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Corannulene is a multifaceted polyaromatic compound. It has many interesting properties; for example, it has a bowl‐shaped molecular structure that, in addition, undergoes a dynamic inversion process. It has attracted much attention within the last decades. This is not only due to its structural properties but also its electronic properties and its various potential applications to materials chemistry. Here, synthetic approaches towards corannulene derivatives with electron‐withdrawing substituents are summarized. This includes both selective and unselective methods. Further, the electrochemical properties, that is, the reduction potentials, are analyzed and compared. As a main conclusion, one can state that the electron affinity depends roughly linearly on the number of substituents. Finally, the structural behavior of the substituted buckybowls in the solid state is highlighted. This also allows a general statement about the influence of the electronic and steric nature of substituents on the molecular structures and the solid‐state packing of the corannulene derivatives. Bowled over: This review summarizes synthetic approaches towards corannulenes with electron‐withdrawing substituents. The article is focused on the introduction of perfluoroalkyl substituents. Recent advances on other functional groups are discussed in detail. The solid‐state structures and the electrochemical properties of the compounds are compared. [ABSTRACT FROM AUTHOR]

Background: Prohormone convertase 1 is involved in maturation of peptides. Rare mutations in gene PCSK1, encoding this enzyme, cause childhood obesity and abnormal glucose homeostasis with elevated proinsulin concentrations. Common single nucleotide polymorphisms (SNPs) within this gene, rs6232 and rs6235, are associated with obesity. We studied whether these SNPs influence the prediabetic traits insulin resistance, β-cell dysfunction, or glucose intolerance. Methods: We genotyped 1498 German subjects for SNPs rs6232 and rs6235 within PCSK1. The subjects were metabolically characterized by oral glucose tolerance test with glucose, insulin, proinsulin, and C-peptide measurements. A subgroup of 512 subjects underwent a hyperinsulinemic-euglycemic clamp. Results: The minor allele frequencies were 25.8% for SNP rs6235 and 6.0% for rs6232. After adjustment for sex and age, we found no association of SNPs rs6235 and rs6232 with BMI or other weight-related traits (all p ≥ 0.07). Both minor alleles, adjusted for sex, age, BMI and insulin sensitivity were associated with elevated AUCproinsulin and AUCproinsulin/ AUCinsulin (rs6235: padditive model ≤ 0.009, effect sizes 8/8%, rs6232: pdominant model ≤ 0.01, effect sizes 10/21%). Insulin secretion was not affected by the variants (different secretion parameters, all p ≥ 0.08). The minor allele of SNP rs6232 was additionally associated with 15% higher OGTT-derived and 19% higher clamp-derived insulin sensitivity (pdom ≤ 0.0047), 4.5% lower HOMAIR (pdom = 0.02) and 3.5% lower 120-min glucose (pdom = 0.0003) independently of BMI and proinsulin conversion. SNP rs6235 was not associated with parameters of glucose metabolism. Conclusions: Like rare mutations in PCSK1, the more common variants tested determine glucose-stimulated proinsulin conversion, but not insulin secretion. In addition, rs6232, encoding the amino acid exchange N221D, influences insulin sensitivity and glucose homeostasis. [ABSTRACT FROM AUTHOR]

BACKGROUND Obesity is a major risk factor for many leading causes of illness and death worldwide. Data are needed regarding the efficacy and safety of the nonpeptide glucagonlike peptide-1 (GLP-1) receptor agonist orforglipron as a once-daily oral therapy for weight reduction in adults with obesity. METHODS In this phase 2, randomized, double-blind trial, we enrolled adults with obesity, or with overweight plus at least one weight-related coexisting condition, and without diabetes. Participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36, or 45 mg) or placebo once daily for 36 weeks. The percentage change from baseline in body weight was assessed at week 26 (primary end point) and at week 36 (secondary end point). RESULTS A total of 272 participants underwent randomization. At baseline, the mean body weight was 108.7 kg, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 37.9. At week 26, the mean change from baseline in body weight ranged from - 8 . 6% to - 1 2 . 6% across the orforglipron dose cohorts and was - 2 . 0% in the placebo group. At week 36, the mean change ranged from - 9 . 4% to - 1 4 . 7% with orforglipron and was - 2 . 3% with placebo. A weight reduction of at least 1 0% by week 36 occurred in 46 to 7 5% of the participants who received orforglipron, as compared with 9 % who received placebo. The use of orforglipron led to improvement in all prespecified weight-related and cardiometabolic measures. The most common adverse events reported with orforglipron were gastrointestinal events, which were mild to moderate, occurred primarily during dose escalation, and led to discontinuation of orforglipron in 10 to 17% of participants across dose cohorts. The safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class. C O N C L U S I O N S Daily oral orforglipron, a nonpeptide GLP-1 receptor agonist, was associated with weight reduction. Adverse events reported with orforglipron were similar to those with injectable GLP-1 receptor agonists. [ABSTRACT FROM AUTHOR]

Background Retatrutide (LY3437943) is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors. Its dose-response relationships with respect to side effects, safety, and efficacy for the treatment of obesity are not known. Methods We conducted a phase 2, double-blind, randomized, placebo-controlled trial involving adults who had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or higher or who had a BMI of 27 to less than 30 plus at least one weight-related condition. Participants were randomly assigned in a 2:1:1:1:1:2:2 ratio to receive subcutaneous retatrutide (1 mg, 4 mg [initial dose, 2 mg], 4 mg [initial dose, 4 mg], 8 mg [initial dose, 2 mg], 8 mg [initial dose, 4 mg], or 12 mg [initial dose, 2 mg]) or placebo once weekly for 48 weeks. The primary end point was the percentage change in body weight from baseline to 24 weeks. Secondary end points included the percentage change in body weight from baseline to 48 weeks and a weight reduction of 5% or more, 10% or more, or 15% or more. Safety was also assessed. Results We enrolled 338 adults, 51.8% of whom were men. The least-squares mean percentage change in body weight at 24 weeks in the retatrutide groups was -7.2% in the 1-mg group, -12.9% in the combined 4-mg group, -17.3% in the combined 8-mg group, and -17.5% in the 12-mg group, as compared with -1.6% in the placebo group. At 48 weeks, the least-squares mean percentage change in the retatrutide groups was -8.7% in the 1-mg group, -17.1% in the combined 4-mg group, -22.8% in the combined 8-mg group, and -24.2% in the 12-mg group, as compared with -2.1% in the placebo group. At 48 weeks, a weight reduction of 5% or more, 10% or more, and 15% or more had occurred in 92%, 75%, and 60%, respectively, of the participants who received 4 mg of retatrutide; 100%, 91%, and 75% of those who received 8 mg; 100%, 93%, and 83% of those who received 12 mg; and 27%, 9%, and 2% of those who received placebo. The most common adverse events in the retatrutide groups were gastrointestinal; these events were dose-related, were mostly mild to moderate in severity, and were partially mitigated with a lower starting dose (2 mg vs. 4 mg). Dose-dependent increases in heart rate peaked at 24 weeks and declined thereafter. Conclusions In adults with obesity, retatrutide treatment for 48 weeks resulted in substantial reductions in body weight. [ABSTRACT FROM AUTHOR]

According to current consensus guidelines for type 2 diabetes management, bodyweight management is as important as attaining glycaemic targets. Retatrutide, a single peptide with agonist activity at the glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and glucagon receptors, showed clinically meaningful glucose-lowering and bodyweight-lowering efficacy in a phase 1 study. We aimed to examine the efficacy and safety of retatrutide in people with type 2 diabetes across a range of doses. In this randomised, double-blind, double-dummy, placebo-controlled and active comparator-controlled, parallel-group, phase 2 trial, participants were recruited from 42 research and health-care centres in the USA. Adults aged 18–75 years with type 2 diabetes, glycated haemoglobin (HbA 1c) of 7·0–10·5% (53·0–91·3 mmol/mol), and BMI of 25–50 kg/m2 were eligible for enrolment. Eligible participants were treated with diet and exercise alone or with a stable dose of metformin (≥1000 mg once daily) for at least 3 months before the screening visit. Participants were randomly assigned (2:2:2:1:1:1:1:2) using an interactive web-response system, with stratification for baseline HbA 1c and BMI, to receive once-weekly injections of placebo, 1·5 mg dulaglutide, or retatrutide maintenance doses of 0·5 mg, 4 mg (starting dose 2 mg), 4 mg (no escalation), 8 mg (starting dose 2 mg), 8 mg (starting dose 4 mg), or 12 mg (starting dose 2 mg). Participants, study site personnel, and investigators were masked to treatment allocation until after study end. The primary endpoint was change in HbA 1c from baseline to 24 weeks, and secondary endpoints included change in HbA 1c and bodyweight at 36 weeks. Efficacy was analysed in all randomly assigned, except inadvertently enrolled, participants, and safety was assessed in all participants who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov , NCT04867785. Between May 13, 2021, and June 13, 2022, 281 participants (mean age 56·2 years [SD 9·7], mean duration of diabetes 8·1 years [7·0], 156 [56%] female, and 235 [84%] White) were randomly assigned and included in the safety analysis (45 in the placebo group, 46 in the 1·5 mg dulaglutide group, and 47 in the retatrutide 0·5 mg group, 23 in the 4 mg escalation group, 24 in the 4 mg group, 26 in the 8 mg slow escalation group, 24 in the 8 mg fast escalation group, and 46 in the 12 mg escalation group). 275 participants were included in the efficacy analyses (one each in the retatrutide 0·5 mg group, 4 mg escalation group, and 8 mg slow escalation group, and three in the 12 mg escalation group were inadvertently enrolled). 237 (84%) participants completed the study and 222 (79%) completed study treatment. At 24 weeks, least-squares mean changes from baseline in HbA 1c with retatrutide were –0·43% (SE 0·20; –4·68 mmol/mol [2·15]) for the 0·5 mg group, –1·39% (0·14; –15·24 mmol/mol [1·56]) for the 4 mg escalation group, –1·30% (0·22; –14·20 mmol/mol [2·44]) for the 4 mg group, –1·99% (0·15; –21·78 mmol/mol [1·60]) for the 8 mg slow escalation group, –1·88% (0·21; –20·52 mmol/mol [2·34]) for the 8 mg fast escalation group, and –2·02% (0·11; –22·07 mmol/mol [1·21]) for the 12 mg escalation group, versus –0·01% (0·21; –0·12 mmol/mol [2·27]) for the placebo group and –1·41% (0·12; –15·40 mmol/mol [1·29]) for the 1·5 mg dulaglutide group. HbA 1c reductions with retatrutide were significantly greater (p<0·0001) than placebo in all but the 0·5 mg group and greater than 1·5 mg dulaglutide in the 8 mg slow escalation group (p=0·0019) and 12 mg escalation group (p=0·0002). Findings were consistent at 36 weeks. Bodyweight decreased dose dependently with retatrutide at 36 weeks by 3·19% (SE 0·61) for the 0·5 mg group, 7·92% (1·28) for the 4 mg escalation group, 10·37% (1·56) for the 4 mg group, 16·81% (1·59) for the 8 mg slow escalation group, 16·34% (1·65) for the 8 mg fast escalation group, and 16·94% (1·30) for the 12 mg escalation group, versus 3·00% (0·86) with placebo and 2·02% (0·72) with 1·5 mg dulaglutide. For retatrutide doses of 4 mg and greater, decreases in weight were significantly greater than with placebo (p=0·0017 for the 4 mg escalation group and p<0·0001 for others) and 1·5 mg dulaglutide (all p<0·0001). Mild-to-moderate gastrointestinal adverse events, including nausea, diarrhoea, vomiting, and constipation, were reported in 67 (35%) of 190 participants in the retatrutide groups (from six [13%] of 47 in the 0·5 mg group to 12 [50%] of 24 in the 8 mg fast escalation group), six (13%) of 45 participants in the placebo group, and 16 (35%) of 46 participants in the 1·5 mg dulaglutide group. There were no reports of severe hypoglycaemia and no deaths during the study. In people with type 2 diabetes, retatrutide showed clinically meaningful improvements in glycaemic control and robust reductions in bodyweight, with a safety profile consistent with GLP-1 receptor agonists and GIP and GLP-1 receptor agonists. These phase 2 data also informed dose selection for the phase 3 programme. Eli Lilly and Company. [ABSTRACT FROM AUTHOR]

Orforglipron, an oral, non-peptide glucagon-like peptide-1 (GLP-1) receptor agonist, is in development for type 2 diabetes and obesity. We assessed the efficacy and safety of orforglipron versus placebo or dulaglutide in participants with type 2 diabetes. In this 26-week, phase 2, double-blind, randomised, multicentre study, participants were recruited from 45 centres (private clinics, hospitals, and research centers) in the USA, Hungary, Poland, and Slovakia. Adult participants aged 18 years or older with type 2 diabetes treated with diet and exercise, with or without metformin, and with a glycated haemoglobin (HbA 1c) of 7·0–10·5%, and stable BMI of 23 kg/m2 or more, were randomly assigned (5:5:5:5:5:3:3:3:3) via an interactive web-response system to placebo, dulaglutide 1·5 mg once per week, or orforglipron 3 mg, 12 mg, 24 mg, 36 mg (group 1), 36 mg (group 2), 45 mg (group 1), or 45 mg (group 2) once per day with no food or water restrictions. Two different dose escalation regimens were evaluated for each of the 36 mg and 45 mg cohorts. Participants were masked to the study drug, dulaglutide, and placebo. The primary efficacy outcome The primary efficacy outcome was mean change in HbA 1c from baseline with orforglipron versus placebo at week 26. Efficacy was analysed in all randomly assigned participants who received at least one dose of study drug and excluded data after the permanent discontinuation of study drug or initiation of rescue medication. Safety was analysed in all participants who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT05048719) and is completed. Between Sept 15, 2021, and Sept 30, 2022, 569 participants were screened and 383 were enrolled and randomly assigned to a group. 352 (92%) completed the study and 303 (79%) completed 26 weeks of treatment. At baseline, the mean age was 58·9 years, HbA 1c was 8·1%, BMI was 35·2 kg/m2, 226 (59%) were men, and 157 (41%) were women. At week 26, mean change in HbA 1c with orforglipron was up to –2·10% (–1·67% placebo adjusted), versus –0·43% with placebo and –1·10% with dulaglutide. HbA 1c reduction was statistically superior with orforglipron versus placebo (estimated treatment difference –0·8% to –1·7%). Change in mean bodyweight at week 26 was up to –10·1 kg (95% CI –11·5 to –8·7; 7·9 kg placebo adjusted [–9·9 to –5·9]) with orforglipron versus –2·2 kg (–3·6 to –0·7) for placebo and –3·9 kg (–5·3 to –2·4) for dulaglutide. The incidence of treatment-emergent adverse events ranged from 61·8% to 88·9% in orforglipron-treated participants, compared with 61·8% with placebo and 56·0% with dulaglutide. The majority were gastrointestinal events (44·1% to 70·4% with orforglipron, 18·2% with placebo, and 34·0% with dulaglutide) of mild to moderate severity. Three participants receiving orforglipron and one participant receiving dulaglutide had clinically significant (<54 mg/dL [<3 mmol/L]) hypoglycaemia and no participants had severe hypoglycaemia. One death occurred in the placebo group and was not related to study treatment. In this phase 2 trial the novel, oral, non-peptide GLP-1 receptor agonist orforglipron at doses of 12 mg or greater showed significant reductions in HbA 1c and bodyweight compared with placebo or dulaglutide. The adverse event profile was similar to other GLP-1 receptor agonists in similar stage of development. Orforglipron might provide an alternative to injectable GLP-1 receptor agonists and oral semaglutide, with the prospect of less burdensome administration to achieve treatment goals in people with type 2 diabetes. Eli Lilly and Company. [ABSTRACT FROM AUTHOR]

Background: Treating hyperglycaemia and obesity in individuals with type 2 diabetes using multi-receptor agonists can improve short-term and long-term outcomes. LY3437943 is a single peptide with agonist activity for glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) receptors that is currently in development for the treatment of type 2 diabetes and for the treatment of obesity and associated comorbidities. We investigated the safety, pharmacokinetics, and pharmacodynamics of multiple weekly doses of LY3437943 in people with type 2 diabetes in a 12-week study.Methods: In this phase 1b, proof-of-concept, double-blind, placebo-controlled, randomised, multiple-ascending dose trial, adults (aged 20-70 years) with type 2 diabetes for at least 3 months, a glycated haemoglobin A1c (HbA1c) value of 7·0-10·5%, body-mass index of 23-50 kg/m2, and stable bodyweight (<5% change in previous 3 months) were recruited at four centres in the USA. Using an interactive web-response system, participants were randomly assigned to receive once-weekly subcutaneous injections of LY3437943, placebo, or dulaglutide 1·5 mg over a 12-week period. Five ascending dose cohorts were studied, with randomisation in each cohort such that a minimum of nine participants received LY3437943, three received placebo, and one received dulaglutide 1·5 mg within each cohort. The top doses in the two highest dose cohorts were attained via stepwise dose escalations. The primary outcome was to investigate the safety and tolerability of LY3437943, and characterising the pharmacodynamics and pharmacokinetics were secondary outcomes. Safety was analysed in all participants who received at least one dose of study drug, and pharmacodynamics and pharmacokinetics in all participants who received at least one dose of study drug and had evaluable data. This trial is registered at ClinicalTrials.gov, NCT04143802.Findings: Between Dec 18, 2019, and Dec 28, 2020, 210 people were screened, of whom 72 were enrolled, received at least one dose of study drug, and were included in safety analyses. 15 participants had placebo, five had dulaglutide 1·5 mg and, for LY3437943, nine had 0·5 mg, nine had 1·5 mg, 11 had 3 mg, 11 had 3/6 mg, and 12 had 3/6/9/12 mg. 29 participants discontinued the study prematurely. Treatment-emergent adverse events were reported by 33 (63%), three (60%), and eight (54%) participants who received LY3437943, dulaglutide 1·5 mg, and placebo, respectively, with gastrointestinal disorders being the most frequently reported treatment-emergent adverse events. The pharmacokinetics of LY3437943 were dose proportional and its half-life was approximately 6 days. At week 12, placebo-adjusted mean daily plasma glucose significantly decreased from baseline at the three highest dose LY3437943 groups (least-squares mean difference -2·8 mmol/L [90% CI -4·63 to -0·94] for 3 mg; -3·1 mmol/L [-4·91 to -1·22] for 3/6 mg; and -2·9 mmol/L [-4·70 to -1·01] for 3/6/9/12 mg). Placebo-adjusted sHbA1c also decreased significantly in the three highest dose groups (-1·4% [90% CI -2·17 to -0·56] for 3 mg; -1·6% [-2·37 to -0·75] for 3/6 mg; and -1·2% [-2·05 to -0·45] for 3/6/9/12 mg). Placebo-adjusted bodyweight reduction with LY3437943 appeared to be dose dependent (up to -8·96 kg [90% CI -11·16 to -6·75] in the 3/6/9/12 mg group).Interpretation: In this early phase study, LY3437943 showed an acceptable safety profile, and its pharmacokinetics suggest suitability for once-weekly dosing. This finding, together with the pharmacodynamic findings of robust reductions in glucose and bodyweight, provides support for phase 2 development.Funding: Eli Lilly and Company. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptors, on biomarkers of nonalcoholic steatohepatitis (NASH) and fibrosis in patients with type 2 diabetes mellitus (T2DM).Research Design and Methods: Patients with T2DM received either once weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo for 26 weeks. Changes from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), keratin-18 (K-18), procollagen III (Pro-C3), and adiponectin were analyzed in a modified intention-to-treat population.Results: Significant (P < 0.05) reductions from baseline in ALT (all groups), AST (all groups except tirzepatide 10 mg), K-18 (tirzepatide 5, 10, 15 mg), and Pro-C3 (tirzepatide 15 mg) were observed at 26 weeks. Decreases with tirzepatide were significant compared with placebo for K-18 (10 mg) and Pro-C3 (15 mg) and with dulaglutide for ALT (10, 15 mg). Adiponectin significantly increased from baseline with tirzepatide compared with placebo (10, 15 mg).Conclusions: In post hoc analyses, higher tirzepatide doses significantly decreased NASH-related biomarkers and increased adiponectin in patients with T2DM. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear., Methods: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH., Results: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity., Conclusions: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.)., (Copyright © 2024 Massachusetts Medical Society.)

Retatrutide is a novel triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon receptors. A 48-week phase 2 obesity study demonstrated weight reductions of 22.8% and 24.2% with retatrutide 8 and 12 mg, respectively. The primary objective of this substudy was to assess mean relative change from baseline in liver fat (LF) at 24 weeks in participants from that study with metabolic dysfunction-associated steatotic liver disease and ≥10% of LF. Here, in this randomized, double-blind, placebo-controlled trial, participants (n = 98) were randomly assigned to 48 weeks of once-weekly subcutaneous retatrutide (1, 4, 8 or 12 mg dose) or placebo. The mean relative change from baseline in LF at 24 weeks was -42.9% (1 mg), -57.0% (4 mg), -81.4% (8 mg), -82.4% (12 mg) and +0.3% (placebo) (all P < 0.001 versus placebo). At 24 weeks, normal LF (<5%) was achieved by 27% (1 mg), 52% (4 mg), 79% (8 mg), 86% (12 mg) and 0% (placebo) of participants. LF reductions were significantly related to changes in body weight, abdominal fat and metabolic measures associated with improved insulin sensitivity and lipid metabolism. The ClinicalTrials.gov registration is NCT04881760 ., (© 2024. The Author(s).)

Background: Fatty acid uptake can be measured using PET and 14-(R,S)-[ 18 F]fluoro-6-thia-heptadecanoic acid ([ 18 F]FTHA). However, the relatively rapid rate of [ 18 F]FTHA metabolism significantly affects kinetic modeling of tissue uptake. Thus, there is a need for accurate chromatographic methods to analyze the unmetabolized [ 18 F]FTHA (parent fraction). Here we present a new radiometabolite analysis (RMA) method, with comparison to a previous method for parent fraction analysis, and its use in a test-retest clinical study under fasting and postprandial conditions. We developed a new thin-layer chromatography (TLC) RMA method for analysis of [ 18 F]FTHA parent fraction and its radiometabolites from plasma, by testing stationary phases and eluent combinations. Next, we analyzed [ 18 F]FTHA, its radiometabolites, and plasma radioactivity from subjects participating in a clinical study. A total of 17 obese or overweight participants were dosed with [ 18 F]FTHA twice under fasting, and twice under postprandial conditions and plasma samples were obtained between 14 min (mean of first sample) and 72 min (mean of last sample) post-injection. Aliquots of 70 plasma samples were analyzed using both methods, enabling head-to-head comparisons. We performed test-retest and group comparisons of the parent fraction and plasma radioactivity., Results: The new TLC method separated seven [ 18 F]FTHA radiometabolite peaks, while the previous method separated three. The new method revealed at least one radiometabolite that was not previously separable from [ 18 F]FTHA. From the plasma samples, the mean parent fraction value was on average 7.2 percentage points lower with the new method, compared to the previous method. Repeated [ 18 F]FTHA investigations on the same subject revealed reproducible plasma SUV and parent fractions, with different kinetics between the fasted and postprandial conditions., Conclusions: The newly developed improved radio-TLC method for [ 18 F]FTHA RMA enables accurate parent fraction correction, which is required to obtain quantitative data for modelling [ 18 F]FTHA PET data. Our test-retest study of fasted and postprandial conditions showed robust reproducibility, and revealed clear differences in the [ 18 F]FTHA metabolic rate under different study settings., Trial Registration: EudraCT No: 2020-005211-48, 04Feb2021; and Clinical Trials registry NCT05132335, 29Oct2021, URL: https://classic., Clinicaltrials: gov/ct2/show/NCT05132335 ., (© 2024. The Author(s).)

Context: In a clinical study, tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1RA), provided superior glycemic control vs the GLP-1RA semaglutide. The physiologic mechanisms are incompletely understood., Objective: To evaluate treatment effects by model-based analyses of mixed-meal tolerance test (MMTT) data., Design: A 28-week double-blind, randomized, placebo-controlled trial., Setting: Two clinical research centers in Germany., Patients: Patients with type 2 diabetes treated with metformin., Interventions: Tirzepatide 15 mg, semaglutide 1 mg, placebo., Main Outcome Measures: Glycemic control, model-derived β-cell function indices including insulin secretion rate (ISR) at 7.2-mmol/L glucose (ISR7.2), β-cell glucose (β-CG) sensitivity, insulin sensitivity, and estimated hepatic insulin-to-glucagon ratio., Results: Tirzepatide significantly reduced fasting glucose and MMTT total glucose area under the curve (AUC) vs semaglutide (P < 0.01). Incremental glucose AUC did not differ significantly between treatments; therefore, greater total glucose AUC reduction with tirzepatide was mainly attributable to greater suppression of fasting glucose. A greater reduction in total ISR AUC was achieved with tirzepatide vs semaglutide (P < 0.01), in the context of greater improvement in insulin sensitivity with tirzepatide (P < 0.01). ISR7.2 was significantly increased with tirzepatide vs semaglutide (P < 0.05), showing improved β-CG responsiveness. MMTT-derived β-CG sensitivity was increased but not significantly different between treatments. Both treatments reduced fasting glucagon and total glucagon AUC, with glucagon AUC significantly reduced with tirzepatide vs semaglutide (P < 0.01). The estimated hepatic insulin-to-glucagon ratio did not change substantially with either treatment., Conclusions: These results suggest that the greater glycemic control observed for tirzepatide manifests as improved fasting glucose and glucose excursion control, due to improvements in ISR, insulin sensitivity, and glucagon suppression., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Hypothesis: Volenrelaxin, is a half-life-extended recombinant human relaxin protein developed for improving kidney perfusion and cardiorenal function. This study assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of volenrelaxin following single- and multiple-ascending doses (SAD and MAD) administration., Methods: In this Phase 1, 4-part, randomized, double-blinded, placebo-controlled SAD and MAD study in healthy participants, SAD participants (n = 56) received an intravenous (IV) or subcutaneous (SC) dose of volenrelaxin or placebo in a dose-ascending manner. MAD participants (n = 77) received volenrelaxin or placebo SC once weekly for 5 weeks. Effective renal plasma flow (ERPF) and measured glomerular filtration rate (mGFR) were determined by para-aminohippurate and iohexol clearance, respectively., Results: Volenrelaxin demonstrated an extended half-life and increased acute and chronic placebo-adjusted ERPF change from baseline by 50% and 44%, respectively (p < 0.0001). Measured GFR was unchanged, while filtration fraction and afferent/efferent renal arteriolar resistances were reduced. Systolic and diastolic blood pressures decreased, and pulse rate increased with increasing volenrelaxin exposures, demonstrating maximal model-derived placebo-adjusted changes (90% confidence interval) of -6.16 (-8.04, -4.28) mmHg, -6.10 (-7.61, -4.58) mmHg, and + 4.39 (3.38, 5.39) bpm, respectively. Adverse events were mild, with no difference in orthostatic hypotension between volenrelaxin and placebo., Conclusion: Volenrelaxin was well-tolerated, safe and suitable for weekly SC dosing. Volenrelaxin showed a sustained improvement in kidney perfusion upon repeated dosing, supporting further clinical development in chronic kidney disease and chronic heart failure. Clinical trial registration: NCT04768855., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: The burden of daily basal insulins often causes hesitancy and delays in the initiation of insulin therapy. Basal insulin Fc (BIF, insulin efsitora alfa), designed for once-weekly administration, is a fusion protein combining a novel single-chain insulin variant with a human immunoglobulin G (IgG) Fc domain. In this study, we explored the safety and efficacy of BIF in people with type 2 diabetes who had been previously treated with basal insulin., Methods: For this phase 2, 44-site (clinical research centres and hospitals), randomised, open-label, comparator-controlled, 32-week study in the USA, Puerto Rico, and Mexico, we enrolled participants with type 2 diabetes. Eligible participants had to be adults (aged ≥18 years) and to have been treated with basal insulin and up to three oral antidiabetic medicines. Participants were randomly assigned (1:1:1) to subcutaneous administration of BIF (BIF treatment group 1 [BIF-A1] or 2 [BIF-A2]) or insulin degludec. Randomisation was stratified by country, baseline HbA 1c values (<8·5% or ≥8·5%; <69·4 or ≥69·4 mmol/mol), use of sulfonylureas (yes or no), and baseline BMI (<30 or ≥30 kg/m 2 ). The randomisation scheme was performed using an interactive web-response system, which ensured balance between treatment groups. Different fasting glucose targets for the BIF-A1 (≤7·8 mmol/L or ≤140 mg/dL; titrated every 2 weeks), BIF-A2 (≤6·7 mmol/L or ≤120 mg/dL; titrated every 4 weeks), and degludec (≤5·6 mmol/L or ≤100 mg/dL) groups were selected. Patients randomly assigned to BIF received a one-time loading dose ranging from 1·5-3 times their calculated weekly dose. The first weekly dose was administered 1 week after the loading dose. We used interstitial fasting glucose measurements from the Dexcom G6 continuous glucose monitoring system to titrate the basal insulin. The primary measure of glycaemic control was change in HbA 1c from baseline to week 32 for BIF. BIF was also compared with degludec (with a non-inferiority margin of 0·40%). The efficacy analysis set consisted of data from all randomised study participants who received at least one dose of the study medication and participants were analysed according to the treatment they were assigned. The safety population was the same as the efficacy analysis set. The completed trial is registered at ClinicalTrials.gov (NCT03736785)., Findings: Between Nov 15, 2018 and Feb 18, 2020, 399 participants were enrolled and randomised to BIF-A1 (n=135), BIF-A2 (n=132), or degludec (n=132); 202 (51%) were female and 197 (49%) were male. 379 were analysed for the primary outcome (BIF-A1: n=130; BIF-A2: n=125; degludec: n=124). Mean HbA1c change from baseline to week 32, the primary outcome, was -0·6% (SE 0·1%) for BIF-A1 and BIF-A2. Degludec achieved a change from baseline of -0·7% (0·1%). The pooled BIF analysis achieved non-inferiority versus degludec for the treatment difference in HbA1c (0·1% [90% CI -0·1 to 0·3]). The hypoglycaemia (≤3·9 mmol/L or ≤70 mg/dL) event rates (hypoglycaemia events per patient per year) in the BIF groups were 25% lower than those in the degludec group (treatment ratio BIF-A1 vs degludec was 0·75 [0·61-0·93]; and BIF-A2 vs degludec was 0·74 [0·58-0·94]). BIF was well tolerated; treatment-emergent adverse events were similar across groups., Interpretation: Weekly BIF achieved a similar efficacy compared with degludec despite higher fasting glucose targets in the BIF groups. Higher fasting glucose targets and lower glucose variability might have contributed to lower hypoglycaemia rates for BIF compared with degludec. These findings support continued development of BIF as a once-weekly insulin treatment for people with diabetes., Funding: Eli Lilly and Company., Competing Interests: Declaration of interests JF declares research support from Allergan, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly and Company, Intercept, Janssen, Madrigal, Metacrine, Merck, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Poxel, Sanofi, and Theracos. JF is also on the speaker bureau from Merck and Sanofi and has participated in advisory boards or as a consultant for Altimmune, Axcella Health, Boehringer Ingelheim, Coherus Therapeutics, Echosens, 89bio, Eli Lilly and Company, Gilead, Intercept, Merck, Novo Nordisk, and Sanofi. JC, QZ, EC, WL, KS, PW, AH, and CK are all employees of Eli Lilly and Company. JC, QZ, EC, WL, PW, AH, and CK are shareholders of Eli Lilly and Company, (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: In the SURPASS-4 trial, the dual GIP and GLP-1 receptor agonist tirzepatide reduced HbA 1c concentrations, bodyweight, and blood pressure more than titrated daily insulin glargine in people with type 2 diabetes inadequately controlled on oral diabetes treatments and with high cardiovascular risk. We aimed to compare the effects of tirzepatide and insulin glargine on kidney parameters and outcomes in people with type 2 diabetes., Methods: We did a post-hoc analysis of data from SURPASS-4, a randomised, open-label, parallel-group, phase 3 study at 187 sites (including private practice, research institutes, and hospitals) in 14 countries. Eligible participants were adults (age ≥18 years), with type 2 diabetes treated with any combination of metformin, sulfonylurea, or SGLT2 inhibitor, and with baseline HbA 1c of 7·5-10·5% (58-91 mmol/mol), BMI of 25 kg/m 2 or greater, and established cardiovascular disease or a high risk of cardiovascular events. Randomisation via an interactive web-response system was 1:1:1:3 to a once-weekly subcutaneous injection of tirzepatide (5 mg, 10 mg, or 15 mg) or a once-daily subcutaneous injection of titrated insulin glargine (100 U/mL). The study included up to 104 weeks of treatment, with a median treatment duration of 85 weeks. We compared the rates of estimated glomerular filtration rate (eGFR) decline and the urine albumin-creatinine ratio (UACR) between the combined tirzepatide groups and the insulin glargine group in the modified intention-to-treat population. The kidney composite outcome was time to first occurrence of eGFR decline of at least 40% from baseline, end-stage kidney disease, death owing to kidney failure, or new-onset macroalbuminuria. This study is registered with ClinicalTrials.gov, NCT03730662., Findings: Between Nov 20, 2018, and Dec 30, 2019, we screened 3045 people, of whom 1043 (34%) were ineligible, and 2002 (66%) were randomly assigned to a study drug (997 to tirzepatide and 1005 to insulin glargine). 1995 (>99%) of 2002 received at least one dose of tirzepatide (n=995) or insulin glargine (n=1000). At baseline, participants had a mean eGFR of 81·3 (SD 21·11) mL/min per 1·73 m 2 and a median UACR of 15·0 mg/g (IQR 5·0-55·8). The mean rate of eGFR decline was -1·4 (SE 0·2) mL/min per 1·73 m 2 per year in the combined tirzepatide groups and -3·6 (0·2) mL/min per 1·73 m 2 per year in the insulin group (between-group difference 2·2 [95% CI 1·6 to 2·8]). Compared with insulin glargine, the reduction in the annual rate of eGFR decline induced by tirzepatide was more pronounced in participants with eGFR less than 60 mL/min per 1·73 m 2 than in those with eGFR 60 mL/min per 1·73 m 2 or higher (between-group difference 3·7 [95% CI 2·4 to 5·1]). UACR increased from baseline to follow-up with insulin glargine (36·9% [95% CI 26·0 to 48·7]) but not with tirzepatide (-6·8% [-14·1 to 1·1]; between-group difference -31·9% [-37·7 to -25·7]). Participants who received tirzepatide showed a significantly lower occurrence of the composite kidney endpoint compared with those who received insulin glargine (hazard ratio 0·58 [95% CI 0·43 to 0·80])., Interpretation: Our analysis suggests that in people with type 2 diabetes and high cardiovascular risk, tirzepatide slowed the rate of eGFR decline and reduced UACR in clinically meaningful ways compared with insulin glargine., Funding: Eli Lilly and Company., Competing Interests: Declaration of interests HJLH has received grants or contracts from AstraZeneca, Boehringer Ingelheim, Janssen, and NovoNordisk; consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, CSL Behring, Chinook, Dimerix, Eli Lilly, Gilead, Goldfinch Bio, Janssen, Mitsubishi Tanabe Pharma, NovoNordisk, MSD, and Travere Therapeutics; payment or honoraria for speaking from AstraZeneca; and support for attending meetings from Eli Lilly. NS has received grants from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics; and consulting fees from Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceutical, MSD, Novartis, Novo Nordisk, Pfizer, and Sanofi. IP, AH, KLD, ZY, and RJW are employees and shareholders of Eli Lilly and Company. AH is a data monitoring committee board member for tirzepatide (Eli Lilly and Company). KRT has received grants or contracts from Bayer, Goldfinch Bio, and Travere; consulting fees from Eli Lilly, Boehringer Ingelheim, AstraZeneca, Goldfinch Bio, Travere Pharmaceuticals, Bayer, and Novo Nordisk; payment or honoraria for speaking from Eli Lilly, AstraZeneca, Bayer, and Novo Nordisk; has participated on data safety monitoring or advisory boards for the US National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health and the George Clinical Institute for Global Health; and reports a leadership or fiduciary role as Chair of the Diabetic Kidney Disease Collaborative Task Force, American Society of Nephrology. DZIC has received grants or contracts from Boehringer Ingelheim–Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL Behring, and Novo Nordisk; and consulting fees and speaking honoraria from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL Behring, Otsuka, Novartis, Yeungene, and NovoNordisk., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, shows a remarkable ability to lower blood glucose, enabling many patients with long-standing type 2 diabetes to achieve normoglycaemia. We aimed to understand the physiological mechanisms underlying the action of tirzepatide in type 2 diabetes., Methods: This multicentre, randomised, double-blind, parallel-arm, phase 1 study was done at two centres in Germany. Eligible patients were aged 20-74 years, had type 2 diabetes for at least 6 months, and were being treated with lifestyle advice and stable doses of metformin, with or without one additional stable dose of another oral antihyperglycaemic medicine, 3 months before study entry. Via a randomisation table, patients were randomly assigned (3:3:2) to subcutaneously receive either tirzepatide 15 mg, semaglutide 1 mg, or placebo once per week. Endpoint measurements were done at baseline and the last week of therapy (week 28). The primary endpoint was the effect of tirzepatide versus placebo on the change in clamp disposition index (combining measures of insulin secretion and sensitivity) from baseline to week 28 of treatment and was analysed in the pharmacodynamic analysis set, which comprised all randomly assigned participants who received at least one dose of a study drug and had evaluable pharmacodynamic data. Safety was analysed in the safety population, which comprised all randomly assigned participants who received at least one dose of a study drug. Secondary endpoints included the effect of tirzepatide versus semaglutide on the change in clamp disposition index from baseline to week 28 of treatment, glucose control, total insulin secretion rate, M value (insulin sensitivity), and fasting and postprandial glucagon concentrations. Exploratory endpoints included the change in fasting and postprandial insulin concentrations. This study is registered with ClinicalTrials.gov, NCT03951753, and is complete., Findings: Between June 28, 2019, and April 8, 2021, we screened 184 individuals and enrolled 117 participants, all of whom were included in the safety population (45 in the tirzepatide 15 mg group, 44 in the semaglutide 1 mg group, and 28 in the placebo group). Because of discontinuations and exclusions due to missing or unevaluable data, 39 patients in each treatment group and 24 patients in the placebo group comprised the pharmacodynamic analysis set. With tirzepatide, the clamp disposition index increased from a least squares mean of 0·3 pmol m -2 L min -2 kg -1 (SE 0·03) at baseline by 1·9 pmol m -2 L min -2 kg -1 (0·16) to total 2·3 pmol m -2 L min -2 kg -1 (SE 0·16) at week 28 and, with placebo, the clamp disposition index did not change much from baseline (least squares mean at baseline 0·4 pmol m -2 L min -2 kg -1 [SE 0·04]; change from baseline 0·0 pmol m -2 L min -2 kg -1 [0·03]; least squares mean at week 28 0·3 [SE 0·03]; estimated treatment difference [ETD] tirzepatide vs placebo 1·92 [95% CI 1·59-2·24]; p<0·0001). The improvement with tirzepatide in clamp disposition index was significantly greater than with semaglutide (ETD 0·84 pmol m -2 L min -2 kg -1 [95% CI 0·46-1·21]). This result reflected significant improvements in total insulin secretion rate (ETD 102·09 pmol min -1 m -2 [51·84-152·33]) and insulin sensitivity (ETD 1·52 mg min -1 kg -1 [0·53-2·52]) for tirzepatide versus semaglutide. On meal tolerance testing, tirzepatide significantly reduced glucose excursions (lower insulin and glucagon concentrations) compared with placebo, with effects on these variables being greater than with semaglutide. The safety profiles of tirzepatide and semaglutide were similar, with gastrointestinal adverse events being the most common (11 [24%], 13 [30%], and seven [25%] with nausea; nine [20%], 13 [30%], and six [21%] with diarrhoea; and three [7%], five [11%], and one [4%] with vomiting, for tirzepatide, semaglutide, and placebo, respectively). There were no deaths., Interpretation: The glycaemic efficacy of GIP/GLP-1 receptor agonist tirzepatide in type 2 diabetes results from concurrent improvements in key components of diabetes pathophysiology, namely β-cell function, insulin sensitivity, and glucagon secretion. These effects were large and help to explain the remarkable glucose-lowering ability of tirzepatide seen in phase 3 studies., Funding: Eli Lilly., Competing Interests: Declaration of interests TH is shareholder of the private research institute Profil, which received research funds from Adocia, Afon Technology, AstraZeneca, Biocon, Boehringer Ingelheim, Eli Lilly, Gan Lee Pharmaceuticals, Johnson & Johnson, Julphar, Mylan, Nestlé, Neuraly, Nordic Bioscience, Novo Nordisk, Sanofi, and Zealand Pharma; has received speaker honoraria and travel grants from Eli Lilly and Novo Nordisk; and is a member of advisory panels for Novo Nordisk and Valbiotis. AM has received financial support from Eli Lilly and is a consultant for Eli Lilly. JHD was on advisory boards for Adocia, Novo Nordisk, and Zealand, and is now at the European Medicines Agency, where he will not be involved in matters relating to tirzepatide; the clinical studies presented here preceded his secondment to the European Medicines Agency. SU, JL, EJP, TC, MKT, KJM, AH, and ZM, are employees and shareholders of Eli Lilly., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Herein, we report the preparation of silver(I) pentafluorooxosulfate from commercially available AgF and OSF 4 . The compound is surprisingly stable in a MeCN solution. Apart from that, AgOSF 5 has been stabilised by the addition of 2,2'-bipyridine ligands. Starting from solutions of the unstabilised silver(I) salt, OSF 5 complexes with Ni II , Cu I , and Cu II -centres have been obtained. In addition, AgOSF 5 has proven to be generally capable of mediating the transfer of OSF 5 groups to aryne moieties, thus furnishing a new and safe method for the preparation of OSF 5 -substituted arenes. X-ray crystal structure analysis of selected transition-metal OSF 5 compounds have revealed distorted octahedral [OSF 5 ] - anions which are extensively stabilised by hydrogen bonding., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Objective: A novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of GIP adds to the established clinical benefits of selective GLP-1 receptor agonists in type 2 diabetes mellitus (T2DM)., Methods: LY3298176 is a fatty acid modified peptide with dual GIP and GLP-1 receptor agonist activity designed for once-weekly subcutaneous administration. LY3298176 was characterised in vitro, using signaling and functional assays in cell lines expressing recombinant or endogenous incretin receptors, and in vivo using body weight, food intake, insulin secretion and glycemic profiles in mice. A Phase 1, randomised, placebo-controlled, double-blind study was comprised of three parts: a single-ascending dose (SAD; doses 0.25-8 mg) and 4-week multiple-ascending dose (MAD; doses 0.5-10 mg) studies in healthy subjects (HS), followed by a 4-week multiple-dose Phase 1 b proof-of-concept (POC; doses 0.5-15 mg) in patients with T2DM (ClinicalTrials.gov no. NCT02759107). Doses higher than 5 mg were attained by titration, dulaglutide (DU) was used as a positive control. The primary objective was to investigate safety and tolerability of LY3298176., Results: LY3298176 activated both GIP and GLP-1 receptor signaling in vitro and showed glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors in mice. With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist. A total of 142 human subjects received at least 1 dose of LY3298176, dulaglutide, or placebo. The PK profile of LY3298176 was investigated over a wide dose range (0.25-15 mg) and supports once-weekly administration. In the Phase 1 b trial of diabetic subjects, LY3298176 doses of 10 mg and 15 mg significantly reduced fasting serum glucose compared to placebo (least square mean [LSM] difference [95% CI]: -49.12 mg/dL [-78.14, -20.12] and -43.15 mg/dL [-73.06, -13.21], respectively). Reductions in body weight were significantly greater with the LY3298176 1.5 mg, 4.5 mg and 10 mg doses versus placebo in MAD HS (LSM difference [95% CI]: -1.75 kg [-3.38, -0.12], -5.09 kg [-6.72, -3.46] and -4.61 kg [-6.21, -3.01], respectively) and doses of 10 mg and 15 mg had a relevant effect in T2DM patients (LSM difference [95% CI]: -2.62 kg [-3.79, -1.45] and -2.07 kg [-3.25, -0.88], respectively. The most frequent side effects reported with LY3298176 were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, and abdominal distension) in both HS and patients with T2DM; all were dose-dependent and considered mild to moderate in severity., Conclusions: Based on these results, the pharmacology of LY3298176 translates from preclinical to clinical studies. LY3298176 has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. The data warrant further clinical evaluation of LY3298176 for the treatment of T2DM and potentially obesity., (Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Trifluoromethylthio-substituted corannulene can be easily synthesized in good yield by the reaction of iodocorannulene with CuSCF 3 . Oxidation with meta-chloroperbenzoic acid (mCPBA) yields the corresponding sulfonyl compound which exhibits the largest anodic shift of the redox potential caused by a single substituent. Similarly, four SCF 3 , SC 6 F 5 and SeC 6 F 5 substituents are introduced in the 1,2,5,6-positions of corannulene starting with 1,2,5,6-tetraiodo- or 1,2,5,6-tetrabromocorannulene, respectively. The reactions are performed in polar aprotic solvents and are believed to follow S N Ar-type substitution mechanisms. Crystal and molecular structures of selected compounds were elucidated by X-ray crystallography. Trifluoromethanesulfonyl corannulene and the fourfold-substituted trifluoromethylthioether exhibit a perfect columnar stacking of the bowls. The substituted corannulenes were investigated electrochemically by cyclic voltammetry giving raise to large anodic shifts owing to substitution with electron-withdrawing groups., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Herein we report general methods allowing the synthesis of various perfluoroalkylated corannulenes with a specific substitution pattern. Variable temperature NMR spectroscopic investigations revealed dynamic behavior which was analyzed by line shape analysis. The activation parameters of these dynamic processes were determined. For a tetrasubstituted compound it was possible to observe through space scalar coupling. The packing motifs were elucidated by X-ray crystallography, showing that the substitution pattern as well as the size of substituents strongly influence intermolecular π-stacking. The reduction potentials of the perfluoroalkylated compounds were determined by cyclic voltammetry., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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