BARCELONA — Insulin degludec (Tresiba, Novo Nordisk) didn’t reduce overall hypoglycemic events compared with insulin glargine U300 (Toujeo, Sanofi) in a head-to-head trial of the two second-generation basal insulins in more than 1600 patients with type 2 diabetes.
But degludec was associated with lower rates of nocturnal and severe hypoglycemia than its rival in the study.
Results from the CONCLUDE (Comparing the Efficacy and Safety of Insulin Degludec and Insulin Glargine 300 units/mL in Subjects with T2D Inadequately Treated With Basal Insulin and Oral Antidiabetic Drugs) study were presented on September 19 by Athena Philis-Tsimikas, MD, of the Scripps Whittier Diabetes Institute, San Diego, California, here at the European Association for the Study of Diabetes (EASD) 2019 Annual Meeting.
Philis-Tsimikas outlined a number of problems that affected the trial, making interpretation somewhat complicated.
Asked to comment, session moderator Tim Heise, MD, lead scientist at the Profil Institute, Neuss, Germany, told Medscape Medical News, “I think everybody has to look at the data as they are.”
“If I had to treat a type 2 diabetes patient prone to hypoglycemia, there is still less nocturnal and less severe hypoglycemia, so I might use [insulin] degludec,” he said.
“Others might disagree. I think you always have to look at all the evidence. You can’t reduce a clinical trial to just one endpoint,” he continued.
Independent commentator Stefano del Prato, MD, University of Pisa, Italy, had this take: “Prevention of hypoglycemia is a main task in treating type 2 diabetes subjects, particularly those on insulin therapy.”
But “too many uncertainties” prevent anyone drawing firm conclusions from the CONCLUDE trial, he summarized.
Study Plagued by Problems
The study didn’t meet its primary endpoint for number of severe or blood glucose-confirmed (< 3.1 mmol/L) symptomatic hypoglycemic episodes during the maintenance period.
Because of the study’s hierarchical testing design, this meant that the secondary endpoints including nocturnal and severe hypoglycemia, A1c, and body weight, aren’t conclusive and can only be considered hypothesis-generating despite showing statistical superiority for degludec, Philis-Tsimikas said.
However, she urged that “consistency of the data across endpoints should be considered…Clinical interpretation of any trial should include the totality of the evidence.”
CONCLUDE was also marred by the fact that mid-way through the trial it was discovered that glucose readings from the study meters were inconsistent with those of the gold-standard central lab. They were reading too high in the low ranges, thereby missing hypoglycemic episodes.
Investigators had to swap out the meters for new ones and amend the study protocol by extending the maintenance period from the planned 36 weeks to 88 weeks following a 16-week titration period.
The primary endpoint didn’t change, but several of the secondary endpoints had to be adjusted to accommodate the longer follow-up.
Heise suspects that the problem wasn’t the meters but the batch of test strips.
In any case, he said that it’s “a real shame…They could have done better with the testing hierarchy, but the meter issue is just bad luck.”
Superiority Not Met, but Secondary Endpoints Favor Degludec
CONCLUDE was an open-label, randomized, treat-to-target multicenter trial of 1609 adults with type 2 diabetes who were already taking basal insulin (glargine U100, detemir, or NPH) with or without oral glucose-lowering agents (sulfonylureas were excluded).
All participants were at increased risk for hypoglycemia having had significant hypoglycemic events within the previous year, insulin exposure for more than 5 years, hypoglycemic unawareness, or moderate chronic renal disease.
Either degludec U200 or glargine U300 was given once daily in the morning or evening. Doses were titrated to glucose targets of 4.0-5.0 mmol/L (71-90 mg/dL).
During the maintenance period, there was no significant difference in the primary endpoint, overall hypoglycemic events, which were 40.6% with degludec versus 46.3% with glargine U300 (rate ratio, 0.88; P = .17).
However, rates of nocturnal symptomatic hypoglycemia were significantly lower with degludec (17.8% vs 24.8%; 0.63; P = .0014) as were severe hypoglycemic events, defined as those requiring third-party assistance (0.5% vs 2.7%; 0.20; P = .0027).
Total insulin dose was about 12% lower with degludec (P < .0001) but body weight was actually 1.18 kg higher (P < .0001).
Adverse event rates didn’t differ between the groups, Philis-Tsimikas reported.
Philis-Tsimikas has reported receiving research and consulting fees from Dexcom, Eli Lilly, Merck, Novo Nordisk, and Sanofi. Heise has reported being a shareholder of Profil, which has received research funds from Adocia, Boehringer Ingelheim, Dance Pharmaceuticals, Eli Lilly, Johnson & Johnson, MedImmune, MSD, Mylan, Nordic Bioscience, Novo Nordisk, Poxel, Roche Diagnostics, Saniona, Sanofi, Senseonics, and Zealand Pharma. He is also on an advisory panel for Novo Nordisk. Del Prato serves or has served on advisory boards for AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Hanmi Pharmaceuticals, Intarcia, Janssen, MSD, Novartis, Novo Nordisk, Sanofi, Servier, and Takeda; serves or has served on speakers’ bureaus for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, MSD, Novartis, Novo Nordisk, Sanofi, and Takeda; and has received research support from Boehringer Ingelheim, MSD, and Novartis.
EASD 2019 Annual Meeting. Presented September 19, 2019.