Orforglipron: A Promising Agent for Treatment of Obesity and Type 2 Diabetes

Orforglipron is a non-peptide glucagon-like receptor-1 (GLP-1R) agonist that can be orally administered once daily irrespective of food intake. Different doses of oeforglipron were evaluated in two phase 2 clinical trials including subjects with obesity and type 2 diabetes, respectively. In the obesity trial, subjects with mean baseline weight of 108.7 kg and body mass index (BMI) of 37.9 kg/m2 had 9.4% to 14.7% of weight loss at 36 weeks compared with 2.3% loss with placebo. In the diabetes study, glycated hemoglobin (HbA1c) levels (baseline 8.1%) decreased from 1.2% to 2.1% in the orforglipron groups, 1.1% with dulaglutide (1.5 mg/week), and 0.5% with placebo at 26 weeks. In the latter trial, mean weight loss at week 26 was 3.7% to 9.6% with orforglipron, 4.0% with dulaglutide, and 2.2% with placebo. While HbA1c reduction seemed to reach a plateau at 20 weeks, weight loss continued to progress up to the end of follow-up at 36 weeks. In general, safety profile of orforglipron resembles that of GLP-1R agonists with gastrointestinal (GI) adverse effects being the most common. Yet, premature discontinuation rates were high; 19.1-21.1% across the orforglipron groups compared with 4% with dulaglutide and 2.0-5.5% with placebo. In addition, there was a pronounced increase in heart rate with the use of orforglipron; placebo-adjusted increase being 7.7-9.2 beats per minute (bpm). Overall, orforglipron is a promising oral GLP-1R agonist for treatment of obesity and type 2 diabetes. Phase 3 trials are urgently needed to clarify its long-term efficacy and safety.

Currently, the peptide semaglutide (Rybelsus) is the only oral GLP-1R approved for treatment of type 2 diabetes [1]. However, oral semaglutide is limited by strict criteria of intake that may potentially limit compliance. Thus, it must be taken in the fasting state with no more than 4 ounces (120 cc) of plain water at least 30 minutes before the first food, beverage, or other oral medications [1].  Several orally administered non-peptide GLP-1R agonists are under development for treatment of obesity and type 2 diabetes, orforglipron being the most studied so far [2,3]. Contrary to oral semaglutide, orforglipron may be taken orally once a day irrespective of food or water intake. Results of phase 2 clinical trials suggest that orforglipron may be an effective anti-obesity and anti-diabetic agent [2,3]. The main purpose of this review is to provide an appraisal on orforglipron with respect to its efficacy and safety profile.

Orforglipron for treatment of obesity 

Orforglipron was evaluated in various doses (12, 24, 36, 45 mg/d) in a randomized phase 2 double-blind, placebo-controlled trial of 272 obese subjects (59% women, mean age 54.2 years, mean weight 108.7 kg, mean BMI 37.9 kg/m2) [2]. The starting dose and titration schedule varied between groups. Throughout the trial, education regarding healthy eating and exercise was provided to all enrolled individuals [2]. The primary and secondary endpoints of the trial were the percentage change from baseline in weight after 26 weeks and 36 weeks respectively [2]. At week 26, the mean change from baseline ranged from -8.6% to -12.6

Orforglipron represents a new class of non-peptide GLP-1R agonists that can be taken orally once a day without food or water restrictions. Other non-peptide GLP-1R agonists, such as danuglipron, are under development [9]. Phase 2 trials lasting 26-36 weeks show that orforglipron cause an average placebo-adjusted substantial weight loss of up to 12.4% and 9.6% in subjects with obesity and type 2 diabetes, respectively [2,3]. A second phase 2 trial suggest that orforglipron is effective as antihyperglycemic agent causing an average reduction of HbA1c levels of up 1.7% [3]. The magnitude of decrease in weight and HbA1c values are close to those achieved by the highest dose of oral semaglutide (50 mg/d) shown in phase 3 clinical trials (table 1). In general, safety profile of orforglipron is comparable to that of the class of GLP-1 agonists. Yet, the incidence of GI adverse effects may be higher with orforglipron compared with other GLP-1R agonists, in part due to patterns of dose initiation and escalation. The latter observation may explain the high rates of orforgliflozin discontinuation due to adverse effects reaching up to 21% (versus 5.5% with placebo) (table 1). Furthermore, the increase in placebo-adjusted heart rate of 7.7 to 9.2 bpm with orforglipron appears to be more pronounced than other GLP-1R agonists.  Phase 3 clinical trials are underway to clarify efficacy and safety of orforglipron in larger patient population of obesity and type 2 diabetes from different ethnic backgrounds. The changes in heart rate and any types of arrhythmias should be included as pre-specified adverse effects in these trials. More importantly, the effects of orforglipron on cardiovascular events and mortality should be evaluated in adequately powered long-term trials. In addition, direct comparison of orforglipron with oral semaglutide should be studied in the setting of double-blind trials.

Table 1: Comparison between orforglipron and oral semaglutide.

Abbreviations in the table: GLP-1R: glucagon-like peptide-1 receptor, FDA: Federal Drug Administration, HbA1c: glycated hemoglobin, bpm: beats per minute.

Conflict of interest

The author has no conflict of interest to declare.