LEADER 2: Prelim Results Show Baseline CT Concentrations High

March 2, 2015

Early results also found an inverse relationship between serum CT levels and estimated glomerular filtration rate.

Preliminary results taken from the LEADER 2 trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results 2), which is designed to evaluate cardiovascular outcomes associated with the GLP-1 receptor agonist liraglutide, indicate that enrolled patients have higher than average baseline serum calcitonin (CT) concentrations, according to data published in Diabetes Obesity and Metabolism.

According to the study by Gilbert H. Daniels, MD, of Massachusetts General Hospital and Harvard Medical School, and colleagues, labeling for liraglutide currently includes a warning that the drug causes thyroid C-cell tumors in rodents, contraindicating its use in people with a history of medullary thyroid carcinoma. A higher serum CT concentration is considered a biomarker for pathological disease of the C-cells, medullary thyroid carcinoma, and C-cell hyperplasia.

The LEADER trial included 9,340 patients with type 2 diabetes and a high risk for cardiovascular disease who were randomly assigned to treatment with liraglutide or placebo. Patients with CT concentrations >100 pg/mL were originally excluded from the trial; however, this level was eventually lowered to ≥50 pg/mL. CT concentration was measured at baseline and will be measured annually as the study progresses. Patients will be followed for 5 years.

The median baseline CT serum value was 3.9 pg/mL among men in the study (n=6,003) and 1.0 pg/mL among the women (n=3,337).   

“In our study, sex was highly determinative of elevated CT concentrations: over 21% of men and nearly 3% of women had serum CT concentrations above their sex-specific normal reference values of 8.4 pg/mL and 5.0 pg/mL respectively,” the researchers wrote.

In fact, sex was the most important determinant of CT concentrations, the researchers found. The reference range for serum CT is accepted to be <10 pg/mL. Serum CT concentrations were >10 pg/mL and ≤20 pg/mL in 7.3% of men and >20 pg/mL and <50 pg/mL in 3.8% of men.

Almost 90% of women had serum CT concentrations <2.0 pg/mL. Only 0.75% of women had CT levels >10 pg/mL and ≤20 pg/mL, and 0.2% had concentrations between 20 pg/mL and 50 pg/mL.

“The maximum C-cell surface area in the adult thyroid gland is twice as high in men as in women, possibly accounting for the differences in baseline and stimulated calcitonin in men compared to women,” the researchers wrote.

Finally, the researchers also identified an inverse association between serum CT levels and estimated glomerular filtration rate (eGFR) in both women and men (Table).

Table.

% subjectseGFR

Chronic kidney disease

0.960-90Stage 2
1.730-59Stage 3
3.9<30Stage 4-5

CT concentration >10 pg/mL, Men 

% subjectseGFRChronic kidney disease
13.460-90Stage 2
14.930-59Stage 3
23.2, 38.0<30Stage 4, Stage 5


Data showed a 20 mL/min/1.73m2 decrease in eGFR was associated with a 14% increase in serum CT in women and an 11% increase in men.

“Of note, a thyroid nodule population thought to be at higher risk for C-cell disorders found 17 patients (0.29%) with a basal CT >50 pg/ml,” the researchers wrote. “Therefore, the reference range for serum CT concentrations in the normal population may not be applicable to subjects with cardiovascular disease and type 2 diabetes mellitus.”

Image by A2-33 (Own work) via Wikimedia Commons

References:

Daniels GH, Hegedüs L, Marso SP, et al. LEADER 2: baseline calcitonin in 9,340 subjects with type 2 diabetes enrolled in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) Trial: preliminary observations. Diabetes Obes Metab. Epub 2015 Feb 5.