John Richard Baker

Regeneration of the Heart in Diabetes by Selective Copper Chelation

Heart disease is the major cause of death in diabetes, a disorder characterized by chronic hyperglycemia and cardiovascular complications. Although altered systemic regulation of transition metals in diabetes has been the subject of previous investigation, it is not known whether changed transition metal metabolism results in heart disease in common forms of diabetes and whether metal chelation can reverse the condition. We found that administration of the Cu-selective transition metal chelator trientine to rats with streptozotocin-induced diabetes caused increased urinary Cu excretion compared with matched controls. A Cu(II)-trientine complex was demonstrated in the urine of treated rats. In diabetic animals with established heart failure, we show here for the first time that 7 weeks of oral trientine therapy significantly alleviated heart failure without lowering blood glucose, substantially improved cardiomyocyte structure, and reversed elevations in left ventricular collagen and beta(1) integrin. Oral trientine treatment also caused elevated Cu excretion in humans with type 2 diabetes, in whom 6 months of treatment caused elevated left ventricular mass to decline significantly toward normal. These data implicate accumulation of elevated loosely bound Cu in the mechanism of cardiac damage in diabetes and support the use of selective Cu chelation in the treatment of this condition.

Clinical trial participation improves outcome: a matched historical cohort study.

Background Well-conducted, investigator-led randomized controlled trials (RCTs) are the gold standard for evaluating the efficacy of new treatments and are a key component of evidence-based medicine. It is unclear whether participating in an RCT is beneficial to the individual before the results of RCTs are known. Purpose In a matched historical cohort study, we examined whether participation in RCTs was associated with improved health outcomes. Methods Participants in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE), Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), or Telmisartan Randomized Assessment Study in ACE-intolerant Subjects with Cardiovascular Disease (TRANSCEND) studies and non-participant controls were selected from patients attending outpatient clinics at Middlemore Hospital between 2001 and 2003. Results A total of 251 RCT participants and 502 randomly selected patients not enrolled in a trial but who met study entry criteria were matched for age, gender, and ethnicity. There was a significant difference in all-cause mortality for trial participants versus non-participants over the study period (unadjusted relative risk reduction (RRR) = 63%; 95% confidence interval (CI) = 28%–81%) and a significant reduction in cardiovascular mortality (unadjusted RRR = 81%; 95% CI = 17%–95%) favouring RCT participants. Allowing for co-morbidity, the adjusted RRR of all-cause mortality associated with trial participation was 55% (95% CI = 10%–77%). Active treatment in an RCT was found to be less explanatory than trial participation. The adjusted RRR for cardiovascular mortality associated with active treatment in a trial was 86% (95% CI = −2% to 98%), with trial participation found to be less explanatory than active treatment. Limitations The main limitations of this trial relate to its design as a retrospective study with a historical cohort comparison group. Limitations include lack of complete data for some patients, bias in selection of the comparison group, and the effects of confounding variables. However, the study design and analysis were planned so as to minimize these as much as possible. Conclusion This study revealed significantly lower all-cause mortality among participants in industry-sponsored RCTs compared with non-participants who received routine hospital outpatient care. This effect was independent of study drug.

Diagnostic delays of adult patients admitted to hospital with diabetic ketoacidosis

© 2004 Diabetes UK. Diabetic Medicine , 21 , 290–291 Diabetic ketoacidosis (DKA) is a life-threatening emergency, which needs to be dealt with urgently [1]. To document diagnostic delays which may affect timely initiation of management and therefore clinical outcomes, we studied patients admitted with DKA to Middlemore Hospital over the period May 1999 and June 2000. The hospital records were reviewed and parameters compared with International Diabetes Federation (IDF) criteria for significant DKA [2]: (i) hyperglycaemia (plasma glucose > 11 mmol/ l); (ii) metabolic acidosis with an arterial bicarbonate (HCO 3 ) concentration of < 15 mmol/ l or arterial pH of < 7.31 associated with ketonaemia (beta hydroxy butyrate > 0.27 mmol/ l). The time of arrival at hospital was taken as the time noted by the triage nurse in the Emergency Department (ED). The time that the doctor reviewed the patient was poorly documented in the clinical record. Therefore, the time taken for diagnosis of DKA was based on the receiving time of arterial blood gases sample at the laboratory. The time of starting intravenous fluids and insulin therapy was read from the fluid balance and therapy sheets. Total duration of intravenous insulin therapy was taken as time of commencement of such therapy to commencement of subcutaneous insulin therapy. Beta hydroxy butyrate level was always measured on the initial venous blood sample taken at the time of arrival at hospital. There were 27 coded episodes of DKA that met our diagnostic criteria. The case notes of three patients could not be located, so that only 24 patient records were reviewed. Two patients had two episodes each of DKA during the 12-month study period. Nineteen patients had Type 1 diabetes and two of them were newly diagnosed. Table 1 illustrates clinical and biochemical characteristics at presentation. We found a wide variation in the time for diagnosis (10– 150 min; median 60 min) for patients arriving at hospital with DKA, with only 43% of the patients diagnosed within the first 30 min. This is contrary to recommended practice of 80% or more patients diagnosed within the first 30 min [3]. The time taken for commencement of intravenous fluids and intravenous insulin were similarly delayed, ranging from 5 to 240 min (median 60 min) and 15–300 min (median 75 min), respectively. The level of arterial HCO 3 at presentation correlated negatively with the duration of hospital stay and the duration of intravenous insulin therapy ( r = − 0.597, P < 0.01; r = − 0.502, P < 0.05, respectively). Therefore, severity of DKA as assessed by HCO 3 measurement was an indicator of these clinical outcomes and may be useful in planning management. In contrast, we found no correlation between beta hydroxy butyrate levels and the severity of metabolic acidosis as judged by HCO 3 level. Clinical features of DKA at presentation can be non-specific and therefore may not alert the medical staff to perform an arterial blood gas measurement required for confirmation of the diagnosis [2]. This could lead to missed diagnoses and delays in initiating therapy. Both these issues could be prevented if plasma HCO 3 had been made part of the routine biochemistry profile performed on all patients presenting to ED. On average, nursing staff drew a venous blood sample within 15 min of hospital entry and results were available 20 min later. Venous HCO 3 is strongly correlated with arterial HCO 3 in DKA [4] and the test would be sufficient to make the diagnosis in most patients. An important exception is those patients with hypoxia (identified by pulse oximetry) where arterial blood gas sampling is needed. Correspondence to : A. M. Dissanayake MRCP(UK), FRACP, Whitiora Diabetes Centre, Middlemore Hospital, Private Bag 93 311, Otahuhu, Auckland 6, New Zealand. E-mail: amdiss@middlemore.co.nz Table 1 Clinical /biochemical characteristics of patient population