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ObjectiveTo 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 methodsPatients 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.ResultsSignificant (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).ConclusionsIn post hoc analyses, higher tirzepatide doses significantly decreased NASH-related biomarkers and increased adiponectin in patients with T2DM.

Summary: Background: The use of histological inclusion criteria for clinical trials of at‐risk metabolic dysfunction‐associated steatohepatitis (MASH) is often associated with high screen failure rates. Aims: To describe the design of a trial investigating tirzepatide treatment of MASH and to examine the effect of new inclusion criteria incorporating the use of the FibroScan‐AST (FAST) score on the proportion of patients meeting histological criteria. Methods: SYNERGY‐NASH is a Phase 2b, multicentre, randomised, double‐blinded, placebo‐controlled trial in patients with biopsy‐confirmed MASH, F2–F3 fibrosis and NAFLD Activity Score ≥4. New inclusion criteria (FAST score >0.35 and an increase in AST inclusion criterion from >20 to >23 U/L) were adopted during the trial, allowing us to examine its impact on the qualification rate. Results: 1583 participants were screened, 651 participants proceeded to liver biopsy and 190 participants were randomised with an overall screen fail rate of 87%. Following the protocol amendment, the overall qualification rate for per‐protocol biopsies was minimally changed from 27.5% to 28.9% with considerable variation among different investigator medical speciality types: endocrinology: from 37.5% to 39.3%; gastroenterology/hepatology: from 26.0% to 23.3%; other specialities: from 21.3% to 29.7%. At 29 sites that performed per‐protocol biopsies before and after the amendment, qualification rates changed as follows: all: 26.1% to 29.1%; endocrinology: from 35.0% to 40.9%; gastroenterology/hepatology: 25.6% to 20.0%; other specialities: from 16.1% to 27.8%. Conclusions: For at‐risk MASH trials based on liver histology, the implementation of inclusion criteria with the proposed FAST score and AST cut‐offs in this trial was most effective at non‐specialist sites. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of orforglipron (LY3502970), an oral, non‐peptide glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) in healthy participants. Materials and Methods: This was a double‐blind, placebo‐controlled, Phase 1 study. Overtly healthy adults aged 18 to 65 years with body mass index of 20 to 40 kg/m2 and glycated haemoglobin concentration of 47.5 mmol/mol (<6.5%) were eligible. In Part A, participants received single‐dose orforglipron, with four cohorts receiving escalating doses (0.3‐6 mg). In Part B, participants received 4 weeks of daily repeated oral orforglipron with doses escalating weekly to four different final target doses (2‐24 mg). Results: Ninety‐two participants enrolled and received at least one study drug dose (32 in Part A [mean age 43.4 years] and 60 in Part B [mean age 42.5 years]). The most common adverse events were gastrointestinal tract‐related. Pharmacokinetics were approximately dose proportional, and the mean t1/2 was 24.6 to 35.3 hours after a single dose (0.3‐6 mg). On Day 28, the mean t1/2 was 48.1 to 67.5 hours across the dose range (2‐24 mg). Substantial reductions in body weight of up to 5.4 kg were observed after 4 weeks in orforglipron‐treated participants, compared to a reduction of 2.4 kg with placebo (P < 0.05). Orforglipron decreased fasting glucose levels across Days 1 to 28, and gastric emptying was delayed on Day 28. Conclusions: Orforglipron's long half‐life (25‐68 hours) allows once‐daily oral dosing, without water and food restrictions. Orforglipron had a pharmacodynamic and safety profile similar to that of injectable GLP‐1RAs, which supports continued clinical development. [ABSTRACT FROM AUTHOR]

Aim: To report the results of a Phase 1b trial evaluating the safety, pharmacokinetics and pharmacodynamics of orforglipron (LY3502970), an oral, non‐peptide glucagon‐like peptide‐1 receptor agonist (GLP‐1RA), in patients with type 2 diabetes (T2D). Materials and Methods: This was a double‐blind, placebo‐controlled Phase 1 study evaluating five different dosing regimens. The first group established that weekly dose escalation of the daily doses of orforglipron was generally well tolerated. This enabled a parallel‐arm design for the four groups following. Participants were randomized 3:1 to daily doses of orforglipron or placebo for 12 weeks. Eligible participants with T2D were aged 18 to 70 years and had glycated haemoglobin (HbA1c) levels ≥53.0 mmol/mol (7.0%) and ≤91.3 mmol/mol (10.5%). Results: A total of 51 participants received orforglipron and 17 received placebo. In the placebo and orforglipron groups, respectively, baseline HbA1c was 8.1% and 8.0%, and baseline body weight was 90.3 and 88.4 kg. The most common adverse events were gastrointestinal‐related, and occurred early in treatment, similar to findings with other GLP‐1RAs. At Week 12, mean t1/2 ranged from 29 to 49 hours. Mean HbA1c change ranged from −1.5% to −1.8% across orforglipron doses, versus −0.4% with placebo, and body weight change was −0.24 to −5.8 kg across orforglipron doses, versus 0.5 kg with placebo. Conclusions: Orforglipron treatment resulted in meaningful reductions in HbA1c and body weight, with an adverse event profile consistent with that of other GLP‐1RAs. Orforglipron may provide a safe and effective once‐daily oral treatment alternative to injectable GLP‐1RAs or peptide oral formulations without water and food restrictions. [ABSTRACT FROM AUTHOR]

In a phase 2 trial of once‐weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo, the dual glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1 receptor agonist tirzepatide dose‐dependently reduced HbA1c and body weight in patients with type 2 diabetes. In this post hoc analysis, inflammation, endothelial dysfunction, and cellular stress biomarkers were measured at baseline, 4, 12, and 26 weeks to evaluate the additional effects of tirzepatide on cardiovascular risk factors. At 26 weeks, tirzepatide 10 and 15 mg decreased YKL‐40 (also known as chitinase‐3 like‐protein‐1), intercellular adhesion molecule 1 (ICAM‐1), leptin, and growth differentiation factor 15 levels versus baseline, and YKL‐40 and leptin levels versus placebo and dulaglutide. Tirzepatide 15 mg also decreased ICAM‐1 levels versus placebo and dulaglutide, and high‐sensitivity C‐reactive protein (hsCRP) levels versus baseline and placebo, but not dulaglutide. GlycA, interleukin 6, vascular cell adhesion molecule 1, and N‐terminal‐pro hormone B‐type natriuretic peptide levels were not significantly changed in any group. YKL‐40, hsCRP, and ICAM‐1 levels rapidly decreased within 4 weeks of treatment with tirzepatide 10 and 15 mg, whereas the decrease in leptin levels was more gradual and did not plateau by 26 weeks. In this hypothesis‐generating exploratory analysis, tirzepatide decreased several biomarkers that have been associated with cardiovascular risk. [ABSTRACT FROM AUTHOR]

The two actin-related subunits of the Arp2/3 complex, Arp2 and Arp3, are proposed to form a pseudo actin dimer that nucleates actin polymerization. However, in the crystal structure of the inactive complex, they are too far apart to form such a nucleus. Here, we show using EM that yeast and bovine Arp2/3 complexes exist in a distribution among open, intermediate and closed conformations. The crystal structure docks well into the open conformation. The activator WASp binds at the cleft between Arp2 and Arp3, and all WASp-bound complexes are closed. The inhibitor coronin binds near the p35 subunit, and all coronin-bound complexes are open. Activating and loss-of-function mutations in the p35 subunit skew conformational distribution in opposite directions, closed and open, respectively. We conclude that WASp stabilizes p35-dependent closure of the complex, holding Arp2 and Arp3 closer together to nucleate an actin filament. [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: 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]

Teriparatide is the recombinant human N-terminal fragment (1-34) of endogenous human parathyroid hormone, and it is the first bone anabolic agent for the treatment of osteoporosis. When given as once-daily subcutaneous injections, teriparatide can reverse the course of osteoporosis by stimulating formation of new bone and restoring lost architecture. Teriparatide (20 microg) treatment of osteoporosis in postmenopausal women rapidly increased markers of bone formation and reduced the incidence of vertebral fractures by 65% and of nonvertebral fragility fractures by 53%. In addition, treatment with this compound increased spine bone mineral density by 10% and hip bone mineral density by 3% at study endpoint. Teriparatide is well tolerated and is not associated with any serious side effects. The compound has been approved in Europe and in the US for the treatment of osteoporosis. Duration of treatment is 18-24 months and the dose does not need to be adjusted for age or gender.