GRADE study: a head-to-head drug comparison

Preliminary data were shared at the American Diabetes Association 81^st Scientific Sessions in June and included in this journal’s report of the conference. Here, we provide an overview of the methodology and of the final microvascular and macrovascular results, which remain unpublished, so no graphical illustrations can be included here.

The primary outcome was the time to an HbA_1c ≥7% (53 mmol/mol), confirmed with a second HbA_1c at the next clinic visit. The secondary outcome was confirmed time to HbA_1c ≥7.5% (59 mmol/mol), after which insulin glargine was to be added to the 3 groups who had not received it previously. The tertiary outcome was time to another HbA_1c of ≥7.5% (59 mmol/mol) after the secondary outcome, at which point the randomised drugs were stopped and insulin therapy was intensified to control glycaemia. Each outcome HbA_1c had to be confirmed at the next clinic visit 3 months later. Drugs were titrated according to their labelling, and sitagliptin dosed as per eGFR recommendations.

Results presented previously demonstrated that the two injectable therapies provided improved ability to keep HbA_1c <7.0% (53 mmol/mol) for longer, while liraglutide and sitagliptin were associated with more weight loss than the other two drugs. As anticipated, liraglutide had the most gastrointestinal side effects and glimepiride was associated with the most hypoglycaemia.

Sodium–glucose cotransporter 2 (SGLT2) inhibitors and thiazolidinediones (TZDs) were not included in the study since, at its inception, the first SGLT2 inhibitor had not yet been licensed by the FDA, and the TZD class was suspected of causing significant side effects and was not appropriate to consider for a long-term study.

Microvascular results

As the participants had relatively short duration of type 2 diabetes, microvascular complication rates were low:

• Moderately increased microalbuminuria (>3.39 mg/mmol): 12%
• Severely increased microalbuminuria (>33.90 mg/mmol): 5%
• eGFR <60 mL/min/1.73 m²: 12%

There were no significant differences between the treatment groups in any of the microvascular complication rates.

Macrovascular results

Only 6% had established cardiovascular (CV) disease at baseline, and people with NYHA class 3 or 4 heart failure or with a major adverse CV event (MACE) in the preceding 12 months were excluded from the study.

There were no significant differences in development of hypertension or hyperlipidaemia between treatment groups in GRADE. All CV events were adjudicated as per recommendations.

Cardiovascular endpoints included:

• 3-point MACE (first occurrence).
• Any CV outcome “6-point MACE” (MACE event, hospitalisation for heart failure, unstable angina requiring hospitalisation or revascularisation, or revascularisation or repair in any vascular bed).
• Hospitalisation for heart failure.
• CV death.
• Total mortality.

The so called “6-point MACE” broad CV outcome demonstrated a statistically significant lower risk with liraglutide (6.6% of events), with no significant differences between the other three drug groups (8.9%–9.5%). For paired comparisons, liraglutide-treated groups had a significant 32% fewer any CV outcomes than those treated with sitagliptin, and 29% fewer than the glimepiride-treated group. There was no significant difference in relation to the glargine group, although it was trending in the same direction. None of the other pairings were significant, so were not presented. There was no heterogeneity in the relative risk of the broad composite “any CV outcome” depending on whether baseline CV disease was present or absent, although absolute event rates were higher in those with pre-existing CV disease.

Although there were numerically fewer 3-point MACE events, hospitalisations for heart failure, CV deaths and total deaths in those treated with liraglutide, these did not reach statistical significance for any of the outcomes, and there was no difference between the other three groups.

Serious adverse events were generally low, with no differences between groups. Severe hypoglycaemia requiring assistance was infrequent, but was higher in the glimepiride group. Pancreatitis and pancreatic cancer were very low, and no differences were reported between groups.

Mean weight at 1 year was significantly lower with liraglutide and sitagliptin, and weight gain of >10% across the whole study period occurred less with liraglutide compared to the other treatment groups, with no significant difference between them.

Providing the independent commentary, Professor David Matthews (University of Oxford) congratulated the study organisers for a well-conducted trial. His further comments were similar to those he made during his presentation at the ADA conference in June, as reported in this journal. He challenged the fact that participants had had type 2 diabetes for differing durations, up to 10 years at baseline, as well as the failure to include TZDs and SGLT2 inhibitors, the use of glimepiride rather than gliclazide, and the fact that the study was undertaken in a US population only. He highlighted that although hypoglycaemia numbers were small, they were 2–3 times more common in those treated with glimepiride than with liraglutide or sitagliptin. He concluded that GRADE was a good study, but that there were very few findings to guide individualisation of therapy.