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LLF580, an FGF21 Analog, Reduces Triglycerides and Hepatic Fat in Obese Adults With Modest Hypertriglyceridemia.
Rader, DJ, Maratos-Flier, E, Nguyen, A, Hom, D, Ferriere, M, Li, Y, Kompa, J, Martic, M, Hinder, M, Basson, CT, et al
The Journal of clinical endocrinology and metabolism. 2022;(1):e57-e70
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Abstract
PURPOSE To evaluate the safety and potential efficacy of LLF580, a genetically engineered variant of human fibroblast growth factor-21, for triglyceride lowering, weight loss, and hepatic fat reduction. METHODS A multicenter, double-blind, parallel design trial in obese, mildly hypertriglyceridemic adults randomized (1:1) to LLF580 300 mg or placebo subcutaneously every 4 weeks for 3 doses. RESULTS Of 64 randomized study participants, 61 (mean ± SD: age 45 ± 11 years, 49% male, 80/15/5% Caucasian/African American/other, body mass index 36.1 ± 3.8 kg/m2) received LLF580 (n = 30) or placebo (n = 31) at 7 research sites in the United States. LLF580 lowered serum triglycerides by 54% (least square mean placebo adjusted change from baseline), total cholesterol 7%, low-density lipoprotein cholesterol 12%, and increased high-density lipoprotein cholesterol 36% compared with placebo (all P < 0.001) over 12 weeks. Substantial reduction of liver fat of 52% over placebo (P < 0.001) was also demonstrated in the setting of improved liver function tests including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, the composite enhanced liver fibrosis score, and N-terminal type III collagen propeptide (all P < 0.05). Insulin and C-peptide levels and insulin resistance by homeostatic model assessment for insulin resistance were all lower, and adiponectin higher with LLF580 treatment compared with placebo, whereas fasting glucose and glycated hemoglobin were unchanged. Reductions in biomarkers of bone formation without differences in markers of bone resorption were observed. LLF580 was generally safe and well tolerated, except for higher incidence of generally mild to moderate gastrointestinal adverse effects. CONCLUSIONS In obese, mildly hypertriglyceridemic adults, LLF580 was generally safe and demonstrated beneficial effects on serum lipids, liver fat, and biomarkers of liver injury, suggesting it may be effective for treatment of select metabolic disorders including hypertriglyceridemia and nonalcoholic fatty liver disease. Assessments of longer term safety and efficacy are warranted. CLINICALTRIALS.GOV IDENTIFIER NCT03466203.
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Effect of a Multicomponent mHealth Intervention on the Composition of Diet in a Population with Overweight and Obesity-Randomized Clinical Trial EVIDENT 3.
Lugones-Sánchez, C, Recio-Rodríguez, JI, Menéndez-Suárez, M, Saz-Lara, A, Ramirez-Manent, JI, Sánchez-Calavera, MA, Gómez-Sánchez, L, Rodríguez-Sánchez, E, García-Ortiz, L, Evident Investigators Group,
Nutrients. 2022;(2)
Abstract
A balanced diet can help in the prevention of chronic diseases. The aim of this study was to evaluate the effect of an mHealth intervention on the distribution of macronutrients and the intake of food groups. A total of 650 participants were included in this multi-center, clinical, randomized, controlled trial (Evident 3 study). All participants were given brief advice about diet and exercise. The intervention group received, in addition, an app (Evident 3) for the self-recording of their diet and an activity tracker wristband for 3 months. Follow-up visits were performed at 3 and 12 months to collect the diet composition using the Food Frequency Questionnaire. There were decreases in the intake of total calories, fat, protein and carbohydrates in both groups throughout the study, without significant differences between them. The intervention group reduced the intake of cholesterol (-30.8; 95% CI -59.9, -1.7) and full-fat dairies (-23.3; 95% CI -42.8, -3.8) and increased the intake of wholemeal bread (3.3; 95% CI -6.7, 13.3) and whole-grain cereals (3.4; 95% CI -6.8, 13.7) with respect to the control group. No differences were found in the rest of the nutritional parameters. The brief advice is useful to promote a healthier diet, and the app can be a support tool to obtain changes in relevant foods, such as integral foods, and the intake of cholesterol. Trial registration: ClinicalTrials.gov with identifier NCT03175614.
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Duodenal-Jejunal Bypass Liner for the management of Type 2 Diabetes Mellitus and Obesity: A Multicenter Randomized Controlled Trial.
Ruban, A, Miras, AD, Glaysher, MA, Goldstone, AP, Prechtl, CG, Johnson, N, Chhina, N, Al-Najim, W, Aldhwayan, M, Klimowska-Nassar, N, et al
Annals of surgery. 2022;(3):440-447
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Abstract
OBJECTIVE The aim of this study was to examine the clinical efficacy and safety of the duodenal-jejunal bypass liner (DJBL) while in situ for 12 months and for 12 months after explantation. SUMMARY BACKGROUND DATA This is the largest randomized controlled trial (RCT) of the DJBL, a medical device used for the treatment of people with type 2 diabetes mellitus (T2DM) and obesity. Endoscopic interventions have been developed as potential alternatives to those not eligible or fearful of the risks of metabolic surgery. METHODS In this multicenter open-label RCT, 170 adults with inadequately controlled T2DM and obesity were randomized to intensive medical care with or without the DJBL. Primary outcome was the percentage of participants achieving a glycated hemoglobin reduction of ≥20% at 12 months. Secondary outcomes included weight loss and cardiometabolic risk factors at 12 and 24 months. RESULTS There were no significant differences in the percentage of patients achieving the primary outcome between both groups at 12 months [DJBL 54.6% (n = 30) vs control 55.2% (n = 32); odds ratio (OR) 0.93, 95% confidence interval (CI): 0.44-2.0; P = 0.85]. Twenty-four percent (n = 16) patients achieved ≥15% weight loss in the DJBL group compared to 4% (n = 2) in the controls at 12 months (OR 8.3, 95% CI: 1.8-39; P = .007). The DJBL group experienced superior reductions in systolic blood pressure, serum cholesterol, and alanine transaminase at 12 months. There were more adverse events in the DJBL group. CONCLUSIONS The addition of the DJBL to intensive medical care was associated with superior weight loss, improvements in cardiometabolic risk factors, and fatty liver disease markers, but not glycemia, only while the device was in situ. The benefits of the devices need to be balanced against the higher rate of adverse events when making clinical decisions. TRIAL REGISTRATION ISRCTN30845205. isrctn.org; Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership reference 12/10/04.
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Relationship Between Obesity and Ventilator-Associated Pneumonia: A Post Hoc Analysis of the NUTRIREA2 Trial.
Nseir, S, Le Gouge, A, Pouly, O, Lascarrou, JB, Lacherade, JC, Mira, JP, Mercier, E, Declercq, PL, Sirodot, M, Piton, G, et al
Chest. 2021;(6):2309-2317
Abstract
BACKGROUND Patients with obesity are at higher risk for community-acquired and nosocomial infections. However, no study has specifically evaluated the relationship between obesity and ventilator-associated pneumonia (VAP). RESEARCH QUESTION Is obesity associated with an increased incidence of VAP? STUDY DESIGN AND METHODS This study was a post hoc analysis of the Impact of Early Enteral vs Parenteral Nutrition on Mortality in Patients Requiring Mechanical Ventilation and Catecholamines (NUTRIREA2) open-label, randomized controlled trial performed in 44 French ICUs. Adults receiving invasive mechanical ventilation and vasopressor support for shock and parenteral nutrition or enteral nutrition were included. Obesity was defined as BMI ≥ 30 kg/m2 at ICU admission. VAP diagnosis was adjudicated by an independent blinded committee, based on all available clinical, radiologic, and microbiologic data. Only first VAP episodes were taken into account. Incidence of VAP was analyzed by using the Fine and Gray model, with extubation and death as competing risks. RESULTS A total of 699 (30%) of the 2,325 included patients had obesity; 224 first VAP episodes were diagnosed (60 and 164 in obese and nonobese groups, respectively). The incidence of VAP at day 28 was 8.6% vs 10.1% in the two groups (hazard ratio, 0.85; 95% CI 0.63-1.14; P = .26). After adjustment on sex, McCabe score, age, antiulcer treatment, and Sequential Organ Failure Assessment at randomization, the incidence of VAP remained nonsignificant between obese and nonobese patients (hazard ratio, 0.893; 95% CI, 0.66-1.2; P = .46). Although no significant difference was found in duration of mechanical ventilation and ICU length of stay, 90-day mortality was significantly lower in obese than in nonobese patients (272 of 692 [39.3%] patients vs 718 of 1,605 [44.7%]; P = .02). In a subgroup of patients (n = 123) with available pepsin and alpha-amylase measurements, no significant difference was found in rate of abundant microaspiration of gastric contents, or oropharyngeal secretions between obese and nonobese patients. INTERPRETATION Our results suggest that obesity has no significant impact on the incidence of VAP.
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The association between vitamin D receptor polymorphisms and tissue-specific insulin resistance in human obesity.
Pramono, A, Jocken, JWE, Adriaens, ME, Hjorth, MF, Astrup, A, Saris, WHM, Blaak, EE
International journal of obesity (2005). 2021;(4):818-827
Abstract
BACKGROUND/OBJECTIVES To investigate (1) the association of four VDR polymorphisms (TaqI/rs731236, ApaI/rs7975232, FokI/rs10735810, and Bsml/rs1544410) with markers of adiposity and tissue-specific insulin resistance at baseline, after weight loss and weight maintenance; (2) the effect of the VDR polymorphisms in the SAT transcriptome in overweight/obese Caucasians of the DiOGenes cohort. METHODS We included 553 adult obese individuals (mean BMI 34.8 kg/m2), men (n = 197) and women (n = 356) at baseline, following an 8-week weight loss intervention and 26 weeks weight maintenance. Genotyping was performed using an Illumina 660W-Quad SNP chip on the Illumina iScan Genotyping System. Tissue-specific IR was determined using Hepatic Insulin Resistance Index (HIRI), Muscle Insulin Sensitivity Index (MISI), and Adipose Tissue Insulin Resistance Index (Adipo-IR). Expression quantitative trait loci (eQTL) analysis was performed to determine the effect of SNPs on SAT gene expression. RESULTS None of the VDR polymorphisms were associated with HIRI or MISI. Interestingly, carriers of the G allele of VDR FokI showed higher Adipo-IR (GG + GA 7.8 ± 0.4 vs. AA 5.6 ± 0.5, P = 0.010) and higher systemic FFA (GG + GA: 637.8 ± 13.4 vs. AA: 547.9 ± 24.7 µmol/L, P = 0.011), even after adjustment with age, sex, center, and FM. However, eQTL analysis showed minor to no effect of these genotypes on the transcriptional level in SAT. Also, VDR polymorphisms were not related to changes in body weight and IR as result of dietary intervention (P > 0.05 for all parameters). CONCLUSIONS The VDR Fokl variant is associated with elevated circulating FFA and Adipo-IR at baseline. Nevertheless, minor to no effect of VDR SNPs on the transcriptional level in SAT, indicating that putative mechanisms of action remain to be determined. Finally, VDR SNPs did not affect dietary intervention outcome in the present cohort.
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Food Insecurity and Weight Loss in an Underserved Primary Care Population: A Post Hoc Analysis of a Cluster Randomized Trial.
Myers, CA, Martin, CK, Apolzan, JW, Arnold, CL, Davis, TC, Johnson, WD, Katzmarzyk, PT, ,
Annals of internal medicine. 2021;(7):1032-1034
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Metabolic, Affective and Neurocognitive Characterization of Metabolic Syndrome Patients with and without Food Addiction. Implications for Weight Progression.
Camacho-Barcia, L, Munguía, L, Lucas, I, de la Torre, R, Salas-Salvadó, J, Pintó, X, Corella, D, Granero, R, Jiménez-Murcia, S, González-Monje, I, et al
Nutrients. 2021;(8)
Abstract
According to the food addiction (FA) model, the consumption of certain types of food could be potentially addictive and can lead to changes in intake regulation. We aimed to describe metabolic parameters, dietary characteristics, and affective and neurocognitive vulnerabilities of individuals with and without FA, and to explore its influences on weight loss progression. The sample included 448 adults (55-75 years) with overweight/obesity and metabolic syndrome from the PREDIMED-Plus cognition sub-study. Cognitive and psychopathological assessments, as well as dietary, biochemical, and metabolic measurements, were assessed at baseline. Weight progression was evaluated after a 3-year follow up. The presence of FA was associated with higher depressive symptomatology, neurocognitive decline, low quality of life, high body mass index (BMI), and high waist circumference, but not with metabolic comorbidities. No differences were observed in the dietary characteristics except for the saturated and monounsaturated fatty acids consumption. After three years, the presence of FA at baseline resulted in a significantly higher weight regain. FA is associated with worse psychological and neurocognitive state and higher weight regain in adults with metabolic syndrome. This condition could be an indicator of bad prognosis in the search for a successful weight loss process.
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Adjustable intragastric balloon for treatment of obesity: a multicentre, open-label, randomised clinical trial.
Abu Dayyeh, BK, Maselli, DB, Rapaka, B, Lavin, T, Noar, M, Hussan, H, Chapman, CG, Popov, V, Jirapinyo, P, Acosta, A, et al
Lancet (London, England). 2021;(10315):1965-1973
Abstract
BACKGROUND Intragastric balloons are anatomy-preserving, minimally invasive obesity therapies. Enhanced tolerance and durability could help broaden clinical adoption. We investigated the safety and efficacy of an adjustable intragastric balloon (aIGB) in adults with obesity. METHODS In this prospective, multicentre, open-label, randomised clinical trial done at seven US sites, adults aged 22-65 years with obesity were randomly assigned (2:1) to aIGB with lifestyle intervention or lifestyle intervention alone (control) for 32 weeks. Balloon volume could be increased to facilitate weight loss or decreased for tolerability. Coprimary endpoints included mean percentage total bodyweight loss and responder rate (≥5% total bodyweight loss) at 32 weeks. We used a multiple imputed intention-to-treat population analysis. This study was registered with ClinicalTrials.gov, NCT02812160. FINDINGS Between Aug 9, 2016, and Dec 7, 2018, we randomly assigned 288 patients to aIGB (n=187 [65%]) or control (n=101 [35%]) groups. Mean total bodyweight loss at 32 weeks was 15·0% (95% CI 13·9-16·1) in the aIGB group versus 3·3% (2·0-4·6) in the control group (p<0·0001). Clinical response was observed in 171 (92%) patients in the aIGB group. Adjustments to the aIGB occurred in 145 (80%) patients for weight loss plateau or intolerance. Upward volume adjustment facilitated an additional mean 5·2% (4·5-5·8) total bodyweight loss. Downward volume adjustment allowed 21 (75%) patients in the aIGB group to complete the full duration of therapy. Intolerance caused early removal of the device in 31 (17%) patients. No micronutrient deficiencies were observed in the aIGB cohort. Device-related serious adverse events were observed in seven (4%) patients, without any deaths. INTERPRETATION When aIGB was combined with lifestyle modification, significant weight loss was achieved and maintained for 6 months following removal. Balloon volume adjustability permitted individualised therapy, maximising weight loss and tolerance. FUNDING Spatz Medical.
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Effect of Behavioral Therapy With In-Clinic or Telephone Group Visits vs In-Clinic Individual Visits on Weight Loss Among Patients With Obesity in Rural Clinical Practice: A Randomized Clinical Trial.
Befort, CA, VanWormer, JJ, Desouza, C, Ellerbeck, EF, Gajewski, B, Kimminau, KS, Greiner, KA, Perri, MG, Brown, AR, Pathak, RD, et al
JAMA. 2021;(4):363-372
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Abstract
IMPORTANCE Rural populations have a higher prevalence of obesity and poor access to weight loss programs. Effective models for treating obesity in rural clinical practice are needed. OBJECTIVE To compare the Medicare Intensive Behavioral Therapy for Obesity fee-for-service model with 2 alternatives: in-clinic group visits based on a patient-centered medical home model and telephone-based group visits based on a disease management model. DESIGN, SETTING, AND PARTICIPANTS Cluster randomized trial conducted in 36 primary care practices in the rural Midwestern US. Inclusion criteria included age 20 to 75 years and body mass index of 30 to 45. Participants were enrolled from February 2016 to October 2017. Final follow-up occurred in December 2019. INTERVENTIONS All participants received a lifestyle intervention focused on diet, physical activity, and behavior change strategies. In the fee-for-service intervention (n = 473), practice-employed clinicians provided 15-minute in-clinic individual visits at a frequency similar to that reimbursed by Medicare (weekly for 1 month, biweekly for 5 months, and monthly thereafter). In the in-clinic group intervention (n = 468), practice-employed clinicians delivered group visits that were weekly for 3 months, biweekly for 3 months, and monthly thereafter. In the telephone group intervention (n = 466), patients received the same intervention as the in-clinic group intervention, but sessions were delivered remotely via conference calls by centralized staff. MAIN OUTCOMES AND MEASURES The primary outcome was weight change at 24 months. A minimum clinically important difference was defined as 2.75 kg. RESULTS Among 1407 participants (mean age, 54.7 [SD, 11.8] years; baseline body mass index, 36.7 [SD, 4.0]; 1081 [77%] women), 1220 (87%) completed the trial. Mean weight loss at 24 months was -4.4 kg (95% CI, -5.5 to -3.4 kg) in the in-clinic group intervention, -3.9 kg (95% CI, -5.0 to -2.9 kg) in the telephone group intervention, and -2.6 kg (95% CI, -3.6 to -1.5 kg) in the in-clinic individual intervention. Compared with the in-clinic individual intervention, the mean difference in weight change was -1.9 kg (97.5% CI, -3.5 to -0.2 kg; P = .01) for the in-clinic group intervention and -1.4 kg (97.5% CI, -3.0 to 0.3 kg; P = .06) for the telephone group intervention. CONCLUSIONS AND RELEVANCE Among patients with obesity in rural primary care clinics, in-clinic group visits but not telephone-based group visits, compared with in-clinic individual visits, resulted in statistically significantly greater weight loss at 24 months. However, the differences were small in magnitude and of uncertain clinical importance. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02456636.
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Effectiveness of liraglutide 3 mg for the treatment of obesity in a real-world setting without intensive lifestyle intervention.
Park, JH, Kim, JY, Choi, JH, Park, HS, Shin, HY, Lee, JM, Kim, JW, Ko, HJ, Chon, S, Kim, BK, et al
International journal of obesity (2005). 2021;(4):776-786
Abstract
OBJECTIVE We investigated the efficacy and safety of liraglutide 3 mg daily in combination with diet and exercise 2, 4, and 6 months after initiation in real-world settings in Korea. METHODS People first using liraglutide starting in 2018 were recruited from ten sites in Korea. Body weight and body mass index (BMI) were measured after 2, 4, and 6 months and compared with baseline values. RESULTS The full cohort comprised 769 participants: 672 in the 2-month group, 427 in the 4-month group, and 219 in the 6-month group. The baseline mean ± standard deviation of BMI and body weight were 32.2 ± 5.1 kg/m2, and 87.5 ± 18.8 kg, respectively. Body weight and BMI decreased after initiation of liraglutide treatment: -2.94 kg and -1.08 kg/m2 at 2 months; -4.23 kg and -1.55 kg/m2 at 4 months, and -5.14 kg and -1.89 kg/m2 at 6 months (all P < 0.001). In the 6-month cohort, 52.5% and 18.3% of subjects lost ≥5% and ≥10% of body weight, respectively. After 6 months, systolic and diastolic blood pressure decreased significantly by 3.90 and 1.93 mmHg, respectively. In those with diabetes mellitus, HbA1c and fasting glucose levels decreased significantly by 1.14% and 27.8 mg/dl, respectively. Among all participants, 27.6% experienced adverse effects, including nausea (20.8%), vomiting (5.2%), diarrhoea (2.5%), and skin rash (3.6%). Documented reasons for discontinuation of treatment were lack of effect (4.4%), adverse events (4.3%), and high cost (3.1%). CONCLUSIONS In real-world settings in Korea, daily treatment with liraglutide 3 mg was associated with clinically meaningful weight loss without serious adverse events.