3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background Liraglutide 3\ub70 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3\ub70 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2\ub77 times longer with liraglutide than with placebo (95% CI 1\ub79 to 3\ub79, p<0\ub70001), corresponding with a hazard ratio of 0\ub721 (95% CI 0\ub713\u20130\ub734). Liraglutide induced greater weight loss than placebo at week 160 (\u20136\ub71 [SD 7\ub73] vs 121\ub79% [6\ub73]; estimated treatment difference 124\ub73%, 95% CI 124\ub79 to 123\ub77, p<0\ub70001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3\ub70 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding Novo Nordisk, Denmark

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Phenotyping and auto-antibody production by liver-infiltrating B cells in primary sclerosing cholangitis and primary biliary cholangitis

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are immune-mediated biliary diseases that demonstrate prominent and restricted genetic association with human leukocyte antigen (HLA) alleles. In PBC, anti-mitochondrial antibodies (AMA) are specific and used as diagnostic biomarkers. PSC-relevant auto-antibodies remain controversial despite a distinct HLA association that mirrors archetypical auto-antigen driven disorders. Herein, we compared antibody-secreting B cells (ASCs) in PSC and PBC liver explants to determine if liver-infiltrating ASCs represent an opportune and novel source of disease-relevant auto-antibodies. Using enzymatic digestion and mechanical disruption, liver mononuclear cells (LIMCs) were isolated from fresh PSC and PBC explants and plasmablast (CD19þCD27þCD38hiCD138) and plasma cell (CD19þCD27þCD38hiCD138þ) ASCs were enumerated by flow cytometry. We observed 45-fold fewer plasma cells in PSC explants (n ¼ 9) compared to PBC samples (n ¼ 5, p &lt; 0.01) and 10-fold fewer IgA-, IgG- and IgM-positive ASCs (p &lt; 0.05). Liver-infiltrating ASCs from PSC and PBC explants were functional and produced similar concentrations of IgA, IgG and IgM following 2 weeks of culture. Antibody production by PBC ASCs (n ¼ 3) was disease-specific as AMA to pyruvate dehydrogenase complex E2 subunit (PDC-E2) was detected by immunostaining, immunoblotting and ELISA. Antibody profiling of PSC supernatants (n ¼ 9) using full-length recombinant human protein arrays (Cambridge Protein Arrays) revealed reactivities to nucleolar protein 3 (5/9) and hematopoietic cell-specific Lyn substrate 1 (3/9). Array analysis of PBC supernatants (n ¼ 3) detected reactivities to PDC-E2 and hexokinase 1 (3/3). In conclusion, we detected unique frequencies of liver infiltrating ASCs in PSC and PBC and in so doing, highlight a feasible approach for understanding disease-relevant antibodies in PSC

Fungal chitinases: diversity, mechanistic properties and biotechnological potential

Chitin derivatives, chitosan and substituted chito-oligosaccharides have a wide spectrum of applications ranging from medicine to cosmetics and dietary supplements. With advancing knowledge about the substrate-binding properties of chitinases, enzyme-based production of these biotechnologically relevant sugars from biological resources is becoming increasingly interesting. Fungi have high numbers of glycoside hydrolase family 18 chitinases with different substrate-binding site architectures. As presented in this review, the large diversity of fungal chitinases is an interesting starting point for protein engineering. In this review, recent data about the architecture of the substrate-binding clefts of fungal chitinases, in connection with their hydrolytic and transglycolytic abilities, and the development of chitinase inhibitors are summarized. Furthermore, the biological functions of chitinases, chitin and chitosan utilization by fungi, and the effects of these aspects on biotechnological applications, including protein overexpression and autolysis during industrial processes, are discussed in this review

A randomized, controlled trial of 3.0 mg of liraglutide in weight management

BACKGROUND Obesity is a chronic disease with serious health consequences, but weight loss is difficult to maintain through lifestyle intervention alone. Liraglutide, a glucagonlike peptide-1 analogue, has been shown to have potential benefit for weight management at a once-daily dose of 3.0 mg, injected subcutaneously. METHODS We conducted a 56-week, double-blind trial involving 3731 patients who did not have type 2 diabetes and who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of at least 30 or a BMI of at least 27 if they had treated or untreated dyslipidemia or hypertension. We randomly assigned patients in a 2:1 ratio to receive once-daily subcutaneous injections of liraglutide at a dose of 3.0 mg (2487 patients) or placebo (1244 patients); both groups received counseling on lifestyle modification. The coprimary end points were the change in body weight and the proportions of patients losing at least 5% and more than 10% of their initial body weight. RESULTS At baseline, the mean (±SD) age of the patients was 45.1±12.0 years, the mean weight was 106.2±21.4 kg, and the mean BMI was 38.3±6.4; a total of 78.5% of the patients were women and 61.2% had prediabetes. At week 56, patients in the liraglutide group had lost a mean of 8.4±7.3 kg of body weight, and those in the placebo group had lost a mean of 2.8±6.5 kg (a difference of -5.6 kg; 95% confidence interval, -6.0 to -5.1; P&lt;0.001, with last-observation-carried-forward imputation). A total of 63.2% of the patients in the liraglutide group as compared with 27.1% in the placebo group lost at least 5% of their body weight (P&lt;0.001), and 33.1% and 10.6%, respectively, lost more than 10% of their body weight (P&lt;0.001). The most frequently reported adverse events with liraglutide were mild or moderate nausea and diarrhea. Serious events occurred in 6.2% of the patients in the liraglutide group and in 5.0% of the patients in the placebo group. CONCLUSIONS In this study, 3.0 mg of liraglutide, as an adjunct to diet and exercise, was associated with reduced body weight and improved metabolic control. (Funded by Novo Nordisk; SCALE Obesity and Prediabetes NN8022-1839 ClinicalTrials.gov number, NCT01272219.)

Noninvasive Assessment of Preclinical Atherosclerosis

Initially considered as a semipermeable barrier separating lumen from vessel wall, the endothelium is now recognised as a complex endocrine organ responsible for a variety of physiological processes vital for vascular homeostasis. These include the regulation of vascular tone, luminal diameter, and blood flow; hemostasis and thrombolysis; platelet and leucocyte vessel-wall interactions; the regulation of vascular permeability; and tissue growth and remodelling. The endothelium modulates arterial stiffness, which precedes overt atherosclerosis and is an independent predictor of cardiovascular events. Unsurprisingly, dysfunction of the endothelium may be considered as an early and potentially reversible step in the process of atherogenesis and numerous methods have been developed to assess endothelial status and large artery stiffness. Methodology includes flow-mediated dilatation of the brachial artery, assessment of coronary flow reserve, carotid intimamedia thickness, pulse wave analysis, pulse wave velocity, and plethysmography. This review outlines the various modalities, indications, and limitations of available methods to assess arterial dysfunction and vascular risk

Effects of total fat intake on body fatness in adults

Background: The ideal proportion of energy from fat in our food and its relation to body weight is not clear. In order to prevent overweight and obesity in the general population, we need to understand the relationship between the proportion of energy from fat and resulting weight and body fatness in the general population. Objectives: To assess the effects of proportion of energy intake from fat on measures of body fatness (including body weight, waist circumference, percentage body fat and body mass index) in people not aiming to lose weight, using all appropriate randomised controlled trials (RCTs) of at least six months duration. Search methods: We searched CENTRAL, MEDLINE, Embase, Clinicaltrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) to October 2019. We did not limit the search by language. Selection criteria: Trials fulfilled the following criteria: 1) randomised intervention trial, 2) included adults aged at least 18 years, 3) randomised to a lower fat versus higher fat diet, without the intention to reduce weight in any participants, 4) not multifactorial and 5) assessed a measure of weight or body fatness after at least six months. We duplicated inclusion decisions and resolved disagreement by discussion or referral to a third party. Data collection and analysis: We extracted data on the population, intervention, control and outcome measures in duplicate. We extracted measures of body fatness (body weight, BMI, percentage body fat and waist circumference) independently in duplicate at all available time points. We performed random-effects meta-analyses, meta-regression, subgrouping, sensitivity, funnel plot analyses and GRADE assessment. Main results: We included 37 RCTs (57,079 participants). There is consistent high-quality evidence from RCTs that reducing total fat intake results in small reductions in body fatness; this was seen in almost all included studies and was highly resistant to sensitivity analyses (GRADE high-consistency evidence, not downgraded). The effect of eating less fat (compared with higher fat intake) is a mean body weight reduction of 1.4 kg (95% confidence interval (CI) -1.7 to -1.1 kg, in 53,875 participants from 26 RCTs, I2 = 75%). The heterogeneity was explained in subgrouping and meta-regression. These suggested that greater weight loss results from greater fat reductions in people with lower fat intake at baseline, and people with higher body mass index (BMI) at baseline. The size of the effect on weight does not alter over time and is mirrored by reductions in BMI (MD -0.5 kg/m2, 95% CI -0.6 to -0.3, 46,539 participants in 14 trials, I2 = 21%), waist circumference (MD -0.5 cm, 95% CI -0.7 to -0.2, 16,620 participants in 3 trials; I2 = 21%), and percentage body fat (MD -0.3% body fat, 95% CI -0.6 to 0.00, P = 0.05, in 2350 participants in 2 trials; I2 = 0%). There was no suggestion of harms associated with low fat diets that might mitigate any benefits on body fatness. The reduction in body weight was reflected in small reductions in LDL (-0.13 mmol/L, 95% CI -0.21 to -0.05), and total cholesterol (-0.23 mmol/L, 95% CI -0.32 to -0.14), with little or no effect on HDL cholesterol (-0.02 mmol/L, 95% CI -0.03 to 0.00), triglycerides (0.01 mmol/L, 95% CI -0.05 to 0.07), systolic (-0.75 mmHg, 95% CI -1.42 to -0.07) or diastolic blood pressure(-0.52 mmHg, 95% CI -0.95 to -0.09), all GRADE high-consistency evidence or quality of life (0.04, 95% CI 0.01 to 0.07, on a scale of 0 to 10, GRADE low-consistency evidence). Authors' conclusions: Trials where participants were randomised to a lower fat intake versus a higher fat intake, but with no intention to reduce weight, showed a consistent, stable but small effect of low fat intake on body fatness: slightly lower weight, BMI, waist circumference and percentage body fat compared with higher fat arms. Greater fat reduction, lower baseline fat intake and higher baseline BMI were all associated with greater reductions in weight. There was no evidence of harm to serum lipids, blood pressure or quality of life, but rather of small benefits or no effect