Retatrutide-Associated Improvements in Cardiovascular Risk Biomarkers in Adults With Obesity With or Without Type 2 Diabetes.
Retatrutide treatment was associated with significant reductions in several cardiovascular risk biomarkers in adults with obesity, but the clinical implications of these findings require further investigation.
Where it sits
this study against the rest of the retatrutide (ly3437943) corpusSummary and findings
This study assessed the effects of retatrutide on cardiovascular risk biomarkers in adults with obesity, with or without type 2 diabetes, over two phase 2 trials. Participants received doses of retatrutide ranging from 0.5 to 12 mg weekly for 36 to 48 weeks. Significant reductions in various lipoprotein and inflammatory biomarkers were observed.
Abstract
<h4>Aims</h4>To further characterise the effects of retatrutide on cardiometabolic risk, lipoprotein and inflammatory biomarkers were assessed post hoc in phase 2 trials of adults with obesity/overweight with or without type 2 diabetes (T2D).<h4>Materials and methods</h4>Data were analysed from two randomised, double-blind, placebo-controlled phase 2 trials. In Study 1, adults with obesity/overweight and T2D received once-weekly retatrutide (0.5/4/8/12 mg), dulaglutide (1.5 mg) or placebo for 36 weeks; in Study 2, adults with clinical obesity without T2D received retatrutide (1/4/8/12 mg) or placebo for 48 weeks. Fasting blood samples were collected at baseline and during treatment to assess lipids, apolipoproteins, lipoprotein particle subclasses and inflammatory biomarkers. Mixed models for repeated measures estimated placebo-adjusted change from baseline. Statistical significance was defined as a false discovery rate-adjusted p < 0.05.<h4>Results</h4>Mean body mass index was 35.4 kg/m<sup>2</sup> (Study 1) and 37.4 kg/m<sup>2</sup> (Study 2). In both studies, retatrutide was associated with significant reductions in non-high-density lipoprotein cholesterol (Study 1: up to -21.0%, Study 2: up to -26.9%), apolipoprotein B (-21.4%, -24.2%), total triglyceride-rich lipoprotein particles (-22.5%, -33.7%), large triglyceride-rich lipoprotein particles (-84.4%, -76.6%), triglyceride-rich lipoprotein cholesterol (-29.4%, -38.6%), total low-density lipoprotein particles (-19.7%, -23.5%) and small low-density lipoprotein particles (-32.6%, -32.3%). Retatrutide was associated with significant reductions in high-sensitivity C-reactive protein (-54.8%) and interleukin-6 (-29.6%) in Study 2 but not Study 1.<h4>Conclusions</h4>In adults with obesity/overweight, with or without T2D, retatrutide treatment was associated with reductions in atherogenic lipoproteins and inflammatory biomarkers linked to cardiovascular disease risk.<h4>Trial registration</h4>ClinicalTrials.gov numbers NCT04881760 and NCT04867785.
Background
This paper addresses the impact of retatrutide on cardiovascular risk factors in adults with obesity and type 2 diabetes. Prior studies have indicated that obesity is linked to increased cardiovascular risk, but the specific effects of retatrutide on biomarkers associated with this risk were not well characterized. Understanding these effects is crucial for evaluating the potential of retatrutide in managing cardiometabolic health.
Methods
Data were analyzed from two randomized, double-blind, placebo-controlled phase 2 trials involving adults with obesity/overweight. Study 1 included participants with type 2 diabetes receiving retatrutide (0.5/4/8/12 mg) or dulaglutide (1.5 mg) or placebo for 36 weeks. Study 2 involved adults without type 2 diabetes receiving retatrutide (1/4/8/12 mg) or placebo for 48 weeks. Primary outcome measures included changes in lipids, apolipoproteins, lipoprotein particle subclasses, and inflammatory biomarkers.
Results
In Study 1, retatrutide was associated with a reduction in non-high-density lipoprotein cholesterol of up to -21.0%. In Study 2, reductions were observed up to -26.9%. Significant reductions in apolipoprotein B were reported as -21.4% and -24.2% respectively. High-sensitivity C-reactive protein decreased by -54.8% in Study 2.
Interpretation
The findings suggest that retatrutide may have a favorable effect on cardiovascular risk biomarkers, particularly in reducing atherogenic lipoproteins and inflammatory markers. However, the clinical significance of these reductions remains uncertain, especially given the small effect sizes in some measures. Limitations such as the small sample sizes and the nature of post hoc analyses may confound the conclusions drawn from this study.
Key findings
- Mean body mass index was 35.4 kg/m2 (Study 1) and 37.4 kg/m2 (Study 2).
- Retatrutide was associated with significant reductions in non-high-density lipoprotein cholesterol (Study 1: up to -21.0%, Study 2: up to -26.9%).
- Apolipoprotein B decreased by -21.4% in Study 1 and -24.2% in Study 2.
- Total triglyceride-rich lipoprotein particles decreased by -22.5% (Study 1) and -33.7% (Study 2).
- High-sensitivity C-reactive protein was reduced by -54.8% in Study 2.
Limitations
- Post hoc analysis may introduce bias.
- Small sample sizes in both studies.
- Short follow-up duration of 36 to 48 weeks.
- Specific populations may limit generalizability.