Metformin added to insulin therapy for type 1 diabetes mellitus in adolescents

Diabetes mellitus is a metabolic disorder resulting from a defect in insulin secretion, insulin action, or both. Metabolic control (glycaemic control, that is long-term blood glucose levels as measured by glycosylated haemoglobin A1c (HbA1c)) often deteriorates during puberty in children with type 1 diabetes possibly due to the development of insulin resistance (insulin does not work effectively in the tissues anymore) and this creates a great need for alternative therapeutic strategies in those patients. We searched for randomised controlled trials of good quality that studied the effects of metformin added to insulin therapy for type 1 diabetes mellitus in adolescents on glycaemic control, insulin sensitivity, health-related quality of life, side-effects as well as effects on body weight, serum lipids and insulin dose.
Only two trials (60 participants, three months treatment) could be included. Both studies suggested that metformin plus insulin treatment lowered HbA1c somewhat more than placebo plus insulin. Improvement in insulin sensitivity, body weight or serum lipids were not seen in either study. However, one study showed a small decrease in insulin dosage by 10%. Side effects were mainly gastrointestinal upset in both studies and hypoglycaemia (low blood sugar) in one study. There was no information on health-related quality of life, costs, morbidity or mortality in either study.

Authors' conclusions: 

There is some evidence suggesting improvement of metabolic control in poorly controlled adolescents with type 1 diabetes, on addition of metformin to insulin therapy. Stronger evidence is required from larger studies, carried out over longer time periods to document the long-term effects on metabolic control, health-related quality of life as well as morbidity and mortality in those patients.

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Background: 

In adolescents with type 1 diabetes, insulin resistance likely plays a role in the deterioration of metabolic control. In type 1 diabetes, addition of metformin to insulin therapy, to improve insulin sensitivity, has been assessed in a few trials involving few patients or in uncontrolled studies of short duration. No systematic reviews are available up to date to summarize the evidence about metformin addition to insulin therapy in adolescents with type 1 diabetes.

Objectives: 

To assess the effects of metformin added to insulin therapy for type 1 diabetes mellitus in adolescents.

Search strategy: 

We searched The Cochrane Library, MEDLINE and EMBASE. We also searched databases of ongoing trials, reference lists of relevant reviews, and we contacted experts, authors and manufacturers.

Selection criteria: 

Any randomised controlled trial (RCT) of at least three months duration of treatment comparing metformin added to insulin therapy versus insulin therapy alone in adolescents with type 1 diabetes was included. Cross-over and quasi-randomised controlled trials were excluded.

Data collection and analysis: 

Two reviewers read all abstracts, assessed quality and extracted data independently. Authors were contacted for missing data.

Main results: 

Only two trials (60 participants) investigating the effect of metformin added to insulin therapy for three months in adolescents with poorly controlled type 1 diabetes could be included. Meta-analysis was not possible due to the clinical and methodological heterogeneity of data. Both studies suggested that metformin treatment lowered glycosylated haemoglobin A1c (HbA1c) in adolescents with type 1 diabetes and poor metabolic control. Improvements in insulin sensitivity, body composition or serum lipids were not documented in either study, however, one study showed a decrease in insulin dosage by 10%. Adverse effects were mainly gastrointestinal in both studies and hypoglycaemia in one study. No data on health-related quality of life, all-cause mortality or morbidity are currently available.

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