Henagliflozin-metformin combo a new therapeutic alternative for T2D

Adding the sodium-glucose cotransporter-2 (SGLT2) inhibitor henagliflozin to metformin led to significant improvements in glycaemic control, body weight, and blood pressure (BP) in Chinese patients with type 2 diabetes (T2D) with insufficient response to metformin alone, a phase III study has shown.

“Henagliflozin is the first SGLT2 inhibitor independently developed in China, and this was the first phase III trial conducted in an all-Chinese T2D population reporting the results obtained with henagliflozin as add-on therapy to metformin,” said the researchers. This combination may provide a new therapeutic option in this patient setting, they added.

A total of 495 participants (mean age 54.8 years, 61.5 percent male) were randomized 1:1:1 to receive QD henagliflozin 5 or 10 mg or placebo for 24 weeks. Following which, a 28-week extension phase ensued (n=427), wherein placebo recipients transitioned to henagliflozin 5 or 10 mg, while those on henagliflozin continued their regimen. Background metformin (1,500 mg/day) was given during lead-in and throughout the study, plus lifestyle modifications. [Diabetes Obes Metab 2021;doi:10.1111/dom.14389]

Placebo-controlled phase

At week 24, significant HbA_1c reductions were seen with both henagliflozin 5 and 10 mg vs placebo (least squares mean [LSM] differences, −0.76 percent and −0.80 percent, respectively; p<0.0001 for both). These tie with evidence on other SGLT2 inhibitors used as add-on to metformin. [Diabetes Care 2014;37:1650-1659; Diabetes Obes Metab 2018;20:520-529]

Compared with placebo, henagliflozin also led to reductions in other glycaemic variables such as fasting plasma glucose (LSM differences, −1.72 [5 mg] and −1.89 mmol/L [10 mg]) and 2-hour post-prandial plasma glucose (LSM differences, −2.85 and −2.73 mmol/L, respectively), as well as body weight (LSM differences, −1.25 [5 mg] and −1.22 kg [10 mg]; p<0.0001 for all). Significant drops in systolic BP were also observed (−4.6 mm Hg; p=0.0002 and −6.6 mm Hg; p<0.0001).

Extension phase

Week 52 saw similar effects with both henagliflozin doses in terms of HbA_1c reductions from baseline, both in the group who switched from placebo (LSM differences, −1.11 percent [5 mg] and −0.94 percent [10 mg]) and in those who continued henagliflozin (LSM differences, −1.06 percent and −1.07 percent, respectively).

The effect on the other parameters were either sustained or improved with both henagliflozin doses vs placebo.

Safety

Treatment discontinuation rates due to adverse events (AEs) were low with henagliflozin (2.4 percent [5 mg] and 2.5 percent [10 mg]), as were the rates of serious AEs (7.9 percent and 3.1 percent, respectively). The treatment-related serious AEs reported with henagliflozin 5 mg (ie, ketosis, UTI, and hypotension) resolved or improved following active treatment.

Week 24 saw a higher incidence of ketosis (3.0 percent and 9.9 percent [henagliflozin 5 and 10 mg, respectively] vs 1.2 percent [placebo]) and urine ketone bodies with henagliflozin vs placebo (14.5 percent and 16.0 percent vs 8.6 percent). “[Nonetheless,] this might be expected from the shift from elevated urine glucose excretion to lipids and ketone bodies as a source of energy fuel,” explained the researchers. These were mostly mild as well, with no cases of diabetic ketoacidosis or major episodes of hypoglycaemia reported.

Consistent benefit

“[T]he glycaemic efficacy of henagliflozin was prominent across all prespecified subgroups, suggesting that a broad spectrum of patients could obtain clinical benefit,” said the researchers. “[Moreover,] the encouraging and durable BP or body weight reductions with henagliflozin [were] sustainable.”

While the antihypertensive capabilities of SGLT2 inhibitors are unclear, this may have been brought about by the improvements in vascular endothelial function and urinary sodium excretion, noted the researchers.

They called for longer trials to ascertain the durability of the observed effects, as well as the underlying mechanisms that could shed light on the antihypertensive effect and potential reduction of cardiovascular events with henagliflozin. Comparisons with other oral antidiabetic drugs should also be explored in future studies.