Eli Lilly’s investigational drug dulaglutide, a long-acting glucagon-like peptide 1 (GLP-1) analog being studied as a once-weekly treatment for type 2 diabetes, met its primary endpoint of non-inferiority for mean 24-hour systolic blood pressure (SBP, or pressure while the heart contracts) after 16 weeks.
The results came from a phase II study that compared two doses of dulaglutide to placebo, using ambulatory blood pressure monitoring (ABPM) to characterize changes in blood pressure and heart rate. In addition, the 1.5mg dulaglutide dose significantly reduced mean 24-hour SBP compared to placebo.
"Cardiologists and hypertension specialists are increasingly involved with evaluating the cardiovascular effects of diabetes medications," said Keith C. Ferdinand, M.D., FACC, FAHA, FASH, professor of clinical medicine, section of cardiology, Tulane University School of Medicine. "This study used the gold standard measurement technique of ABPM to evaluate the blood pressure and heart rate effects of dulaglutide, an investigational GLP-1 receptor agonist."
ABPM is a non-invasive, fully automated technique to measure blood pressure at specific intervals (usually every 15-30 minutes) throughout an entire 24-hour period. This approach allows clinicians to more accurately characterize a person's blood pressure levels throughout a normal day.
The phase II, randomized, double-blind, placebo-controlled, 26-week, parallel study included 755 patients with type 2 diabetes on one or more oral diabetes medications, of whom about 67% had a pre-existing diagnosis of hypertension. Patients who were hypertensive took three or fewer anti-hypertensive medications, with a stable regimen for at least 30 days and no change on study. The study evaluated whether changes from baseline to week 16 in mean 24-hour SBP of dulaglutide 0.75mg and dulaglutide 1.5mg, dosed once-weekly, were non-inferior to placebo, as measured by ABPM, using a non-inferior margin of 3mmHg.
Both dulaglutide doses were shown to be non-inferior compared to placebo at week 16 for mean 24-hour SBP, which was the primary objective of the study: dulaglutide 0.75mg: -1.07 mmHg (97.3% CI: -2.83, 0.68); dulaglutide 1.5mg: -2.79 mmHg (97.3% CI: -4.58, -1.00). Similar results were garnered at week 26. Since the non-inferior criterion was satisfied, superiority testing was conducted, and the 1.5mg dose demonstrated statistically significant reductions in mean 24-hour SBP compared to placebo.
The study also had several secondary objectives, including effects on mean 24-hour diastolic blood pressure (DBP, or pressure when the heart relaxes between beats) and mean 24-hour heart rate. For mean 24-hour DBP, the NI criterion (2.5 mmHg) was met for both dulaglutide doses compared to placebo at weeks 16 and 26.
For mean 24-hour heart rate, the 0.75mg dulaglutide dose met the NI criterion (3 bpm) at both weeks 16 and 26 compared to placebo (1.62 bpm [97.3% CI: 0.32, 2.92] and 1.26 bpm [97.3% CI: -0.13, 2.64], respectively). The 1.5mg dose did not meet the NI criterion at either week 16 (2.84 bpm [97.3% CI: 1.52, 4.16] or week 26 (3.50 bpm [97.3% CI: 2.10, 4.91]). This effect on heart rate is consistent with what has been observed for other compounds in the GLP-1 agonist class.
Both doses of dulaglutide demonstrated statistically significant reductions in HbA1c (average blood glucose levels over a three-month period) from baseline, compared to placebo, at weeks 16 and 26. The most frequently reported adverse events were gastrointestinal (including diarrhea, nausea and vomiting). This is consistent with other GLP-1 agonists.
"We are very encouraged by these clinical trial results, in addition to the rest of the clinical trial data we've seen to date for dulaglutide," said Gwen Krivi, Ph.D., vice president, product development, Lilly Diabetes. "Dulaglutide is currently in phase III clinical trials, where it will continue to be evaluated on its efficacy to lower blood glucose levels, overall safety, weight effects and effects on cardiovascular outcomes. We believe dulaglutide, if approved, can bring significant benefits to people with type 2 diabetes."