Aims
To evaluate the effects of dulaglutide vs placebo on liver and glycaemic/metabolic measurements in a population with Type 2 diabetes and in a subgroup with non‐alcoholic fatty ...liver/non‐alcoholic steatohepatitis.
Methods
A total of 1499 participants from AWARD‐1, AWARD‐5, AWARD‐8 and AWARD‐9 clinical trials were included in this analysis (dulaglutide 1.5 mg, n=971 and placebo, n=528). Thresholds of alanine aminotransferase levels ≥30 IU/l in men and ≥19 IU/l in women were used to determine the subgroup who had non‐alcoholic fatty liver/non‐alcoholic steatohepatitis. Objectives included changes from baseline to 6 months in: (1) alanine aminotransferase, aspartate transaminase and gamma‐glutamyl transpeptidase levels in the overall population and (2) alanine aminotransferase, aspartate transaminase, gamma‐glutamyl transpeptidase and glycaemic/metabolic measurements (e.g. HbA1c, fasting serum glucose, body weight, lipids and homeostatic model assessment) in the non‐alcoholic fatty liver/non‐alcoholic steatohepatitis subgroup.
Results
In the overall population at 6 months, dulaglutide significantly reduced alanine aminotransferase, aspartate transaminase and gamma‐glutamyl transpeptidase levels vs placebo least squares mean treatment differences: –1.7 IU/l (95% CI –2.8, –0.6), P=0.003; –1.1 IU/l (95% CI –2.1, –0.1), P=0.037; –6.6 IU/l (95% CI –12.4, –0.8), P=0.025, respectively. In the subgroup with non‐alcoholic fatty liver/non‐alcoholic steatohepatitis (alanine aminotransferase levels greater than or equal to the upper limit of normal), mean baseline liver enzyme values were 38.0 IU/l, 27.8 IU/l and 43.9 IU/l for alanine aminotransferase, aspartate transaminase and gamma‐glutamyl transpeptidase, respectively. In this population, more pronounced reductions from baseline in alanine aminotransferase were observed with dulaglutide vs placebo (–8.8 IU/l vs –6.7 IU/l). In the subgroup of people with alanine aminotransferase levels less than the upper limit of normal, changes from baseline in alanine aminotransferase did not significantly differ between treatment groups (0.0 IU/l vs 0.7 IU/l).
Conclusions
Once‐weekly dulaglutide improved alanine aminotransferase, aspartate transaminase and gamma‐glutamyl transpeptidase levels compared with placebo in a pattern consistent with liver fat reductions. Our results add further weight to the notion that glucagon‐like peptide‐1 receptor agonists may provide benefit in lowering liver fat in addition to their other metabolic actions.
What's new?
Non‐alcoholic fatty liver disease is present in >75% of people with Type 2 diabetes.
Dulaglutide is a once‐weekly glucagon‐like peptide‐1 receptor agonist approved for the treatment of Type 2 diabetes.
This analysis evaluated the effects of dulaglutide on liver and glycaemic/metabolic measurements in a subgroup of people with non‐alcoholic fatty liver/non‐alcoholic steatohepatitis and Type 2 diabetes.
Treatment response of dulaglutide in the subgroup was similar to that in the overall population.
Dulaglutide improved plasma aminotransferases and gamma‐glutamyl transpeptidase in a pattern consistent with liver fat reductions.
Abstract Prospective, controlled clinical trials in postmenopausal osteoporosis typically compare effects of an active drug with placebo in addition to vitamin D and calcium supplementation in both ...treatment arms. While clinical benefits are documented, the effect of this supplementation in the placebo arm and in clinical practice on bone material composition properties is unknown. The purpose of the present study was to evaluate these bone quality indices (specifically mineral/matrix, nanoporosity, glycosaminoglycan content, mineral maturity/crystallinity, and pyridinoline content) in patients that either received long-term vitamin D (400
–
1200 IU) and calcium (1.0
–
1.5 g) supplementation, or did not. We have analyzed by Raman microspectroscopy the bone forming trabecular surfaces of iliac crest in pre-treatment samples of a teriparatide study and the endpoint biopsies of the control arm obtained from the HORIZON trial. In general, the mineral/matrix ratio and the glycosaminoglycan (GAG) content was higher while nanoporosity, (a surrogate for tissue water content), the mineral maturity/crystallinity (MMC) and the pyridinoline (Pyd) content was lower in patients without long-term supplementation. Moreover, all indices were significantly dependent on tissue age. In conclusion, vitamin D and calcium supplementation is associated with altered mineral and organic matrix properties.
Aim
To examine the hypothesis that, based on their glucose curves during a seven‐point oral glucose tolerance test, people at elevated type 2 diabetes risk can be divided into subgroups with ...different clinical profiles at baseline and different degrees of subsequent glycaemic deterioration.
Methods
We included 2126 participants at elevated type 2 diabetes risk from the Diabetes Research on Patient Stratification (IMI‐DIRECT) study. Latent class trajectory analysis was used to identify subgroups from a seven‐point oral glucose tolerance test at baseline and follow‐up. Linear models quantified the associations between the subgroups with glycaemic traits at baseline and 18 months.
Results
At baseline, we identified four glucose curve subgroups, labelled in order of increasing peak levels as 1–4. Participants in Subgroups 2–4, were more likely to have higher insulin resistance (homeostatic model assessment) and a lower Matsuda index, than those in Subgroup 1. Overall, participants in Subgroups 3 and 4, had higher glycaemic trait values, with the exception of the Matsuda and insulinogenic indices. At 18 months, change in homeostatic model assessment of insulin resistance was higher in Subgroup 4 (β = 0.36, 95% CI 0.13–0.58), Subgroup 3 (β = 0.30; 95% CI 0.10–0.50) and Subgroup 2 (β = 0.18; 95% CI 0.04–0.32), compared to Subgroup 1. The same was observed for C‐peptide and insulin. Five subgroups were identified at follow‐up, and the majority of participants remained in the same subgroup or progressed to higher peak subgroups after 18 months.
Conclusions
Using data from a frequently sampled oral glucose tolerance test, glucose curve patterns associated with different clinical characteristics and different rates of subsequent glycaemic deterioration can be identified.
Summary
The results of the present study, involving analysis of biopsies from patients who received teriparatide for 2 years and were previously either treatment-naïve or on long-term alendronate ...therapy, suggest that prior alendronate use does not blunt the favorable effects of teriparatide on bone quality.
Introduction
Examine the effect of 2 years of teriparatide (TPTD) treatment on mineral and organic matrix properties of the newest formed bone in patients who were previously treatment-naïve (TN) or on long-term alendronate (ALN) therapy.
Methods
Raman and Fourier transform infrared microspectroscopic analyses were used to determine the mineral/matrix (M/M) ratio, the relative proteoglycan (PG) content, and the mineral maturity/crystallinity (MMC; determined by three methods: carbonate content, full width at half height of the
v
1
PO
4
band FWHH, and wavelength at maxima of the
v
1
PO
4
band), as well as collagen maturity (ratio of pyridinoline/divalent cross-links), in paired iliac crest biopsies at trabecular, endosteal, and osteonal surfaces of newly formed bone in postmenopausal osteoporotic women who were previously either TN (
n
= 16) or receiving long-term ALN treatment (
n
= 24).
Results
Trabecular M/M ratio increased and matrix content decreased significantly in the ALN pretreated group. Collagen maturity decreased in both patient groups. Endosteal M/M ratio increased significantly in the TN group. Trabecular M/M ratio was higher at endpoint in the ALN pretreated group than in the TN group. Overall, no changes from baseline were observed in PG content, except that PG content was higher in the ALN pretreated group than in the TN group at endosteal surfaces at endpoint. The ability of TPTD treatment to reduce MMC in both patient groups and at the different bone surfaces depended on the measurement tool (relative carbonate content or wavelength at maxima of the
v
1
PO
4
band). None of the changes in MMC were different between the two patient groups.
Conclusions
The results suggest some favorable impact of TPTD on bone mineral and organic matrix properties of in situ forming bone in terms of increased initial mineralization and decreased MMC and collagen maturity. Moreover, prior long-term ALN administration may have only limited influence on these properties in bone newly formed after 2 years of TPTD treatment.
Summary The level of increased bone formation after 24 months of treatment with teriparatide (rhPTH (1-34), TPTD) is similar in patients who were either treatment-naïve (TN) or had lower bone ...turnover initially due to previous alendronate (ALN) therapy. Introduction Bone anabolic effects of TPTD in postmenopausal women with osteoporosis may be blunted during the initial phase after switching from ALN to TPTD. To explore the long-term implications, we examined histomorphometric and biochemical markers of bone turnover of patients on TPTD therapy after long-term ALN treatment. Methods Paired biopsies were obtained after tetracycline double labeling at baseline and after 24 months of TPTD treatment from 29 ALN-pretreated (64.5 ± 16.4 months) and 16 TN patients. Biochemical markers were measured at baseline, during the treatment, or at study end. Results Compared with the baseline, after 24-month TPTD, activation frequency (Ac.F.) and osteoid surface (OS) increased in both groups: 0.11-0.34 cycles per year, 3.96-9.8% in the ALN-pretreated group and 0.19-0.33 cycles per year, 6.2-11.3% (p < 0.05) in the TN group, respectively. Biochemical and histomorphometric markers correlated positively both at baseline and endpoint. Serum amino terminal propeptide of type I procollagen (PINP) correlated with Ac.F. (r = 0.57, p < 0.001 and r = 0.48, p < 0.01) and OS (r = 0.51, p < 0.01 and r = 0.56, p < 0.01) at baseline and endpoint, respectively. Following 3 months of treatment, increases in biochemical markers like PINP predicted the increase in Ac.F. (r = 0.52, p < 0.01) and OS (r = 0.54, p < 0.01) after 24 months. Conclusions The increased level of formation is similar in patients who were either TN or had lower bone turnover initially due to previous ALN therapy. Elevated bone formation in postmenopausal women with osteoporosis was sustained over a 24-month period by TPTD. Biochemical markers of bone formation are a good surrogate for the assessment of TPTD effects.
We investigated the protective effect of ischaemic preconditioning (IP) on the maintenance of coronary patency using on-line measurements of coronary pressures and blood flow in a closed-chest ...reperfused acute myocardial infarction (MI) model in pigs. Catheter-based 90-min occlusion followed by 60-min reperfusion of the left anterior descending coronary artery (LAD) was performed in anesthetised pigs (MI group). IP was applied (IP group) through two cycles of 5-min occlusion and 5-min reperfusion of the LAD before MI induction. Coronary patency was determined by measurements of coronary wedge pressure, collateral fractional flow reserve (FFRcoll), collateral pressure index (CPI) and absolute coronary blood flow (CBF). Inducible and constitutive nitric oxide synthase (iNOS/cNOS) activities and expressions were determined in the myocardium. Plasma levels of myeloperoxidase (MPO, index of activated leukocytes) and mean platelet volume (MPV, index of activated platelets) were measured. IP resulted in significantly lower levels of MPO (0.52 ± 0.19 vs. 1.05 ± 0.24 U/l, p<0.001) and MPV (9.1 ± 0.6 vs. 9.6 ± 1.0 fl, p=0.04), higher FFRcoll (0.17 ± 0.05 vs. 0.04 ± 0.05, p<0.001), CPI (0.13 ± 0.05 vs. 0.02 ± 0.05, p<0.001) and CBF (70.7 ± 4.2 vs. 50.8 ± 4.8 m/min, p<0.001) post-reperfusion as compared with the MI group. IP resulted in significantly higher cNOS activity and eNOS expression. Significant negative correlation was found between MPO and measures of coronary patency (FFRcoll, CPI and CBF) and cNOS activity. Moreover, cNOS activity correlated significantly with FFRcoll, CPI and CBF. In conclusion, IP attenuates the release of MPO and platelet activation, thereby contributing to the maintenance of vessel patency at microvascular level after reperfusion of the infarct-related artery.
Cell-based therapy is a promising, novel therapeutic strategy for cardiovascular disease. The rapid transition of this approach from the benchside to clinical trials has left a gap in the ...understanding of the mechanisms of cell therapy. Monitoring of cell homing and the fate of cardially delivered stem cells is fundamental for clarification of the myocardial regenerative process. Noninvasive imaging techniques allow an in vivo evaluation of the survival, migration and differentiation of implanted stem cells over time, and by this means, can help to answer unresolved questions. The most promising in vivo tracking methods involve the direct, nonspecific labeling of cells including MRI, radionuclide imaging and the use of reporter-gene imaging. This review summarizes the most important results of animal and human studies in which the fate and biodistribution of cardially delivered stem cells are assessed through different in vivo tracking methods.
The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment
. The ...origins of specific compounds are known, including metabolites that are highly heritable
, or those that are influenced by the gut microbiome
, by lifestyle choices such as smoking
, or by diet
. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites-in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts
that were not available to us when we trained the algorithms. We used feature attribution analysis
to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.
ABSTRACT
Objectives: The aim was to investigate patient compliance with different osteoporosis medications commonly prescribed in clinical practice, to determine risk factors associated with ...discontinuation and to evaluate quality of life changes.
Research design and methods: We conducted a 1-year observational study of patients of age ≥ 60 years in a clinical setting at 917 sites in 10 European countries (Germany, Greece, UK, Sweden, Netherlands, Romania, Norway, Finland, Denmark, Estonia), Lebanon and South Africa. Demographic data, concomitant diseases, the reasons for intervention, educational, socio-economical status and disease knowledge were captured at baseline. Self-reported compliance, discontinuation data and health status were collected.
Main outcome measures: Out of 5198 patients, 3490 (67.1%) patients received 60 mg daily raloxifene (RAL), 452 (8.7%) 10 mg daily alendronate (AQD), 769 (14.8%) 70 mg once weekly alendronate (AQW) and 487 (9.4%) 5 mg daily risedronate (RIS). Among patients completing the study (4231, 81%), the percentage of patients with high compliance was 80% (RAL), 79% (AQD), 65% (AQW) and 76% (RIS). The discontinuation due to side effects was highest on AQW (7.0%), followed by AQD (6.4%), RAL (3.8%) and RIS (3.4%). The discontinuation-rate was higher for patients with a history of surgical menopause, increased age, lack of knowledge about medical prevention of osteoporosis and thin frame as a reason for intervention. The EQ-5D weighted index showed the highest improvement for RIS (0.13), followed by RAL (0.11), AQD (0.08) and AQW (0.07).
Conclusions: Data from this non-interventional observational study indicate moderate overall compliance and discontinuation rate with the prescribed osteoporosis medications.
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