GRADE puts liraglutide through an independent five-year test

Results from GRADE, a government-funded head-to-head trial of four diabetes drugs added to metformin, were published September 22, 2022 in the New England Journal of Medicine. Over a mean of five years, insulin glargine and the GLP-1 drug liraglutide were the most effective at keeping blood sugar at target, and liraglutide led to the most weight loss and the most gastrointestinal complaints ^[1].

GRADE enrolled 5,047 adults who had type 2 diabetes for less than 10 years, were already taking metformin, and had glycated hemoglobin (A1C) levels of 6.8% to 8.5%. Participants were randomly assigned to add one of four drugs: insulin glargine U-100, the sulfonylurea glimepiride, liraglutide (a GLP-1 receptor agonist), or sitagliptin (a DPP-4 inhibitor). The group was more diverse than many industry trials: 19.8% Black and 18.6% Hispanic or Latinx ^[1]. The trial was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others, not by a single drugmaker ^[1].

What the glucose results showed

The main measure was how often a participant's A1C rose to 7.0% or higher and was confirmed on a repeat test. Rates differed significantly across the four groups (P<0.001). Glargine (26.5 events per 100 participant-years) and liraglutide (26.1) were similar to each other and lower than glimepiride (30.4) and sitagliptin (38.1) ^[1]. Results for the secondary threshold of A1C above 7.5% followed the same pattern ^[1].

The authors called the advantage for glargine and liraglutide significant but "modest" ^[1]. All four drugs lowered A1C. Results were similar across subgroups defined by sex, age, or race and ethnicity, though people who started with higher A1C appeared to gain more from glargine, liraglutide and glimepiride than from sitagliptin ^[1].

On side effects, severe hypoglycemia was rare overall but most common with glimepiride, affecting 2.2% of participants, compared with 1.3% on glargine, 1.0% on liraglutide and 0.7% on sitagliptin ^[1]. People taking liraglutide reported gastrointestinal side effects more often and lost more weight than those in the other three groups ^[1]. The abstract does not give the exact pounds or percentage of weight lost, so that number is not available here.

Complications and heart outcomes

A companion paper reported microvascular and cardiovascular results over the same five years. There were no material differences among the four treatments for new high blood pressure, abnormal cholesterol, kidney measures, or nerve damage. Across the whole trial, the rates per 100 participant-years were 2.6 for moderately increased albuminuria, 1.1 for severely increased albuminuria, 2.9 for kidney impairment and 16.7 for diabetic peripheral neuropathy ^[2].

The groups also did not differ on major adverse cardiovascular events (overall rate 1.0 per 100 participant-years), hospitalization for heart failure (0.4), death from cardiovascular causes (0.3), or death from any cause (0.6) ^[2]. There were small differences in "any cardiovascular disease": 1.9 with glargine, 1.9 with glimepiride, 1.4 with liraglutide and 2.0 with sitagliptin. Compared with the other three treatments combined, the hazard ratio for any cardiovascular disease was 0.7 (95% CI, 0.6 to 0.9) for liraglutide ^[2]. The authors caution that these confidence intervals were not adjusted for multiple comparisons, so the cardiovascular findings point to "possible differences" rather than a settled conclusion ^[2].

Why it matters for patients

Most comparisons between diabetes drugs come from trials paid for by the company that makes one of them, or from short studies of a year or less. GRADE ran for a mean of 5.0 years with federal funding and compared four drugs directly ^[1]. That makes it a useful reference point when a clinician and patient weigh what to add after metformin.

The trade-offs are concrete. Liraglutide matched insulin glargine on blood sugar control and produced more weight loss, but also the most nausea, vomiting, bloating and diarrhea ^[1]. Glimepiride, typically the cheapest option, carried the highest rate of severe low blood sugar at 2.2% ^[1]. Over five years, none of the four drugs clearly protected the kidneys, eyes or nerves better than the others ^[2].

It is also worth noting what GRADE did not test. The trial did not include an SGLT2 inhibitor arm, and it studied liraglutide rather than semaglutide (Ozempic, Wegovy, Rybelsus) or tirzepatide (Mounjaro, Zepbound). How those newer drugs would have performed in the same five-year design is not known from this trial.