HTD1801 as a multisystem cardio-kidney-metabolic therapy in type 2 diabetes: phase 3 SYMPHONY Trials demonstrate early CKM risk modification
A M E Surmont, L P Liu, M Yu, K Liu, L MacConell, C N Nie, L N JiAbstract
Background
Cardiovascular-kidney-metabolic (CKM) syndrome is a systemic disorder linking metabolic dysfunction, chronic kidney disease (CKD), and subclinical vascular injury to overt cardiovascular disease (CVD) and excess cardiovascular mortality. Early CKM stages, where metabolic risk factors and mild kidney involvement coexist but overt CVD is not yet established, represent critical windows for cardioprotective intervention. HTD1801 is an oral anti-inflammatory metabolic modulator (AIMM) that activates AMPK and inhibits the NLRP3 inflammasome. Data from clinical trials in patients with type 2 diabetes (T2DM) suggest a broad cardiometabolic risk–modifying profile across the CKM continuum .
Methods
SYMPHONY-1 (mono therapy) and SYMPHONY-2 (add-on to metformin) were double-blind, placebo-controlled Phase 3 trials in adults with T2DM. Participants were randomized 2:1 to HTD1801 1.0 g twice daily or placebo and treated for 24 weeks. Patients then entered a 28-week open-label extension in which all received HTD1801. Primary endpoint was change in HbA1c at week 24. Additional endpoints included LDL-C, non-HDL-C, GGT and blood pressure. A post-hoc pooled analysis assessed eGFR trajectories in baseline hyperfiltration (eGFR ≥120 mL/min/1.73 m²) and mild renal impairment (eGFR 60–90 mL/min/1.73 m²).
Results
In SYMPHONY-1 and -2, HTD1801 significantly improved cardiometabolic parameters. Reductions vs. placebo in HbA1c were 0.66% and 0.53%, LDL-C 0.37 and 0.36 mmol/L, and non–HDL-C 0.48 and 0.48 mmol/L respectively. GGT decreased by 5 U/L in each study. Across the two trials, a total of 959 patients were enrolled, including 123 with mild renal impairment and 85 with hyperfiltration; data from these subgroups were pooled. In patients with mild renal impairment, HbA1c was reduced by 0.51% vs. placebo (p<0.01). Both LDL-C and non-HDL-C decreased by 0.39 mmol/L vs. placebo (p<0.01), and GGT was reduced by 8.8 U/L vs. placebo (p<0.05); blood pressure was stable. In the same subgroup, HTD1801 improved the calculated annualised eGFR slope vs. placebo by 9.81 (95% CI 2.33–17.30) mL/min/1.73 m²/year (p<0.01). In the hyperfiltration subgroup, HTD1801 lowered eGFR vs. near-stable placebo, consistent with normalisation of hyperfiltration (difference in annualised slope −3.00 [95% CI −8.17, 2.16] mL/min/1.73 m²/year), a recognised precursor of downstream CKD and CVD events. In both subgroups, sodium and potassium levels were stable.
Conclusions
In patients with early CKM syndrome, clustering of metabolic, renal, and vascular risk factors is associated with marked increases in incident CVD and cardiovascular mortality. In patients with T2DM, HTD1801 improved glycemic control, decreased inflammation and atherogenic lipids, and showed favourable kidney signals in early CKM phenotypes. These multisystem effects support further evaluation of HTD1801 for long-term cardiovascular risk modification in early CKM stages.eGFR data HTD-1801