GRADE: Insulin glargine, liraglutide better maintain glycemic control than other agents
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Insulin glargine and the GLP-1 receptor agonist liraglutide are more effective at achieving an HbA1c of less than 7% than the sulfonylurea glimepiride or the DPP-IV inhibitor sitagliptin, according to data from the GRADE trial.
Researchers conducted a head-to-head comparison of four glucose-lowering drugs used by adults with type 2 diabetes. All four medications helped to lower HbA1c and were deemed safe, but more participants randomly assigned insulin glargine (Lantus, Sanofi) and liraglutide (Victoza, Novo Nordisk) reached the primary metabolic outcome of an HbA1c of less than 7% than those randomly assigned glimepiride or sitagliptin (Januvia, Merck).
“A limitation of our trial is the exclusion of thiazolidinediones and the SGLT2 inhibitor class of glucose-lowering medications, owing to safety concerns at the time of planning and the timing of FDA approval, respectively. Although the selection of single agents within the four medication classes facilitated the conduct of the trial, this selection limited extrapolation of the current results to other medications within the classes,” the researchers wrote in study results published in The New England Journal of Medicine.
“Each of the four medications under study lowered glycemia as measured by HbA1c levels,” David M. Nathan, MD, chair of the GRADE trial, director of the Diabetes Center at Massachusetts General Hospital and professor of medicine, Harvard Medical School, told Healio. “However, the two injectable medications, glargine and liraglutide, were more effective in maintaining HbA1c levels of less than 7% than glimepiride and sitagliptin. There were other differences among the medications. Liraglutide resulted in more weight loss than the other three medications but was accompanied by more gastrointestinal side effects. Although severe hypoglycemia was rare, it was more common with glimepiride. Finally, although the GRADE cohort was at relatively low risk for cardiovascular disease, liraglutide appeared to be associated with a lower occurrence of any CVD events than the other three medications.”
Nathan and colleagues enrolled 5,047 adults with type 2 diabetes for less than 10 years at screening who were taking at least 500 mg metformin daily without the use of glucose-lowering medications for at least 6 months (mean age, 57.2 years; 63.6% men; 65.7% white). Participants completed a run-in period in which metformin was increased to at least 1,000 mg per day with a target of 2,000 mg per day. Participants were randomly assigned insulin glargine with an initial dose of 20 U per day and adjusted according to glucose levels; 1 mg to 2 mg glimepiride per day with adjustments up to 8 mg per day according to glucose levels; liraglutide with a starting dose of 0.6 mg per day escalating up to 1.8 mg depending on gastrointestinal adverse events; or 100 mg sitagliptin per day with the dose adjusted according to kidney function. The primary outcome was primary metabolic failure of the treatment, defined as reaching an HbA1c of 7% or higher. The secondary outcome was reaching an HbA1c of 7.5% or higher.
Insulin, liraglutide more effective than other agents
Participants were followed for a mean of 5 years. During follow-up, 71% reached an HbA1c of 7% or higher. Adults taking insulin glargine had a lower risk of reaching an HbA1c of 7% or higher than those taking sitagliptin (HR = 0.71; 95% CI, 0.64-0.78; P < .001) or glimepiride (HR = 0.89; 95% CI, 0.81-0.98; P = .02). The glimepiride group had a higher risk for a HbA1c of greater than 7% than the liraglutide group (HR = 1.15; 95% CI, 1.04-1.27; P < .01) and a lower risk than those taking sitagliptin (HR = 0.79; 95% CI, 0.72-0.88; P < .001). Adults taking liraglutide had a lower risk for an HbA1c of less than 7% than the sitagliptin group (HR = 0.69; 95% CI, 0.63-0.76; P < .001).
Findings for the secondary outcome were similar to the primary outcome, with 55% of those in the sitagliptin group reaching an HbA1c of 7.5% or higher compared with 50% or fewer participants in the other three groups.
A higher proportion of adults using glimepiride (38%) and insulin glargine (37%) experienced adverse events compared with liraglutide (34%). Severe hypoglycemia was most prevalent in those taking glimepiride (2.2%) compared with insulin glargine (1.3%), liraglutide (1%) or sitagliptin (0.7%).
“All four medications had an acceptable safety profile, as expected with FDA-approved medications,” the researchers wrote. “However, glargine and liraglutide were more effective at maintaining HbA1c levels in the target range over time. This translated into a HbA1c of less than 7% for approximately a half-year longer with glargine and liraglutide than with sitagliptin, which was the least effective treatment in maintaining target HbA1c levels.”
Lower risk for CVD with liraglutide
In a secondary analysis of GRADE data published in NEJM, researchers analyzed the effect of the four glucose-lowering agents on microvascular and CV outcomes. Outcomes analyzed during follow-up included hypertension, dyslipidemia, moderately or severely increased albuminuria, CV events and CV death.
There were no differences in microvascular outcomes between the four groups. Mean systolic blood pressure was higher in those taking insulin glargine (129.1 mm Hg) and glimepiride (128.7 mm Hg) compared with those taking sitagliptin (128.1 mm Hg) and liraglutide (126.9 mm Hg). The liraglutide group had a lower risk for any CVD than the other three groups combined (HR = 0.71; 95% CI, 0.56-0.9). However, there were no differences in major adverse CV events, heart failure hospitalization or CV death between the four therapies.
“The reason for conducting the GRADE study was to perform a comprehensive head-to-head comparison of the major glucose-lowering medications added to metformin,” Nathan said. “The relative benefits of glargine and liraglutide in lowering glycemia over time must be balanced against the need for injection therapy, their expense and side effects, such as increased gastrointestinal side effects with liraglutide. The results of GRADE should be used in discussions between clinicians and their patients to determine which medication to use for the individual patient.”
Older agents ‘still have a role’
In a related editorial published in NEJM, Lars Rydén, MD, senior professor of cardiology at the Karolinska Institute in Sweden, and Eberhard Standl, MD, PhD, professor of medicine at the Munich Diabetes Research Group e.V. at Helmholtz Centre in Germany, wrote that the overall findings in GRADE were crucial, though there were unanswered questions regarding microvascular outcomes.
“The fact that all four randomly assigned glucose-lowering agents appeared to be equivalent in their effects, including their effects on the risk of hypoglycemia, is of great clinical importance,” Rydén and Standl wrote. “The data confirm that older generic or biosimilar low-cost agents still have a role in the treatment of persons with early type 2 diabetes who are at low CV risk.”
Rydén and Standl also wrote that it was interesting to see how liraglutide was associated with a lower risk for CVD.
“The results of the GRADE trial provide support for the notion that GLP-1 receptor agonists have a primary preventive effect [for CVD],” Rydén and Standl wrote. “The authors did not focus on that observation, but early use of such compounds may be worth considering in the management of type 2 diabetes.”
For more information:
David M. Nathan, MD, can be reached at dnathan@mgh.harvard.edu.
References:
- GRADE Study Research Group. N Engl J Med. 2022;doi:10.1056/NEJMoa2200436.
- Rydén L, et al. N Engl J Med. 2022;doi:10.1056/NEJMe2210531.
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