Comparative efficacy and safety of oral hypoglycaemic drugs as adjunctive therapy in the management of type 1 diabetes mellitus: A systematic review and meta-analysis.

Aims: To evaluate the efficacy and safety of oral hypoglycaemic drugs (OHDs) as an adjunct to insulin therapy in patients with type 1 diabetes mellitus (T1DM), addressing the need for optimized glycaemic control and reduced insulin dependency.

Materials and methods: A systematic literature search was conducted across PubMed, Embase and the Cochrane Library to identify randomized clinical trials (RCTs) published up to October 31, 2024. Primary outcomes included changes in glycated haemoglobin (HbA1c) and hypoglycaemia risk. Secondary endpoints assessed six efficacy and seven safety measures using meta-analysis. Treatment effects were quantified using weighted mean difference (WMD) and risk ratios (RRs) with 95% confidence intervals (CIs). Subgroup and indirect comparisons were performed to explore variations across patient demographics and drug classes.

Results: The meta-analysis included 51 RCTs with 8664 participants. Overall, compared with placebo, OHDs demonstrated significant reductions in HbA1c (WMD -0.32%, p < 0.001), fasting plasma glucose (WMD -0.91 mmol/L, p < 0.001), postprandial plasma glucose (WMD -2.08 mmol/L, p < 0.001), daily insulin dosage(WMD -4.88 IU/day, p < 0.001) and body weight (WMD -1.89 kg, p < 0.001), while improving the percentage time in the target glucose range of 3.9-10.0 mmol/L (WMD 6.04%, p = 0.04). However, no significant change was observed in BMI (WMD -0.18 kg/m², p = 0.08). Compared with placebo, OHDs did not increase the risk of hypoglycaemia (RR 1.01, p = 0.08), severe hypoglycaemia (RR 0.95, p = 0.73) or nocturnal hypoglycaemia (RR 0.97, p = 0.24), but were associated with elevated risks of serious adverse events (RR 1.30, p = 0.005), discontinuation due to adverse events (RR 1.88, p < 0.001), genital tract infection (RR 3.30, p < 0.001), gastrointestinal side effects (RR 1.98, p < 0.001) and ketoacidosis (RR 3.14, p < 0.001). Indirect comparisons favoured alpha glucosidase inhibitor (AGI) over thiazolidinediones for HbA1c reduction (mean difference -0.46%, p < 0.001). Subgroup analysis revealed greater fasting glucose reduction in adults compared to children/adolescents (WMD -1.15 mmol/L vs. -0.26 mmol/L, p of group difference = 0.02).

Conclusions: OHDs as adjunctive therapy in T1DM significantly improve glycaemic control and reduce insulin requirements. However, their use is associated with notable safety concerns, particularly ketoacidosis and other adverse events. Clinicians must conduct thorough risk assessments and tailor treatment plans to individual patient profiles to balance efficacy and safety. Future research should focus on long-term outcomes and strategies to mitigate adverse effects.