Effects of exercise, metformin and their combination on glucose metabolism in individuals with abnormal glycaemic control: a systematic review and network meta-analysis

Objective To compare the efficacy of exercise, metformin and their combination on glucose metabolism in individuals with abnormal glycaemic control. Design Systematic review and network meta-analysis. Data sources Embase, Web of Science, PubMed/MEDLINE and SPORTDiscus. Eligibility criteria Randomised controlled trials involving exercise, metformin or their combined treatments in individuals with prediabetes or type 2 diabetes mellitus (T2DM) were included. Outcomes included haemoglobin A1c (HbA1c), 2-hour glucose during oral glucose tolerance test, fasting glucose, fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR). Results 407 articles with 410 randomised controlled trials (n=33 802) were included. In prediabetes, the exercise showed greater efficacy than metformin on HbA1c levels (mean difference −0.16%, 95% CI (−0.23 to −0.09) vs −0.10%, 95% CI (−0.21 to 0.02)), 2-hour glucose (−0.68 mmol/L, 95% CI (−0.97 to −0.39) vs 0.01 mmol/L, 95% CI (−0.38 to 0.41)) and HOMA-IR (−0.54, 95% CI (−0.71 to −0.36) vs −0.23, 95% CI (−0.55 to 0.10)), while the efficacy on fasting glucose was comparable (−0.26 mmol/L, 95% CI (−0.32 to −0.19) vs −0.33 mmol/L, 95% CI (−0.45 to −0.21)). In T2DM, metformin was more efficacious than exercise on HbA1c (−0.88%, 95% CI (−1.07 to −0.69) vs −0.48%, 95% CI (−0.58 to −0.38)), 2-hour glucose (−2.55 mmol/L, 95% CI (−3.24 to −1.86) vs −0.97 mmol/L, 95% CI (−1.52 to −0.42)) and fasting glucose (−1.52 mmol/L, 95% CI (−1.73 to −1.31) vs −0.85 mmol/L, 95% CI (−0.96 to −0.74)); exercise+metformin also showed greater efficacy in improving HbA1c (−1.23%, 95% CI (−2.41 to –0.05)) and fasting glucose (−2.02 mmol/L, 95% CI (−3.31 to –0.74)) than each treatment alone. However, the efficacies were modified by exercise modality and metformin dosage. Conclusion Exercise, metformin and their combination are efficacious in improving glucose metabolism in both prediabetes and T2DM. The efficacy of exercise appears to be superior to metformin in prediabetes, but metformin appears to be superior to exercise in patients with T2DM. PROSPERO registration number CRD42023400622.