The promise of a new orally active body weight reducer

Comment on ‘Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity’ which was published in the New England Journal of Medicine, doi.org/10.1056/NEJMoa2302392 This phase 2, industry-funded, randomized, multicentre, double-blind trial1 investigated the efficacy and safety of orforglipron, an oral non-peptide partial agonist of the glucagon-like peptide-1 (GLP-1) receptor, in adults with obesity (body mass index [BMI] ≥ 30 kg/m2) or overweight (BMI between 27 and 30 kg/m2) plus at least one weight-related co-existing condition (hypertension, dyslipidaemia, cardiovascular disease, or sleep apnoea) and without diabetes (glycated haemoglobin level <6.5%). 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 by oral capsule in the morning without meal-timing restrictions. During the treatment period, dose escalation was performed in all orforglipron dose cohorts. The primary endpoint was the percentage change from baseline in body weight (BW) at week 26. Secondary endpoints included the percentage change from baseline in BW at week 36; the absolute change from baseline in BW, BMI, and waist circumference (WC) at week 26 and week 36; and weight reductions of at least 5% and at least 10% by week 26 and week 36. A total of 272 participants underwent randomization. Overall, 235 participants (86%) completed the trial, and 207 participants (76%) completed the assigned orforglipron or placebo. Mean age of the participants was 54 years (59% females and 91% Whites). Mean BW was 109 kg, and mean BMI was 38. At week 26, the estimated mean BW change from baseline was −8.6% with the 12 mg dose of orforglipron, −11.2% with the 24 mg dose, −12.3% with the 36 mg dose, −12.6% with the 45 mg dose, and −2.0% with placebo. At week 36, the estimated mean BW change from baseline was −9.4% with the 12 mg dose of orforglipron, −12.5% with the 24 mg dose, −13.5% with the 36 mg dose, −14.7% with the 45 mg dose, and −2.3% with placebo. Across dose cohorts, the placebo-corrected absolute BW changes from baseline ranged from −6.9 to −11.2 kg at week 26 and from −7.4 to −13.0 kg at week 36. The placebo-corrected change from baseline in BMI ranged from −2.4 to −3.9 at week 26 and from −2.5 to −4.6 at week 36. The placebo-corrected change from baseline in WC ranged from −4.4 to −8.7 cm at week 26 and from −5.6 to −9.6 cm at week 36. In the orforglipron-treated subjects, systolic blood pressure was reduced by 10.5 mmHg at week 26 and by 10.5 mmHg at week 36 as compared with 3.6 mmHg and 1.8 mmHg reduction, respectively, with placebo. Orforglipron also reduced levels of triglycerides and cholesterol (total, high-density lipoprotein [HDL], non-HDL, low-density lipoprotein [LDL], and very-LDL). Adverse events were mostly gastrointestinal symptoms that were dose-related and caused discontinuation of orforglipron in up to 17% of subjects. A consistent increase in heart rate was recorded in the cohorts receiving orforglipron, ranging from 3.2 to 7.4 beats per min, while it was −1.8 beats per min in the placebo group. The overall safety profile was similar to that reported for other GLP-1 receptor agonists. Obesity represents an epidemic involving more than 600 million people worldwide, with a much higher number of overweight subjects.2 Beside bariatric surgery, which represents an effective strategy to achieve weight loss of up to 20–25%, different pharmacological strategies have been developed in the last decade.3 Among these, GLP-1 receptor agonists are becoming first-line strategies in obesity management. Indeed, these drugs mimic the effects of endogenous GLP-1 which delays gastric emptying and decreases appetite.4 In the SCALE Obesity and Prediabetes study, subcutaneous liraglutide 3.0 mg daily was associated with a BW reduction of 8.4 ± 7.3 kg. Among the liraglutide-treated subjects, a total of 63% and 33% lost at least 5% and at least 10% of their BW, respectively.5 In the Semaglutide Treatment Effect in People with obesity (STEP) 1 study, subcutaneous semaglutide 2.4 mg once weekly produced a 5% reduction of BW in >90% of subjects and a 20% reduction in ∼35%, these results being comparable with bariatric surgery.6 Although these results have generated great enthusiasm, injectable treatments may encounter patients’ reluctance and impair adherence. A once-daily oral formulation of semaglutide 14 mg has been introduced in the treatment of type 2 diabetes,7 and doses of 25 and 50 mg are currently being investigated for the management of obesity. A promising alternative strategy may be represented by subcutaneous retatrutide, an agonist of the glucose-dependent insulinotropic polypeptide, GLP-1, and glucagon receptors administered once weekly.8 The development of oral orforglipron, which produces cAMP signalling similar to that produced by native GLP-1 but causes less activation of the β-arrestin pathway that regulates receptor internalization, may open new treatment opportunities. In this phase 2 trial,1 orforglipron produced significant benefits in terms of BW and WC reduction and improvement in cardiovascular risk factor profile, including blood pressure and lipid levels. These changes may have a potential impact on cardiovascular risk, although the consistent increase in heart rate associated with the administration of orforglipron moves in the opposite direction. Consistently with previous studies of GLP-1 receptor agonists, 10–17% of enrolled subjects discontinued treatment with orforglipron, mainly due to mild to moderate gastrointestinal adverse events. The results of this phase 2 study suggest that orforglipron may represent a new, effective anti-obesity agent. Some limitations of the study, however, deserve consideration. While allowing once-daily dosing, the long half-life of orforglipron (48–68 h in otherwise healthy subjects9) is responsible for drug accumulation potentially accounting for the relatively flat dose–response relationship. Although the weight loss had not yet plateaued at 36 weeks, suggesting the possibility of additional effects with prolonged treatment, the limited study duration prevents assessing long-term efficacy and safety. Due to the nature of the study, each group included only a small number of participants and a large proportion were White subjects from industrialized countries with a higher percentage of women, thus limiting generalizability of the findings. In addition, subjects with BMI <30 were poorly represented in this phase 2 study, and thus, the effects of orforglipron in overweight subjects will require further investigation. Furthermore, the study did not clarify whether key pharmacokinetic variables (e.g. oral bioavailability, half-life, and accumulation factor) are modified by the degree of obesity and did not address the mechanism(s) and determinants of the increase in heart rate. From the standpoint of cardiologists, the important question is whether GLP-1 receptor agonists will reduce cardiovascular events in obese and overweight subjects without diabetes. To address this question, the Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) study10 is investigating the efficacy of subcutaneous semaglutide 2.4 mg once weekly compared with placebo in preventing major adverse cardiovascular events in obese and overweight patients with history of cardiovascular diseases, and the results of this study are expected soon. In conclusion, the present study demonstrates that daily oral orforglipron, a non-peptide GLP-1 receptor agonist, can mimic BW reduction and side effects observed with injectable agents with a similar mechanism of action. Head-to-head comparisons of the effects of orforglipron vis-à-vis other oral and injectable agents on BW and other surrogate endpoints would be desirable and informative of its potential role in the pharmacological management of obesity. Supplementary data are not available at European Heart Journal online. M.V. reports personal fees for speaker bureau and/or consulting in Advisory Board from AstraZeneca, Bayer, Kalos Medical, Menarini Int, Novartis Pharma, Novo Nordisk, GSK, Pfizer, Sanofi, and Zentiva outside of the present work. D.P. received speaker’s fees from Daiichi Sankyo, outside the submitted work.