Trial GRADEs effectiveness of four common second-line type 2 diabetes drugs
medwireNews: Findings from the GRADE study, a head-to-head comparison of four commonly used diabetes drugs given together with metformin, suggest that liraglutide and insulin may result in better glycemic control than glimepiride and sitagliptin among people with type 2 diabetes.
Introducing the trial at the virtual ADA 81st Scientific Sessions, study chair David Nathan (Massachusetts General Hospital, Boston, USA) said that at present there are “almost no head-to-head comparisons to guide the choice of which medications to add to metformin” and “very little data to guide individualization of therapy.”
Therefore, “GRADE was designed as a comparative effectiveness trial with the potential for immediate translation,” using agents approved by the US FDA in 1999–2010 that were prescribed and adjusted according to their labeling, he added.
Deborah Wexler discusses the findings from GRADE, a head-to-head study comparing glimepiride, sitagliptin, insulin glargine, and liraglutide when used in combination with metformin for the treatment of type 2 diabetes (5:22).
The phase 3 trial included 5047 participants from the USA with a type 2 diabetes duration of less than 10 years (median 4.2 years) and glycated hemoglobin (HbA1c) levels of 6.8–8.5% (51–69 mmol/mol) who were treated with metformin monotherapy at a dose of at least 500 mg/day at the time of screening.
Metformin was increased to a target dose of 2000 mg/day as tolerated during a 6–12-week run-in period, with a minimum dose of 1000 mg/day at study baseline. Participants were then randomly assigned to receive the sulfonylurea glimepiride, the dipeptidyl peptidase-4 inhibitor sitagliptin, the glucagon-like peptide-1 receptor agonist liraglutide, or insulin glargine in addition to continued metformin treatment.
Presenting the primary metabolic outcome results, John Lachin (George Washington University, Washington, DC, USA) said that the proportion of participants who developed HbA1c levels above 7.0% (53 mmol/mol) during an average follow-up of approximately 5 years was lowest in the insulin glargine and liraglutide groups (67% and 68%, respectively), followed by the glimepiride arm (72%), and highest in the sitagliptin group (77%).
In pairwise comparisons, glargine and liraglutide were associated with a significantly lower risk for the primary metabolic outcome than sitagliptin and glimepiride, while sitagliptin was associated with a significantly higher risk than all the other medications.
In accordance with these findings, rates of any cardiovascular (CV) disease – defined as major adverse CV events, heart failure hospitalization, unstable angina, transient ischemic attack, or revascularization – were lowest in the liraglutide and glargine arms (5.8% and 7.6%, respectively), followed by the glimepiride (8.0%) and sitagliptin (8.6%) groups. Rates of microvascular complications including nephropathy and distal sensory polyneuropathy were comparable in all four study arms, however.
The GRADE investigators cautioned that the adjudication of CV events was not complete at the time of reporting, and therefore the findings should be considered preliminary.
In the safety analysis, rates of serious adverse events were comparable across the four groups, ranging from 33% with liraglutide to 37% with glimepiride. Severe hypoglycemia occurred more commonly among participants treated with glimepiride (2.3%) compared with the other treatments (0.7–1.4%). There were no significant between-group differences in rates of pancreatitis or pancreatic cancer.
Commenting on the GRADE results, David Matthews (University of Oxford, UK) commended the investigators for their “ethically straightforward” trial of widely used agents with adjudicated endpoints.
He noted, however, that the trial did not include sodium-glucose cotransporter-2 inhibitors, which are commonly used in current clinical practice, and that the findings may not be generalizable to people with newly diagnosed or longstanding type 2 diabetes.
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Patrick Holmes discusses whether the GRADE study answers the question of which type 2 diabetes medication should be used after metformin, and comments on the generalizability of the findings (3:54).