BARCELONA – data presented at the annual meeting of the European Association for the Study of Diabetes.
During a 36-week maintenance treatment period, the rate ratio (RR) for the primary endpoint of the study – severe or confirmed symptomatic hypoglycemia, defined as a blood-glucose level of less than 3.1 mmol/L (56 mg/dL) – was 0.88 (95% confidence interval, 0.73-1.06; P = .17) in a comparison the two long-acting insulins.
There were some differences that favored insulin degludec over insulin glargine when other endpoints were considered, but because a statistical testing hierarchy was used, “no confirmatory results can be made from CONCLUDE,” one of the study investigators,, MD, of Scripps Whittier Diabetes Institute, San Diego, said during a special symposium at the meeting.
“If the primary endpoint was not achieved, the testing hierarchy stopped after the first occurrence of nonsignificance,” she explained. Although that occurred, the other endpoints could still be analyzed as they were all prespecified, she argued. These showed that during the maintenance treatment period, there were lower rates of nocturnal symptomatic hypoglycemic episodes (RR, 0.63; 95% CI, 0.48-0.84; P = .0014) and severe episodes (those requiring third-party assistance; RR, 0.20; 95% CI, 0.07-0.57; P = .0027) with insulin degludec, compared with insulin glargine.
The trial came under fire, however, from Stefano Del Prato, MD, professor of endocrinology in the department of endocrinology metabolism and chief of the section of diabetes at the University of Pisa, Italy, who provided the EASD-invited independent commentary on the study’s findings. “This is the CONCLUDE trial. You’d could expect a CONCLUDE trial to be conclusive in its conclusions!” he said, noting that there were “too many uncertainties” in the trial.
CONCLUDE was a randomized, open-label, head-to-head study of insulin degludec versus insulin glargine in 1,609 adult patients with type 2 diabetes who were inadequately treated with basal insulin with or without oral antidiabetic drugs. The aim of the trial was to evaluate the risk of hypoglycemia associated with the two long-acting insulins.
“Hypoglycemia is a very common event in both type 1 and type 2 diabetes,”, MD, Medical University Graz, Austria, reminded the audience. Severe hypoglycemia is associated with insulin use, and data show that patients with type 2 diabetes are at as much risk as are those with type 1 diabetes in the longer term ( ).
The rationale for the CONCLUDE study comes from evidence from other trials, he said. Specifically, there was a pharmacodynamic/pharmacokinetic study comparing insulin degludec U200 with insulin glargine U300 that showed four times lower day-to-day variability in favor of insulin degludec (Diabetes Obes Metab. 2017;19:1032-9). Dr. Pieber noted that there was also a 30% lower potency of insulin glargine U300 versus insulin degludec U200. Those findings, together with findings from the SWITCH 2 (JAMA. 2017;318:45-56) and EDITION II (Diabetes Care. 2014;37:3235-43) trials, led to the hypothesis that there might be lower rates of hypoglycemia with insulin degludec U200 than with insulin glargine U300.
Dr. Pieber noted that one early issue with the trial was how patients’ blood glucose had been initially measured, because the blood glucose monitoring system that patients were first using seemed to display falsely higher values than what was actually expected, potentially putting patients’ safety at risk. This called for a protocol amendment () and a new blood glucose monitoring system being used.
A similar proportion of patients in each group discontinued treatment during the study – 12.3% in the insulin degludec arm, and 11.4% in the insulin glargine arm – for reasons including adverse events (2.9% vs. 2.1%, respectively) and lack of efficacy (1.0% vs. 1.6%), he said.
Post hoc analyses hinted at slight benefits of insulin degludec over insulin glargine in terms of end of treatment hemoglobin A1c and the daily observed insulin dose, but less weight gain for insulin glargine.
Commenting further on the study, Dr. Del Prato said there was much debate around the pharmacokinetics and pharmacodynamic differences between insulin degludec and insulin glargine, and that the data should be interpreted “with a lot of caution.”
He said that it was not clear from the findings why there might be a lower risk of hypoglycemia with insulin degludec. He noted that the rate of diurnal hypoglycemia should be considered, and that the statistical interpretation of the data may be “a matter of uncertainty as well.”
Dr. Del Prato agreed that “prevention of hypoglycemia remained a major task in treating type 2 diabetic patients, particularly those on insulin therapy.” He proposed that differentiating between new basal insulin analogs may need “better tools for characterization of PK/PD, rigorous interpretation of the results, careful assessment of the generalizability of results from randomized controlled trials performed in selected study populations, and independent research and careful real-world studies to be performed.”
Furthermore, he said translating the potential benefit of new insulin analogs “cannot just rely on their properties, rather it requires validation over the time of the accuracy of glucose meters, and adequate patient education, and even more, education reinforcement.”
All of the speakers disclosed ties with Novo Nordisk, which funded the study, as well as other pharmaceutical companies.
SOURCES: Philis-Tsimikas A. EASD 2019, Oral Presentation 90; Pieber T. EASD 2019, Oral Presentation S38.1; Philis-Tsimikas A. EASD 2019, Oral Presentation S38.2; Del Prato S. EASD 2019. Oral Presentation S38.3.