Discussion
Here we have shown data from two subanalyses of the BALANCE study stratified by pre-diabetes status, BMI, and age at baseline. These are commonly observed clinical variables in patients with diabetes and these subanalyses could help to identify response to efpeglenatide in particular patient subgroups.
In patients who had pre-diabetes at baseline, all doses of efpeglenatide led to numerically greater proportions of patients reverting to normoglycemia at the end of the study versus placebo. We observed some potential differences between efpeglenatide groups in terms of achievement of normoglycemia, although statistical testing was not performed. The mean baseline HbA1c and FPG of the group with pre-diabetes were approximately 5.7% (39 mmol/mol) and 102 mg/dL (5.7 mmol/L), respectively. This is close to the lower limit of pre-diabetes as defined by the American Diabetes Association (HbA1c 5.7%–6.4% (39–47 mmol/mol) and FPG of 100–125 mg/dL (5.6–6.9 mmol/L)),8 suggesting that some patients in the pre-diabetes group were very close to being normoglycemic. This may explain, at least in part, the high proportions of patients returning to normoglycemia following efpeglenatide treatment and why the highest rate of reversion was observed with the 4 mg QW dose, despite larger reductions in HbA1c and FPG in the other efpeglenatide dose groups.
Treatment with efpeglenatide was also associated with greater improvements from baseline in HbA1c, FPG, body weight, waist circumference, and total cholesterol compared with placebo. Due to the exploratory nature of the study design, statistical testing was not performed to compare efpeglenatide groups.
In subgroups of patients from the overall BALANCE population, stratified by baseline BMI or age, all doses of efpeglenatide were associated with greater reductions in body weight versus placebo across all subgroups of patients stratified by age and BMI. For waist circumference, the highest QW and Q2W doses of efpeglenatide were associated with reductions versus placebo. Therefore, these exploratory data suggest that efpeglenatide may be beneficial in people with pre-diabetes and that this is an area that requires further study. The results of these subgroup analyses were consistent with those of the overall BALANCE study, with all doses of efpeglenatide associated with greater reductions in body weight compared with placebo across all patient subgroups examined.23 Similarly, the benefits of efpeglenatide on glycemic control and cholesterol levels seen in BALANCE23 were also seen in patients with pre-diabetes, who experienced greater reductions in HbA1c, FPG, and total cholesterol, compared with patients receiving placebo. In the overall BALANCE study population, all doses of efpeglenatide led to greater reductions in waist circumference compared with placebo;23 this treatment effect was seen with most doses of efpeglenatide across the subgroups investigated, with more consistent benefits observed at the higher doses examined. In line with the overall BALANCE population and the GLP-1 RA class, the most common AEs in these subgroup analyses were GI AEs such as nausea, vomiting, and diarrhea. The goal of treatment for pre-diabetes is preventing progression to diabetes, and lifestyle modification is considered as the first-line therapy.24 25 Intensive behavioral lifestyle intervention programs have been shown to reduce the risk of progression to diabetes.25 Several pharmacologic agents, primarily metformin, have also been shown to reduce the risk of disease progression, although further study is needed. In practice, however, pre-diabetes often goes unaddressed in primary care settings.26
Currently, there are two GLP-1 RAs approved for body weight management in patients with obesity and without diabetes: liraglutide, administered as a once-daily injection;27 and semaglutide, administered QW.11 In a trial in patients with obesity and without T2D, 20-week treatment with liraglutide 1.8–3.0 mg once daily led to an 84%–96% decrease in the prevalence of pre-diabetes (defined as FPG 5.6–6.9 mmol/L (100–125 mg/dL) or glucose tolerance 7.8–11.0 mmol/L (140–199 mg/dL) measured during an oral glucose tolerance test).28 Liraglutide was also shown to reduce the incidence of progression to T2D in a study of adults with pre-diabetes and a BMI ≥30 kg/m² (or ≥27 kg/m² with comorbidities). Of patients treated with liraglutide, 2% were diagnosed with diabetes after 3 years compared with 6% of the placebo group, and the time from randomization to diagnosis was 2.7 times longer with liraglutide than with placebo (p<0.0001).29 The recent Semaglutide Treatment Effect in People with Obesity (STEP) phase III clinical trial program explored the efficacy and safety of once-weekly semaglutide in overweight adults without diabetes with a BMI of ≥30 kg/m2 or ≥27 kg/m2 (STEP 1, STEP 3, and STEP 4)30–32 or in adults with T2D with BMI ≥27 kg/m2 (STEP 2).33 All trials showed that semaglutide was associated with significantly greater body weight reductions and a greater proportion of patients achieved weight loss of 5% or greater compared with placebo.30–33 The STEP 1 study also showed that, of patients with pre-diabetes, 84.1% of those in the once-weekly semaglutide group reverted to normoglycemia after 68 weeks of treatment, compared with 47.8% in the placebo group.30
In the BALANCE study, the rates of GI AEs (ie, nausea, vomiting, diarrhea, dyspepsia, and constipation) with efpeglenatide in the pre-diabetes population were consistent with those in the overall study population23; these rates were similar to those observed with liraglutide and semaglutide in phase II studies in patients with obesity.28 34 In the present analysis, the rates of GI AEs were generally slightly higher in patients with BMI below the median compared with BMI at the median or greater. Although one study found lower weight to be associated with GI AEs in univariate analyses among patients taking liraglutide, another found similar rates of GI AEs in patients with BMI <35 kg/m2 compared with BMI ≥35 kg/m2.35 36 Statistical comparisons of GI AEs between the different efpeglenatide dose groups were not performed in either subgroup analysis.
The limitations of the BALANCE 205 study have been described previously.23 This was a phase II study with associated limitations in terms of sample size and study duration. The small sample size could have limited the statistical power needed to detect significance for some endpoints; this issue of small sample size was exacerbated further by dividing the sample into even smaller subgroups. Small group sizes and large variability may have contributed to the finding that reductions in total cholesterol were significantly greater with all doses of efpeglenatide versus placebo, but the differences in change in LDL, HDL, and triglycerides were not. Finally, adjustments for multiple comparisons were not used for these exploratory analyses. As such, the p values reported are nominal and these results are considered hypothesis-generating. Further research is needed to confirm these outcomes.
Overall, the findings from these subgroup analyses are consistent with those of the BALANCE study and suggest that efpeglenatide leads to improvements in weight reduction in key subgroups of patients with obesity or who are overweight (with comorbidity) and without diabetes. They suggest that treatment effects are independent of baseline characteristics such as patient age or BMI. In addition, the benefits of efpeglenatide on glycemic control in patients with pre-diabetes suggest that it may help patients at risk of developing diabetes to achieve normoglycemia. These promising results would need to be replicated in larger, long-term studies in patients with pre-diabetes. However, while these findings are hypothesis-generating, they support further investigation and development of efpeglenatide in patients with obesity and who are overweight (with comorbidity) and without diabetes, and suggest a potential role of efpeglenatide in the management of pre-diabetes and obesity.