Metformin, the first-line therapy for type 2 diabetes and prediabetes, is widely recognized for lowering blood glucose and improving insulin sensitivity. However, it can cause gastrointestinal side effects and may lose its effectiveness with long-term use. Studies are increasingly exploring natural agent as adjunct therapies to boost outcomes, reduce complications, and delay disease progression.
A12-week placebo-controlled trial tested whether a citrus bioflavonoid-based nutraceutical could complement metformin therapy. The participants were assigned to receive either metformin plus the supplement (250 mg/day) or metformin with placebo. This study then monitored a broad range of outcomes, including glucose control, inflammation, oxidative stress, hormonal responses, and nutritional-clinical indicators.
By the end of the study, participants in the nutraceutical group showed notable metabolic improvements when compared with the placebo group. These included a 5% reduction in two-hour glucose levels during the oral glucose tolerance test (OGTT) and preservation of active GLP-1 levels, which is a hormone critical for insulin secretion. In contrast, the placebo group experienced declining GLP-1 activity and rising insulin resistance.
The levels of TNF-α, an inflammatory cytokine, dropped by 12%, while plasma antioxidant capacity increased by 7.5%, suggesting enhanced defense against oxidative damage. The participants taking the supplement lost weight, reduced fat mass, and lowered their body mass index (BMI). Although the changes were modest, they were statistically significant, indicating real metabolic benefits.
The nutraceutical group experienced a 4% reduction in systolic blood pressure, which researchers linked to higher dietary potassium intake and strengthened antioxidant capacity.
Also, the results highlight the potential role of citrus flavonoids as a nutritional adjunct to metformin therapy in individuals with prediabetes. The benefits spanned across glycemic control, hormonal stability, inflammation, oxidative balance, and cardiovascular support. Overall, this study found short-term effects that are promising, longer trials are needed to determine sustained efficacy and mechanisms of action.
Reference:
Cesar, T., Oliveira, M. R., Sandrim, V., Mendes, A., Bruder, R., Oliveira, R., Sivieri, K., & Milenkovic, D. (2025). Citrus flavonoid supplement enhances glycemic and metabolic control in prediabetic patients on metformin: a randomized controlled trial. Frontiers in Nutrition, 12(1639901), 1639901. https://doi.org/10.3389/fnut.2025.1639901
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