Glucagon-Like Peptide 1- Receptor Agonists as Adjunct in Type 1 Diabetes

insulin testing
Blood sugar self-testing equipment, for diabetes, blue filter
People with type 1 diabetes often have trouble achieving strict glycemic control, even with new insulin analogs and glucose monitoring systems. Researchers investigated whether efficacy could be improved with adjunct therapy.

Two randomized, placebo-controlled, phase 3 trials supported the use of glucagon-like peptide-1 receptor agonists (GLP-1 RA) as an adjunct therapy to insulin among patients with type 1 diabetes (T1D). These findings were published in Diabetes, Obesity and Metabolism.

The ADJUNCT ONE trial was conducted at 177 centers in 17 countries and recruited 1398 patients with T1D. The ADJUNCT TWO trial was conducted at 59 centers in 12 countries and recruited 835 patients with T1D. Participants were randomized in a 3:1 ratio to receive once-daily subcutaneous liraglutide injections plus insulin for 52-weeks (ADJUNCT ONE) and 26-weeks of subcutaneous injections plus insulin (ADJUNCT TWO) or placebo plus insulin. Liraglutide was given in a dose-escalation manner to reach randomized targets (1:1:1 ratio) of 0.6, 1.2, or 1.8 mg/day. Participants used either basal bolus insulin or continuous subcutaneous insulin infusion (CSII). Liraglutide is a GLP-1 RA and is sold under the brand name Victoza® by Novo Nordisk.

At baseline, subgroups were similar, except patients who used CSII tended to have a longer duration of diabetes and fasting plasma glucose was lower.

At week 26 in AJUNCT ONE, glycated hemoglobin (HbA1C) changed from baseline between -0.78% to -0.59% among the liraglutide cohort and by -0.48% for placebo; body weight by -4.7 to -2 kg for liraglutide and +0.3 kg for placebo; and insulin dose by -10% to -2% for liraglutide and +2% for placebo (all comparisons, P <.0001).

In both trials, incidence of hyperglycemia with ketosis tended to be higher among liraglutide recipients but were not significant (all P >.05). Clinically significant hypoglycemia was also higher for liraglutide recipients, reaching significance among the intermediate- (rate ratio [RR], 1.29; 95% CI, 1.06-1.57; P =.0125) and high- (RR, 1.34; 95% CI, 1.10-1.63; P =.0033) dose cohorts.

These data, according to the researchers, indicated that there were no major trends in negative clinical outcomes among subgroups of individuals with T1D who received GLP-1 RA as an adjunct therapy to insulin, and HbA1C, body weight, and insulin doses were more effectively reduced than insulin alone. Researchers also noted that these benefits came with an increased risk of hypoglycemia and seldomly with hyperglycemia with ketosis but without diabetic ketoacidosis.

Researchers said the study findings should be treated as a hypothetical-like strategy. “Overall, these limitations imply that the findings of our evaluation are not confirmatory and that the results should be validated in future studies using an estimand applying a ‘treatment policy’ strategy (intention-to-treat) in line with regulatory guidelines,” they wrote.

Disclosure: Multiple study authors declared affiliations with pharmaceutical companies.  Please refer to the original article for a full list of authors’ disclosures.


Dejgaard TF, von Scholten BJ, Christiansen E, et al. Efficacy and safety of liraglutide in type 1 diabetes by baseline characteristics in the ADJUNCT ONE and ADJUNCT TWO randomized clinical trials. Diabetes Obes Metab. Published online August 31, 2021. doi:10.1111/dom.14532