Intensive insulin therapy in the medical ICU – not so sweet?

Citation

Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R: Intensive insulin therapy in the medical ICU. N.Engl.J.Med 2006; 354: 449-61 [1].

Background

Intensive insulin therapy reduces morbidity and mortality in patients in surgical intensive care units (ICUs), but its role in patients in medical ICUs is unknown.

Methods

Objective

To investigate the efficacy of intensive insulin therapy in medical ICU patients.

Design

Prospective, randomized, controlled trial

Setting

Medical ICU in Leuven, Belgium.

Subjects

1200 medical ICU patients anticipated to need intensive care for at least three days.

Intervention

On admission, patients were randomly assigned to strict normalization of blood glucose levels (80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]) with the use of insulin infusion or to conventional therapy (insulin administered when the blood glucose level exceeded 215 mg per deciliter [12 mmol per liter], with the infusion tapered when the level fell below 180 mg per deciliter [10 mmol per liter]).

Measurements and main results

There was a history of diabetes in 16.9 percent of the patients. In the intention-to-treat analysis of 1200 patients, intensive insulin therapy reduced blood glucose levels but did not significantly reduce in-hospital mortality (40.0 percent in the conventional-treatment group vs. 37.3 percent in the intensive-treatment group, P = 0.33). However, morbidity was significantly reduced by the prevention of newly acquired kidney injury, accelerated weaning from mechanical ventilation, and accelerated discharge from the ICU and the hospital. Although length of stay in the ICU could not be predicted on admission, among 433 patients who stayed in the ICU for less than three days, mortality was greater among those receiving intensive insulin therapy. In contrast, among 767 patients who stayed in the ICU for three or more days, inhospital mortality in the 386 who received intensive insulin therapy was reduced from 52.5 to 43.0 percent (P = 0.009) and morbidity was also reduced.

Conclusion

Intensive insulin therapy significantly reduced morbidity but not mortality among all patients in the medical ICU. Although the risk of subsequent death and disease was reduced in patients treated for three or more days, these patients could not be identified before therapy. Further studies are needed to confirm these preliminary data. (ClinicalTrials.gov number, {"type":"clinical-trial","attrs":{"text":"NCT00115479","term_id":"NCT00115479"}}NCT00115479).     

Intensive insulin therapy in the ICU: Is it now time to jump off the bandwagon?

Following the publication of the Leuven Intensive Insulin Therapy (IIT) study in 2001, tight glycemic control has become regarded as the standard of care in intensive care units throughout the world. The Leuven IIT study, was however, an unblinded, single center study with unique patient and institutional characteristics that may not extrapolate to practice elsewhere in the world. Indeed, recent randomized controlled studies have been unable to demonstrate any benefit from tight glucemic control. We suggest that the widespread adoption of tight glycemic control be abandoned at this time.     

Incretins in the ICU: is insulin on its way out?

Incretins such as glucagon-like peptide-1 (GLP-1) are gut-derived hormones that stimulate insulin secretion and suppress glucagon secretion, thus playing a key role in glucose homeostasis. While incretin mimetics and enhancers are approved for treatment of outpatients with diabetes, evidence is only starting to accumulate regarding the therapeutic potential of incretins in hospitalized patients. Small exploratory studies suggest that GLP-1 safely reduces hyperglycemia without causing hypoglycemia, a key advantage over insulin if efficacy is established in larger studies. Potential limitations include the need for a continuous infusion for delivery, attenuation but not normalization of glucose levels, increased deceleration of gastric emptying and nausea. The exact mechanism of action, dosing, adverse effects, patient subgroups that would be most suitable and safety of combination treatment with insulin remain to be studied. While promising, additional research is required studying effects on hard clinical endpoints.     

Pro/con debate: Is intensive insulin therapy targeting tight blood glucose control of benefit in critically ill patients?

You have decided to develop a protocol for insulin therapy in your intensive care unit (ICU). You wonder about the merit of using intensive insulin therapy (IIT) to maintain tight blood glucose control in your patients.     

Remission versus response as the goal of therapy in ADHD: a new standard for the field?

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) has a substantial negative impact; however, within long-term follow-up studies, a proportion of patients do very well, both symptomatically and functionally, suggesting that the lower the symptom burden, the greater the functional improvements. Studies in major depressive disorder have identified a relationship between symptomatic remission and restoration of normal functioning. OBJECTIVE: The purpose of this article was to propose a definition of remission in ADHD, review remission rates in clinical trials for commonly used medications, and explore the relationship between symptomatic remission and optimal functioning. METHODS: Remission and response rates for medications were obtained through MEDLINE searches of English-language citations (1999-2005) and meeting abstracts (2003-2005) using the terms amphetamine, atomoxetine, methylphenidate, ADHD, efficacy, effectiveness, and controlled trial, as well as hand searches of efficacy studies. Evidence from randomized controlled trials, as well as effectiveness studies, where the proportions of patients achieving predefined cutoff points for remission or response are reported, was reviewed. Because higher remission rates were identified with the oral, osmotic, controlled-release system (OROS) of methylphenidate, a relationship between symptomatic response/remission and optimal functioning was explored further. RESULTS: Remission in ADHD should be defined as a loss of diagnostic status, minimal or no symptoms, and optimal functioning when individuals are being treated with or without medication. Symptomatic remission can be operationalized as a mean total score of S1 on most standardized questionnaires. For the medications examined (OROS methylphenidate, immediate-release methylphenidate, atomoxetine, and mixed amphetamine salts), response rates were comparable at approximately 70% to 75%; however, remission rates were higher with OROS methylphenidate compared with either immediate-release methylphenidate or atomoxetine (remission rates with amphetamines were not found). Benefits, including decreased illness burden as well as improved psychosocial and academic functioning, were associated with treatment versus no treatment and were greater with medication that offered higher remission rates. CONCLUSIONS: The literature provided evidence that greater symptom improvements are associated with greater functional improvements, emphasizing that remission of ADHD as defined should be the goal of therapy. Treatment ought to include the early use of strategies with the greatest chance of achieving remission. Future clinical research should use remission as the primary outcome.     

Conventional or functional insulin therapy?

The main difference between "conventional" and "functional" insulin replacement is that the former requires meals to be taken at set times throughout the day to avoid hypoglycaemic insulin reactions, while the latter separates insulin replacement in the basal ("fasting") state from that required with food intake. Such strategy reverses conventional insulin treatment (namely balancing the action of administered insulin by a fixed dietary intake), by substitution with a functional control of hyperglycaemia on the basis of tailored insulin doses. To this end blood glucose self control and systemic blood glucose correction are a must during functional insulin substitution, but not necessarily so during conventional insulin therapy. From this it is apparent that "conventional" and "functional" insulin therapy refer to different strategies, both of which may be intensified by more strict rules, although the term "intensified" remains without any conceptional meaning per se. However, whatever the therapeutic recommendation, the attending physician has to be aware that he must appropriately inform and train the insulin-deficient patient (a) on how to deal with a proposed treatment schedule, and (b) to the point that he fully understands the available therapeutic possibilities and the difference in their quality. Experience has shown that a majority of informed patients opt for functional therapy.     

Is it time for implementation of tight glycaemia control by intensive insulin therapy in every ICU?

The second study on tight glycaemia control by intensive insulin therapy (IIT) confirmed in medical intensive care unit patients the decrease in hospital mortality reported by the same team in the first IIT trial in surgical patients. However, methodological concerns, the high rate of hypoglycaemia in spite of the infusion of large doses of parenteral glucose and the frequent use of steroids presently preclude considering these results as recommendations in other intensive care units, but rather argue for the need for large-scale assessment of the IIT approach by multi-centre studies to confirm the efficacy and safety of this therapeutic modality.     

Obviating much of the need for insulin therapy in type 2 diabetes mellitus: A re-assessment of insulin therapy’s safety profile

Current processes of care for diabetes mellitus (DM) were shaped during the era when insulin therapy was considered inexorable to the management of advanced stage type 2 (T2DM), though this no longer appears to be categorically true. There are also dashed hopes that insulin therapy can prevent or stall diabetes. While exogenous insulin remains a life-sparing tool for fully insulin-dependent DM, insulin therapy-induced hyperinsulinemia now appears to contribute to serious safety issues beyond hypoglycemia and weight gain. Iatrogenic and compensatory hyperinsulinemia are metabolic disruptors of β-cells, liver, muscle, kidney, brain, heart and vasculature, inflammation, and lipid homeostasis, among other systems. This may compromise β-cells, exacerbate insulin resistance (IR), and increase risk of cardiovascular (CV) disease. Striking associations between exogenous insulin and risks of CV events, cancer, and all-cause mortality in clinical trial and real-world cohorts caution that insulin may pose more harm than previously evidenced. At our disposal are numerous alternate tools that, alone or in combination, efficaciously manage hyperglycemia and glucolipotoxicity, and do so without inducing hypoglycemia, weight gain, or hyperinsulinemia. Moreover, these new tools support true precision therapy, as modern day drug classes can be aligned with the various mediating pathways of hyperglycemia at work in any given patient. Some also appear to promote β-cell survival, with intriguing data being presented for newer agents, such as incretins. As such, we encourage preferential use of non-insulin antidiabetic agents to injected insulin for the management of non-insulin-dependent patients with T2DM, including in advanced stage T2DM. The goal of this article is to augment existing literature to 1) correct misconceptions on the rationale and necessity for insulin therapy in T2DM, 2) discuss emerging negative safety data with insulin therapy, and, 3) offer a practical means to reduce reliance on insulin through delayed initiation, minimized dose, and, drug switching to safer agents, and, potentially, reframes processes of care.