Efficacy and safety of glucagon-like peptide-1/glucagon receptor co-agonist JNJ-64565111 in individuals with type 2 diabetes mellitus and obesity: A randomized dose-ranging study

Weight loss has been shown to improve metabolic parameters and cardiovascular risk in people with type 2 diabetes mellitus (T2DM). This phase 2 study evaluated the safety and efficacy of JNJ-64565111, a dual agonist of GLP-1 and glucagon receptors, in individuals with T2DM and class II/III obesity. In this randomized, double-blind study, participants with T2DM (HbA1c 6.5%-9.5%), body mass index of 35 to 50 kg/m(2) and stable weight were randomly assigned (1:1:1:1) to placebo or JNJ-64565111 (5.0 mg, 7.4 mg or 10.0 mg). The primary endpoint was percent change from baseline in body weight at week 12. Of 195 dosed participants, 144 (73.8%) completed treatment. At week 12, placebo-subtracted body weight changes were -4.6%, -5.9% and -7.2% with JNJ-64565111 5.0 mg, 7.4 mg and 10.0 mg, respectively. All JNJ-64565111 doses were associated with no change in HbA1c and slight numerical elevation of fasting insulin. Numerical increases in fasting plasma glucose were observed with JNJ-64565111 5.0 mg and 7.4 mg. Incidence of treatment-emergent adverse events, especially nausea and vomiting, was higher with JNJ-64565111 vs placebo. Overall, JNJ-64565111 significantly reduced body weight in a dose-dependent manner vs placebo but was associated with greater incidence of treatment-emergent adverse events, no HbA1c reductions, and increased fasting plasma glucose and fasting insulin.