Dorzagliatin a new hope for T2D
In drug-naïve Chinese patients with type 2 diabetes (T2D), treatment with the first-in-class, glucose sensitizer dorzagliatin led to sustained glycaemic control, according to updated findings from the 52-week phase III SEED* study presented at ADA 2021.
“This is the first successful global phase III trial on a drug with a new mechanism targeting the restoration of glucose homeostasis,” said Dr Dalong Zhu from Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China, who presented the findings. “As a glucose sensitizer, dorzagliatin provides a new hope for T2D treatment.”
The primary efficacy endpoint was met, as reflected by the greater HbA1c reduction with dorzagliatin vs placebo at week 24 (least-squares mean [LSM], –1.07 percent vs –0.50 percent; p<0.001). [ADA 2021, abstract 235-OR]
The HbA1c reduction with dorzagliatin was seen from week 4, dropping further at week 12. By week 24, HbA1c was 7.18, which was sustained until week 52 (7.20). This is important, stressed Zhu, as this signifies stable glycaemic control with dorzagliatin across the study duration. With placebo, the HbA1c drop was only observed during the transition to the open-label phase, which was from week 24 to 52 (from 7.71 to 6.95).
Secondary efficacy endpoints were also achieved, as shown by the greater reduction in 2-hour post-prandial plasma glucose (2h PPG) from baseline with dorzagliatin vs placebo (LSM, –2.83 vs –0.50 mmol/L), with more dorzagliatin recipients achieving an HbA1c of <7 percent (42.5 percent vs 17.3 percent) and the composite** response rate at week 24 (29.4 percent vs 13.3 percent; p<0.001 for all).
The changes from baseline HOMA2-β*** (LSM, 2.56 vs –0.72; p<0.05 [week 24]) and HOMA2-IR# (–0.16,–0.22, and –0.26; p<0.001 for all [at three different timepoints across 52 weeks]) signify greater improvements in β-cell function and insulin resistance, respectively, with dorzagliatin vs placebo.
Adverse events (AEs) were mostly mild, with similar fractions of participants reporting moderate AEs (8.4 percent vs 10.5 percent) and investigator-assessed drug-related AEs (8.7 percent vs 8.5 percent). There were no deaths, drug-related serious AEs, severe hypoglycaemia, or discontinuations owing to hypoglycaemia with dorzagliatin. “[These imply that dorzagliatin has a] good safety profile and was well-tolerated during the 52-week treatment,” said Zhu.
Add-on to metformin
The effects were consistent in a cohort of participants who also had metformin 1,500 mg daily (n=376 and 375 in the dorzagliatin and placebo arm, respectively). Dorzagliatin outdid placebo in terms of HbA1c reduction (–1.02 percent vs –0.36 percent) and 2h PPG (–5.45 vs –2.97 mmol/L; p<0.0001 for both).
HOMA2-β was also markedly better with dorzagliatin vs placebo (3.82 vs 1.40; p<0.01), as was HOMA2-IR (–0.11, –0.15, and –0.17; p<0.001 for all). “[These suggest that] patients with inadequately controlled T2D with metformin alone also improved their β-cell function and insulin resistance, which is consistent with its mechanism of action,” said Zhu.
Reliable mechanism of action
SEED randomized 463 participants (mean age 53 years, 65 percent male) 2:1 to receive dorzagliatin 75 mg BID or placebo for 24 weeks. In the ensuing 28-week open-label phase, all participants received dorzagliatin.
With superior glycaemic control, improved β-cell function, sustained insulin resistance, and favourable safety profile with low hypoglycaemia risk, dorzagliatin – be it alone or with metformin – provides a new alternative for treating T2D, concluded Zhu. “[Our current findings] further confirm that the mechanism of action of dorzagliatin is a reliable way of treating T2D.”