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Increased circulation mobilization of endothelial progenitor cells in preterm infants with retinopathy of prematurity.
Babaei, H, Alibabrdel, M, Asadian, S, Siavashi, V, Jabarpour, M, Nassiri, SM
Journal of cellular biochemistry. 2018;(8):6575-6583
Abstract
Retinopathy of prematurity (ROP) is a result of increased pathological neoangiogenesis of the retina in preterm infants. Cells responsible for the pathogenesis of ROP are unclear, but some evidence indicates that bone marrow derived cells are involved in this disorder. Endothelial progenitor cells (EPCs), play a role in angiogenesis in response to tissue ischemia or endothelial damage. In this study, the number of cEPCs in preterm infants with ROP was determined to identify whether the circulation mobilization of EPCs is associated with ROP. We evaluated 99 participants in this study: 22 preterm infants with ROP, 35 preterm infants without ROP, and 42 full-term infants. The release of EPCs in the circulation was first quantified. Thereafter, cEPCs were harvested and cultivated, then the biological features of these cells including migratory, proliferative, and tubulogenic activities were analyzed. The mRNA levels of some proangiogenic factors were also measured in preterm infants. Our results showed greater numbers of cEPCs in infants with ROP, which was associated with increased serum concentrations of angiogenic factors and with augmented proliferative, migratory, and tubulogenic activity of these cells. Western blotting showed increased protein levels of VEGF and HIF-α in cEPCs harvested from ROP infants. This study showed that ROP in preterm infants is associated with increased mobilization of EPCs into the circulation. Therefore, increased cEPCs along with elevated levels of angiogenic factors and tubulogenesis suggest that these cells may play a role in the development and progression of ROP.
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Effect of beef ingestion by humans on plasma concentrations of creatinine, urea, and cystatin C.
Toffaletti, JG, Hammett-Stabler, C, Handel, EA
Clinical biochemistry. 2018;:26-31
Abstract
PURPOSE The effect of eating meat on serum concentrations of creatinine has varied among previous reports, with some finding no effect and others finding 50-100% increases, which appears related to how the beef is cooked. For other analytes related to kidney function, urea is well known to increase following a protein meal, and the effect of eating meat on cystatin C concentrations has been studied once. METHODS We had 32 participants eat a measured amount of cooked beef (5-6 or 10-12 oz; 142-170 or 284-340 g) and collected blood for measurements at 1 h before and immediately before eating beef, then at 1, 2, and 4 h after eating the beef. We measured creatinine using both alkaline picrate and enzymatic methods, cystatin C using a nephelometric immunoassay, and urea using an enzymatic method. RESULTS For creatinine, both the picrate and enzymatic methods showed similar responses, with a peak average increases of 5.9 μmol/L (0.07 mg/dL) and 4.6 μmol/L (0.05 mg/dL), respectively, at 2 h. Cystatin C had a very slightly maximal decrease of -0.037 mg/L at 2 h. Urea had the largest change, increasing by 0.30 and 0.77 mmol/L at 2 and 4 h respectively. CONCLUSIONS Healthy individuals were found to have minor increases in serum creatinine (~5 μmol/L) following the ingestion of 5/6 or 10/12 oz of fried beef. Cystatin C appears to decrease very slightly in some people after beef ingestion, possibly due either to circadian variation or to a hormonal effect of eating. We conclude that ingesting these amounts of fried beef has a small effect on plasma creatinine concentrations. Although these increases would likely not affect the diagnosis of a kidney impairment in this population or in those with kidney disease, eating meat before collecting blood for creatinine measurement should be avoided.
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Lack of Longitudinal Association Between Thiazolidinediones and Incidence and Progression of Diabetic Eye Disease: The ACCORD Eye Study.
Gower, EW, Lovato, JF, Ambrosius, WT, Chew, EY, Danis, RP, Davis, MD, Goff, DC, Greven, CM, ,
American journal of ophthalmology. 2018;:138-147
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Abstract
PURPOSE To report the longitudinal association between use of thiazolidinediones (TZDs), visual acuity (VA) change, and diabetic eye disease incidence and progression. DESIGN Cohort study ancillary to a randomized clinical trial. METHODS We analyzed baseline and 4-year follow-up data of 2856 ACCORD trial participants with no history of proliferative diabetic retinopathy. Based on stereoscopic fundus photographs, we evaluated diabetic macular edema (DME) progression and DR progression. We also evaluated 10- and 15-letter change on the ETDRS visual acuity chart. Main outcome measures were incidence or progression of DME or DR and change in visual acuity. RESULTS TZD use was not associated with DME incidence in either the analysis of any use (adjusted odds ratio [aOR] [95% CI]: 1.22 [0.72-2.05]) or duration of use (aOR: 1.02 [0.99-1.04]). Diabetic retinopathy (DR) incidence/progression was more common in patients with no or mild DR at baseline who were ever treated with TZDs (aOR: 1.68 [1.11-2.55]), but this association disappeared when adjusting for the time on TZD (aOR: 1.02 [1.00-1.04]). DR progression among those with moderate or worse DR at baseline was no different between TZD users and non-users. TZD usage had no effect on the ultimate visual acuity outcome. CONCLUSION In this longitudinal study of patients with type 2 diabetes, we found no association between TZD use and visual acuity outcomes or DME progression, and no consistent evidence of increased DR progression in patients ever treated with TZDs vs those never treated with TZDs.
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CD5 expression promotes IL-10 production through activation of the MAPK/Erk pathway and upregulation of TRPC1 channels in B lymphocytes.
Garaud, S, Taher, TE, Debant, M, Burgos, M, Melayah, S, Berthou, C, Parikh, K, Pers, JO, Luque-Paz, D, Chiocchia, G, et al
Cellular & molecular immunology. 2018;(2):158-170
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Abstract
CD5 is constitutively expressed on T cells and a subset of mature normal and leukemic B cells in patients with chronic lymphocytic leukemia (CLL). Important functional properties are associated with CD5 expression in B cells, including signal transducer and activator of transcription 3 activation, IL-10 production and the promotion of B-lymphocyte survival and transformation. However, the pathway(s) by which CD5 influences the biology of B cells and its dependence on B-cell receptor (BCR) co-signaling remain unknown. In this study, we show that CD5 expression activates a number of important signaling pathways, including Erk1/2, leading to IL-10 production through a novel pathway independent of BCR engagement. This pathway is dependent on extracellular calcium (Ca2+) entry facilitated by upregulation of the transient receptor potential channel 1 (TRPC1) protein. We also show that Erk1/2 activation in a subgroup of CLL patients is associated with TRPC1 overexpression. In this subgroup of CLL patients, small inhibitory RNA (siRNA) for CD5 reduces TRPC1 expression. Furthermore, siRNAs for CD5 or for TRPC1 inhibit IL-10 production. These findings provide new insights into the role of CD5 in B-cell biology in health and disease and could pave the way for new treatment strategies for patients with B-CLL.
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Vonoprazan prevents ulcer recurrence during long-term NSAID therapy: randomised, lansoprazole-controlled non-inferiority and single-blind extension study.
Mizokami, Y, Oda, K, Funao, N, Nishimura, A, Soen, S, Kawai, T, Ashida, K, Sugano, K
Gut. 2018;(6):1042-1051
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OBJECTIVE To assess the non-inferiority of vonoprazan to lansoprazole for secondary prevention of non-steroidal anti-inflammatory drug (NSAID)-induced peptic ulcer (PU) and the safety of vonoprazan during extended use. DESIGN A phase 3, 24-week, multicenter, randomised, double-blind (DB), active-controlled study, followed by a phase 3, ≥28 week, multicenter, single-blind, parallel-group extension study (EXT) in outpatients (n=642) receiving long-term NSAID therapy who are at risk of PU recurrence. The patients received vonoprazan (10 mg or 20 mg) or lansoprazole 15 mg once daily. For DB, non-inferiority of the proportion of patients with recurrent PU within 24 weeks was analysed by Farrington and Manning test (significance level 2.5%, non-inferiority margin 8.3%; primary endpoint), recurrent PU within 12 weeks, bleeding and time-to-event of PU (secondary endpoint) and treatment-emergent adverse events (TEAEs). For EXT, TEAEs (primary endpoint), recurrent PU and safety (secondary) were assessed up to 104 weeks for patients in the extension study. RESULTS The non-inferiority of vonoprazan 10 mg and 20 mg to lansoprazole 15 mg was verified (percentage difference -2.2%,95% CI -6.2% to 1.8%, p<0.001; -2.1%,95% CI -6.1% to 2.0%, p<0.001, respectively). The proportion of patients with endoscopically confirmed recurrent PU within 24 weeks was 3.3%, 3.4% and 5.5%, for vonoprazan 10 mg, 20 mg and lansoprazole 15 mg, respectively. No significant safety concerns were identified. CONCLUSION The non-inferiority of vonoprazan (10 and 20 mg) was verified in patients receiving long-term NSAIDs in DB; it was effective and well tolerated in EXT for longer than 1 year, with a safety profile similar to lansoprazole (15 mg). TRIAL REGISTRATION NUMBERS NCT01452750, NCT01456260; Results.
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Oxygenation of the Immature Infant: A Commentary and Recommendations for Oxygen Saturation Targets and Alarm Limits.
Saugstad, OD
Neonatology. 2018;(1):69-75
Abstract
BACKGROUND For 70 years, there has been a search for the optimal oxygenation of premature infants. In spite of the lack of evidence, guidelines have successively reduced oxygenation targets during these years. OBJECTIVES (1) To present a summary of previously published meta-analyses of 5 randomized studies (NeOProM) which tested a low (85-89%) versus a high (91-95%) oxygen saturation target the first weeks after birth on outcome of immature newborn infants. (2) To present international recommendations for oxygenation the first weeks after birth. METHODS Data were retrieved from meta-analyses and reviews of these studies. RESULTS Mortality and necrotizing enterocolitis (NEC) are significantly higher in patients with a low saturation target (relative risk, RR 1.16 and 1.24, respectively), while severe retinopathy of prematurity (ROP) is reduced (RR 0.74), fortunately without a change in the rate of blindness. Severe intraventricular hemorrhage, patent ductus arteriosus, and bronchopulmonary dysplasia (defined physiologically) were not significantly affected by the oxygen targets in the range of these studies. Based on these data, it is recommended that SpO2 targets from birth to 36 weeks postconceptional age for infants < 28 weeks gestational age (GA) should be between 90 and 94% (with alarm limits of 89 and 95%), respectively. It is recommended to keep infants small for GA well oxygenated within the suggested targets avoiding fluctuations. CONCLUSIONS The ideal oxygen saturation targets for infants < 28 weeks GA are not known. Mortality, ROP, and NEC seem to be particularly oxygen-sensitive outcome variables. The optimal oxygen saturation for premature infants > 28 weeks GA has not been carefully studied.
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[Risk factors analysis of renal replacement therapy after liver transplantation and prognosis effect of initial treatment time].
Dong, Z, Shi, L, Ye, L, Xu, Z, Zhou, L
Zhonghua wei zhong bing ji jiu yi xue. 2018;(11):1056-1060
Abstract
OBJECTIVE To analyze the risk factors of renal replacement therapy (RRT) in acute kidney injury (AKI) patients after liver transplantation, and to investigate the prognosis effect of initial RRT treatment time. METHODS Clinical data of 132 recipients undergoing organ donation for cardiac death (DCD) allograft orthotopic liver transplantation admitted to Ningbo Medical Center Lihuili Hospital and Ningbo Medical Center Lihuili Eastern Hospital from July 2014 to July 2018 was retrospectively analyzed. AKI was defined and staged by the criteria of Kidney Disease Improving Global Outcomes (KDIGO) guideline in the first 7 days. According to the implementation of RRT, the patients were divided into non-RRT group and RRT group. The differences in gender, age, body mass index (BMI), model for end-stage liver disease with serum sodium (MELD-Na) score, serum creatinine (SCr), and intraoperative norepinephrine (NE) dose, blood loss, fluid infusion, anhepatic phase time, duration of operation between two groups were compared. The statistically significant risk factors of AKI found by univariate analysis were selected and analyzed to find independent risk factors of RRT in AKI patients after liver transplantation with multivariate Logistic regression analysis. The receiver operating characteristic (ROC) curve was drawn to evaluate the test efficiency of all risk factors of RRT implementation. According to the implementation of RRT on KDIGO stage-2, all the patients on KDIGO stage-2 and stage-3 were divided into early group (initial RRT on KDIGO stage-2) and delayed group (including self-improvement without RRT on KDIGO stage-2 and initial RRT on KDIGO stage-3). The duration of mechanical ventilation, the length of intensive care unit (ICU) stay, AKI duration, incidence of catheter related bloodstream infection (CRBSI) and 28-day mortality were compared between the two groups. RESULTS All 132 receptors were enrolled in the final analysis, and 77 patients developed AKI, accounting for 58.3%, among which 52 cases were in RRT group (67.5%) and 25 were in non-RRT group (32.5%). As shown by univariate analysis, the MELD-Na score (21.6±4.4 vs. 18.0±4.3), intraoperative NE dose (μg×kg-1×h-1: 7.5±1.2 vs. 5.2±1.7), blood loss [mL: 3 000 (2 200, 4 000) vs. 2 600 (1 800, 3 200)], fluid infusion [mL: 6 400 (4 500, 7 800) vs. 5 600 (4 200, 6 800)], and anhepatic period (minutes: 65.6±4.5 vs. 63.0±5.0) were significantly increased in RRT group as compared with those in non-RRT group (all P < 0.05). There was no significant difference in gender, age, BMI, SCr before operation or the duration of operation. It was shown by multivariate Logistic regression analysis that MELD-Na score before operation [odds ratio (OR) = 1.398, 95% confidence interval (95%CI) = 1.062-1.841, P = 0.017], intraoperative NE dose (OR = 4.724, 95%CI = 2.036-10.961, P = 0.000) and fluid infusion (OR = 1.002, 95%CI = 1.001-1.004, P = 0.010) were independent risk factors of RRT implementation in AKI patients after liver transplantation. It was shown by ROC curve analysis that the area under the ROC curve (AUC) of MELD-Na score, NE dose and fluid infusion for predicting the implementation of RRT in AKI patients after liver transplantation was 0.719, 0.867, and 0.670, respectively, which suggesting that NE dose had moderate predictive value, but MELD-Na score and fluid infusion had low predicative value. When the optimal cut-off value of NE dose was 6.5 μg×kg-1×h-1, the sensitivity was 84.6% and the specificity was 80.0%. The 28-day mortality was both 0 in early group (n = 25) and delayed group (n = 39). Compared with the early group, the duration of mechanical ventilation (hours: 41.0±1.0 vs. 35.8±6.7) and the length of ICU stay (hours: 98.8±6.6 vs. 94.2±7.3) were significantly increased in delayed group (both P < 0.05), there was no significant difference in AKI duration (days: 11.8±4.2 vs. 10.6±4.9) or the incidence of CRBSI [5.1% (2/39) vs. 4.0% (1/25), both P > 0.05]. CONCLUSIONS MELD-Na score, intraoperative NE dose and fluid infusion were the independent risk factors of RRT implementation in AKI patients after liver transplantation. NE dose had moderate predictive value, but MELD-Na score and fluid infusion had low predicative value. Initial RRT on KDIGO stage-2 could reduce the duration of mechanical ventilation and the length of ICU stay.
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Hedonic Eating and the "Delicious Circle": From Lipid-Derived Mediators to Brain Dopamine and Back.
Coccurello, R, Maccarrone, M
Frontiers in neuroscience. 2018;:271
Abstract
Palatable food can be seductive and hedonic eating can become irresistible beyond hunger and negative consequences. This is witnessed by the subtle equilibrium between eating to provide energy intake for homeostatic functions, and reward-induced overeating. In recent years, considerable efforts have been devoted to study neural circuits, and to identify potential factors responsible for the derangement of homeostatic eating toward hedonic eating and addiction-like feeding behavior. Here, we examined recent literature on "old" and "new" players accountable for reward-induced overeating and possible liability to eating addiction. Thus, the role of midbrain dopamine is positioned at the intersection between selected hormonal signals involved in food reward information processing (namely, leptin, ghrelin, and insulin), and lipid-derived neural mediators such as endocannabinoids. The impact of high fat palatable food and dietary lipids on endocannabinoid formation is reviewed in its pathogenetic potential for the derangement of feeding homeostasis. Next, endocannabinoid signaling that regulates synaptic plasticity is discussed as a key mechanism acting both at hypothalamic and mesolimbic circuits, and affecting both dopamine function and interplay between leptin and ghrelin signaling. Outside the canonical hypothalamic feeding circuits involved in energy homeostasis and the notion of "feeding center," we focused on lateral hypothalamus as neural substrate able to confront food-associated homeostatic information with food salience, motivation to eat, reward-seeking, and development of compulsive eating. Thus, the lateral hypothalamus-ventral tegmental area-nucleus accumbens neural circuitry is reexamined in order to interrogate the functional interplay between ghrelin, dopamine, orexin, and endocannabinoid signaling. We suggested a pivotal role for endocannabinoids in food reward processing within the lateral hypothalamus, and for orexin neurons to integrate endocrine signals with food reinforcement and hedonic eating. In addition, the role played by different stressors in the reinstatement of preference for palatable food and food-seeking behavior is also considered in the light of endocannabinoid production, activation of orexin receptors and disinhibition of dopamine neurons. Finally, type-1 cannabinoid receptor-dependent inhibition of GABA-ergic release and relapse to reward-associated stimuli is linked to ghrelin and orexin signaling in the lateral hypothalamus-ventral tegmental area-nucleus accumbens network to highlight its pathological potential for food addiction-like behavior.
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The Effect of Special Diets on Weight and Nutritional Intake in Hematological Cancer Patients: A Randomized Study.
Bille, SJ, Fjalstad, BW, Clausen, MB, Andreasen, BJ, Andersen, JR
Nutrition and cancer. 2018;(6):874-878
Abstract
Major weight loss and taste changes are well documented in patients with hematological cancer during chemotherapy. We have previously documented, that such patients have preferences for much umami, a little sweet, sour and salt, and no bitter. We wanted to convert these results into real diets. Patients participated in two sensory pilot studies (n = 10), where dishes were tested for preferences before and after chemotherapy. From these results, four dishes were selected and tested on 32 patients in 30 days in a cross-over design. The diets resulted in a beneficial and statistically significant difference in weight development (p = 0.0008), with 1.2 ± 1.9 kg (+2%) in the intervention period and -2.8 ± 5.2 kg (-4%) in the control period. This difference persisted after sensitivity analysis (±10%) P = 0.005. However, the nutritional intake was still low in both periods, and the treatment with cytarabine turned out to be a major confounder as dosage was significantly higher in the control period.
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Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial.
Frias, JP, Nauck, MA, Van, J, Kutner, ME, Cui, X, Benson, C, Urva, S, Gimeno, RE, Milicevic, Z, Robins, D, et al
Lancet (London, England). 2018;(10160):2180-2193
Abstract
BACKGROUND LY3298176 is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that is being developed for the treatment of type 2 diabetes. We aimed to examine the efficacy and safety of co-stimulation of the GLP-1 and GIP receptors with LY3298176 compared with placebo or selective stimulation of GLP-1 receptors with dulaglutide in patients with poorly controlled type 2 diabetes. METHODS In this double-blind, randomised, phase 2 study, patients with type 2 diabetes were randomly assigned (1:1:1:1:1:1) to receive either once-weekly subcutaneous LY3298176 (1 mg, 5 mg, 10 mg, or 15 mg), dulaglutide (1·5 mg), or placebo for 26 weeks. Assignment was stratified by baseline glycated haemoglobin A1c (HbA1c), metformin use, and body-mass index (BMI). Eligible participants (aged 18-75) had type 2 diabetes for at least 6 months (HbA1c 7·0-10·5%, inclusive), that was inadequately controlled with diet and exercise alone or with stable metformin therapy, and a BMI of 23-50 kg/m2. The primary efficacy outcome was change in HbA1c from baseline to 26 weeks in the modified intention-to-treat (mITT) population (all patients who received at least one dose of study drug and had at least one postbaseline measurement of any outcome). Secondary endpoints, measured in the mITT on treatment dataset, were change in HbA1c from baseline to 12 weeks; change in mean bodyweight, fasting plasma glucose, waist circumference, total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides, and proportion of patients reaching the HbA1c target (≤6·5% and <7·0%) from baseline to weeks 12 and 26; and proportion of patients with at least 5% and 10% bodyweight loss from baseline to 26 weeks. This study is registered with ClinicalTrials.gov, number NCT03131687. FINDINGS Between May 24, 2017, and March 28, 2018, 555 participants were assessed for eligibility, of whom 318 were randomly assigned to one of the six treatment groups. Because two participants did not receive treatment, the modified intention-to-treat and safety populations included 316 participants. 258 (81·7%) participants completed 26 weeks of treatment, and 283 (89·6%) completed the study. At baseline, mean age was 57 years (SD 9), BMI was 32·6 kg/m2 (5·9), duration from diagnosis of diabetes was 9 years (6), HbA1c was 8·1% (1·0), 53% of patients were men, and 47% were women. At 26 weeks, the effect of LY3298176 on change in HbA1c was dose-dependent and did not plateau. Mean changes from baseline in HbA1c with LY3298176 were -1·06% for 1 mg, -1·73% for 5 mg, -1·89% for 10 mg, and -1·94% for 15 mg, compared with -0·06% for placebo (posterior mean differences [80% credible set] vs placebo: -1·00% [-1·22 to -0·79] for 1 mg, -1·67% [-1·88 to -1·46] for 5 mg, -1·83% [-2·04 to -1·61] for 10 mg, and -1·89% [-2·11 to -1·67] for 15 mg). Compared with dulaglutide (-1·21%) the posterior mean differences (80% credible set) for change in HbA1c from baseline to 26 weeks with the LY3298176 doses were 0·15% (-0·08 to 0·38) for 1 mg, -0·52% (-0·72 to -0·31) for 5 mg, -0·67% (-0·89 to -0·46) for 10 mg, and -0·73% (-0·95 to -0·52) for 15 mg. At 26 weeks, 33-90% of patients treated with LY3298176 achieved the HbA1c target of less than 7·0% (vs 52% with dulaglutide, 12% with placebo) and 15-82% achieved the HbA1c target of at least 6·5% (vs 39% with dulaglutide, 2% with placebo). Changes in fasting plasma glucose ranged from -0·4 mmol/L to -3·4 mmol/L for LY3298176 (vs 0·9 mmol/L for placebo, -1·2 mmol/L for dulaglutide). Changes in mean bodyweight ranged from -0·9 kg to -11·3 kg for LY3298176 (vs -0·4 kg for placebo, -2·7 kg for dulaglutide). At 26 weeks, 14-71% of those treated with LY3298176 achieved the weight loss target of at least 5% (vs 22% with dulaglutide, 0% with placebo) and 6-39% achieved the weight loss target of at least 10% (vs 9% with dulaglutide, 0% with placebo). Changes in waist circumference ranged from -2·1 cm to -10·2 cm for LY3298176 (vs -1·3 cm for placebo, -2·5 cm for dulaglutide). Changes in total cholesterol ranged from 0·2 mmol/L to -0·3 mmol/L for LY3298176 (vs 0·3 mmol/L for placebo, -0·2 mmol/L for dulaglutide). Changes in HDL or LDL cholesterol did not differ between the LY3298176 and placebo groups. Changes in triglyceride concentration ranged from 0 mmol/L to -0·8 mmol/L for LY3298176 (vs 0·3 mmol/L for placebo, -0·3 mmol/L for dulaglutide). The 12-week outcomes were similar to those at 26 weeks for all secondary outcomes. 13 (4%) of 316 participants across the six treatment groups had 23 serious adverse events in total. Gastrointestinal events (nausea, diarrhoea, and vomiting) were the most common treatment-emergent adverse events. The incidence of gastrointestinal events was dose-related (23·1% for 1 mg LY3298176, 32·7% for 5 mg LY3298176, 51·0% for 10 mg LY3298176, and 66·0% for 15 mg LY3298176, 42·6% for dulaglutide, 9·8% for placebo); most events were mild to moderate in intensity and transient. Decreased appetite was the second most common adverse event (3·8% for 1 mg LY3298176, 20·0% for 5 mg LY3298176, 25·5% for 10 mg LY3298176, 18·9% for 15 mg LY3298176, 5·6% for dulaglutide, 2·0% for placebo). There were no reports of severe hypoglycaemia. One patient in the placebo group died from lung adenocarcinoma stage IV, which was unrelated to study treatment. INTERPRETATION The dual GIP and GLP-1 receptor agonist, LY3298176, showed significantly better efficacy with regard to glucose control and weight loss than did dulaglutide, with an acceptable safety and tolerability profile. Combined GIP and GLP-1 receptor stimulation might offer a new therapeutic option in the treatment of type 2 diabetes. FUNDING Eli Lilly and Company.