Treatment with the glucagon receptor antagonist LY2409021 increases ambulatory blood pressure in patients with type 2 diabetes

Abstract

Aims: To assess the effect of LY2409021 on systolic blood pressure (SBP) in patients with type 2 diabetes.

Materials and methods: This 6-week, randomized, crossover study evaluated the effects of once-daily administration of LY2409021 20 mg vs those of placebo on SBP, diastolic BP (DBP), and mean arterial pressure (MAP) using 24-hour ambulatory BP monitoring (ABPM) in 270 subjects treated with diet/exercise ± metformin. Other measures included changes in glycemic control, serum lipids, and hepatic safety markers.

Results: At 6 weeks of LY2409021 treatment, 24-hour mean SBP was increased, with a least squares mean (LSM) difference of 2.26 mm Hg vs placebo (95% CI: 1.11, 3.40; P < .001). The 24-hour mean DBP and MAP also increased, with LSM differences of 1.37 mm Hg (95% CI: 0.66, 2.08; P < .001) and 1.67 mm Hg (95% CI: 0.86, 2.47; P < .001) vs placebo, respectively. At week 6, LY2409021 treatment reduced glycated hemoglobin (HbA1c) levels, with an LSM difference of -0.49% (-5.4 mmol/mol) (95% CI: -0.56%, -0.42% [-6.1, -4.6 mmol/mol]; P < .001) vs placebo. Mean HbA1c at baseline was 7.3% (56 mmol/mol). Small but significant changes in serum lipid and aminotransferase levels were observed with LY2409021 treatment (all P < .05 vs placebo).

Conclusions: Statistically significant increases in BP, MAP and serum lipid levels were observed with LY2409021 treatment at a dose that lowered HbA1c and glucose levels. These effects may limit the clinical utility of LY2409021 as a chronic treatment for type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT02111096.

Keywords: clinical trial; glucagon receptor antagonist; type 2 diabetes.