and nutrition (either meals or enteral or parenteral nutrition) in a dynamic fashion.

Changing patient circumstances also drive modifications to insulin regimens in the hospital. These include transitions from ICU to noncritical care settings, which call for changes from IV infusion to SQ injections of insulin; nutrition therapy transitions between enteral or parenteral therapy and solid foods; or perioperative glycemic control. Patients admitted for diabetic hyperglycemic crises (diabetes ketoacidosis or hyperglycemic hyperosmolar state) also will require insulin therapy along with close monitoring of blood glucose values to reduce the risk of hypoglycemia. Of course, these patients also require extensive management decisions related to fluids and electrolytes, beyond mere glycemic control.

Monitoring the patient’s glycemic status falls to point-of-care (POC) capillary blood glucose meters, which provide nearly instantaneous results and have become the standard measurement technique at the hospital bedside. Caution is required in interpreting the results from POC meters in patients who have anemia, polycythemia, or hypoperfusion or who use certain medications. Newer technologies, including continuous glucose monitoring, are under study.

Ongoing education of hospital personnel in these protocols is essential not only to ensure proper implementation but also to gain support of those involved in the care of inpatients with hyperglycemia, including the hospital administration. Evidence supporting the cost-effectiveness of a rational systems approach to inpatient glycemic management will help persuade administrators to provide necessary financial and operational support.^27,28

Status of Glycemic Control in the Hospital Setting

The health-care community at large now generally accepts that both hyperglycemia and hypoglycemia are markers of poor clinical outcomes, and many institutions have made important strides to improve glycemia at their facilities. Multiple barriers persist, however, and the frequency of poor glycemic control remains high. In an analysis of a database containing information on 70,000 admissions of patients with diabetes, an HbA_1c was recorded for only 18% of cases.²⁹ The authors of this study found that, when A1C was measured, a value >8% prompted a change in antihyperglycemic regimen for only two-thirds of patients (64%). Additionally, several studies have documented failures to reliably follow hypoglycemia management protocols, with long delays in glucose retesting after hypoglycemic events, poor documentation of the hypoglycemic and subsequent treatment, and long intervals before hypoglycemia resolution.^30–32 The root of the problem may be in poor communication and coordination between health-care teams,^30,33 but knowledge gaps also appear to contribute. In a recent survey of health-care professionals working in an urban, community teaching hospital, only about half of questions regarding best practices for managing inpatient hyperglycemia were answered correctly by physicians, nurses, and dietitians (mean scores of 53%, 52%, and 48%, respectively). Pharmacists performed somewhat better (mean score 64%), whereas patient care assistants correctly answered only about a third of the questions (38%). In general, this group of health-care workers acknowledged the importance of controlling hyperglycemia, but they still preferred the perceived convenience of sliding-scale insulin, and this preference influenced clinical decision making.³⁴

Many institutions rely on a systematic analysis of their glucose measurements to address these problems. Sometimes referred to as “glucometrics,” this approach incorporates the tracking of glycemic exposure, the efficacy of glycemic control, and the rates of adverse events and allows hospitals to measure the success of inpatient glucose management efforts. Individual health-care professionals can use glucometrics to identify and address the causes of hyper- and hypoglycemia. Institutions can use these metrics to identify opportunities for improvement in glycemic management across the health system. A goal of 85% of blood glucose levels within the target range has been proposed as a gold standard, and some groups recommend use of the patient-day unit of measure, because it may more accurately reflect the frequency of hypoglycemia and severe hyperglycemic events. Glucometric approaches have not been standardized, however, and various methods continue to be implemented. Of course, merely tracking glycemic values does not appear to improve outcomes.³⁵ The data obtained must be used to guide the actions of health-care professionals across disciplines^10,11,36 and to advise institutions to make strategic decisions regarding support staff, protocol development, and practitioner education.

Emerging Evidence to Control Glucose in the Inpatient Setting

Recent interest has focused on the potential of incretin-based therapies as a supplement or alternative to insulin therapy in the hospital setting. These agents carry a low risk of hypoglycemia and may offer cardioprotective benefits.³⁷ One pilot study involving 90 patients randomly assigned general medical and surgery patients with type 2 diabetes to glucose management with the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin alone, sitagliptin plus insulin glargine, or a basal-bolus insulin regimen. Overall, the three treatment groups experienced similar glycemic control, although basal-bolus insulin provided better control in patients whose admission glucose was >180 mg/dL.³⁸ In addition, patients in the sitagliptin-only group required correction doses with rapid-acting insulin as often as patients in the other groups to maintain target glucose levels. Rates of hypoglycemia were also similar among the three groups.

Glucagon-like peptide 1 (GLP-1) receptor agonists for inpatient management have shown some potential to control glucocorticoid-induced and stress hyperglycemia in several small studies, but so far no randomized, controlled trials have been conducted.³⁷ In one pilot study involving 40 patients in a cardiac ICU, exenatide infusion successfully maintained a steady-state glucose value of 132 mg/dL without incidence of hypoglycemia; however, a large proportion of patients experienced nausea.³⁹

Areas for future research include investigations of the following:

1. Glycemic quality measures needed to improve patient outcomes

2. Safe and effective methods of point-of-care testing for the management of glycemia in critically ill patients

3. The role of continuous glucose monitoring in the inpatient setting

4. Appropriate glycemic targets for different patient populations in the hospital setting

5. Efficacy and safety of incretin-based therapies in the management of hyperglycemia in the hospital setting

Conclusion

Management of glycemic control in the hospital setting continues to evolve. We have witnessed several shifts in treatment paradigms over the past two decades, from essentially ignoring blood glucose levels except for extremes, to overly stringent approaches stemming from initial clinical trials that reported benefits from achieving euglycemia, to a more rational approach over the past several years. Professional organizations and leading experts now advise controlling glucose, especially in the ICU, within the high-normal to mildly elevated range, while avoiding hypoglycemia. The overriding primary goal of treating hyperglycemia among hospital inpatients is now patient safety, because overtreatment and undertreatment of hyperglycemia are associated with adverse outcomes. Any validated protocols for the management of hyperglycemia should include provisions for glucose monitoring and the treatment of hypoglycemia as well as guidance on dynamically matching insulin doses to glucose levels. Smooth transitioning between IV and SQ insulin regimens is also important. Discharge planning, which should begin at hospital admission, is equally vital. A clear plan for outpatient glucose management, including transition to previous antihyperglycemic therapy before discharge, patient education about diabetes self-management, and clear communication with outpatient providers, will ensure a safe and successful transition to the outpatient arena. Developing reliable diabetes management systems in our hospitals, developed and tracked by a multidisciplinary group of key stakeholders, will ensure best practice in each of these domains.

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