Diabetes mellitus is a progressive disorder of glucose metabolism. It is estimated that about 285 million people between the ages of 20 and 79 years had diabetes worldwide in 2010, or 5% of the adult population. Type 2 diabetes may occur with obesity, hypertension, and dyslipidaemia (the metabolic syndrome), which are powerful predictors of cardiovascular disease. Without adequate blood-glucose-lowering treatment, blood glucose levels may rise progressively over time in people with type 2 diabetes. Microvascular and macrovascular complications may develop.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of blood-glucose-lowering medications in adults with type 2 diabetes? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 194 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: alpha-glucosidase inhibitors (AGIs), combination treatment (single, double, and triple), dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogues, insulins (including conventional [human] and analogue, different regimens, different length of action), meglitinides, metformin, sulphonylureas, and thiazolidinediones.
Diabetes mellitus affects about 6.5% of people aged 20 to 79 years worldwide. In 2010, an estimated 285 million people have diabetes, over 85% of whom have type 2 diabetes.
Type 2 diabetes is often associated with obesity, hypertension, and dyslipidaemia, which are all powerful predictors of cardiovascular disease. For that reason, the treatment of type 2 diabetes requires a multifactorial approach, including lifestyle advice, treatment of hypertension, and lowering of lipid levels.
Without adequate blood-glucose-lowering treatment, blood glucose levels may rise progressively over time in people with type 2 diabetes. Microvascular and macrovascular complications may develop.
Metformin reduces HbA1c effectively compared with placebo.
The UK Prospective Diabetes Study (UKPDS) RCT found that metformin may be moderately protective against mortality and cardiovascular morbidity, but further high-quality studies are needed.We found no evidence to suggest that metformin increases the risk of lactic acidosis.
Sulphonylureas reduce HbA1c by 1% compared with placebo, and they may reduce microvascular complications compared with diet alone. They can cause weight gain and hypoglycaemia. One review found that the risk of hypoglycaemia was highest with glibenclamide compared with other second-generation sulphonylureas.
The effectiveness of the combination of metformin and sulphonylurea on mortality and morbidity is unknown.
Meglitinides reduce HbA1c by about 0.4–0.9% compared with placebo, but robust data are sparse.
Alpha-glucosidase inhibitors reduce HbA1c by about 0.8% compared with placebo. We found no reports of dangerous adverse effects.
Thiazolidinediones reduce HbA1c by 1.0% compared with placebo but may increase the risk of congestive heart failure and bone fractures. Rosiglitazone increases the risk of MI.
DRUG ALERT: Rosiglitazone has been withdrawn from the market in many countries because the benefits of treatment are no longer thought to outweigh the risks.
Dipeptidyl peptidase-4 (DPP-4) inhibitors reduce HbA1c by about 0.6–0.7% compared with placebo. We found no long-term data on effectiveness and safety.
Glucagon-like peptide-1 (GLP-1) analogues reduce HbA1c compared with placebo and result in weight loss. We found no long-term data on effectiveness and safety.
Combined oral drug treatment may reduce HbA1c levels more than monotherapy, but increases the risk of hypoglycaemia.
Insulin improves glycaemic control in people with inadequate control of HbA1c on oral drug treatment, but is associated with weight gain, and an increased risk of hypoglycaemia.
Adding metformin to insulin may reduce HbA1c levels compared with insulin alone, with less weight gain.
Insulin analogues, short-acting, long-acting, and combined in various regimens, seem no more effective than conventional (human) insulin in reducing HbA1c levels. However, in people presenting with recurrent hypoglycaemic episodes, long-acting insulin analogues may be preferred above human insulin.
Long-acting insulin analogues seem equally effective at reducing HbA1c.
There is lack of evidence about the effectiveness of various insulin analogue regimens after once-daily long-acting insulin has failed.
The effectiveness of insulin basal bolus regimens is not well established.