Vascular and metabolic effects of metformin added to insulin therapy in patients with type 1 diabetes: A systematic review andmeta‐analysis

Abstract

Background The incidence of type 1 diabetes mellitus (T1DM) is increasing among youth worldwide, translating to an increased risk ofearly‐onset cardiovascular disease (CVD). Mounting studies have shown that metformin may reduce maximal carotidintima‐media thickness (cIMT), improve insulin resistance and metabolic control in subjects with T1DM, and thus, may extend cardioprotective benefits. This systematic review and meta‐analysis was performed to assess the efficacy and safety of metformin added to insulin therapy on reducing CVD risks and improving metabolism in T1DM. Methods PubMed, EMBASE, and the Cochrane Library were systematically searched for randomized controlled trials (RCTs) that compared metformin and insulin combination (duration ≥3 months) to insulin treatment alone in T1DM. Data were expressed as weighted/standardized mean differences (MDs/SMDs) for continuous outcomes and risk ratios (RRs) for dichotomous outcomes, along with 95% confidence intervals (CIs). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to evaluate the overall certainty of the evidence. Results Nineteen RCTs (n = 1540) met the eligibility criteria. Metformin treatment significantly reduced carotid artery intima‐media thickness (MD −0.06 mm [95% CI −0.88, −0.28], P < .001). Though no significant difference was found in insulin sensitivity (SMD 2.21 [95% CI −1.88, 6.29], P = .29), the total daily insulin dosage (SMD −0.81 [95% CI −1.25, −0.36], P < .001) along with traditional CVD risk factors showed improvement by better glycaemic control, partial lipid profiles, diastolic blood pressure, and limited weight gain, with neutral effect on diabetic ketoacidosis, lactic acidosis, and hypoglycaemia. However, metformin therapy increased the incidence of gastrointestinal adverse events. Conclusions Metformin with insulin has the potential to retard the progression of atherosclerosis and provides better metabolic control in patients with T1DM, and thus, providing a potential therapeutic strategy for patients with T1DM on reducing CVD risks.

The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

“…Metformin has been evaluated in numerous small trials in people with type 1 diabetes with hopes that its insulin-sensitising properties would improve glycaemic management and/or reduce cardiovascular risk [ 244 , 245 ]. The largest study to date assessed the use of metformin 1 g, twice daily, in 428 people with type 1 diabetes who were treated for 3 years, with a primary endpoint of changes in mean carotid intima–media thickness, a marker of cardiovascular disease risk.…”

Metformin improves glycemic variability in adults with type 1 diabetes mellitus: an open-label randomized control trial

“…These results align well with previous research on youth with T1DM ( 16 ). In contrast, conflicting conclusions were reported by Liu et al who found improvement in partial lipid profiles and diastolic blood pressure in T1DM patients with additional metformin ( 24 ).…”

“…According to the previous literature, metformin supposedly increases the risk of gastrointestinal adverse effects and may induce more hypoglycemia events in patients with T1DM ( 24 , 40 ). In the present study, no severe adverse events were observed, and only four participants (11.8%) in the metformin group had the insulin dose thereof down escalated due to gastrointestinal side effects.…”

“…Conversely, new evidence has revealed modest improvements in the HbA1c level of T1DM patients with adjuvant metformin therapy. One meta-analysis highlighted that metformin reduced the HbA1c level by 0.26% in T1DM ( 24 ). These discrepancies may be attributed to different study durations with a 3-month cutoff point, implying that the reduction in the HbA1c level caused by metformin could not sustain over time ( 24 ).…”

“…One meta-analysis highlighted that metformin reduced the HbA1c level by 0.26% in T1DM ( 24 ). These discrepancies may be attributed to different study durations with a 3-month cutoff point, implying that the reduction in the HbA1c level caused by metformin could not sustain over time ( 24 ). Moreover, a study of T1DM patients under real-world conditions reported that the HbA1c level decreased after a 1-year follow-up owing to scheduled follow-up visits rather than additional metformin treatment ( 25 ).…”