Durable treatment response seen with dapagliflozin-saxagliptin add-on in T2D patients on metformin
Reductions in liver fat and adipose tissue volumes were sustained in patients with type 2 diabetes (T2D) with the addition of the SGLT-2* inhibitor dapagliflozin (DAPA) and the DPP-4** inhibitor saxagliptin (SAXA) to metformin (MET), compared with a regimen comprising glimepiride (GLIM)+MET, according to the extension period results of a phase IIIb trial.
“[The] improvements in liver fat and adipose tissue volumes [observed at week 52] were maintained over a 122-week period during treatment with a fixed-dose combination of DAPA+SAXA+MET vs GLIM+MET,” said Dr Lars Johansson from Antaros Medical AB, Mölndal, Sweden, who presented the findings at AASLD 2020. The safety and tolerability profile of DAPA+SAXA+MET over 156 weeks was also consistent with the established profiles of the individual components, he added.
The initial study population comprised 444 participants who were randomized 1:1 to receive dapagliflozin 10 mg and saxagliptin 5 mg, or glimepiride 1–6 mg (12-week up-titration), on top of metformin. Each component was administered once-daily orally. In the 52-week analyses of this cohort, DAPA+SAXA+MET led to improvements in glycaemic control and reductions in liver fat and adipose tissue volumes compared with GLIM+MET. [Diabetes Obes Metab 2020;22:1083-1093; Diabetes Obes Metab 2020;22:1094-1101]
The current sub-study was conducted using MRI-PDFF*** to determine the long-term effects of DAPA+SAXA+MET on total liver fat content and visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volumes. “[A]ssessing the effect of treatment on liver fat in addition to glycaemic control is of significant interest, [as] T2D is a risk factor for nonalcoholic fatty liver disease,” said Johansson.
Of the 338 participants who completed the 104-week extension phase, 82 consented to participate in the MRI sub-study. Of these, 46 patients were receiving DAPA+SAXA+MET (mean age 58.9 years, 47.8 percent female) while 36 were on GLIM+MET (mean age 56.9 years, 52.8 percent female). MRI outcomes were evaluated at week 122. [AASLD 2020, abstract 1719]
Week 122 saw significantly greater reductions in liver fat percentage (adjusted mean change, –4.49 percent vs 0.4 percent; pnominal<0.001) and adipose tissue volumes (adjusted mean change, –0.35 vs 0.06 L; pnominal=0.003 [VAT] and –0.43 vs 0.01 L; pnominal=0.008 [SAT]) with DAPA+SAXA+MET vs GLIM+MET. These also correlated with the week 52 MRI results.
These findings translate to relative mean reductions in liver fat by 32 percent, 10-percent reduction in VAT volume, and a 9-percent drop in SAT volume, noted Johansson.
These reductions were accompanied by greater mean reductions in total body weight (adjusted mean change, –4.36 vs 1.96 kg; pnominal<0.001) and HbA1c (adjusted mean change, –1.1 percent vs –0.73 percent; pnominal=0.241) in favour of DAPA+SAXA+MET over GLIM+MET through 156 weeks.
Both arms had consistent mean baseline Fibrosis-4 scores of <1.45 throughout 156 weeks which, as per Johansson, signifies the absence of advanced fibrosis.
DAPA+SAXA+MET also resulted in greater mean reduction in ALT# serum levels compared with GLIM+MET. The corresponding mean reduction in AST## serum levels was slightly greater with GLIM+MET vs DAPA+SAXA+MET, noted Johansson.
“[Taken together,] these data provide evidence on the long-term durability of treatment response [with DAPA+SAXA+MET] in patients with T2D,” said Johansson. “[I]n addition to reducing liver fat and associated markers of liver inflammation, DAPA+SAXA+MET also improves metabolic control.”