Background
Type 2 diabetes is a condition that causes high levels of sugar in the blood. Blood sugar levels are controlled by insulin, a hormone made by the pancreas. Insulin instructs the liver, muscles and fat cells to remove sugar from the blood and store it. When the pancreas does not make enough insulin, or the body does not respond to insulin, too much sugar stays in the blood. Many medicines for treating type 2 diabetes are available. These aim to lower the amount of sugar in the blood and reduce long-term complications of diabetes. The first medicine that is usually prescribed to people with type 2 diabetes is metformin. Metformin works by reducing the amount of sugar that the liver releases into the blood. It also improves the way the body responds to insulin.
We wanted to find out whether metformin is an effective treatment for type 2 diabetes, and whether it causes any unwanted effects. We also wanted to compare its effects with other antidiabetic medicines, and with diets, exercise or both. The outcomes we were specifically interested in were death, serious unwanted events, health-related quality of life, death from cardiovascular causes, and non-fatal complications of diabetes (for example heart attacks, strokes or kidney failure).
What did we look for?
We searched medical databases for studies that:
— were randomised controlled trials: randomised controlled trials are medical studies where participants are put randomly into one of the treatment groups. This type of study provides the most reliable evidence about whether treatments make a difference;
— included people aged 18 years or older, with type 2 diabetes;
— compared metformin with: a placebo (fake treatment); no treatment; diet programmes to help people eat well; or another medicine that lowers blood sugar levels;
— lasted at least one year.
What did we find?
We found 18 studies with multiple study arms including a total of 10,680 participants. The studies lasted between one year and approximately 11 years. They compared metformin with:
— insulin injections (two studies);
— other medicines that lower blood sugar levels: sulphonylureas (seven studies); thiazolidinediones (seven studies); dipeptidyl peptidase-4 inhibitors (three studies); a glucagon-like peptide-1 analogue (one study); a meglitinide (one study);
— no treatment (two studies).
No study compared metformin with a placebo or with diet or exercise programmes.
Key results
Almost all studies investigated laboratory measurements of blood sugar control like fasting blood glucose. However, there was few information on patient-important outcomes such as death, serious unwanted events, health-related quality of life, death from cardiovascular causes, and non-fatal complications of diabetes when comparing metformin with other medicines that lower blood sugar levels, placebo or no intervention. The available data did not show any clear benefit or harm of metformin.
Four ongoing studies with 5824 participants will report one or more of our outcomes of interest andwill be completed between 2018 and 2024. Furthermore, 24 studies with 2369 participants could be used in a future update of our review once results are published.
Certainty of the evidence
All the studies in this review were poorly conducted. The number of participants in most treatment comparisons was small. Even if studies reported some data we have very little confidence in the results of the comparisons. Future studies may substantially change our findings.
How up to date is this review?
This evidence is up to date as of 2 December 2019.
There is no clear evidence whether metformin monotherapy compared with no intervention, behaviour changing interventions or other glucose-lowering drugs influences patient-important outcomes.
Worldwide, there is an increasing incidence of type 2 diabetes mellitus (T2DM). Metformin is still the recommended first-line glucose-lowering drug for people with T2DM. Despite this, the effects of metformin on patient-important outcomes are still not clarified.
To assess the effects of metformin monotherapy in adults with T2DM.
We based our search on a systematic report from the Agency for Healthcare Research and Quality, and topped-up the search in CENTRAL, MEDLINE, Embase, WHO ICTRP, and ClinicalTrials.gov. Additionally, we searched the reference lists of included trials and systematic reviews, as well as health technology assessment reports and medical agencies. The date of the last search for all databases was 2 December 2019, except Embase (searched up 28 April 2017).
We included randomised controlled trials (RCTs) with at least one year's duration comparing metformin monotherapy with no intervention, behaviour changing interventions or other glucose-lowering drugs in adults with T2DM.
Two review authors read all abstracts and full-text articles/records, assessed risk of bias, and extracted outcome data independently. We resolved discrepancies by involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall certainty of the evidence by using the GRADE instrument.
We included 18 RCTs with multiple study arms (N = 10,680). The percentage of participants finishing the trials was approximately 58% in all groups. Treatment duration ranged from one to 10.7 years. We judged no trials to be at low risk of bias on all 'Risk of bias' domains. The main outcomes of interest were all-cause mortality, serious adverse events (SAEs), health-related quality of life (HRQoL), cardiovascular mortality (CVM), non-fatal myocardial infarction (NFMI), non-fatal stroke (NFS), and end-stage renal disease (ESRD).
Two trials compared metformin (N = 370) with insulin (N = 454). Neither trial reported on all-cause mortality, SAE, CVM, NFMI, NFS or ESRD. One trial provided information on HRQoL but did not show a substantial difference between the interventions.
Seven trials compared metformin with sulphonylureas. Four trials reported on all-cause mortality: in three trials no participant died, and in the remaining trial 31/1454 participants (2.1%) in the metformin group died compared with 31/1441 participants (2.2%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on SAE: in two trials no SAE occurred (186 participants); in the other trial 331/1454 participants (22.8%) in the metformin group experienced a SAE compared with 308/1441 participants (21.4%) in the sulphonylurea group (very low-certainty evidence). Two trials reported on CVM: in one trial no CVM was observed and in the other trial 4/1441 participants (0.3%) in the metformin group died of cardiovascular reasons compared with 8/1447 participants (0.6%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on NFMI: in two trials no NFMI occurred, and in the other trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 15/1441 participants (1.0%) in the sulphonylurea group (very low-certainty evidence). One trial reported no NFS occurred (very low-certainty evidence). No trial reported on HRQoL or ESRD.
Seven trials compared metformin with thiazolidinediones (very low-certainty evidence for all outcomes). Five trials reported on all-cause mortality: in two trials no participant died; the overall RR was 0.88, 95% CI 0.55 to 1.39; P = 0.57; 5 trials; 4402 participants). Four trials reported on SAE, the RR was 0,95, 95% CI 0.84 to 1.09; P = 0.49; 3208 participants. Four trials reported on CVM, the RR was 0.71, 95% CI 0.21 to 2.39; P = 0.58; 3211 participants. Three trial reported on NFMI: in two trials no NFMI occurred and in one trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 25/1456 participants (1.7%) in the thiazolidinedione group. One trial reported no NFS occurred. No trial reported on HRQoL or ESRD.
Three trials compared metformin with dipeptidyl peptidase-4 inhibitors (one trial each with saxagliptin, sitagliptin, vildagliptin with altogether 1977 participants). There was no substantial difference between the interventions for all-cause mortality, SAE, CVM, NFMI and NFS (very low-certainty evidence for all outcomes).
One trial compared metformin with a glucagon-like peptide-1 analogue (very low-certainty evidence for all reported outcomes). There was no substantial difference between the interventions for all-cause mortality, CVM, NFMI and NFS. One or more SAEs were reported in 16/268 (6.0%) of the participants allocated to metformin compared with 35/539 (6.5%) of the participants allocated to a glucagon-like peptide-1 analogue. HRQoL or ESRD were not reported.
One trial compared metformin with meglitinide and two trials compared metformin with no intervention. No deaths or SAEs occurred (very low-certainty evidence)
no other patient-important outcomes were reported.
No trial compared metformin with placebo or a behaviour changing interventions.
Four ongoing trials with 5824 participants are likely to report one or more of our outcomes of interest and are estimated to be completed between 2018 and 2024. Furthermore, 24 trials with 2369 participants are awaiting assessment.