Pathogen-specific antibody profiles in patients with severe systemic infections.

Infections are often caused by pathobionts, endogenous bacteria that belong to the microbiota. Trauma and surgical intervention can allow bacteria to overcome host defences, ultimately leading to sepsis if left untreated. One of the main defence strategies of the immune system is the production of highly specific antibodies. In the present proof-of-concept study, plasma antibodies against 9 major pathogens were measured in sepsis patients, as an example of severe systemic infections. The binding of plasma antibodies to bacterial extracellular proteins was quantified using a semi-automated immunoblot assay. Comparison of the pathogen-specific antibody levels before and after infection showed an increase in plasma IgG in 20 out of 37 tested patients. This host-directed approach extended the results of pathogen-oriented microbiological and PCR diagnostics: a specific antibody response to additional bacteria was frequently observed, indicating unrecognised poly-microbial invasion. This might explain some cases of failed, seemingly targeted antibiotic treatment.

Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression.

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.

Associations of insulin-like growth factor-I and insulin-like growth factor binding protein-3 with bone quality in the general adult population.

OBJECTIVE: Growth hormone (GH) and its main mediator, insulin-like growth factor-I (IGF-I), play a significant role in bone metabolism. The relations between IGF-I and bone mineral density (BMD) or osteoporosis have been assessed in previous studies but whether the associations are sex-specific remains uncertain. Moreover, only a few studies examined bone quality assessed by quantitative ultrasound (QUS). We aimed to investigate these associations in the general population of north-east Germany. DESIGN AND MEASUREMENTS: Data from 1759 men and 1784 women who participated in the baseline examination of the Study of Health in Pomerania (SHIP)-Trend were used. IGF-I and IGF-binding protein-3 (IGFBP-3) concentrations were measured on the IDS-iSYS multidiscipline automated analyser (Immunodiagnostic Systems Limited). QUS measurements were performed at the heel (Achilles InSight, GE Healthcare). Sex-specific linear and multinomial logistic regression models adjusted for potential confounders were calculated. RESULTS: Linear regression analyses revealed significant positive associations between IGF-I and IGF-I/IGFBP-3 ratio, a marker for free IGF-I, with all QUS parameters in men. Among women, we found an inverse association between IGF-I and the QUS-based fracture risk but no association with any other QUS parameter. There was no association between IGFBP-3 and the QUS-based fracture risk. CONCLUSIONS: Our data suggest an important role of IGF-I on bone quality in men. The observed association of IGF-I with the QUS-based stiffness index and QUS-based fracture risk in this study might animate clinicians to refer patients with low IGF-I levels, particularly men, to a further evaluation of risk factors for osteoporosis and a detailed examination of the skeletal system.

Estimating the causal effect of body mass index on hay fever, asthma and lung function using Mendelian randomization.

BACKGROUND: Observational studies have shown that body mass index (BMI) is positively associated with asthma. However, observational data are prone to confounding and reverse causation. In Mendelian randomization, genetic variants are used as unconfounded markers of exposures to examine causal effects. We examined the causal effect of BMI on asthma, hay fever, allergic sensitization, serum total immunoglobulin E (IgE), forced expiratory volume in one-second (FEV1) and forced vital capacity (FVC). METHODS: We included 490 497 participants in the observational and 162 124 participants in the genetic analyses. A genetic risk score (GRS) was created using 26 BMI-associated single nucleotide polymorphisms (SNPs). Results were pooled in meta-analyses and expressed as odds ratios (ORs) or ß-estimates with 95% confidence interval (CI). RESULTS: The GRS was significantly associated with asthma (OR=1.009; 95% CI: 1.004, 1.013), but not with hay fever (OR= 0.998; 95% CI: 0.994, 1.002) or allergic sensitization (OR=0.999; 95% CI: 0.986, 1.012) per BMI-increasing allele. The GRS was significantly associated with decrease in FEV1: ß=-0.0012 (95% CI: -0.0019, -0.0006) and FVC: ß=-0.0022 (95% CI: -0.0031, -0.0014) per BMI-increasing allele. Effect sizes estimated by instrumental variable analyses were OR=1.07 (95% CI: 1.03, 1.10) for asthma, a 9 ml decrease in FEV1 (95% CI: 2.0-15 mL decrease) and a 16 ml decrease in FVC (95% CI: 7.0-24 mL decrease) per 1 kg/m2 higher BMI. CONCLUSIONS: The results support the conclusion that increasing BMI is causally related to higher prevalence of asthma and decreased lung function, but not with hay fever or biomarkers of allergy.

Kappa free light chains in cerebrospinal fluid to identify patients with oligoclonal bands.

BACKGROUND AND PURPOSE: The gold standard for detection of intrathecal immunoglobulin synthesis is the measurement of oligoclonal bands (OCB). In the diagnosis of multiple sclerosis, the kappa free light chains (KFLC) index has a similar sensitivity and specificity as OCB. This study investigated whether determination of the KFLC index could be used to predict the presence of OCB. METHODS: The KFLC index was determined prospectively from 295 paired serum and cerebrospinal fluid samples. KFLC were determined by nephelometry using the N Latex FLC kappa kit (Siemens Healthcare Diagnostics Products GmbH) on the BN Prospec analyzer (Siemens Healthcare Diagnostics Products GmbH) (cohort I). A cut-off value was determined using receiver operating characteristic analysis in relation to OCB positivity. These results were validated prospectively in 96 samples (cohort II) as well as retrospectively in samples of 46 patients known to be OCB positive (cohort III). We also compared the agreement of two commercially available nephelometric KFLC assays. RESULTS: In cohort I, a KFLC index of 3.61 yielded 100% sensitivity and 88% specificity. Prospective validation of this cut-off value in cohort II showed 92% sensitivity and 96% specificity. In cohort III, a sensitivity of 93% was achieved. Comparison of Siemens and Binding Site (Birmingham, UK) assays revealed good agreement (r2  = 0.86). CONCLUSIONS: The KFLC index with a cut-off value of 3.61 had high diagnostic accuracy to predict immunoglobulin G synthesis via OCB analysis. Determination of the KFLC index provided a quantitative parameter that could be used as an initial diagnostic step in inflammatory central nervous system disorders before measuring OCB.

A case series of verrucae vulgares mimicking hyperkeratosis in individuals with diabetic foot ulcers.

BACKGROUND: Diabetic foot ulcers are a common complication in the advanced stages of diabetes mellitus. Certain lesions may be refractory to usual treatments with prolonged healing. In these cases, differential diagnoses to classical ulcers should be considered. Although plantar warts are a common and easy-to-diagnose finding in the general population, diagnosis can be challenging in people with diabetic foot ulcers, as they mimic hyperkeratosis in these people. CASE REPORT: We report seven cases of people with diabetic foot ulcers and verrucae vulgares mimicking treatment-refractory hyperkeratosis, presenting to our centre between 2014 and 2016. Diagnosis was aided by the clinical presentation, followed by dermoscopy and punch biopsy. Treatment included topical application of 5-fluoruracil and salicylic acid (four people), cryotherapy (three people) and surgical excision (three people), all in combination with local pressure offloading. In five people, the verrucae were completely removed after a mean treatment period of 9.4 months; two individuals were lost to follow-up. CONCLUSION: Verrucae may be more common in people with diabetic foot lesions and polyneuropathy than generally assumed. Typical findings include small, pinhead-sized bleedings within and surrounding hyperkeratous lesions. These findings should alert the clinician for the potential presence of a verruca. In such cases, biopsy should be performed to enable specific diagnosis and treatment.

Meta-analysis of genome-wide association studies of anxiety disorders.

Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 × 10(-8)); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 × 10(-9)). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.

Effect of body shape and inflammation on tooth loss in men and women.

OBJECTIVES: Android and gynoid adiposity is differently involved on inflammatory responses in men or women in periodontitis and tooth loss. We tested the hypothesis whether identical waist-to-hip ratios (WHR) in men and women could abolish this disparity. MATERIALS AND METHODS: Data of 2746 participants from the Study of Health in Pomerania (SHIP) were analysed. Men and women were 1:1 matched, N = 344:344, in three age strata for waist-to-hip ratio. We determined anthropometric measures, attachment loss, tooth loss and markers of systemic inflammation. RESULTS: Women matched with men by WHR had increased periodontal measures as compared to women of the general population. Nevertheless, in the matched pairs incidence risk (IRR) ratios for any tooth loss associated with elevated C-reactive protein were IRR = 2.15 (CI 1.33-3.40) and 1.04 (0.66-1.66) in men and women, respectively. Regression with tooth loss due to any cause as dependent variable showed dose dependency on C-reactive protein levels in men but not in women. The adjusted IRR associated with high C-reactive protein in men was 1.37 (CI 1.05-1.78) and 2.63 (1.58-4.38) in general and in matched subjects, respectively. CONCLUSION: Systemic inflammation was associated with tooth loss in men but not in women even in women with wide girth. Despite worsened periodontal measures and inflammation in women matched for body shape with men, these women do not lose more teeth even when they are exposed to increased markers of systemic inflammation. CLINICAL RELEVANCE: This is an attempt to disentangle the unclear relationship between obesity and periodontitis, both of them having public health relevance.

Thyrotropin serum levels are differentially associated with biochemical markers of bone turnover and stiffness in women and men: results from the SHIP cohorts.

UNLABELLED: In two large German population-based cohorts, we showed positive associations between serum thyrotropin (TSH) concentrations and the Fracture Risk Assessment score (FRAX) in men and positive associations between TSH concentrations and bone turnover markers in women. INTRODUCTION: The role of thyroid hormones on bone stiffness and turnover is poorly defined. Existing studies are confounded by differences in design and small sample size. We assessed the association between TSH serum concentrations and bone stiffness and turnover in the SHIP cohorts, which are two population-based cohorts from a region in Northern Germany comprising 2654 men and women and 3261 men and women, respectively. METHODS: We calculated the bone stiffness index using quantitative ultrasound (QUS) at the calcaneus, employed FRAX score for assessment of major osteoporotic fractures, and measured bone turnover markers, N-terminal propeptide of type I procollagen (P1NP), bone-specific alkaline phosphatase (BAP), osteocalcin, and type I collagen cross-linked C-telopeptide (CTX) in all subjects and sclerostin in a representative subgroup. RESULTS: There was no association between TSH concentrations and the stiffness index in both genders. In men, TSH correlated positively with the FRAX score both over the whole TSH range (p < 0.01) and within the reference TSH range (p < 0.01). There were positive associations between TSH concentrations and P1NP, BAP, osteocalcin, and CTX (p < 0.01) in women but not in men. There was no significant association between TSH and sclerostin levels. CONCLUSIONS: TSH serum concentrations are associated with gender-specific changes in bone turnover and stiffness.

Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.

Over the last few years, incretin-based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon-like peptide 1 (GLP-1), which is partly responsible for augmenting glucose-dependent insulin secretion in response to nutrient intake (the 'incretin effect'). In patients with T2D, pharmacological doses/concentrations of GLP-1 can compensate for the inability of diabetic ß cells to respond to the main incretin hormone glucose-dependent insulinotropic polypeptide, and this is therefore a suitable parent compound for incretin-based glucose-lowering medications. Two classes of incretin-based therapies are available: GLP-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1RAs promote GLP-1 receptor (GLP-1R) signalling by providing GLP-1R stimulation through 'incretin mimetics' circulating at pharmacological concentrations, whereas DPP-4 inhibitors prevent the degradation of endogenously released GLP-1. Both agents produce reductions in plasma glucose and, as a result of their glucose-dependent mode of action, this is associated with low rates of hypoglycaemia; however, there are distinct modes of action resulting in differing efficacy and tolerability profiles. Furthermore, as their actions are not restricted to stimulating insulin secretion, these agents have also been associated with additional non-glycaemic benefits such as weight loss, improvements in ß-cell function and cardiovascular risk markers. These attributes have made incretin therapies attractive treatments for the management of T2D and have presented physicians with an opportunity to tailor treatment plans. This review endeavours to outline the commonalities and differences among incretin-based therapies and to provide guidance regarding agents most suitable for treating T2D in individual patients.

Impact of diabetes duration on achieved reductions in glycated haemoglobin, fasting plasma glucose and body weight with liraglutide treatment for up to 28 weeks: a meta-analysis of seven phase III trials.

This meta-analysis of seven randomized, placebo-controlled studies (total 3222 patients) evaluated whether type 2 diabetes (T2D) duration affects the changes in blood glucose control and body weight that can be achieved with liraglutide and placebo. With liraglutide 1.2 mg, shorter diabetes duration was associated with a significantly greater, but clinically non-relevant, difference in glycated haemoglobin (HbA1c) reduction (p < 0.05), i.e. a 0.18% (1.96 mmol/mol) reduction in HbA1c per 10 years shorter diabetes duration. With liraglutide 1.8 mg, shorter diabetes duration was associated with a small but statistically significant trend for greater fasting plasma glucose (FPG) reduction (p < 0.05), i.e. a 0.38 mmol/l reduction in FPG per 10 years shorter diabetes duration. Neither the liraglutide 1.8 mg nor placebo results showed a significant association between HbA1c and diabetes duration and neither the liraglutide 1.2 mg nor placebo results showed a significant association between FPG and diabetes duration. Likewise, neither liraglutide nor placebo showed a significant association between change in weight and diabetes duration. These results suggest diabetes duration has a clinically negligible effect on achievable blood glucose control and weight outcomes with liraglutide and placebo in patients with T2D.

Improvement in glycated haemoglobin evaluated by baseline body mass index: a meta-analysis of the liraglutide phase III clinical trial programme.

In the liraglutide clinical trial programme, liraglutide 1.2 and 1.8 mg were found to effectively lower glycated haemoglobin (HbA1c) in patients with type 2 diabetes (T2D). It is unknown whether baseline body mass index (BMI) is a predictor of change in HbA1c observed during a clinical trial with liraglutide or placebo treatment. The present meta-analysis of patient-level data, using pooled data from seven phase III trials [LEAD-1-6 and the liraglutide versus sitagliptin trial (LIRA-DPP-4)] for liraglutide 1.2, 1.8 mg and placebo (n = 3222), identified no significant correlation between baseline BMI (<20 kg/m(2) up to 45 kg/m(2) ) and HbA1c reduction for placebo or liraglutide 1.2 mg, and a modest, clinically non-relevant, association for liraglutide 1.8 mg [-0.010 (95% confidence interval -0.020, -0.001)], whereby a 10 kg/m(2) increase in baseline BMI corresponded to 0.10%-point (1.1 mmol/mol) greater HbA1c reduction. In summary, reductions in HbA1c obtained during clinical trials with liraglutide or placebo treatment were independent of baseline BMI.

Vitamin D is associated with cardiopulmonary exercise capacity: results of two independent cohorts of healthy adults.

Vitamin D has an important role in calcium homeostasis and is known to have various health-promoting effects. Moreover, potential interactions between vitamin D and physical activity have been suggested. This study aims to investigate the relationship between 25-hydroxyvitamin D (25(OH)D) and exercise capacity quantified by cardiopulmonary exercise testing (CPET). For this, 1377 participants from the Study of Health in Pomerania (SHIP-1) and 750 participants from the independent SHIP-TREND cohort were investigated. Standardised incremental exercise tests on a cycle ergometer were performed to assess exercise capacity by VO2 at anaerobic threshold, peakVO2, O2 pulse and peak power output. Serum 25(OH)D levels were measured by an automated chemiluminescence immunoassay. In SHIP-1, 25(OH)D levels were positively associated with all considered parameters of cardiopulmonary exercise capacity. Subjects with high 25(OH)D levels (4th quartile) showed an up to 25% higher exercise capacity compared with subjects with low 25(OH)D levels (1st quartile). All associations were replicated in the independent SHIP-TREND cohort and were independent of age, sex, season and other interfering factors. In conclusion, significant positive associations between 25(OH)D and parameters of CPET were detected in two large cohorts of healthy adults.

[Recurrent hypoglycemia due to an occult insulinoma]. / Okkultes Insulinom als Ursache rezidivierender Hypoglykämien.

A 64-year-old woman presented with a history of recurrent hypoglycemia. A prolonged fasting test revealed an increased "amended" insulin-glucose ratio. Transabdominal ultrasound (US), computed tomography (CT) scan, and magnetic resonance imaging (MRI) did not show abnormal results. An insulinoma was suspected based on a contrast-enhanced endoscopic US examination as well as a (68)gallium-DOTA-exendin-4 positron-emission tomography (PET)/CT. The diagnosis of an insulinoma was confirmed histologically after surgical removal of the tumor. Hypoglycemia did not occur during the postoperative period. The prolonged fasting test is the gold standard for the diagnosis of an insulinoma. Novel imaging procedures, such as contrast-enhanced endoscopic US or (68)gallium-DOTA-exendin-4 PET/CT are valuable additions to the diagnostic workup.

Positive Association Between Adipose Tissue and Bone Stiffness.

Obesity is often considered to have a protective effect against osteoporosis. On the other hand, several recent studies suggest that adipose tissue may have detrimental effects on bone quality. We therefore aimed to investigate the associations between body mass index (BMI), waist circumference (WC), visceral adipose tissue (VAT) or abdominal subcutaneous adipose tissue (SAT), and bone stiffness. The study involved 2685 German adults aged 20-79 years, who participated in either the second follow-up of the population-based Study of Health in Pomerania (SHIP-2) or the baseline examination of the SHIP-Trend cohort. VAT and abdominal SAT were quantified by magnetic resonance imaging. Bone stiffness was assessed by quantitative ultrasound (QUS) at the heel (Achilles InSight, GE Healthcare). The individual risk for osteoporotic fractures was determined based on the QUS-derived stiffness index and classified in low, medium, and high risk. Linear regression models, adjusted for sex, age, physical activity, smoking status, risky alcohol consumption, diabetes, and height (in models with VAT or abdominal SAT as exposure), revealed positive associations between BMI, WC, VAT or abdominal SAT, and the QUS variables broadband-ultrasound attenuation or stiffness index. Moreover, BMI was positively associated with speed of sound. Our study shows that all anthropometric measures including BMI and, WC as well as abdominal fat volume are positively associated with bone stiffness in the general population. As potential predictors of bone stiffness, VAT and abdominal SAT are not superior to easily available measures like BMI or WC.

Safety and efficacy of once-weekly dulaglutide versus sitagliptin after 2 years in metformin-treated patients with type 2 diabetes (AWARD-5): a randomized, phase III study.

AIMS: To compare the once-weekly glucagon-like peptide-1 (GLP-1) receptor dulaglutide with the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin after 104 weeks of treatment. METHODS: This AWARD-5 study was a multicentre, double-blind trial that randomized participants to dulaglutide (1.5 or 0.75 mg) or sitagliptin 100 mg for 104 weeks or placebo (reported separately) for 26 weeks. Change in glycated haemoglobin (HbA1c) concentration from baseline was the primary efficacy measure. A total of 1098 participants with HbA1c concentrations ≥7.0% (≥53.0 mmol/mol) and ≤9.5% (≤80.3 mmol/mol) were randomized, and 657 (59.8%) completed the study. We report results for dulaglutide and sitagliptin at the final endpoint. RESULTS: Changes in HbA1c at 104 weeks were (least squares mean ± standard error) -0.99 ± 0.06% (-10.82 ± 0.66 mmol/mol), -0.71 ± 0.07% (-7.76 ± 0.77 mmol/mol) and -0.32 ± 0.06% (-3.50 ± 0.66 mmol/mol) for dulaglutide 1.5 mg, dulaglutide 0.75 mg and sitagliptin, respectively (p < 0.001, both dulaglutide doses vs sitagliptin). Weight loss was greater with dulaglutide 1.5 mg (p < 0.001) and similar with 0.75 mg versus sitagliptin (2.88 ± 0.25, 2.39 ± 0.26 and 1.75 ± 0.25 kg, respectively). Gastrointestinal adverse events were more common with dulaglutide 1.5 and 0.75 mg versus sitagliptin (nausea 17 and 15% vs 7%, diarrhoea 16 and 12% vs 6%, vomiting 14 and 8% vs 4% respectively). Pancreatic, thyroid, cardiovascular and hypersensitivity safety were similar across groups. CONCLUSIONS: Dulaglutide doses provided superior glycaemic control and dulaglutide 1.5 mg resulted in greater weight reduction versus sitagliptin at 104 weeks, with acceptable safety.

Improved glucose control with reduced hypoglycaemic risk when linagliptin is added to basal insulin in elderly patients with type 2 diabetes.

AIM: To assess the efficacy, hypoglycaemia risk and other safety markers of linagliptin as an additional therapy in older patients (aged ≥70 years) inadequately controlled with basal insulin. METHODS: A prespecified safety analysis from the linagliptin trials programme was carried out to explore the hypoglycaemia risk when linagliptin was added to background basal insulin therapy in elderly patients (≥70 years). To do this, two eligible, randomized, placebo-controlled, clinical trials (NCT00954447 and NCT01084005) of 24 and ≥52 weeks, respectively, were analysed. RESULTS: A total of 247 elderly individuals [mean ± standard deviation (s.d.) age 74 ± 4 years, glycated haemoglobin (HbA1c) 8.2 ± 0.8%] on basal insulin (mean ± s.d. baseline dose 36 ± 25 IU/day) were identified. Alongside placebo-adjusted change in HbA1c with linagliptin of -0.77% [95% confidence interval (CI) -0.95 to 0.59; p < 0.0001] after 24 weeks, the hazard ratios (HRs) of both overall and confirmed hypoglycaemia [blood glucose ≤3.9 mmol/l (70 mg/dl)], were significantly lower with linagliptin than with placebo: HR 0.61 (95% CI 0.39-0.97) versus 0.59 (95% CI 0.37-0.94), respectively (both p < 0.05). Moreover, significantly less confirmed hypoglycaemia was present in linagliptin-treated patients with renal impairment [HR 0.45 (95% CI 0.27-0.76)], moderate hyperglycaemia [HbA1c 7.5 to <9.0%; HR 0.51 (95% CI 0.27-0.99)], lower fasting plasma glucose levels [<152 mg/dl; HR 0.49 (95% CI 0.28-0.86)] and those treated with higher insulin doses [insulin ≥35.6 IU/day; HR 0.46 (95% CI 0.23-0.91); p < 0.05 for all]. Severe hypoglycaemia was rare and the incidence was lower with linagliptin (0.8%) versus placebo (2.5%): HR 0.21 (95% CI 0.02-2.30). CONCLUSIONS: Despite improvements in hyperglycaemia and no relevant on-trial insulin dose reductions, adding linagliptin to basal insulin appears to decrease hypoglycaemia risk. The biological basis of this phenomenon warrants further research but may involve counter-regulatory effects of incretin hormones.

Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in patients with type 2 diabetes: 4-year data.

AIMS: To assess the long-term efficacy and tolerability of dapagliflozin versus glipizide as add-on to metformin in patients with inadequately controlled type 2 diabetes. METHODS: The present study was an extension of an earlier randomized, double-blind, phase III study of dapagliflozin (n = 406) vs glipizide (n = 408) to 208 weeks (4 years). Patients continued to receive their assigned medication. No statistical treatment-group comparisons were calculated. RESULTS: At 208 weeks, dapagliflozin compared with glipizide produced sustained reductions in glycated haemoglogin (HbA1c): -0.30% [95% confidence interval (CI), -0.51 to -0.09], in total body weight: -4.38 kg (95% CI -5.31 to -3.46) and in systolic blood pressure (SBP): -3.67 mmHg (95% CI -5.92 to -1.41). The HbA1c coefficient of failure was significantly lower for dapagliflozin than for glipizide: 0.19 (95% CI 0.12-0.25) versus 0.61 (95% CI 0.49-0.72, difference -0.42; p = 0.0001). Dapagliflozin was not associated with glomerular function deterioration, while this occurred more frequently in patients in the glipizide group. Fewer patients reported hypoglycaemia in the dapagliflozin compared with the glipizide group (5.4 vs 51.5%). Genital and urinary tract infections were more common with dapagliflozin than with glipizide, but their incidence decreased with time and all events responded well to antimicrobial treatment. CONCLUSIONS: In patients completing 4 years of treatment, dapagliflozin was well tolerated and associated with sustained glycaemic efficacy and greater reductions in body weight and SBP versus glipizide.

Efficacy and safety of liraglutide versus placebo added to basal insulin analogues (with or without metformin) in patients with type 2 diabetes: a randomized, placebo-controlled trial.

AIM: To confirm the superiority, compared with placebo, of adding liraglutide to pre-existing basal insulin analogue ± metformin in adults with inadequately controlled type 2 diabetes [glycated haemoglobin (HbA1c) 7.0-10.0% (53-86 mmol/mol)]. METHODS: In this 26-week, double-blind, parallel-group study, conducted in clinics or hospitals, 451 subjects were randomized 1 : 1 to once-daily liraglutide 1.8 mg (dose escalated from 0.6 and 1.2 mg/day, respectively, for 1 week each; n = 226) or placebo (n = 225) added to their pre-existing basal insulin analogue (≥20 U/day) ± metformin (≥1500 mg/day). After randomization, insulin adjustments above the pre-study dose were not allowed. The primary endpoint was HbA1c change. RESULTS: After 26 weeks, HbA1c decreased more with liraglutide [-1.3% (-14.2 mmol/mol)] than with placebo [-0.1% (-1.2 mmol/mol); p < 0.0001]. More subjects on liraglutide reached HbA1c targets: <7.0% (59% vs 14%; p < 0.0001) and ≤6.5% (43% vs 4%; p < 0.0001) using slightly less insulin (35.8 IU vs 40.1 IU). Greater decreases from baseline (estimated treatment differences vs placebo; p < 0.0001) occurred in fasting plasma glucose (-1.3 mmol/l), seven-point glucose profiles (-1.6 mmol/l), body weight (-3.1 kg) and systolic blood pressure (-5.0 mmHg). Transient gastrointestinal adverse events (nausea: 22.2% vs 3.1%) and minor hypoglycaemia (18.2% vs 12.4%) were more frequent with liraglutide than placebo, and pulse increased (4.5 beats/min) compared with placebo. No severe hypoglycaemia or pancreatitis occurred. CONCLUSIONS: Adding liraglutide to a basal insulin analogue ± metformin significantly improved glycaemic control, body weight and systolic blood pressure compared with placebo. Typical gastrointestinal symptoms and minor hypoglycaemia were more frequent with liraglutide.

LEADER 2: baseline calcitonin in 9340 people with type 2 diabetes enrolled in the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial: preliminary observations.

AIMS: To report preliminary data on baseline serum calcitonin concentrations and associated clinical characteristics in a global population with type 2 diabetes before liraglutide or placebo randomization. METHODS: The ongoing LEADER trial has enrolled 9340 people with type 2 diabetes and at high risk of cardiovascular disease at 410 centres worldwide. People with baseline serum calcitonin ≤ 50 ng/l were randomized to liraglutide once daily or placebo and will be followed for up to 5 years. Serum calcitonin was measured at baseline and will be measured annually thereafter. An independent committee of thyroid experts will oversee calcitonin monitoring throughout the trial and will review all calcitonin concentrations ≥ 20 ng/l. RESULTS: The mean age of participants was 64.3 ± 7.2 years, 64.3% were men, and mean the body mass index was 32.5 ± 6.3 kg/m(2). The median (interquartile range) baseline serum calcitonin values were 3.9 (1.0 to >7.6) ng/l in men and 1.0 (1.0 to >1) ng/l in women. Serum calcitonin was >10 ng/l in 14.6% of men and in 0.96% of women. In sex-specific multivariable linear analysis of covariance models, a reduced glomerular filtration rate (GFR) was associated with higher serum calcitonin concentrations that were statistically significant. A 20 ml/min/1.73 m(2) decrease in estimated GFR (eGFR) was associated with a 14% increase in serum calcitonin in women and an 11% increase in men. CONCLUSIONS: In the LEADER population, the prevalence of elevated serum calcitonin concentrations at baseline was high, and there was an inverse association between eGFR and serum calcitonin concentrations.