Koutaro Yokote

BACKGROUND: Orforglipron, a small-molecule, nonpeptide oral glucagon-like peptide-1 (GLP-1) receptor agonist, is being investigated as a treatment for obesity. METHODS: In this phase 3, multinational, randomized, double-blind trial, we examined the safety and efficacy of once-daily orforglipron at doses of 6 mg, 12 mg, or 36 mg, as compared with placebo (assigned in a 3:3:3:4 ratio) as an adjunct to healthy diet and physical activity for 72 weeks. All the patients had obesity without diabetes mellitus. The primary end point was the percent change in body weight from baseline to week 72, as assessed according to the treatment-regimen estimand in the intention-to-treat population. RESULTS: A total of 3127 patients underwent randomization. The mean change in body weight from baseline to week 72 was -7.5% (95% confidence interval [CI], -8.2 to -6.8) with 6 mg of orforglipron, -8.4% (95% CI, -9.1 to -7.7) with 12 mg of orforglipron, and -11.2% (95% CI, -12.0 to -10.4) with 36 mg of orforglipron, as compared with -2.1% (95% CI, -2.8 to -1.4) with placebo (P<0.001 for all comparisons with placebo). Among the patients in the orforglipron 36-mg group, 54.6% had a reduction of 10% or more, 36.0% had a reduction of 15% or more, and 18.4% had a reduction of 20% or more, as compared with 12.9%, 5.9%, and 2.8% of the patients, respectively, in the placebo group. Waist circumference, systolic blood pressure, triglyceride levels, and non-HDL cholesterol levels significantly improved with orforglipron treatment as compared with placebo. Adverse events resulted in treatment discontinuation in 5.3 to 10.3% of the patients in the orforglipron groups and in 2.7% of those in the placebo group. The most common adverse events with orforglipron were gastrointestinal effects, which were mostly mild to moderate. CONCLUSIONS: In adults with obesity, 72-week treatment with orforglipron led to significantly greater reductions in body weight than placebo; the adverse-event profile was consistent with that of other GLP-1 receptor agonists. (Funded by Eli Lilly; ATTAIN-1 ClinicalTrials.gov number, NCT05869903.).

Abstract Aims This analysis aimed to assess the influence of selected baseline factors on tirzepatide treatment response in Japanese patients with obesity disease. Materials and Methods This was a prespecified subgroup analysis of the SURMOUNT‐J trial. Japanese adults with obesity disease, excluding diabetes, were randomised 1:1:1 to receive once‐weekly subcutaneous tirzepatide 10 mg, tirzepatide 15 mg, or placebo. Key safety and efficacy outcomes at week 72 were analysed by baseline characteristics, including sex, age (&lt;65, ≥65 years), and body mass index (BMI; &lt;35 kg/m 2 , ≥35 kg/m 2 ). Post hoc analyses were conducted to examine cardiometabolic parameters by subgroup. Results Overall, 225 participants were examined (tirzepatide 10 mg: n = 73; tirzepatide 15 mg: n = 77; placebo: n = 75). Weight reduction at week 72 was generally similar across subgroups. Numerically greater reductions in percent body weight at week 72 were observed in females (estimated treatment differences: 10 mg, −17.5%; 15 mg, −24.9%) compared with males (10 mg, −15.1%; 15 mg, −18.1%) and in the BMI &lt;35 kg/m 2 subgroup (10 mg, −18.7%; 15 mg, −21.7%) compared with the BMI ≥35 kg/m 2 subgroup (10 mg, −11.7%; 15 mg, −20.4%) with tirzepatide compared with placebo. Higher proportions of participants achieved ≥5% weight reduction following week 72 of tirzepatide (86%–100%) compared with placebo (18%–30%) across subgroups, and all subgroups showed improvements in cardiometabolic parameters with tirzepatide. Safety profiles did not substantially differ by subgroup. Conclusions These results suggest that tailored interventions such as tirzepatide dosage adjustments may help optimise the treatment management of Japanese patients with obesity disease. Study registration ClinicalTrials.gov , NCT04844918.

BACKGROUND: Acute intermittent porphyria (AIP) is a rare but treatable disease. COVID-19 has various possible complications including posterior reversible encephalopathy syndrome (PRES). COVID-19 was reported to trigger an acute attack in patients with acute hepatic porphyria (AHP). The pathophysiology of AHP-associated PRES is not fully elucidated. CASE PRESENTATION: A 31-year-old Vietnamese female initially presented with seizures, severe hyponatremia, and hypertension after COVID-19. Despite the initial treatment, she had recurrent seizures and developed PRES as confirmed by magnetic resonance imaging. Further investigations revealed a genetic mutation of c.517 C > T in HMBS, leading to a diagnosis of AHP. Treatment with hemin significantly improved her symptoms and corrected her electrolyte imbalance. CONCLUSIONS: This case highlights the potential for COVID-19 to trigger acute attacks in patients with underlying porphyria, potentially leading to complications such as PRES. Also, we observed elevated catecholamine levels during an acute porphyria attack and PRES, suggesting their involvement in the pathogenesis of AIP-associated PRES. Clinicians should consider the possibility of porphyria in patients with COVID-19-associated PRES, especially when they present with gastrointestinal and neuropsychiatric symptoms.