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OBJECTIVE To evaluate the effects of tirzepatide on body composition, appetite, and energy intake to address the potential mechanisms involved in body weight loss with tirzepatide. RESEARCH DESIGN AND METHODS In a secondary analysis of a randomized, double-blind, parallel-arm study, the effects of tirzepatide 15 mg (N = 45), semaglutide 1 mg (N = 44), and placebo (N = 28) on body weight and composition, appetite, and energy intake were assessed at baseline and week 28. RESULTS Tirzepatide treatment demonstrated significant reductions in body weight compared with placebo and semaglutide, resulting in greater fat mass reduction. Tirzepatide and semaglutide significantly reduced appetite versus placebo. Appetite scores and energy intake reductions did not differ between tirzepatide and semaglutide. CONCLUSIONS Differences in energy intake during ad libitum lunch were not sufficient to explain the different weight outcomes. Further evaluation is needed to assess mechanistic differences related to tirzepatide actions on 24-h energy intake, substrate utilization, and energy expenditure.

OBJECTIVE: To evaluate effects of tirzepatide on body composition, appetite and energy intake to address the potential mechanisms involved in body weight loss with tirzepatide. RESEARCH DESIGN AND METHODS: In a secondary analysis of a randomized, double-blind, parallel-arm study, the effects of tirzepatide 15 mg (N=45), semaglutide 1 mg (N=44) and placebo (N=28) on body weight and composition, appetite, and energy intake were assessed at baseline and Week 28. RESULTS: Tirzepatide treatment demonstrated significant reductions in body weight compared to placebo and semaglutide, resulting in greater fat mass reduction. Tirzepatide and semaglutide significantly reduced appetite vs placebo. Appetite scores and energy intake reductions did not differ between tirzepatide and semaglutide. CONCLUSIONS: Differences in energy intake during ad libitum lunch were not sufficient to explain the different weight outcomes. Further evaluation is needed to assess mechanistic differences related to tirzepatide actions on 24-hour energy intake, substrate utilization and energy expenditure.

Tirzepatide (TZP) , a dual GIP and GLP-1 receptor agonist (RA) has shown superior improvement in glycemic control and body weight than selective GLP-1 RA. Rodent models indicate that GIP RA augments GLP-1 RA induced food intake suppression and causes body weight loss, mainly by reducing fat mass. This randomized, double-blind, parallel study compared the effects of TZP 15 mg (N=45) , semaglutide (SEMA) 1 mg (N=44) and placebo (PBO) (N=28) on energy intake (assessed by an ad libitum lunch) , appetite (visual analog scale [VAS] ratings of hunger, satiety, prospective food consumption [PFC], and fullness) and body composition (air displacement plethysmography) at baseline and at 28 weeks of treatment. At 28 weeks, reductions in body weight from baseline were observed with TZP 15 mg (-11.2 kg) and SEMA 1 mg (-6.9 kg) , and significantly differed between treatment groups (-4.3 kg [95% confidence interval [CI]: -6.8, -1.9]; p Disclosure T.Heise: Advisory Panel; Novo Nordisk A/S, Research Support; ADOCIA, AstraZeneca, Biocon, Boehringer Ingelheim International GmbH, Crinetics Pharmaceuticals, Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Genova, Nestlé, Neuraly Inc., Novo Nordisk A/S, Sanofi, Zealand Pharma A/S, Speaker's Bureau; Eli Lilly and Company, Gan & Lee Pharmaceuticals, Novo Nordisk A/S. A.Haupt: Employee; Lilly, Stock/Shareholder; Lilly. Z.Milicevic: Employee; Eli Lilly and Company. J.De vries: Advisory Panel; ADOCIA, Novo Nordisk A/S, Zealand Pharma A/S, Speaker's Bureau; Novo Nordisk A/S. T.Coskun: Employee; Eli Lilly and Company. S.Urva: Employee; Eli Lilly and Company. J.Li: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. E.J.Pratt: Employee; Eli Lilly and Company. M.K.Thomas: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. K.J.Mather: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.P.Dunn: Employee; Eli Lilly and Company, Eli Lilly and Company. Funding Eli Lilly and Company

We investigated the effect of tirzepatide (TZP) 15 mg (novel GIP-GLP-1 dual receptor agonist) , placebo and semaglutide 1 mg (SEMA) on beta-cell function using euglycaemic and hyperglycemic glucose clamps (EGC, HGC) and Mixed Meal Tolerance Tests (MMTT) in a 28-week double-blind randomized controlled trial of people with type 2 diabetes. During EGC and HGC, TZP improved insulin sensitivity (M-value) , first and second phase insulin secretion (ISR) and beta-cell glucose sensitivity (ratio of ISR and glucose increments) more than SEMA and placebo (Table; EASD symposium 2021) . During MMTT, both fasting and AUC glucose were reduced more with TZP than with SEMA or placebo, while incremental glucose AUC was reduced with TZP and SEMA vs. placebo similarly. Despite similarly reduced incremental glucose AUC, insulin AUC and incremental insulin AUC were reduced by TZP but not by SEMA. Model-derived beta-cell glucose sensitivity was increased with TZP and SEMA from baseline similarly. In contrast, ISR at 7.2 mmol/L glucose increased more with TZP than with placebo and SEMA (Table) . The glucose-lowering effect of TZP is mediated through improvements in multiple aspects of beta-cell function, including beta-cell glucose sensitivity and ISR, and in insulin sensitivity, resulting in pronounced lowering of fasting and postprandial glucose. These effects help explain the superior improvement in glucose control seen with TZP vs. comparators in clinical trials. Disclosure A. Mari: Consultant; Lilly. Research Support; Lilly. J. Li: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. S. Urva: Employee; Eli Lilly and Company. T. Heise: Advisory Panel; Novo Nordisk A/S. Research Support; ADOCIA, AstraZeneca, Biocon, Boehringer Ingelheim International GmbH, Crinetics Pharmaceuticals, Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Genova, Nestlé, Neuraly Inc., Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker's Bureau; Eli Lilly and Company, Gan & Lee Pharmaceuticals, Novo Nordisk A/S. J. De Vries: Advisory Panel; ADOCIA, Novo Nordisk A/S, Zealand Pharma A/S. Speaker's Bureau; Novo Nordisk A/S. E.J. Pratt: Employee; Eli Lilly and Company. R.J. Heine: Employee; Eli Lilly and Company. M.K. Thomas: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Z. Milicevic: Employee; Eli Lilly and Company. K.J. Mather: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company

Background: LY3502970 (LY) is a novel, highly potent, orally bioavailable nonpeptide GLP-1 receptor agonist (RA) , and a potential alternative to injectable therapies or oral peptides whose absorption is affected by food or water intake. Objectives of this study were to evaluate safety, tolerability, pharmacokinetics (PK) , and pharmacodynamics (PD) of single and multiple doses of LY in healthy subjects. Methods: This was a multi-part, randomized, double-blind, phase 1 study (NCT03929744) . In Part A, subjects received placebo or single-dose LY with 5 cohorts receiving escalating doses. In Part B, subjects received 4 weeks of daily placebo or repeated oral LY escalating weekly to 5 different final target doses. Overtly healthy adults 18-65 yrs old with body mass index 20-40 kg/m2 and A1c Results: Of 133 subjects enrolled, 32 participated in Part A (mean age 43.4 yrs) and 60 participated in Part B (mean age 42.5 yrs) . There were no deaths or serious adverse events. Most common (occurring in ≥3 subjects) treatment-emergent adverse events in Part A were vomiting, nausea, and headache, and in Part B were nausea, headache, and constipation. PK was approximately proportional; mean Cmax in Part A was 1.4-14.9 ng/mL and mean t½ was 24.6-35.3 hrs across the dose range after single dose. In Part B, mean Cmax was 11.1-99.6 ng/mL and mean t½ was 48.1-67.5 hrs on Day 28 across the dose range. Single and repeated doses of LY decreased mean fasting glucose compared to baseline across Days 1-28. In Part B, significant reductions in body weight from baseline were observed after 4 weeks in 4 cohorts (except for the lowest dose) . Gastric emptying was delayed after initial LY dose but was no longer evident at Day 28. Conclusion: This oral nonpeptide had safety and PD marker profiles similar to injectable GLP-1 RAs and PK enabling once daily dosing. These data support further clinical development. Disclosure E.J.Pratt: Employee; Eli Lilly and Company. X.Ma: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. R.Liu: Employee; Eli Lilly and Company. D.A.Robins: Employee; Eli Lilly and Company. K.Sloop: Employee; Eli Lilly and Company. C.Benson: None.

Agonists of G-protein-coupled receptor 142 (GPR142) are reported to increase insulin secretion and lower glucose in preclinical models. We identified a novel agonist, LY3325656 (LY) that selectively activates GPR142 in humans and mice. In preclinical models, LY increased glucose-dependent insulin secretion (GDIS) and secretion of glucagon and incretin hormones GLP-1 and GIP. To elucidate mechanisms of LY in humans, we designed a multi-part, single-dose study in 24 healthy volunteers (HV) and 12 patients with type 2 diabetes (T2D) (NCT03115099). LY was well tolerated through dose escalation up to 1950 mg in HV, with a median time to peak concentration of 4 hours and half-life of 4.59 hours. A graded glucose infusion evaluated GDIS, and LY demonstrated increased insulin secretion at higher doses (750-1950 mg). A 4-period, crossover design consisting of placebo (Pb), LY (1950mg), LY+DPP-IV inhibitor, and GLP-1R agonist treatment investigated glucose-lowering and incretin pharmacology in patients with T2D. LY significantly reduced post-meal glucose levels (2-hour glucose AUC) by >10% during a mixed meal tolerance test. Increases in post-meal GLP-1 AUC concentrations with LY compared to Pb were seen in a few, but not all patients with T2D. Serum glucagon levels were consistently increased by LY in patients with T2D and HV. We conclude that GPR142 activation in humans increases GDIS and augments glucagon secretion but does not substantively augment GIP or GLP-1 secretion. Our data suggest that acute stimulatory effects of GPR142 on insulin and glucagon secretion translate from preclinical models to man, unlike preclinical effects on gut peptide secretion. Innovative and efficient single-dose studies can provide key mechanistic understanding of the translatability of preclinical findings for the treatment of T2D. Disclosure E.J. Pratt: Employee; Self; Eli Lilly and Company. T. Oura: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. X. Ma: Employee; Self; Eli Lilly and Company. H.V. Lin: Employee; Self; Eli Lilly and Company, Forkhead BioTherapeutics, Inc. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Eli Lilly and Company, Forkhead BioTherapeutics, Inc. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. T. Ma: None. A.M. Efanov: Employee; Self; Eli Lilly and Company. M.K. Thomas: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.

An optimally designed once-weekly basal insulin with reduced day-to-day pharmacokinetic (PK)/pharmacodynamic (PD) fluctuations compared to daily basal insulins should have a low peak-to-trough ratio at steady state. An insulin with this flat profile could improve glycemic efficacy while reducing hypoglycemia. Basal insulin Fc (BIF; LY3209590) is an insulin IgG Fc-fusion protein developed for once weekly dosing. The results of the first in-human studies of BIF assessing the safety, tolerability, PK, and PD following single and once-weekly doses of BIF are presented below. The single ascending dose (SAD) study assessed 6 dose levels of BIF, administered to healthy subjects or patients with type 2 diabetes mellitus (T2DM). In the multiple ascending dose (MAD) study, patients with T2DM previously treated with basal insulin received a one-time loading dose at Week 1 followed by a once-weekly maintenance dose for 5 additional weeks. Four fixed-dose maintenance dose levels were evaluated. The loading dose was implemented to rapidly achieve steady-state BIF concentration at each dose level. Patients with T2DM in the control group received insulin glargine at the same dose as their previous daily insulin dose. Key objectives were safety and tolerability, PK endpoints with a focus on half-life and peak-to-trough ratio at steady state, and finally PD measures. The SAD study included 57 patients with T2DM and 16 healthy subjects. The mean age of patients with T2DM was 58.4 years and the mean BMI was 29.5±3.2 kg/m2. The mean age of healthy subjects was 35.8±9.3 years and the mean BMI was 26.1±3.1 kg/m2. In the SAD study, BIF demonstrated linear PK with dose-proportional concentration profiles in healthy subjects and patients with T2DM. The maximum BIF concentration was reached on Day 4. BIF had a mean half-life of approximately 17 days in patients with T2DM. Following a single dose of BIF, a decrease in FBG was observed on Day 1 and was sustained until at least 5 days post-dose. In the MAD study in 33 subjects with T2DM aged between 40 and 69 years, BIF demonstrated a nearly peak-less PK profile over a one-week dosing interval with a peak-to-trough ratio of ~1.1 at steady state. This flat profile is in contrast to insulin glargine. Following once-daily dosing, insulin glargine has a daily peak-to-trough ratio of ~2. Over the 6-week duration, the 7-point glucose profiles remained constant over time and were similar to insulin glargine profiles. BIF was well tolerated and had a safety profile similar to insulin glargine-treated subjects. In particular, hypoglycemia rates were also similar to insulin glargine and there was no occurrence of hypoglycemic events with cognitive dysfunction. These data support continued development of BIF as a once-weekly insulin treatment of diabetes mellitus.

The G protein-coupled receptor 40 (GPR40) also known as free fatty acid receptor 1 (FFAR1) is highly expressed in pancreatic, islet β-cells and responds to endogenous fatty acids, resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity, and pharmacokinetic properties. Compounds 1 (LY2881835), 2 (LY2922083), and 3 (LY2922470) demonstrated potent, efficacious, and durable dose-dependent reductions in glucose levels along with significant increases in insulin and GLP-1 secretion during preclinical testing. A clinical study with 3 administered to subjects with T2DM provided proof of concept of 3 as a potential glucose-lowering therapy. This manuscript summarizes the scientific rationale, medicinal chemistry, preclinical, and early development data of this new class of GPR40 agonists.