The long-awaited GRADE trial showed only small differences in outcomes between insulin, GLP-1 receptor agonists, sulfonylureas and DPP-4 inhibitors. 

Selecting a second glucose-lowering agent for patients who are already taking metformin is a commonly encountered decision in clinical practice, but head-to-head comparisons of medications have been limited. Researchers conducted the US multicentre GRADE trial to compare the effect of four medications, added to metformin, in about 5000 patients with type 2 diabetes.

Participants had recent-onset diabetes (mean duration, four years), were taking only metformin and had baseline glycated haemoglobin (HbA1c) values of 51 to 69 mmol/mol, mean 58 mmol/mol (6.8% to 8.5%; mean, 7.5%). Six per cent of patients had known cardiovascular disease. Participants were randomised to add a sulfonylurea (glimepiride), a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin), a glucagon-like peptide-1 (GLP-1) receptor agonist (liraglutide) or insulin glargine.

Key results during the mean five-year follow up were as follows:

• a minority of patients in all groups had HbA1c values consistently lower than 53mmol/mol (7.0%). More patients who took liraglutide (32%) or glargine (33%) maintained HbA1c below 53mmol/mol (7.0%), compared with those who took glimepiride (28%) or sitagliptin (23%)
• severe hypoglycaemia, although rare, occurred most frequently in patients taking glimepiride (i.e. in 2.2% of glimepiride users vs about 1% of other groups)
• incidences of major adverse cardiovascular events (MACE; i.e. nonfatal myocardial infarction, stroke or death from cardiac cause), hypertension, dyslipidaemia, albuminuria or peripheral neuropathy were similar among groups
• incidence of any adverse cardiovascular event (i.e. MACE, unstable angina or heart failure requiring hospitalisation, and revascularisation) was less common with liraglutide: 6.6% of liraglutide users, compared with 9% of patients in other groups (number needed to treat with liraglutide for five years to prevent one event, about 40).

Comment: Overall, GRADE showed few differences between these four medications. Liraglutide produced modestly better cardiovascular outcomes and equivalent or better glycaemic results, whereas glimepiride was slightly less safe than the other medications. A few caveats: retinopathy was not studied, the trial was underpowered to detect differences in albuminuria, and sodium–glucose cotransporter-2 (SGLT-2) inhibitors were not included (they were not yet FDA approved). Furthermore, results cannot be generalised to patients with longer-standing diabetes or poorer baseline glycaemic control. In everyday practice, selection of a second agent is often governed less by efficacy and more by drug costs: although outcome differences reported in GRADE were modest, there are big differences in cost between these medications.
MOLLY S. BRETT, MD
Instructor in Medicine, University of Colorado, Boulder, USA.

The GRADE Study Research Group. Glycemia reduction in type 2 diabetes – microvascular and cardiovascular outcomes. N Engl J Med 2022; 387: 1075-1088.
The GRADE Study Research Group. Glycemia reduction in type 2 diabetes – glycemic outcomes. N Engl J Med 2022; 387: 1063-1074.

This summary is taken from the following Journal Watch title: General Medicine.