Pantothenic acid plays an important role in reducing body weight

Introduction and Objective: Time to treatment target is a consideration in clinical decision making. Additionally, greater magnitudes of sustained body weight (BW) reduction are shown to provide added health benefits. In SURMOUNT-5, once weekly tirzepatide (TZP) at the maximum tolerated dose (MTD) (10/15mg) resulted in significantly greater BW reduction vs semaglutide (SEMA) MTD (1.7/2.4mg) in adults living with obesity. This post hoc analysis assessed time to reach BW reduction thresholds and continuous time spent in BW control with TZP vs SEMA in SURMOUNT-5. Methods: Participants randomized (1:1) to receive TZP MTD (N=374) or SEMA MTD (N=376) and with an on-treatment BW measurement at week 72 were included in analysis. Among participants achieving BW reduction thresholds (≥5%, ≥10%, ≥15%, ≥20%, ≥25%, ≥30%) at week 72, time to first reaching thresholds and continuous time spent at each threshold was descriptively analyzed. Sustained BW reduction was defined as achieving BW reduction threshold at a postbaseline visit and at all subsequent visits (±3%) up to week 72. Results: At week 72, time to reach thresholds was shorter with TZP vs SEMA except ≥25%, which was similar (median weeks: 8 vs 12 for ≥5%, 16 vs 20 for ≥10%, 24 vs 36 for ≥15%, 36 vs 48 for ≥20%, 48 vs 48 for ≥25%, and 48 vs 52 for ≥30%). Of the participants who achieved and sustained the defined thresholds during the 72-week trial, median duration in weeks of sustained BW reduction was longer with TZP vs SEMA: 64 vs 60 for ≥5%, 56 vs 52 for ≥10%, 48 vs 36 for ≥15%, 36 vs 25 for ≥20%, 25 vs 24 for ≥25%, and 24 vs 21 for ≥30%. Conclusion: In this post hoc analysis, participants in the TZP arm reached clinically meaningful BW reduction sooner vs SEMA in adults living with obesity. For participants who achieved BW reduction thresholds during the 72-week trial, both treatment groups had sustained BW reduction. ​Additional studies are needed to further assess sustainability of BW reduction and its clinical impact​. Disclosure D.B. Horn: Consultant; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Research Support; Eli Lilly and Company. Consultant; Amgen Inc. Advisory Panel; Novo Nordisk. Consultant; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Research Support; Novo Nordisk. L.J. Aronne: Consultant; Novo Nordisk. Research Support; Novo Nordisk. Consultant; Lilly USA LLC. Research Support; Lilly USA LLC. J.P. Dunn: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. H.T. Hoffmann: Employee; Eli Lilly and Company. B.L. Falcon: Employee; Eli Lilly and Company. D. Cao: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. C. Lee: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company

Objective: In addition to achieving glycemic control, weight loss and blood pressure (BP) reduction are important components of type 2 diabetes mellitus (T2DM) management, as many patients with T2DM are overweight/obese and/or have hypertension. Canagliflozin, an SGLT2 inhibitor, has demonstrated improvements in HbA1c, body weight (BW), and systolic BP across a broad range of patients with T2DM. This analysis evaluated achievement of composite endpoints of HbA1c, BW, and systolic BP targets with canagliflozin versus placebo.Methods: This post hoc analysis evaluated the proportion of T2DM patients achieving the composite endpoint of HbA1c reduction ≥0.5%, BW reduction ≥3%, and systolic BP reduction ≥4mmHg with canagliflozin 100 and 300mg compared with placebo using pooled data from four 26-week, phase 3 studies (N = 2313; NCT01081834, NCT01106677, NCT01106625, NCT01106690). The proportion of patients achieving the composite endpoint of HbA1c <7.0%, BW reduction ≥3%, and BP <130/80 mmHg was also evaluated.Results: At week 26, greater proportions of patients met individual HbA1c, BW, and systolic BP targets with canagliflozin versus placebo. A greater proportion of patients treated with canagliflozin 100 or 300 mg versus placebo also achieved the composite endpoint of HbA1c reduction ≥0.5%, BW reduction ≥3%, and systolic BP reduction ≥4 mmHg at week 26 (21.1%, 25.3%, and 5.7%, respectively; odds ratios [95% CI] of 4.5 [3.1, 6.5] and 5.6 [3.8, 8.2]). A greater proportion of patients also achieved the composite endpoint of HbA1c <7.0%, BW reduction ≥3%, and BP <130/80 mmHg with canagliflozin 100 and 300 mg versus placebo (14.7%, 20.9%, and 3.3%, respectively; odds ratios [95% CI] of 5.2 [3.2, 8.4] and 8.4 [5.2, 13.5]). Canagliflozin was generally well tolerated, with a safety profile similar to that seen in other phase 3 studies.Conclusions: Patients with T2DM were more likely to achieve clinically important reductions in HbA1c, BW, and systolic BP with canagliflozin versus placebo.

Treatment with tirzepatide (TZP) led to substantial improvements in body weight (BW) and glycemia compared to placebo in participants with obesity and type 2 diabetes (T2D) in SURMOUNT (SM)-2. In this analysis, we assessed whether baseline markers of pancreatic beta cell function and insulin sensitivity were associated with the magnitudes of BW and glycemic reductions. Post hoc analyses examined changes from baseline in BW and HbA1c in SM-2 at 72 weeks across HOMA2-B (computed with C-peptide) and HOMA2-IR (computed with insulin) quartiles (Q) from low (lower beta cell function/insulin resistance) (Q1) to high (Q4) as assessed by a mixed model for repeated measures using efficacy estimand. BW and HbA1c reductions were greater with TZP 10 mg and 15 mg than placebo within each HOMA2-B and HOMA2-IR baseline Q. More participants across all Qs achieved ≥15% BW reduction with TZP (36-63%) than placebo (up to 4%). More participants across all Qs reached HbA1c &amp;lt;5.7% with TZP (ranging from 42-71%) than placebo (up to 6%). TZP was more effective than placebo in reducing BW and HbA1c regardless of beta cell function and insulin resistance in participants with obesity and T2D. BW reductions with TZP trended greater with higher beta cell function, whereas HbA1c reduction trended greater with lower beta cell function. Disclosure T. Heise: Research Support; ADOCIA, AstraZeneca, Biocon, Crinetics Pharmaceuticals, Inc., Eli Lilly and Company, Genova, Novo Nordisk A/S. Consultant; Gan&amp;Lee Pharmaceuticals. Speaker's Bureau; Eli Lilly and Company. Research Support; Altimmune Inc., Sanofi, Zealand Pharma A/S, BIOTON, Civica Foundation, Enyo Pharma, Gan&amp;Lee Pharmaceuticals, Nanexa AB, SamChunDang Pharm. Co. H. Wang: None. C.J. Mast: Employee; Eli Lilly and Company. I. Benabbad: Employee; Eli Lilly and Company. C. Lee: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. B. Liao: Employee; Eli Lilly and Company.

To identify predictors of body weight (BW) reduction of ≥15% with tirzepatide treatment and to describe associated clinical parameters of participants with type 2 diabetes (T2D) who achieved different categorical measures of BW reduction (<5%, ≥5 to <10%, ≥10 to <15%, and ≥15%)across four studies from the phase 3 SURPASS clinical trial program for T2D. The multivariate model for predictor of a BW reduction of ≥15% included age, sex, race, BW, HbA1c, tirzepatide dose and baseline metformin use, fasting serum glucose, and non-HDL cholesterol. Baseline characteristics and change from baseline to week 40/42 for efficacy parameters were described and analyzed in treatment-adherent participants (≥75% doses administered and on treatment at week 40/42) receiving once weekly tirzepatide (5 mg, 10 mg, or 15 mg) (N = 3,188). Factors significantly associated with achieving a BW reduction of ≥15% with tirzepatide were higher tirzepatide doses, female sex, White or Asian race, younger age, metformin background therapy, and lower HbA1c, fasting serum glucose, and non-HDL cholesterol at baseline. With higher categorical BW reduction, there were greater reductions in HbA1c, triglycerides, ALT, waist circumference, and blood pressure. Baseline factors associated with a higher likelihood of achieving a BW reduction of ≥15% with tirzepatide were higher tirzepatide doses, female sex, White or Asian race, younger age, metformin background therapy, better glycemic status, and lower non-HDL cholesterol. With greater BW reduction, participants with T2D achieved larger improvements in glycemia and cardiometabolic risk parameters. These findings help inform which people with T2D are most likely to achieve greater BW reduction with improved cardiometabolic risk factors with tirzepatide.

The aim of this prospective study was to assess the results of a standard low-calorie dietary intervention (7.5MJ/day) on body weight (BW) and the metabolic profile of obese patients with type 2 diabetes mellitus (T2DM) on intensive insulin therapy (IIT: 4insulin injections/day) versus conventional insulin therapy (CIT: 2/3insulin injections/day). A total of 60patients (n=60, 23 males and 37 postmenopausal females) were recruited and categorized into two groups according to the scheme of insulin treatment. Thirty were on IIT (13 males and 17 females) and an equal number on CIT (10 males and 20 females). BW, body mass index (BMI), HbA1c, and metabolic parameters were compared at 6 and 12months after baseline. Significant reductions were observed in the BW, BMI, HbA1c (p≤0.001 for all) and cholesterol (p≤0.05) at 6months post-intervention. At 1year, median BW reduction was 4.5kg (3.3, 5.8) for patients on IIT and 4.8kg (3.6, 7.0) for those on CIT. The 12-month dietary intervention increased prevalence of normoglycemia in the IIT group and reduced the prevalence of obesity prevalence among the CIT participants (all p<0.001). CIT patients with BW reduction≥5.0% demonstrated 11-fold greater chances of being normoglycemic (odds ratio 11.3, 95%CI 1.1-110.5). BW reduction≥7.0% was associated with CIT, being overweight, and having normal HDLc, LDLc, and cholesterol levels. A reduction in BW between 5.0% and 6.9% was associated with IIT, normoglycemia, and obesity. A 12-month 1800-kcal dietary intervention achieved significant BW and HbA1c reductions irrespectively of insulin regimen. CIT was associated with BW reduction greater than 8.0%, whereas IIT was associated with higher rates of normoglycemia.

Dismounted military personnel operate in physically and psychologically demanding environments, with energy intake from combat rations often falling short of their requirements, leading to reductions in body weight and changes in body composition, which can impact both their health and performance. This review systematically investigated the effects of the continual use of combat rations for periods of 3-40 d on body weight and/or body composition in military personnel engaged in training or deployment. In all, ten databases were searched from their inception until October 2016. Outcome data were described narratively, with studies assessed for quality and risk of bias. A total of thirty studies undertaken over 3-34 d were included. Studies were rated positive, neutral or negative in quality according to the Academy of Nutrition and Dietetics Quality Checklist, with many at risk of bias. Reductions in mean body weight varied, from a negligible decrease of 0·1 % during 8 d of combat training to a substantial decrease of approximately 8·3 % during 12 d of energy restriction during a US Army Ranger course. Decreases in fat mass, fat-free mass and percentage body fat were also reported. There is thus evidence that the continual use of combat rations for periods of 3-34 d results in reductions in body weight and body composition changes which, in some scenarios, may impact on the performance of troops. Body weight and composition should be routinely monitored before and after field activities, and at more regular intervals depending on the length, intensity and type of activity being undertaken.

Growth Differentiation Factor‐15 (GDF15) is a circulating polypeptide linked to cellular stress and metabolic adaptation. GDF15's half‐life is ~3 h and activates the glial cell line‐derived neurotrophic factor family receptor alpha‐like (GFRAL) receptor expressed in the area postrema. To characterize sustained GFRAL agonism on food intake (FI) and body weight (BW), we tested a half‐life extended analog of GDF15 (Compound H [CpdH]) suitable for reduced dosing frequency in obese cynomolgus monkeys. Animals were chronically treated once weekly (q.w.) with CpdH or long‐acting GLP‐1 analog dulaglutide. Mechanism‐based longitudinal exposure‐response modeling characterized effects of CpdH and dulaglutide on FI and BW. The novel model accounts for both acute, exposure‐dependent effects reducing FI and compensatory changes in energy expenditure (EE) and FI occurring over time with weight loss. CpdH had linear, dose‐proportional pharmacokinetics (terminal half‐life ~8 days) and treatment caused exposure‐dependent reductions in FI and BW. The 1.6 mg/kg CpdH reduced mean FI by 57.5% at 1 week and sustained FI reductions of 31.5% from weeks 9–12, resulting in peak reduction in BW of 16 ± 5%. Dulaglutide had more modest effects on FI and peak BW loss was 3.8 ± 4.0%. Longitudinal modeling of both the FI and BW profiles suggested reductions in BW observed with both CpdH and dulaglutide were fully explained by exposure‐dependent reductions in FI without increase in EE. Upon verification of the pharmacokinetic/pharmacodynamic relationship established in monkeys and humans for dulaglutide, we predicted that CpdH could reach double digit BW loss in humans. In summary, a long‐acting GDF15 analog led to sustained reductions in FI in overweight monkeys and holds potential for effective clinical obesity pharmacotherapy.

Aims/hypothesisThe aim of this study was to assess the efficacy and safety of oral semaglutide vs sitagliptin in a predominantly Chinese population with type 2 diabetes inadequately controlled with metformin treatment.MethodsThe Peptide Innovation for Early Diabetes Treatment (PIONEER) 12 trial was a randomised, double-dummy, active-controlled, parallel-group, Phase IIIa trial conducted over 26 weeks at 90 sites across the China region (including mainland China, Taiwan and Hong Kong) and five other countries. Adults aged ≥18 years (≥20 years in Taiwan) with a diagnosis of type 2 diabetes, HbA1c between 53 and 91 mmol/mol (inclusive) and treated with a stable daily dose of metformin were eligible for inclusion. Participants were randomised (1:1:1:1) using a web-based randomisation system to either once-daily oral semaglutide (3 mg, 7 mg or 14 mg) or once-daily oral sitagliptin 100 mg. Treatment allocation was masked to both participants and investigators. Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary endpoint was change in HbA1c from baseline to week 26. The confirmatory secondary endpoint was change in body weight (kg) from baseline to week 26. All randomised participants were included in the full analysis set (FAS). All participants exposed to at least one dose of trial product were included in the safety analysis (SAS).ResultsOf 1839 participants screened, 1441 were randomly assigned to oral semaglutide 3 mg (n=361), 7 mg (n=360), 14 mg (n=361) or sitagliptin 100 mg (n=359) and included in the FAS. A total of 1438 participants were included in the SAS. In total, 75.2% of participants were from the China region. A total of 1372 (95.2%) participants completed the trial and 130 participants prematurely discontinued treatment (8.3%, 8.6% and 15.0% for oral semaglutide 3 mg, 7 mg and 14 mg, respectively; 4.2% for sitagliptin 100 mg). Significantly greater reductions in HbA1c from baseline to week 26 were reported for all doses of oral semaglutide vs sitagliptin 100 mg. For oral semaglutide 3 mg, 7 mg and 14 mg vs sitagliptin 100 mg, the estimated treatment differences (ETDs [95% CI]) were –2 (–4, –1) mmol/mol, –8 (–9, –6) mmol/mol and –11 (–12, –9) mmol/mol, respectively. The corresponding ETDs (95% CI) in percentage points vs sitagliptin 100 mg were –0.2 (–0.3, –0.1), –0.7 (–0.8, –0.6) and –1.0 (–1.1, –0.8), respectively. Reductions in body weight were significantly greater for all doses of oral semaglutide vs sitagliptin 100 mg (ETD [95% CI] –0.9 [–1.4, –0.4] kg, –2.3 [–2.8, –1.8] kg and –3.3 [–3.8, –2.8] kg for 3 mg, 7 mg and 14 mg, respectively). In the subpopulation of participants from the China region (75.2% of trial participants), reductions in HbA1c and body weight from baseline to week 26 were similar to those seen in the overall population. The most frequent adverse events in the semaglutide treatment arms were gastrointestinal, although these were mostly transient and mild/moderate in severity.Conclusions/interpretationSignificantly greater reductions in both HbA1c and body weight over 26 weeks were seen with oral semaglutide 3 mg, 7 mg and 14 mg than with sitagliptin 100 mg in a predominantly Chinese population with type 2 diabetes inadequately controlled with metformin treatment. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials.Trial registrationClinicalTrials.gov NCT04017832.FundingThis trial was funded by Novo Nordisk A/S, Søborg, Denmark.Graphical

Pramlintide acetate injection for the treatment of type 1 and type 2 diabetes mellitus

Tirzepatide is a first-in-class combination glucose-dependent insulinotropic polypeptide (GIP) receptor agonist and glucagon-like peptide 1 receptor agonist (GLP1-RA) approved for treatment of adults with type 2 diabetes mellitus (T2DM) and chronic weight management. The aim of this analysis was to assess the real-world efficacy of tirzepatide in patients with T2DM. This retrospective observational study evaluated patients with T2DM from a large urban academic medical centre who received at least 3 months of continuous tirzepatide treatment. The primary outcome was change in A1C from following tirzepatide treatment. Secondary outcomes included change in body weight and body mass index (BMI) after tirzepatide was initiated. A total of 1896 patient charts were reviewed, and 612 patients were evaluated for the primary outcome. Over a median time period of 10.4 months, treatment with tirzepatide resulted in a mean A1C reduction of 1.02 ± 1.48% (p < 0.001). A total of 570 patients were evaluated for the secondary outcomes. Tirzepatide was associated with a mean reduction in body weight of 7.3 ± 9.3 kg (p < 0.001) and a mean reduction in BMI of 2.5 kg/m2. Greater A1C lowering and weight loss was observed in patients without prior GLP1-RA treatment compared to those switched to tirzepatide from GLP1-RA. In a real-world population of US patients with T2DM, tirzepatide was associated with clinically and statistically significant reductions in A1C and body weight. Greater reductions in both A1C and body weight were observed among patients who were GLP1-RA naïve compared to patients switched from GLP1-RA to tirzepatide.

Eficacia y seguridad de la metformina y de los inhibidores del cotransportador-2 de sodio-glucosa en adultos con diabetes tipo 1: una revisión sistemática y metaanálisis en red

Efficacy and safety of metformin and sodium-glucose co-transporter-2 inhibitors in adults with type 1 diabetes: A systematic review and network meta-analysis

Over past centuries, Cannabis sativa (Delta(9)-tetrahydrocannabinol being the principal active ingredient) has been used extensively for both medicinal and recreational uses, and one widely reported effect is the onset of a ravenous appetite and eating behaviour. The pharmacological properties of such exogenous cannabinoids are mediated through the activation of two receptor subtypes, the CB(1) and CB(2) receptors. A number of endogenous ligands for these receptors, the endocannabinoids, have now also been identified allowing their effects on ingestive behaviour to be determined. In a number of species, including man, the administration of exogenous and endogenous cannabinoids leads to robust increases in food intake and can promote body weight gain. These effects are believed to be mediated through activation of the CB(1) receptor. Conversely, experiments with selective CB(1) receptor antagonists have demonstrated reductions in food intake and body weight with repeated compound administration. These reductions in body weight appear to be greater in obese animals and may be the result of a dual effect on both food intake and metabolic processes. Such findings have led to a number of pharmaceutical companies developing selective CB(1) receptor antagonists for the treatment of obesity. The most advanced compound is Sanofi-Synthelabo's inverse agonist, rimonabant (Acomplia; SR-141716), and early Phase III results have recently demonstrated significant reductions in body weight, waist circumference and improvement of lipid and glucose metabolism in overweight and obese humans. Accordingly, the cannabinoid system appears to have an important role in the regulation of ingestive behaviour in man and animals.

Results of teratogenicity testing of m-aminophenol in Sprague-Dawley rats

In previous 1-yr trials, treatment with pramlintide (120 microg), an analog of the beta-cell hormone amylin, induced sustained reductions in A1C and body weight in insulin-using subjects with type 2 diabetes. To assess the potential of pramlintide as an antiobesity agent, we assessed the weight effect, safety, and tolerability of pramlintide in non-insulin-treated obese subjects with and without type 2 diabetes at doses greater than previously studied. We performed a randomized, double-blind, placebo-controlled, multicenter study. A total of 204 obese subjects [80/20% female/male, age 48 +/- 10 yr, and body mass index 37.8 +/- 5.6 kg/m(2) (mean +/- SD)] participated in the study. For 16 wk, without concomitant lifestyle intervention, subjects self-administered pramlintide (nonforced dose escalation < or = 240 microg) or placebo via sc injection three times a day before meals. Weight, waist circumference, tolerability, and safety were the main outcome measures. Pramlintide was generally well tolerated, with 88% of subjects able to escalate to the maximum dose of 240 microg. Withdrawal rates were similar between placebo (25%) and pramlintide-treated subjects (29%). Subjects completing 16 wk of pramlintide treatment experienced placebo-corrected reductions in body weight of 3.7 +/- 0.5% (3.6 +/- 0.6 kg; P < 0.001) and waist circumference (3.6 +/- 1.1 cm; P < 0.01). Approximately 31% of pramlintide-treated subjects achieved > or =5% weight loss (vs. 2% placebo; P < 0.001). More pramlintide than placebo-treated subjects reported improvements in appetite control (72% vs. 31%), weight control (63% vs. 24%), and overall well-being (52% vs. 17%). No unexpected safety signals were observed. The most common adverse event reported was mild, transient nausea. Pramlintide-treated subjects not reporting nausea experienced weight loss similar to those who did (3.6 +/- 0.5% and 3.9 +/- 0.5%, respectively). These results support continued evaluation of pramlintide as a potential treatment for obesity.