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.
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.
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.
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.
Eli Lilly and Company.
Prevailing recommendations on reporting weight loss after bariatric and metabolic surgery are not evidence-based. They promote the outcome metric percentage excess weight loss (%EWL), sometimes ...indicated as percentage excess body mass index loss (%EBMIL). Many studies proved that this popular outcome measure, in contrast to other weight loss metrics, is inaccurate and error-sensitive when comparing weight loss within and between studies. It is inappropriate for assessing poor weight loss response and weight regain as well. The percentage (total) weight loss metric is the best alternative. The Dutch Society for Metabolic and Bariatric Surgery (DSMBS) recommends to stop using the %EWL (or %EBMIL) metric as primary outcome measure in all cases and calls on the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) to propagate this evidence-based recommendation.
Graphical Abstract
Obesity is the primary risk factor for obstructive sleep apnea (OSA). Tongue fat is increased in obese persons with OSA, and may explain the relationship between obesity and OSA. Weight loss improves ...OSA, but the mechanism is unknown.
To determine the effect of weight loss on upper airway anatomy in subjects with obesity and OSA. We hypothesized that weight loss would decrease soft tissue volumes and tongue fat, and that these changes would correlate with reductions in apnea-hypopnea index (AHI).
A total of 67 individuals with obesity and OSA (AHI ≥ 10 events/h) underwent a sleep study and upper airway and abdominal magnetic resonance imaging before and after a weight loss intervention (intensive lifestyle modification or bariatric surgery). Airway sizes and soft tissue, tongue fat, and abdominal fat volumes were quantified. Associations between weight loss and changes in these structures, and relationships to AHI changes, were examined.
Weight loss was significantly associated with reductions in tongue fat and pterygoid and total lateral wall volumes. Reductions in tongue fat were strongly correlated with reductions in AHI (Pearson's rho = 0.62,
< 0.0001); results remained after controlling for weight loss (Pearson's rho = 0.36,
= 0.014). Reduction in tongue fat volume was the primary upper airway mediator of the relationship between weight loss and AHI improvement.
Weight loss reduced volumes of several upper airway soft tissues in subjects with obesity and OSA. Improved AHI with weight loss was mediated by reductions in tongue fat. New treatments that reduce tongue fat should be considered for patients with OSA.
IMPORTANCE: Laparoscopic sleeve gastrectomy for treatment of morbid obesity has increased substantially despite the lack of long-term results compared with laparoscopic Roux-en-Y gastric bypass. ...OBJECTIVE: To determine whether laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass are equivalent for weight loss at 5 years in patients with morbid obesity. DESIGN, SETTING, AND PARTICIPANTS: The Sleeve vs Bypass (SLEEVEPASS) multicenter, multisurgeon, open-label, randomized clinical equivalence trial was conducted from March 2008 until June 2010 in Finland. The trial enrolled 240 morbidly obese patients aged 18 to 60 years, who were randomly assigned to sleeve gastrectomy or gastric bypass with a 5-year follow-up period (last follow-up, October 14, 2015). INTERVENTIONS: Laparoscopic sleeve gastrectomy (n = 121) or laparoscopic Roux-en-Y gastric bypass (n = 119). MAIN OUTCOMES AND MEASURES: The primary end point was weight loss evaluated by percentage excess weight loss. Prespecified equivalence margins for the clinical significance of weight loss differences between gastric bypass and sleeve gastrectomy were −9% to +9% excess weight loss. Secondary end points included resolution of comorbidities, improvement of quality of life (QOL), all adverse events (overall morbidity), and mortality. RESULTS: Among 240 patients randomized (mean age, 48 SD, 9 years; mean baseline body mass index, 45.9, SD, 6.0; 69.6% women), 80.4% completed the 5-year follow-up. At baseline, 42.1% had type 2 diabetes, 34.6% dyslipidemia, and 70.8% hypertension. The estimated mean percentage excess weight loss at 5 years was 49% (95% CI, 45%-52%) after sleeve gastrectomy and 57% (95% CI, 53%-61%) after gastric bypass (difference, 8.2 percentage units 95% CI, 3.2%-13.2%, higher in the gastric bypass group) and did not meet criteria for equivalence. Complete or partial remission of type 2 diabetes was seen in 37% (n = 15/41) after sleeve gastrectomy and in 45% (n = 18/40) after gastric bypass (P > .99). Medication for dyslipidemia was discontinued in 47% (n = 14/30) after sleeve gastrectomy and 60% (n = 24/40) after gastric bypass (P = .15) and for hypertension in 29% (n = 20/68) and 51% (n = 37/73) (P = .02), respectively. There was no statistically significant difference in QOL between groups (P = .85) and no treatment-related mortality. At 5 years the overall morbidity rate was 19% (n = 23) for sleeve gastrectomy and 26% (n = 31) for gastric bypass (P = .19). CONCLUSIONS AND RELEVANCE: Among patients with morbid obesity, use of laparoscopic sleeve gastrectomy compared with use of laparoscopic Roux-en-Y gastric bypass did not meet criteria for equivalence in terms of percentage excess weight loss at 5 years. Although gastric bypass compared with sleeve gastrectomy was associated with greater percentage excess weight loss at 5 years, the difference was not statistically significant, based on the prespecified equivalence margins. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00793143
Summary
Quantitative information is scarce in current obesity medication guidelines, and they do not clearly reflect the differences in the efficacy characteristics among various drugs. This study ...quantitatively assessed the efficacy characteristics of five FDA‐approved long‐term weight loss drugs. Potentially eligible studies were obtained from public databases. Using the differences in the weight change from baseline between the drug group and the corresponding placebo group as the major indicator of efficacy, a time‐effect model was established, and crucial pharmacodynamic parameters, such as the maximal efficacy, drug onset time and rate of body weight regain after the maximal efficacy point, were used to reflect the differences in efficacy among the five drugs. Finally, 50 reports (involving 43,443 participants) were included. After deducting the placebo effects, the maximal efficacies (95% CI) of orlistat (120 mg), lorcaserin, naltrexone–bupropion, phentermine–topiramate (PT, 7.5/46 mg) and liraglutide were −2.94 (−5.82, −1.27), −3.06 (−4.39, −1.71), −6.15 (−9.78, −3.25), −7.45 (−9.76, −3.88) and −5.50 (−10.62, −2.97) kg at weeks 60, 54, 67, 59 and 65 respectively, and their rates of body weight regain were 0.51, 0.48, 0.91, 1.27and 0.43 kg per year respectively. The 1‐year dropout rates of orlistat, lorcaserin, naltrexone‐bupropion, PT and liraglutide were 29.0, 40.9, 49.1, 34.9 and 24.3% respectively. In addition, a significant dose–effect correlation was observed for orlistat and PT. This study provides valid quantitative information for medication guidelines.
Obesity is a major public health issue, and new pharmaceuticals for weight management are needed. Therefore, we evaluated the efficacy and safety of the glucagon-like peptide-1 (GLP-1) analogue ...semaglutide in comparison with liraglutide and a placebo in promoting weight loss.
We did a randomised, double-blind, placebo and active controlled, multicentre, dose-ranging, phase 2 trial. The study was done in eight countries involving 71 clinical sites. Eligible participants were adults (≥18 years) without diabetes and with a body-mass index (BMI) of 30 kg/m2 or more. We randomly assigned participants (6:1) to each active treatment group (ie, semaglutide 0·05 mg, 0·1 mg, 0·2 mg, 0·3 mg, or 0·4 mg; initiated at 0·05 mg per day and incrementally escalated every 4 weeks or liraglutide 3·0 mg; initiated at 0·6 mg per day and escalated by 0·6 mg per week) or matching placebo group (equal injection volume and escalation schedule to active treatment group) using a block size of 56. All treatment doses were delivered once-daily via subcutaneous injections. Participants and investigators were masked to the assigned study treatment but not the target dose. The primary endpoint was percentage weight loss at week 52. The primary analysis was done using intention-to-treat ANCOVA estimation with missing data derived from the placebo pool. This study is registered with ClinicalTrials.gov, number NCT02453711.
Between Oct 1, 2015, and Feb 11, 2016, 957 individuals were randomly assigned (102–103 participants per active treatment group and 136 in the pooled placebo group). Mean baseline characteristics included age 47 years, bodyweight 111·5 kg, and BMI 39·3 kg/m2. Bodyweight data were available for 891 (93%) of 957 participants at week 52. Estimated mean weight loss was −2·3% for the placebo group versus −6·0% (0·05 mg), −8·6% (0·1 mg), −11·6% (0·2 mg), −11·2% (0·3 mg), and −13·8% (0·4 mg) for the semaglutide groups. All semaglutide groups versus placebo were significant (unadjusted p≤0·0010), and remained significant after adjustment for multiple testing (p≤0·0055). Mean bodyweight reductions for 0·2 mg or more of semaglutide versus liraglutide were all significant (−13·8% to −11·2% vs −7·8%). Estimated weight loss of 10% or more occurred in 10% of participants receiving placebo compared with 37–65% receiving 0·1 mg or more of semaglutide (p<0·0001 vs placebo). All semaglutide doses were generally well tolerated, with no new safety concerns. The most common adverse events were dose-related gastrointestinal symptoms, primarily nausea, as seen previously with GLP-1 receptor agonists.
In combination with dietary and physical activity counselling, semaglutide was well tolerated over 52 weeks and showed clinically relevant weight loss compared with placebo at all doses.
Novo Nordisk A/S.
Summary
Background
Discerning the determinants of weight loss maintenance is important in the planning of future interventions and policies regarding overweight and obesity. We have therefore ...systematically synthesized recent literature on determinants of weight loss maintenance for individuals with overweight and obesity.
Methods
With the use of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses statement, prospective studies were identified from searches in PubMed and PsycINFO from 2006 to 2016. We included articles investigating adults with overweight and obesity undergoing weight loss without surgery or medication. Included articles were scored on their methodological quality, and a best‐evidence synthesis was applied to summarize the results.
Results
Our search resulted in 8,222 articles of which 67 articles were selected. In total, 124 determinants were identified of which 5 were demographic, 59 were behavioural, 51 were psychological/cognitive and 9 were social and physical environmental determinants. We found consistent evidence that demographic determinants were not predictive of weight loss maintenance. Behavioural and cognitive determinants that promote a reduction in energy intake, an increase in energy expenditure and monitoring of this balance are predictive determinants.
Conclusion
This review identifies key determinants in weight loss maintenance. However, more research regarding cognitive and environmental determinants of weight loss maintenance is needed to advance our knowledge on determinants of weight loss maintenance.
Abstract
Context
Mitochondria are essential for cellular energy homeostasis, yet their role in subcutaneous adipose tissue (SAT) during different types of weight-loss interventions remains unknown.
...Objective
To investigate how SAT mitochondria change following diet-induced and bariatric surgery–induced weight-loss interventions in 4 independent weight-loss studies.
Methods
The DiOGenes study is a European multicenter dietary intervention with an 8-week low caloric diet (LCD; 800 kcal/d; n = 261) and 6-month weight-maintenance (n = 121) period. The Kuopio Obesity Surgery study (KOBS) is a Roux-en-Y gastric bypass (RYGB) surgery study (n = 172) with a 1-year follow-up. We associated weight-loss percentage with global and 2210 mitochondria-related RNA transcripts in linear regression analysis adjusted for age and sex. We repeated these analyses in 2 studies. The Finnish CRYO study has a 6-week LCD (800-1000 kcal/d; n = 19) and a 10.5-month follow-up. The Swedish DEOSH study is a RYGB surgery study with a 2-year (n = 49) and 5-year (n = 37) follow-up.
Results
Diet-induced weight loss led to a significant transcriptional downregulation of oxidative phosphorylation (DiOGenes; ingenuity pathway analysis IPA z-scores: −8.7 following LCD, −4.4 following weight maintenance; CRYO: IPA z-score: −5.6, all P < 0.001), while upregulation followed surgery-induced weight loss (KOBS: IPA z-score: 1.8, P < 0.001; in DEOSH: IPA z-scores: 4.0 following 2 years, 0.0 following 5 years). We confirmed an upregulated oxidative phosphorylation at the proteomics level following surgery (IPA z-score: 3.2, P < 0.001).
Conclusions
Differentially regulated SAT mitochondria-related gene expressions suggest qualitative alterations between weight-loss interventions, providing insights into the potential molecular mechanistic targets for weight-loss success.
Growth/differentiation factor 15 (GDF15), also known as MIC-1, is a distant member of the transforming growth factor-β (TGF-β) superfamily and has been implicated in various biological functions, ...including cancer cachexia, renal and heart failure, atherosclerosis and metabolism. A connection between GDF15 and body-weight regulation was initially suggested on the basis of an observation that increasing GDF15 levels in serum correlated with weight loss in individuals with advanced prostate cancer. In animal models, overexpression of GDF15 leads to a lean phenotype, hypophagia and other improvements in metabolic parameters, suggesting that recombinant GDF15 protein could potentially be used in the treatment of obesity and type 2 diabetes. However, the signaling and mechanism of action of GDF15 are poorly understood owing to the absence of a clearly identified cognate receptor. Here we report that GDNF-family receptor α-like (GFRAL), an orphan member of the GFR-α family, is a high-affinity receptor for GDF15. GFRAL binds to GDF15 in vitro and is required for the metabolic actions of GDF15 with respect to body weight and food intake in vivo in mice. Gfral
mice were refractory to the effects of recombinant human GDF15 on body-weight, food-intake and glucose parameters. Blocking the interaction between GDF15 and GFRAL with a monoclonal antibody prevented the metabolic effects of GDF15 in rats. Gfral mRNA is highly expressed in the area postrema of mouse, rat and monkey, in accordance with previous reports implicating this region of the brain in the metabolic actions of GDF15 (refs. 4,5,6). Together, our data demonstrate that GFRAL is a receptor for GDF15 that mediates the metabolic effects of GDF15.
Unintentional weight loss is a common clinical problem with a broad differential diagnosis that is clinically important because of the associated risks of morbidity and mortality. Community-dwelling ...adults are often diagnosed with malignancy, nonmalignant gastrointestinal disorders, and psychiatric disorders as the cause of unintentional weight loss, whereas institutionalized older adults are diagnosed most often with psychiatric disorders. Up to a quarter of patients do not have a diagnosis after comprehensive workup, and close follow-up is warranted. Treatment involves management of underlying causes.
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