Oral diabetes and obesity meds danuglipron and orforglipron show promise but have gastrointestinal drawbacks

By Dr. Chinta SidharthanReviewed by Susha Cheriyedath, M.Sc.Oct 17 2023

In a recent study published in the journal Metabolism, a team of scientists conducted a systematic review of recent randomized controlled trials that investigated the safety and efficacy of two novel glucagon-like peptide 1 receptor agonists (GLP-1RAs) developed for the treatment of type 2 diabetes mellitus and obesity.

Study: Safety and efficacy of the new, oral, small-molecule, GLP-1 receptor agonists orforglipron and danuglipron for the treatment of type 2 diabetes and obesity: systematic review and meta-analysis of randomized controlled trials. Image Credit: New Africa / Shutterstock

Background

Type 2 diabetes mellitus has become a significant public health concern in recent years. Among the various treatment options being explored to help type 2 diabetes patients maintain euglycemia, GLP-1RAs have been a promising option with beneficial cardio-renal effects. However, the currently available GLP-1RAs are peptidic agonists that need to be subcutaneously administered, which is often difficult for most patients and lowers the adherence and uptake of the medication.

Obesity is another global health concern that exerts a significant burden on the economy and public health systems, and it is often closely linked to type 2 diabetes. Clinical guidelines include the use of medications for weight management for individuals with obesity and obesity-related comorbidities, and injectable GLP-1RAs have exhibited substantial potential for long-term effectiveness. Given the success of GLP-1RAs in treating obesity and type 2 diabetes, current research has been focused on developing and testing the safety and efficacy of small-molecule GLP-1RAs that can be orally administered.

About the study

In the present study, the team conducted a systematic review and meta-analysis to summarize the current evidence on the safety and efficacy of two orally administered GLP-1RAs — danuglipron and orforglipron — in the treatment of obesity and type 2 diabetes mellitus. The review included only randomized controlled trials that examined the safety and efficacy of oral, small-molecule GLP-1RAs in comparison with other antidiabetic medications or placebo in a study group comprising adults above the age of 18 years with type 2 diabetes, obesity, or both.

Studies were excluded if they examined a pediatric population, healthy controls, or type 1 diabetes patients. Observational or experimental studies, as well as those conducted on animal models or in vitro, were also excluded from the study.

The primary examined outcome consisted of how different the absolute changes in the percentage of glycated hemoglobin (HbA1c) from baseline were between the treatment and control groups. Secondary outcomes included endpoint differences in body weight, fasting plasma glucose (FPG), systolic and diastolic blood pressure, body mass index (BMI), and heart rate between the treatment and control groups when absolute changes from baseline values were measured.

For evaluating the safety profiles of danuglipron and orforglipron, the review examined the rates of constipation, dyspepsia, nausea, adverse events emerging after the initiation of the treatment, serious adverse events, events of hypoglycemia, and any other adverse events resulting in the discontinuation of the treatment.

Data such as the sample size, demographic and major clinical characteristics, and endpoints related to the primary and secondary outcomes and those associated with the safety outcomes were extracted and analyzed. A risk-of-bias analysis was also conducted for all the included studies.

The mean difference and the odds ratios were calculated to estimate the differences in continuous and dichotomous outcomes, respectively, between the intervention or treatment groups and the control groups. Subgroup analyses independently examined these differences based on the underlying conditions, namely, obesity, diabetes, or both. The dose-response relationship between doses of GLP-1RAs and changes in weight or HbA1c from baseline was also examined.

Results

The preliminary findings indicated that the orally administered small molecule GLP-1RAs danuglipron and orforglipron were effective in weight reduction and glycemic control in individuals with type 2 diabetes, obesity, or both. As compared to the controls, the novel small molecule GLP-1RAs not only resulted in a significant lowering of HbA1c levels in patients with type 2 diabetes mellitus but in patients with obesity and type 2 diabetes, danuglipron and orforglipron also brought about significant weight reduction.

While the safety profiles indicated that the orally administered danuglipron and orforglipron did not increase the odds of serious adverse reactions or hypoglycemic events, the odds of adverse gastrointestinal events such as diarrhea, nausea, constipation, and vomiting were higher. These adverse gastrointestinal events were also linked to higher odds of treatment discontinuation.

Conclusions

Overall, the review reported that the novel, orally administered, small molecule GLP-1RAs danuglipron and orforglipron effectively reduced the HbA1c levels and lowered body weight in patients with type 2 diabetes mellitus and obesity. Furthermore, no serious adverse effects or hypoglycemia was observed. However, adverse gastrointestinal events that could lead to treatment discontinuation were noted. Further, longitudinal studies are required to understand these treatment options' long-term efficacy, tolerability, and safety.