Highlight
– In the 24-week RECAM phase III trial, chiglitazar 32 mg and 48 mg added to metformin reduced HbA1c by a least-squares mean of -0.91% and -1.14%, respectively, versus -0.49% with placebo (both active doses p < 0.001 versus placebo). 48 mg produced a greater reduction than 32 mg (p = 0.008).
– Chiglitazar also improved fasting and postprandial glucose and produced favorable lipid effects (lower triglycerides and free fatty acids, higher HDL-C).
– Safety profile was broadly comparable to placebo; the most notable treatment-related findings were modest weight gain and mild peripheral oedema in the chiglitazar arms.
Background: Clinical need and pharmacologic rationale
Type 2 diabetes mellitus (T2DM) remains a leading cause of morbidity worldwide, with persistent unmet needs for therapies that improve glycaemic control while addressing associated dyslipidaemia and cardiometabolic risk. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate glucose, lipid and energy metabolism. PPAR-γ agonists (thiazolidinediones) improve insulin sensitivity but have historically been limited by weight gain, fluid retention, and concerns about heart-failure risk and other adverse outcomes. Dual and pan-PPAR agonists have been developed to simultaneously target PPAR-α (lipid metabolism), PPAR-γ (insulin sensitivity) and other isoforms to achieve combined glycaemic and lipid benefits, but prior agents raised safety signals.
Chiglitazar is a novel oral PPAR pan-agonist designed to modulate glucose and lipid metabolism with a balanced activation profile. The RECAM study assessed whether adding chiglitazar to metformin improves metabolic outcomes in patients with T2DM inadequately controlled on metformin alone, while providing an acceptable safety profile.
Study design
RECAM (NCT04807348) was a randomized, double-blind, placebo-controlled phase III trial conducted in China. A total of 533 adults with T2DM inadequately controlled on metformin were randomized 1:1:1 to chiglitazar 32 mg (n = 178), chiglitazar 48 mg (n = 177), or placebo (n = 178), all on a background of metformin, for 24 weeks. The primary endpoint was change in glycosylated haemoglobin (HbA1c) from baseline to week 24. Secondary endpoints included changes in fasting plasma glucose (FPG), 2-hour postprandial glucose (PPG), key lipid parameters (triglycerides, free fatty acids [FFA], high-density lipoprotein cholesterol [HDL‑C]), and safety/tolerability measures. The trial was double-blind and reported intention-to-treat efficacy analyses with least-squares mean estimates and 95% confidence intervals.
Key findings
Glycaemic outcomes
At week 24 the least-squares mean changes in HbA1c were:
– Chiglitazar 32 mg: -0.91% (95% CI: -1.03% to -0.79%)
– Chiglitazar 48 mg: -1.14% (95% CI: -1.26% to -1.02%)
– Placebo: -0.49% (95% CI: -0.62% to -0.36%)
Both chiglitazar doses achieved statistically significant HbA1c reductions versus placebo (both p < 0.001). The 48 mg dose produced greater glycaemic lowering than 32 mg (p = 0.008). The absolute placebo‑adjusted differences were approximately -0.42% for 32 mg and -0.65% for 48 mg, changes that are clinically relevant when combined with metformin.
In addition to HbA1c, chiglitazar significantly improved fasting plasma glucose and 2-hour postprandial glucose relative to placebo, confirming consistent effects on both fasting and postprandial glycaemia.
Lipid and metabolic effects
Chiglitazar treatment was associated with favorable changes in several lipid parameters: reductions in triglyceride levels and free fatty acids, as well as increases in HDL-C. These effects are consistent with the PPAR-α activity component of a pan-agonist and may represent an advantage over agents that target glycaemia alone. Detailed magnitudes of lipid changes were reported as statistically significant in the primary publication.
Safety and tolerability
The overall incidence of adverse events (AEs) was comparable across treatment arms. Notable treatment-associated effects included modest weight gain and mild peripheral oedema in the chiglitazar groups; these findings are directionally consistent with PPAR-γ activation. There were no unexpected safety signals reported in the 24-week period, and severe or treatment-limiting events were uncommon. The trial report did not identify a marked increase in cardiovascular events over the short follow-up, but the study was not powered or long enough to assess major adverse cardiovascular outcomes (MACE).
Expert commentary: interpretation, strengths, and limitations
Interpretation
Chiglitazar added to metformin produced clinically meaningful reductions in HbA1c at both tested doses, with the 48 mg dose achieving around two-thirds of a percentage point greater HbA1c lowering than placebo. The accompanying improvements in triglycerides, FFA and HDL-C point to a complementary effect on lipid metabolism, which is an attractive attribute in patients with T2DM and underlying atherogenic dyslipidaemia.
Strengths
– Randomized, double-blind, placebo-controlled design with a substantial sample size (n = 533) provides robust internal validity for the 24-week efficacy and tolerability findings.
– Assessment of both glycaemic and lipid endpoints aligns with the pharmacologic rationale for a PPAR pan-agonist.
– Dose comparison allowed demonstration of a dose–response relationship for glycaemic efficacy.
Limitations
– The study population was Chinese and the treatment duration was 24 weeks; generalizability to other ethnic groups and longer-term safety and efficacy remain uncertain.
– Short-term trials are limited in their ability to detect rare but clinically important adverse events, particularly cardiovascular outcomes, heart-failure exacerbations, bone fractures, or long-term effects on weight and adiposity distribution.
– Historical context: prior development programs for dual/pan-PPAR agonists have been hampered by safety concerns (for example, fluid retention, cardiovascular events). While RECAM reported an acceptable short-term safety profile, the wider safety picture requires longer follow-up and dedicated cardiovascular outcome studies.
Clinical context
Current treatment algorithms for T2DM emphasize not only glucose lowering but also reduction of cardiovascular and renal risk. Newer classes such as SGLT2 inhibitors and GLP-1 receptor agonists have demonstrated robust cardiovascular and renal outcome benefits. A PPAR pan-agonist with combined glycaemic and lipid benefits could fill an important niche—especially for patients with dyslipidaemia and insulin resistance—provided that long-term safety and cardiovascular neutrality or benefit are demonstrated.
Practical implications and research agenda
Short-term clinical implications
For clinicians practicing in settings where chiglitazar becomes available, the RECAM data support considering chiglitazar as an add-on option to metformin for patients requiring additional glycaemic lowering, particularly when dyslipidaemia coexists. The modest weight gain and risk of oedema should be discussed with patients, and monitoring for signs of fluid retention and heart failure is prudent, particularly in those with pre-existing cardiac disease.
Required future studies
– Longer-term randomized controlled trials with diverse populations to clarify durability of glycaemic and lipid effects.
– Dedicated cardiovascular outcome trials (MACE and heart-failure endpoints) to assess net cardiovascular benefit or risk, given historical concerns about PPAR-targeting agents.
– Comparative trials versus contemporary agents (e.g., SGLT2 inhibitors, GLP-1 receptor agonists, and pioglitazone) to position chiglitazar in modern treatment algorithms.
– Mechanistic and safety studies examining fluid dynamics, bone health, and adipose tissue distribution to better define adverse-event risk profiles.
Regulatory perspective
Approval and clinical adoption will likely depend on demonstration of an acceptable long-term cardiovascular safety profile and a favorable benefit–risk balance compared with established therapies that have proven cardiovascular and renal benefits.
Conclusion
The RECAM phase III trial shows that chiglitazar added to metformin produces statistically significant and clinically meaningful improvements in HbA1c and beneficial effects on atherogenic lipids over 24 weeks in Chinese patients with T2DM. The safety profile over this timespan appears acceptable, with the most salient adverse effects being modest weight gain and mild oedema. These findings support further development and larger, longer-duration studies—including cardiovascular outcome trials—and assessment in broader, multiethnic populations before chiglitazar’s role in routine clinical practice can be established.
Funding and trial registration
The RECAM trial is registered at ClinicalTrials.gov (NCT04807348). Funding sources and study sponsors are reported in the primary publication (Gao L et al., Diabetes Obes Metab. 2025).
References
1. Gao L, Ji L, Yan X, Cheng Z, Zhang X, Sun W, Ma J, Song W, Liu Y, Lin X, Pang W, Cao H, Chen B, Li Z, Lu X; RECAM Study Group. Efficacy and safety of chiglitazar add-on to metformin in type 2 diabetes mellitus (RECAM study). Diabetes Obes Metab. 2025 Nov;27(11):6243-6253. doi: 10.1111/dom.70009. Epub 2025 Aug 22. PMID: 40842343.
2. American Diabetes Association. Standards of Care in Diabetes—2024. Diabetes Care. 2024;47(Suppl 1):S1–S200. (Standards provide current guidance on individualized glycaemic targets and considerations for cardiometabolic risk management.)
3. Dormandy JA, Charbonnel B, Eckland DJ, et al.; PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study: a randomized controlled trial. Lancet. 2005;366(9493):1279–1290. (Examines cardiovascular outcomes with pioglitazone and informs safety considerations for PPAR-γ activation.)
4. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457–2471. (Meta-analysis that highlighted cardiovascular safety concerns with a TZD, underscoring the need for outcome data with new PPAR-targeted agents.)
