Hans-Henrik Lervang

Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials

BACKGROUND Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes. METHODS We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0·2 nM. Patients in the canakinumab trial were aged 6-45 years and those in the anakinra trial were aged 18-35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00947427 and NCT00711503, and EudraCT number 2007-007146-34. FINDINGS Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0·01 nmol/L (95% CI -0·11 to 0·14; p=0·86), and between the anakinra and the placebo groups at 9 months was 0·02 nmol/L (-0·09 to 0·15; p=0·71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0·018), which was mainly because of a higher number of injection site reactions in the anakinra group. INTERPRETATION Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders. FUNDING National Institutes of Health and Juvenile Diabetes Research Foundation.

Liraglutide, a once‐daily human GLP‐1 analogue, improves pancreatic B‐cell function and arginine‐stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitus

Aims  To assess the effect of liraglutide, a once‐daily human glucagon‐like peptide‐1 analogue on pancreatic B‐cell function.

Diabetes, Glycemic Control, and Risk of Hospitalization With Pneumonia A population-based case-control study

OBJECTIVE—To examine whether diabetes is a risk factor for hospitalization with pneumonia and to assess the impact of A1C level on such risk. RESEARCH DESIGN AND METHODS—In this population-based, case-control study we identified patients with a first-time pneumonia-related hospitalization between 1997 and 2005, using health care databases in northern Denmark. For each case, 10 sex- and age-matched population control subjects were selected from Denmarks Civil Registration System. We used conditional logistic regression to compute relative risk (RR) for pneumonia-related hospitalization among subjects with and without diabetes, controlling for potential confounding factors. RESULTS—The study included 34,239 patients with a pneumonia-related hospitalization and 342,390 population control subjects. The adjusted RR for pneumonia-related hospitalization among subjects with diabetes was 1.26 (95% CI 1.21–1.31) compared with nondiabetic individuals. The adjusted RR was 4.43 (3.40–5.77) for subjects with type 1 diabetes and 1.23 (1.19–1.28) for subjects with type 2 diabetes. Diabetes duration ≥10 years increased the risk of a pneumonia-related hospitalization (1.37 [1.28–1.47]). Compared with subjects without diabetes, the adjusted RR was 1.22 (1.14–1.30) for diabetic subjects whose A1C level was <7% and 1.60 (1.44–1.76) for diabetic subjects whose A1C level was ≥9%. CONCLUSIONS—Type 1 and type 2 diabetes are risk factors for a pneumonia-related hospitalization. Poor long-term glycemic control among patients with diabetes clearly increases the risk of hospitalization with pneumonia.

Statin use and mortality within 180 days after bacteremia: a population-based cohort study.

Objective:To examine the association between preadmission statin use and mortality among patients with bacteremia in a population-based setting. Design:Observational study based on prospective registration of bacteremia episodes and mortality over a 6-yr period. Setting:North Jutland County, Denmark (population, 500,000). Patients:A total of 5,353 adult patients hospitalized with bacteremia from 1997 to 2002. Individuals treated with statins (n = 176) were identified by record-linkage with the County Prescription Database. Interventions:None. Measurements and Main Results:We compared mortality rates 0–30 and 31–180 days after bacteremia in patients with and without preadmission statin use, adjusted for gender, age group, level of comorbidity, alcohol-related conditions, use of immunosuppressive drugs and systemic antibiotics, and focus on infection. The 30-day mortality in statin users vs. nonusers was similar (20.0% vs. 21.6%, adjusted mortality rate ratio 0.93, 95% confidence interval 0.66–1.30). Among survivors after 30 days, however, statin therapy was associated with a substantially decreased mortality up until 180 days after the bacteremia (8.4% vs. 17.5%, adjusted mortality rate ratio 0.44, 95% confidence interval 0.24–0.80). This tendency toward similar short-term and decreased longer term mortality associated with statin use was observed consistently in both community-acquired and nosocomial bacteremia episodes and when analyses were restricted to patients with previous cardiovascular discharge diagnoses or diabetes. Conclusions:This study provides evidence against the hypothesis that statin use has an effect on short-term mortality after bacteremia. Statin use was, however, associated with a substantially decreased mortality between 31 and 180 days after bacteremia.

Type 2 diabetes and pneumonia outcomes: a population-based cohort study.

OBJECTIVE—We sought to examine whether type 2 diabetes increases risk of death and complications following pneumonia and to assess the prognostic value of admission hyperglycemia. RESEARCH DESIGN AND METHODS—This was a population-based cohort study of adults with a first-time hospitalization for pneumonia between 1997 and 2004 (n = 29,900) in northern Denmark. Information on diabetes, comorbidity, laboratory findings, pulmonary complications, and bacteremia was obtained from medical databases. We used regression to compute adjusted relative risks of pulmonary complications, bacteremia, and mortality rate ratios (MRRs) within 90 days following hospitalization among patients with and without type 2 diabetes. The prognostic impact of admission hyperglycemia was studied in a subcohort (n = 13,574). RESULTS— In total, 2,931 (9.8%) pneumonia patients had type 2 diabetes. Mortality among diabetic patients was greater than that among other patients: 19.9 vs. 15.1% after 30 days and 27.0 vs. 21.6% after 90 days, respectively, corresponding to adjusted 30- and 90-day MRRs of 1.16 (95% CI 1.07–1.27) and 1.10 (1.02–1.18). Presence of type 2 diabetes did not predict pulmonary complications or bacteremia. Adjustment for hyperglycemia attenuated the association between type 2 diabetes and mortality. High glucose level on admission was a predictor of death among patients with diabetes and more so among those without diagnosed diabetes: adjusted 30-day MRRs for glucose level ≥14 mmol/l were 1.46 (1.01–2.12) and 1.91 (1.40–2.61), respectively. CONCLUSIONS—Type 2 diabetes and admission hyperglycemia predict increased pneumonia-related mortality.

Early glomerular hyperfiltration and the development of late nephropathy in type 1 (insulin-dependent) diabetes mellitus

SummaryWe performed a follow-up study of the glomerular function in a series of 29 Type 1 (insulin-dependent) diabetic patients who had been studied 18 years previously. Initial median duration of diabetes was 2 years (range 0–9) and at follow-up 21 (17–27) years. At follow-up, 8 diabetic patients exhibited increased urinary albumin excretion rate 515 (32-3234) μg/min with glomerular filtration rates significantly lower than 21 diabetic patients with normal urinary albumin excretion (85 vs 126ml/min/1.73 m2; p<0.01). The patients with increased urinary albumin excretion rate also had higher arterial blood pressure (145/90 vs 120/80) mm Hg; p<0.02) and increased frequency of proliferative retinopathy (7 out of 8 vs 2 out of 21; p = 0.0001) as compared to the group with normal urinary albumin excretion. However, we found no association of increased urinary albumin excretion rate (incipient or overt nephropathy) to early glomerular hyperfiltration as median initial glomerular filtration rate was 142 ml/min/1.73 m2 in the diabetic patients with increased urinary albumin excretion and 147 ml/min/1.73 m2 in the patients with normal excretion rate (p>0.05)

Diabetes mellitus as a risk and prognostic factor for community-acquired bacteremia due to enterobacteria: a 10-year, population-based study among adults.

Diabetes was examined as a risk factor and a prognostic factor for community-acquired bacteremia caused by Escherichia coli and other enterobacteria in a series of 1317 adult case patients, with 10 population control subjects per case. Persons with diabetes had a substantially increased risk for enterobacterial bacteremia (adjusted odds ratio, 2.9; 95% confidence interval, 2.4-3.4). Among patients with bacteremia, diabetes was also associated with a poorer prognosis.

Risk and short-term prognosis of myocardial infarction among users of antidiabetic drugs.

Old sulphonylureas have been linked with adverse cardiovascular effects; however, data on the clinical implications are sparse. We examined the association between use of sulphonylureas and other antidiabetic drugs and the risk and case fatality rate (CFR) of myocardial infarction (MI) in a population-based case–control and follow-up study, respectively. A total of 6738 cases of first-time MI and 67,374 age- and gender-matched population controls were identified from the Hospital Discharge Registry and the Civil Registration System of North Jutland County, Denmark, in the period 1994 through 2002. Prescriptions for antidiabetic drugs before the index date were retrieved from a prescription database. We estimated odds ratios (ORs) of MI (case–control study) and 30-day CFR (follow-up study) associated with antidiabetic drug use adjusted for possible confounding factors and using nondiabetic subjects as the reference group. The risk of MI appeared higher among users of old sulphonylureas (adjusted OR, 2.07; 95% confidence interval (CI), 1.81–2.37) than among users of new sulphonylureas (adjusted OR, 1.36; 95% CI, 1.01–1.84). The adjusted ORs among users of nonsulphonylurea oral antidiabetic drugs, insulin, and patients with diabetes not receiving pharmacotherapy were 1.38 (95% CI, 0.90–2.11), 2.56 (95% CI, 2.16–3.03), and 3.51 (95% CI, 2.92–4.22), respectively. The overall 30-day CFR was 24.6%, but varied between 9.5% and 37.0% among the different categories. New sulphonylureas may be associated with a lower risk of MI than old sulphonylureas. Furthermore, the 30-day CFR may vary according to type of antidiabetic drug. These differences indicate the need for further examination of the cardiovascular safety of antidiabetic drugs.

The North Jutland County Diabetic Retinopathy Study. Population characteristics

Background: Several population-based studies have reported blood glucose levels and blood pressure to be risk factors for the development of diabetic retinopathy. These studies were initiated more than two decades ago and may therefore reflect the treatment and population composition of a previous era, suggesting new studies of the present population with diabetes. Aim and methods: This cross-section study included 656 people with type 1 diabetes and 328 with type 2 diabetes. Crude prevalence rates of proliferative diabetic retinopathy, clinically significant macular oedema and several specific retinal lesions were assessed, together with their association to a simplified and internationally approved retinal grading. Results: The point prevalence of proliferative retinopathy was found to be 0.8% and 0.3% for type 1 and type 2 diabetes. Equivalent prevalence rates of clinically significant macular oedema were 7.9% and 12.8%, respectively. The most frequently occurring retinal manifestations increased in number until retinopathy level 3, and then decreased. Conclusion: The point prevalence of proliferative retinopathy is lower than that found in previous studies, whereas it is increased for clinically significant macular oedema. These data suggest different risk factors for these clinical entities.

Does increased glomerular filtration rate or disturbed tubular function early in the course of childhood type 1 diabetes predict the development of nephropathy

To clarify whether glomerular hyperfiltration or disturbances in renal tubular function may be early markers of the later development of nephropathy a follow‐up study was performed in 34 young Type 1 diabetic patients, who had originally been investigated 12 years previously. The initial median age was 14 (range 7–18) years and median diabetes duration 7 (2–14) years. At initial examination only one of the 34 diabetic patients exhibited increased urinary albumin excretion rate. The median glomerular filtration rate was increased (136 vs 107 ml min−1 1.73 m−2; p < 0.0001) and median threshold concentration of phosphate per litre of glomerular filtrate was decreased (1.27 vs 1.76 mmol I−1; p < 0.0001) in the diabetic group as compared to that of 28 healthy children. At follow‐up 17 patients showed increased urinary albumin excretion rate and the median glomerular filtration rate in this group was significantly lower than that of 17 patients with normal urinary albumin excretion rate (108 vs 125 ml min−1 1.73 m−2; p < 0.05). However, no relationships were found between the increased urinary albumin excretion (incipient and/or overt diabetic nephropathy) at follow‐up to either the initial glomerular filtration rate (134 vs 137 ml min−1 1.73 m−2; p > 0.05) or to renal tubular function assessed from urinary excretion rate of β2‐microglobulin (0.059 vs 0.069 μg min−1; p > 0.05) and the renal threshold concentration of phosphate per litre of glomerular filtrate (1.29 vs 1.22 mmol I−1; p > 0.05).