Fifty-five randomized controlled trials with 16,610 participants evaluated the efficacy and safety of anti-prediabetic drugs.
Most anti-prediabetic drugs significantly reduced hemoglobin A1c (HbA1c) levels, fasting plasma glucose (FPG), weight, and body mass index (BMI) compared to placebo.
2.4 mg of semaglutide showed the highest weight loss (mean difference -13.59 kg) and a notable reduction in HbA1c (mean difference -0.39%).
15 mg of tirzepatide effectively lowered FPG (mean difference -9.58 mg/dL) and was potent in reducing BMI.
30 mg of pioglitazone demonstrated strong efficacy in lowering lipid levels and FPG.
There was no significant difference in the incidence of adverse events across interventions, although 100 mg of sitagliptin had a higher incidence of serious adverse events.
GLP-1 receptor agonists, GIP/GLP-1 receptor agonists, and thiazolidinediones showed favorable effects on management with acceptable safety.
Simplified
BACKGROUND: refers to the transitional stage from normal glucose metabolism to diabetes. The International Diabetes Federation guidelines reported that, as of 2024, approximately 1.12 billion people globally were in the prediabetes stage. Without intervention, individuals with prediabetes are highly likely to progress to type 2 diabetes mellitus. It can be seen that prediabetes is posing a threat to human health and life and leads to a significant global public health concern.
METHODS: PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched before March 29, 2025. Eligible randomized controlled trials (RCTs) enrolled adults with prediabetes, compared the efficacy and safety of placebo and anti-prediabetic drugs (e.g., metformin, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and thiazolidinedione) with a follow-up duration of at least 12 weeks. was employed in statistical analysis.
RESULTS: Fifty-five eligible RCTs involving 37 interventions with 16,610 participants were included in this study. Compared with placebo, most anti-prediabetic drugs significantly reduced levels of hemoglobin A1c (HbA1c) (mean difference (MD), - 0.94 ~ - 0.27%), fasting plasma glucose (FPG) (MD, - 26.42 ~ - 0.15 mg/dL), weight loss (WL) (MD, - 13.59 ~ - 5.99 kg) and body mass index (BMI) (MD, - 4.50 ~ - 0.08 kg/m). Specifically, 2.4 mg of semaglutide SC demonstrated the most optimal efficacy in WL (MD - 13.59 kg; 95% confidence interval (CI) - 17.30 to - 9.91) and favorable efficacy in lowering HbA1c (MD - 0.39%; 95% CI - 0.55 to - 0.25); 15 mg of tirzepatide showed significant efficacy in lowering FPG (MD - 9.58 mg/dL; 95% CI - 12.00 to - 7.15), and potent efficacy in lowering BMI. Thirty milligrams of pioglitazone showed excellent efficacy in lowering lipid and FPG. Among the interventions, there was no significant difference in the incidence of adverse events (AEs), while 100 mg of sitagliptin demonstrated higher incidence of serious adverse events (SAEs). 2
CONCLUSIONS: Among all the included interventions, GLP-1RAs, GIP/GLP-1RAs, and TZDs demonstrated favorable anti-prediabetic efficacy and acceptable safety. 2.4 mg of semaglutide SC and 15 mg of tirzepatide were the best option among the included interventions considering favorable glucose and BMI control.
Declarations. Ethics approval and consent to participate: As this study did not involve clinical trials or animal experiments, and had no access to individual participants or their personal information, obtaining consent for publication was not applicable. Consent for publication: Current study did not involve individual participants directly, so there was no access to participants or their personal information. Therefore, obtaining consent for publication was not applicable. There are no patient representatives or members of the public attend the study’s planning, design, conduct, or reporting. Competing interests: The authors declare no competing interests.
