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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]

Weight loss has been associated with improvement in insulin sensitivity. It is consequently a cornerstone in the management of type 2 diabetes mellitus (T2DM). However, the strictly quantitative relationship between weight loss, insulin sensitivity, and clinically relevant glucose homeostasis biomarkers as well as changes therein as T2DM progresses is not yet fully understood. Therefore, the objective of our research was to establish a body weight–directed disease trial model for glucose homeostasis. To that end, we conducted a model‐based meta‐analysis using time course data of body weight loss (following lifestyle change or surgical procedure) and corresponding improvement of insulin sensitivity expressed as the Matsuda index. Changes in body weight were best described by a sigmoidal Emax model, whereas changes in the Matsuda index were best described by a linear model with a slope of 3.49. Once developed and verified, the model‐based meta‐analysis was linked to a disease‐drug trial model for T2DM previously developed by our group to characterize and predict the impact of weight loss on clinically relevant glucose homeostasis biomarkers. The joint model was then used to conduct clinical trial simulations, which showed that weight loss can greatly improve clinically relevant glucose homeostasis biomarkers in T2DM patients. [ABSTRACT FROM AUTHOR]

In gestational diabetes mellitus (GDM), women are unable to compensate for the increased insulin resistance during pregnancy. Data are limited regarding the pharmacodynamic effects of metformin and glyburide during pregnancy. This study characterized insulin sensitivity (SI), β‐cell responsivity, and disposition index (DI) in women with GDM utilizing a mixed‐meal tolerance test (MMTT) before and during treatment with glyburide monotherapy (GLY, n = 38), metformin monotherapy (MET, n = 34), or GLY and MET combination therapy (COMBO; n = 36). GLY significantly decreased dynamic β‐cell responsivity (31%). MET and COMBO significantly increased SI (121% and 83%, respectively). Whereas GLY, MET, and COMBO improved DI, metformin (MET and COMBO) demonstrated a larger increase in DI (P = 0.05) and a larger decrease in MMTT peak glucose concentrations (P = 0.03) than subjects taking only GLY. Maximizing SI with MET followed by increasing β‐cell responsivity with GLY or supplementing with insulin might be a more optimal strategy for GDM management than monotherapy. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus is a condition similar to type 2 diabetes mellitus (T2DM) in that patients are unable to compensate for the degree of insulin resistance, and both conditions are often treated with metformin. The comparative pharmacodynamic response to metformin in these 2 populations has not been studied. This study characterized insulin sensitivity, β‐cell responsivity, and disposition index following a mixed‐meal tolerance test utilizing a minimal model of glucose, insulin, and C‐peptide kinetics before and during treatment with metformin. The study included women with gestational diabetes mellitus (n = 34), T2DM (n = 14), and healthy pregnant women (n = 30). Before treatment, the gestational diabetes mellitus group had significantly higher baseline (45%), dynamic (68%), static (71%), and total β‐cell responsivity (71%) than the T2DM group. Metformin significantly increased insulin sensitivity (51%) as well as disposition index (97%) and decreased mixed‐meal tolerance test peak glucose concentrations (8%) in women with gestational diabetes mellitus after adjustment for gestational age–dependent effects; however, in women with T2DM metformin only significantly affected peak glucose concentrations (22%) and had no significant effect on any other parameters. Metformin had a greater effect on the change in disposition index (Δ disposition index) in women with gestational diabetes mellitus than in those with T2DM (P =.01). In conclusion, response to metformin in women with gestational diabetes mellitus is significantly different from that in women with T2DM, which is likely related to the differences in disease severity. [ABSTRACT FROM AUTHOR]