Tight Glucose Control Research Articles

Effects of Measurement Frequency on Analytical Quality Required for Glucose Measurements in Intensive Care Units: Assessments by Simulation Models

Total error allowances have been proposed for glucose meters used in tight-glucose-control (TGC) protocols. It is unclear whether these proposed quality specifications are appropriate for continuous glucose monitoring (CGM). We performed Monte Carlo simulations of patients on TGC protocols. To simulate use of glucose meters, measurements were made hourly. To simulate CGM, glucose measurements were made every 5 min. Glucose was measured with defined bias (varied from -20% to 20%) and imprecision (0% to 20% CV). The measured glucose concentrations were used to alter insulin infusion rates according to established treatment protocols. Changes in true glucose were calculated hourly on the basis of the insulin infusion rate, the modeled patient's insulin sensitivity, and a model of glucose homeostasis. We modeled 18 000 patients, equally divided between the hourly and every-5-min measurement schemas and distributed among 45 combinations of bias and imprecision and 2 treatment protocols. With both treatment protocols and both measurement frequencies, higher measurement imprecision increased the rates of hypoglycemia and hyperglycemia and increased glycemic variability (SD). These adverse effects of measurement imprecision were lower at the higher measurement frequency. The rate of hypoglycemia at an imprecision (CV) of 5% with hourly measurements was similar to the rate of hypoglycemia at 10% CV when measurements were made every 5 min. With measurements every 5 min, imprecision up to 10% had minimal effects on hyperglycemia or glycemic variability. Effects of simulated analytical bias on glycemia were unaffected by measurement frequency. Quality specifications for imprecision of glucose meters are not transferable to CGM.

Human islet transplantation

that achieves insulin-independent, constant normoglycemic state and avoidance of hypoglycemic episodes is the replacement of a patient’s islet of Langerhans either by pancreas transplantation or by isolated islet transplantation. The cost of this benefit, however, is the need for immunosupressive treatment of the recipient with all its potential risks. Currently, only vascularized pancreas transplantation can re-establish long-term normoglycemia however this has been associate with significant morbidity and mortality. Approximately 25.000 patients worldwide underwent this procedure and it has been shown to improve quality of life and even reverse some secondary complications of diabetes.4 Simultaneous pancreas and kidney transplantation are presently considered the standard of care for selected patients with type I diabetes with end-stage renal failure.5 Diabetes is a major burden to healthcare economies despite the use of exogenous insulin injections. Type I diabetes mellitus is a chronic metabolic disorder that currently afflicts 5 million individuals in the world. It results from auto-immune mediated destruction of insulin secreting beta cells in islet of Langerhans of the pancreas.1 Long-term studies strongly suggest that tight control of blood glucose achieved by conventional or intensive insulin treatment, self blood glucose monitoring, and patient education can significantly prevent developing and retard the progression of chronic complications of this disease.2 On the other hand, the cost of this benefit was a threefold increase in the number of severe hypoglycemic episodes, a significant increase of body weight and dietary and other lifestyle restrictions affecting the quality of life.3 The only treatment for Type I diabetes mellitus Human islet transplantation

Evaluation of Malnutrition in Orthopaedic Surgery

Malnutrition can increase the risk of surgical site infection in both elective spine surgery and total joint arthroplasty. Obesity and diabetes are common comorbid conditions in patients who are malnourished. Despite the relatively high incidence of nutritional disorders among patients undergoing elective orthopaedic surgery, the evaluation and management of malnutrition is not generally well understood by practicing orthopaedic surgeons. Serologic parameters such as total lymphocyte count, albumin level, prealbumin level, and transferrin level have all been used as markers for nutrition status. In addition, anthropometric measurements, such as calf and arm muscle circumference or triceps skinfold, and standardized scoring systems, such as the Rainey-MacDonald nutritional index, the Mini Nutritional Assessment, and institution-specific nutritional scoring tools, are useful to define malnutrition. Preoperative nutrition assessment and optimization of nutritional parameters, including tight glucose control, normalization of serum albumin, and safe weight loss, may reduce the risk of perioperative complications, including infection.

PS-031 Insulin infusion: the right equipment for good care!

BackgroundPolyvinyl chloride (PVC) infusion tubes are too widely used in our hospital. Even in intensive care units (ICU), PVC is commonly used although polyethylene (PE) is specifically recommended to limit...

Tight glucose control in critically ill children--a systematic review and meta-analysis.

It is unclear if tight glucose control (TGC) with intensive insulin therapy (IIT) can improve outcomes in critically ill children admitted to the intensive care unit (ICU). The objective of this systematic review and meta-analysis is to describe the benefits and risks of TGC with IIT in critically ill children and explore differences between published studies. Prospective randomized controlled trials (RCTs) of TGC with IIT in critically ill children admitted to the ICU were identified through a search of MEDLINE, PubMed, EMBASE, Scopus, ISI Web of Science and Cochrane Database of Systematic Reviews as well as detailed citation review of relevant primary and review articles. RCTs of TGC with IIT in critically ill adults and preterm neonates were excluded. Data on study design and setting, sample size, incidence of hypoglycemia, incidence of acquired infection, and 30-day mortality were abstracted. Meta-analytic techniques were used for analysis of outcomes including 30-day mortality, acquired infection, and incidence of hypoglycemia. We identified four RCTs of TGC with IIT in critically ill children that included 3288 subjects. Overall, TGC with IIT did not result in a decrease in 30-day mortality [odds ratio (OR): 0.79; 95% confidence interval (CI): 0.55-1.15, p = 0.22]. TGC with IIT was associated with decrease in acquired infection (OR: 0.76; 95% CI: 0.59-0.99, p = 0.04). TGC with IIT was also associated with significant increase in hypoglycemia (OR: 6.14; 95% CI: 2.74-13.78, p < 0.001). TGC with IIT does not result in decrease in 30-day mortality, but appears to reduce acquired infection in critically ill children. However, TGC with IIT is associated with higher incidence of hypoglycemia. Large multi-center studies of TGC with IIT using continuous glucose monitoring in critically ill children are needed to determine if this strategy can definitively improve clinical outcomes in this population without increasing hypoglycemia.

Dexamethasone, Light Anaesthesia, and Tight Glucose Control (DeLiT) Randomized Controlled Trial

Abstract Background The inflammatory response to surgical tissue injury is associated with perioperative morbidity and mortality. We tested the primary hypotheses that major perioperative morbidity is reduced by three potential anti-inflammatory interventions: (i) low-dose dexamethasone, (ii) intensive intraoperative glucose control, and (iii) lighter anaesthesia. Methods We enrolled patients having major non-cardiac surgery who were ≥40 yr old and had an ASA physical status ≤IV. In a three-way factorial design, patients were randomized to perioperative i.v. dexamethasone (a total of 14 mg tapered over 3 days) vs placebo, intensive vs conventional glucose control 80–110 vs 180–200 mg dl−1, and lighter vs deeper anaesthesia (bispectral index target of 55 vs 35). The primary outcome was a collapsed composite of 15 major complications and 30 day mortality. Plasma high-sensitivity (hs) C-reactive protein (CRP) concentration was measured before operation and on the first and second postoperative days. Results The overall incidence of the primary outcome was about 20%. The trial was stopped after the second interim analysis with 381 patients, at which all three interventions crossed the futility boundary for the primary outcome. No three-way (P=0.70) or two-way (all P>0.52) interactions among the interventions were found. There was a significantly smaller increase in hsCRP in patients given dexamethasone than placebo [maximum 108 (64) vs 155 (69) mg litre−1, P Conclusions Among our three interventions, dexamethasone alone reduced inflammation. However, no intervention reduced the risk of major morbidity or 1 yr mortality. Trial Registration Identifier NCT00433251 at www.clinicaltrials.gov.

A Randomized Trial of Hyperglycemic Control in Pediatric Intensive Care

BackgroundWhether an insulin infusion should be used for tight control of hyperglycemia in critically ill children remains unclear.MethodsWe randomly assigned children (≤16 years of age) who were admitted to the pediatric intensive care unit (ICU) and were expected to require mechanical ventilation and vasoactive drugs for at least 12 hours to either tight glycemic control, with a target blood glucose range of 72 to 126 mg per deciliter (4.0 to 7.0 mmol per liter), or conventional glycemic control, with a target level below 216 mg per deciliter (12.0 mmol per liter). The primary outcome was the number of days alive and free from mechanical ventilation at 30 days after randomization. The main prespecified subgroup analysis compared children who had undergone cardiac surgery with those who had not. We also assessed costs of hospital and community health services.ResultsA total of 1369 patients at 13 centers in England underwent randomization: 694 to tight glycemic control and 675 to conventional glycemic control; 60% had undergone cardiac surgery. The mean between-group difference in the number of days alive and free from mechanical ventilation at 30 days was 0.36 days (95% confidence interval [CI], −0.42 to 1.14); the effects did not differ according to subgroup. Severe hypoglycemia (blood glucose, <36 mg per deciliter [2.0 mmol per liter]) occurred in a higher proportion of children in the tight-glycemic-control group than in the conventional-glycemic-control group (7.3% vs. 1.5%, P<0.001). Overall, the mean 12-month costs were lower in the tight-glycemic-control group than in the conventional-glycemic-control group. The mean 12-month costs were similar in the two groups in the cardiac-surgery subgroup, but in the subgroup that had not undergone cardiac surgery, the mean cost was significantly lower in the tight-glycemic-control group than in the conventional-glycemic-control group: −$13,120 (95% CI, −$24,682 to −$1,559).ConclusionsThis multicenter, randomized trial showed that tight glycemic control in critically ill children had no significant effect on major clinical outcomes, although the incidence of hypoglycemia was higher with tight glucose control than with conventional glucose control. (Funded by the National Institute for Health Research, Health Technology Assessment Program, U.K. National Health Service; CHiP Current Controlled Trials number, ISRCTN61735247.)

Glucose, acid, and aspartate: Friends and foes of the axon

Annals of NeurologyVolume 75, Issue 4 p. 490-491 Commentary Glucose, acid, and aspartate: Friends and foes of the axon Raymond A. Swanson MD, Raymond A. Swanson MD Department of Neurology, University of California, San Francisco and Neurology Service San Francisco Veterans Affairs Medical Center, San Francisco, CASearch for more papers by this author Raymond A. Swanson MD, Raymond A. Swanson MD Department of Neurology, University of California, San Francisco and Neurology Service San Francisco Veterans Affairs Medical Center, San Francisco, CASearch for more papers by this author First published: 23 November 2013 https://doi.org/10.1002/ana.24071Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume75, Issue4April 2014Pages 490-491 RelatedInformation

Hyperglycemia in the pediatric intensive care unit: Innocent bystander or villain of the piece?

Hyperglycemia in the pediatric intensive care unit: Innocent bystander or villain of the piece?

Glycemic Control and Cardiovascular Outcomes in Diabetes

While type 1 Diabetes Mellitus (DM) is characterized by insulin deficiency due to pancreatic beta cell destruction, type 2 DM is characterized by a state of long standing insulin resistance (IR), compensatory hyperinsulinemia and varying degrees of elevated plasma glucose (PG), associated with clustering of cardiovascular (CV) risk and development of macrovascular disease prior to diagnosis of DM. Coronary artery disease (CAD) accounts for 70% of mortality and morbidity in patients with diabetes. Studies made in diabetes care have helped prevent or reduce microvascular complications in type 1 and 2 diabetes. However the same cannot be said about macrovascular disease. Despite all data concerning the association of diabetes and cardiovascular disease (CVD), the exact mechanism by which diabetes is linked to atherosclerosis is incompletely understood, this is especially true in case of hyperglycemia. The positive effect of intensive glucose management in comparison to non intensive glucose control is far from proven. DCCT and UKPDS studies have shown that while a glycemic control is important for reaching long term macrovascular complications, early glucose control is far more rewarding (metabolic memory). Later trials like ACCORD, ADVANCE and VADT don’t advocate tight glycemic control. In fact, ACCORD trial has shown increased mortality with tight glucose control. Tight glucose control may be beneficial in selected patients with short disease duration, long life expectancy and no CVD. In critically ill patients a blood glucose target of 140-180 mg% is fairly reasonable and achievable. The ESC/EASD guidelines of October 2013,Iike those of ADA, AHA and ACC continue to endorse a treatment target for glucose control in diabetes of HbAlc <7%, based predominantly on microvascular disease with acknowledged uncertainty regarding the effect of the intensive glucose control on CVD risk. Management of hyperglycemia in diabetics should not be considered in isolation; diabetics require multifactorial intervention for hypertension, dyslipidemia and microalbuminuria besides hyperglycemia. In fact combined use of antihypertensives, aspirin and lipid lowering agent makes it difficult to discern salutary effects of anti hyperglycemic therapy.

Glycated hemoglobin HbA1c - a new risk marker for the outcome of cardiac surgery?

IntroductionAbout 30% of patients undergoing cardiac surgery are diabetic, and glycated hemoglobin (HbA1c) is a reliable marker for long-term glucose control. The aim of our study was to examine whether tight glucose control before a cardiac operation results in a better outcome of the surgical treatment.Material and methodsWe performed a retrospective record review of 350 diabetic patients undergoing cardiac surgery in our institution. Preoperative glycemia control was assessed by measurement of the glycated hemoglobin level. The patient population was divided into three groups: group I – patients with HbA1c below 7% (n = 195); group II – patients with HbA1c between 7% and 8% (n = 88); and group III – patients with HbA1c above 8% (n = 67).ResultsThe demographic data and operating risk in all groups of patients were similar. There were 2 deaths (1.02%) in group I, 2 deaths (2.27%, p = 0.78) in group II and 3 deaths (4.47%, p = 0.20) in group III. Cardiac accidents occurred in 9 patients (4.60%) from group I, 7 patients (7.95%, p = 0.20) from group II, and in 6 patients (9.05%, p = 0.40) from group III. Cerebrovascular accidents (CVA) occurred in 7 (3.58%), 5 (5.68%, p = 0.67) and 5 (7.46%, p = 0.61) patients, respectively. Acute renal dysfunction requiring renal replacement therapy occurred in 4 patients from group I (2.05%), 3 patients from group II (3.40%, p = 0.78) and 4 patients from group III (5.97%, p = 0.23).ConclusionsA large percentage of diabetic patients referred for cardiac operations have poorly controlled glycemia. Optimal preoperative glycemia control results in lower postoperative mortality and morbidity. In addition, the preoperative HbA1c level is a good indicator of the risk of postoperative complications in diabetic patients undergoing cardiac operations.

Insulin infusion on postoperative complications of coronary artery bypass graft in patients with diabetes mellitus.

Background:Cardiovascular events are common in patients with diabetes mellitus (DM), which make coronary artery bypass graft (CABG) a highly demanded surgery in this population. Tight control of blood glucose in patients with DM is beneficial in reducing postoperative complications; however, the adequate range has not been determined yet.Objectives:This study aimed to investigate the effect of semi-tight (moderate) control of DM on complications and serum glucose levels during and after CABG.Patients and Methods:In this prospective clinical trial, 18 and 31 patients with and without DM, respectively, who were referred to Shahid Chamran Hospital, Isfahan, Iran, for elective CABG surgery, were enrolled. For DM group, patients with controlled DM (i.e. glycosylated hemoglobin levels [HgA1C] ≤ 7%) were recruited. Blood glucose level (blood sugar, BS) was measured after anesthesia, during pumping, warming, off pumping, six and 12 hours after Intensive Care Unit (ICU) admission, and at discharging from the hospital. The hemodynamic state of the patients, bleeding, need of blood transfusion, infection, and duration of hospitalization were also monitored and recorded.Results:None of the BS measurements (FBS, after anesthesia, on-pump, warming, off pump, six and 12 hours after ICU admission, and at discharge) were significantly different between study groups (P > 0.05). Frequency of surgery site bleeding and blood transfusion need were not significantly different between these groups (P > 0.05).Conclusions:Semi-tight control of DM with insulin infusion during operation did not led to any difference in the type and rate of CABG complications between patients with well-controlled and those without DM; however, BS levels in patients with well-controlled DM could be more easily controlled.

Role of metabolic environment on nitric oxide mediated inhibition of neointimal hyperplasia in type 1 and type 2 diabetes

Nitric oxide (NO) is well known to inhibit neointimal hyperplasia following arterial injury. Previously, we reported that NO was more effective at inhibiting neointimal hyperplasia in a type 2 diabetic environment than control. We also found that NO was ineffective in an uncontrolled type 1 diabetic environment; however, insulin restored the efficacy of NO. Thus, the goal of this study was to more closely evaluate the effect of insulin and glucose on the efficacy of NO at inhibiting neointimal hyperplasia in both type 1 and type 2 diabetic environments using different doses of insulin as well as pioglitazone. Type 1 diabetes was induced in male lean Zucker (LZ) rats with streptozotocin (60mg/kg IP). Groups included control, moderate glucose control, and tight glucose control. Zucker diabetic fatty (ZDF) rats fed Purina 5008 chow were used as a type 2 diabetic model. Groups included no therapy, insulin therapy, or pioglitazone therapy. After 4weeks of maintaining group assignments, the carotid artery injury model was performed. Treatment groups included: control, injury and injury plus NO. 2weeks following arterial injury, in the type 1 diabetic rats, NO most effectively reduced the neointimal area in the moderate and tightly controlled groups (81% and 88% vs. 33%, respectively, p=0.01). In type 2 diabetic rats, the metabolic environment had no impact on the efficacy of NO (81–82% reduction for all groups). Thus, in this study, we show NO is effective at inhibiting neointimal hyperplasia in both type 1 and type 2 diabetic environments. A greater understanding of how the metabolic environment may impact the efficacy of NO may lead to the development of more effective NO-based therapies for patients with diabetes.

Diabetes and Hyperglycemia in the Critical Care Setting: Has the Evidence for Glycemic Control Vanished? (Or … Is Going Away?)

Hyperglycemia is associated with increased mortality and other complications amongst hospitalized patients. However, the studies of tight glycemic control in a range of critical illness settings, including intensive care, acute myocardial infarction, and stroke, have produced inconsistent and divergent results. We examine some of the factors that may have contributed to the differing results, and their implications for targeting tight glucose control in critical illness. With these in mind, most clinical guidelines now recommend moderate glucose control with an upper glucose target of <10 mmol/L (180 mg/dL) in critical illness while avoiding hypoglycemia.

Glycemic control and diabetes management in hospitalized patients in Brazil

BackgroundThe importance of tight blood glucose control among outpatients with diabetes mellitus is well established, however, the management of diabetes in the hospital setting is generally considered secondary in importance. This study sought to assess glycemic control and diabetes management in adult patients admitted to hospitals in Brazil.MethodsA cross-sectional and nationwide survey was conducted from July 2010 to January 2012. Eligible cases were 18 years of age or older, had a diagnosis of diabetes and a hospitalization length of stay ≥72 hours. Socio-demographic information, hospitalization details, and data on diabetes diagnosis, management and treatment were collected for all patients by chart review. Information on all blood glucose (BG) readings for a maximum of 20 consecutive days of hospitalization was recorded for each patient.ResultsOverall, 2,399 patients were surveyed in 24 hospitals located in 13 cities from all five Brazilian regions. The prevalence of patients presenting hyperglycemic (BG >180 mg/dL) or hypoglycemic (BG <70 mg/dL) events was 89.4% and 30.9% in patients in general wards, and 88.2% and 27.7% in those in Intensive Care Units (ICUs), respectively. In addition, a BG measure >180 mg/dL was recorded in two-thirds of the patient-days. A high proportion of patients were treated with sliding-scale insulin regimen alone in the general wards (52.0%) and in the ICUs (69.2%), and only 35.7% and 3.9% received appropriate insulin therapy in general wards (basal + bolus insulin) and in ICUs (continuous IV insulin), respectively.ConclusionsInpatient glycemic control and diabetes management needs improvement. Opportunities to improve care in Brazilian hospitals include expanded use of intravenous insulin and subcutaneous basal-bolus insulin protocols, avoiding use of sliding-scale insulin alone, increased frequency of blood glucose monitoring, and institution wide quality improvement efforts targeting both physician and nursing behavior.

Phenylboronic acid modified silver nanoparticles for colorimetric dynamic analysis of glucose

The development of advanced nanostructures that allow dynamic quantification of glucose level can contribute to tight glucose control in diabetes management and other medical/biological fields. In this paper, we demonstrated that the assemblies of the 5-amino-2-fluorophenylboronic acid modified silver nanoparticles (FPBA-AgNPs) can be employed for highly modulating, sensitive, and selective colorimetric sensing of glucose over a physiologically important concentration range of 0–20mM at a physiological pH of 7.4. The glucose-modulated assembly of the FPBA-AgNPs occurred by the regulable formation of interparticle linkages via the bridged binding of 1,2-cis-diols and 5,6-cis-diols (for furanose form; or 4,6-cis-diols for pyranose form), respectively, of a glucose molecule to two FPBA-AgNPs. The detection limit was 89.0μM. The mean error of glucose detection in a macro-bio-system, blood serum of adult, was smaller than 10%. Furthermore, we show that the glucose level variations associated with a model biological reaction process can be monitored by using the FPBA-AgNPs, whilst with the reaction mechanism remaining nearly unchanged.

Glycemic Control in Pediatric Patients on Extracorporeal Membrane Oxygenation

OBJECTIVES To determine whether glycemic control has an effect on outcomes for pediatric patients on extracorporeal membrane oxygenation (ECMO) therapy, while controlling for multiple factors. METHODS A single-center retrospective chart review was performed on 82 patients who required ECMO from January 1, 2008, to December 31, 2010. All glucose concentrations collected while patients were on ECMO were analyzed; multiple other factors that may have affected mortality were also recorded. Primary outcome was mortality, and secondary outcomes were length of time on ECMO and length of time until death or discharge from the hospital. RESULTS Of 82 patients, 53 patients survived ECMO (64.6%). Glucose control had no effect on survival of patients on ECMO (p=0.56), even when controlling for multiple factors (p=0.48). Similarly, statistical evaluation showed no differences for hospital mortality in relationship to controlled serum glucose (p=0.50). Patients with controlled glucose spent an average of 31.5% more time on ECMO than non-controlled patients (p=0.048). CONCLUSIONS In this study, glycemic control, defined as serum glucose concentration between 60 mg/dL and 250 mg/dL for >95% of the time on ECMO, had no statistically significant effect on mortality for patients on ECMO. Future studies could focus on tighter glucose control or specific dextrose/glucose protocols to evaluate whether improved glucose control would have an effect on morbidity and mortality.

Dexamethasone, light anaesthesia, and tight glucose control (DeLiT) randomized controlled trial

BackgroundThe inflammatory response to surgical tissue injury is associated with perioperative morbidity and mortality. We tested the primary hypotheses that major perioperative morbidity is reduced by three potential anti-inflammatory interventions: (i) low-dose dexamethasone, (ii) intensive intraoperative glucose control, and (iii) lighter anaesthesia. MethodsWe enrolled patients having major non-cardiac surgery who were ≥40 yr old and had an ASA physical status ≤IV. In a three-way factorial design, patients were randomized to perioperative i.v. dexamethasone (a total of 14 mg tapered over 3 days) vs placebo, intensive vs conventional glucose control 80–110 vs 180–200 mg dl−1, and lighter vs deeper anaesthesia (bispectral index target of 55 vs 35). The primary outcome was a collapsed composite of 15 major complications and 30 day mortality. Plasma high-sensitivity (hs) C-reactive protein (CRP) concentration was measured before operation and on the first and second postoperative days. ResultsThe overall incidence of the primary outcome was about 20%. The trial was stopped after the second interim analysis with 381 patients, at which all three interventions crossed the futility boundary for the primary outcome. No three-way (P=0.70) or two-way (all P>0.52) interactions among the interventions were found. There was a significantly smaller increase in hsCRP in patients given dexamethasone than placebo [maximum 108 (64) vs 155 (69) mg litre−1, P<0.001], but none of the other two interventions differentially influenced the hsCRP response to surgery. ConclusionsAmong our three interventions, dexamethasone alone reduced inflammation. However, no intervention reduced the risk of major morbidity or 1 yr mortality. Trial Registration IdentifierNCT00433251 at www.clinicaltrials.gov.

The Future of Closed Loop

The Future of Closed Loop

Letter to the Editor - responses to Weisntein D, Simon M, Yehezkel E, Laron Z, Werner H. Insulin analogues display IGF-I-like mitogenic and antiactivity in cultured cancer cells.

We thank the team of Eli Lilly and Company for their critical appraisal of our study and for giving us the opportunity to clarify a number of points [1]. We agree with Kazda et al. that randomized clinical trials will best address any direct relationship between insulin analogues and cancer in man. We do not question the fact that tight control of blood glucose has dramatically advanced the lives of patients with diabetes. This article is protected by copyright. All rights reserved.