Tirzepatide psoriasis trials point to 30 percent lower predicted heart risk with ixekizumab
An analysis of the TOGETHER trials found that adding tirzepatide to ixekizumab cut predicted 10 year cardiovascular risk by about 30% at week 36 in people with psoriatic disease and obesity. The figure is a risk score, not counted heart attacks.
What's new
A congress analysis of the TOGETHER trials found ixekizumab plus tirzepatide lowered predicted 10 year cardiovascular risk by about 30% at week 36 versus ixekizumab alone.
Why it matters
People with psoriatic disease often carry obesity and higher heart risk, and skin or joint treatment alone does not change traditional risk factors.
What's next
A peer reviewed paper and an outcomes trial counting heart attacks and strokes would be needed; phase 4 TOGETHER AMPLIFY studies are under way.
Adding tirzepatide to ixekizumab lowered predicted 10 year cardiovascular risk by about 30% in two tirzepatide psoriasis trials, according to an analysis presented at the European Academy of Dermatology and Venereology congress in Vienna. Healio reported the abstract on October 21. The finding comes from TOGETHER-PsO and TOGETHER-PsA, two Lilly phase 3b studies in adults with psoriatic disease and overweight or obesity. It is based on risk calculators, not on heart attacks or strokes observed in the trials.
How the TOGETHER trials were designed
The analysis, abstract 4328, was led by Brittany Weber of UT Southwestern Medical Center, according to Healio. The psoriasis study, TOGETHER-PsO, took in 274 adults whose plaque psoriasis was moderate to severe, while TOGETHER-PsA took in 271 adults with active psoriatic arthritis. Every participant also had obesity, or overweight with at least one weight related condition. People were randomly assigned in equal numbers to ixekizumab, an injected antibody that blocks interleukin 17A and is sold as Taltz, either alone or together with tirzepatide, the GIP and GLP 1 peptide sold as Zepbound. Both groups received counselling on diet and physical activity for 52 weeks. The trials were open label with blinded assessors, so participants knew which treatment they received.
The main endpoints combined skin or joint response with weight loss of at least 10%, and Lilly reported earlier that both trials met them at week 36. At week 52, according to a company release summarised by BioPharm International, 30.6% of combination patients in TOGETHER-PsO had completely clear skin and at least 10% weight loss, against 4.4% on ixekizumab alone. In TOGETHER-PsA, 39.2% reached a 50% improvement in arthritis activity plus 10% weight loss, against 1.7%. The week 52 analyses were prespecified but exploratory, without correction for multiple testing. Both studies are listed as completed in the US trial registry and its companion record.
Tirzepatide psoriasis results on heart risk markers
At week 36, the combination groups lost far more weight than those on ixekizumab alone. Mean weight change was minus 16.5 kilograms in TOGETHER-PsO and minus 18.5 kilograms in TOGETHER-PsA, against minus 1.1 kilograms with ixekizumab alone in each trial. Systolic blood pressure fell by about 10 points with the combination. HbA1c dropped by 0.5 and 0.6 percentage points, while people on ixekizumab alone stayed in the prediabetes range on average. LDL cholesterol, non HDL cholesterol and triglycerides fell and HDL cholesterol rose. C reactive protein, a blood marker of inflammation, also fell more with the combination, according to the Healio account of the abstract.
Mean weight change was minus 16.5 kilograms in TOGETHER-PsO and minus 18.5 kilograms in TOGETHER-PsA, against minus 1.1 kilograms with ixekizumab alone in each trial.
The researchers fed these changes into the Framingham Risk Score, which estimates the chance of a major cardiovascular event over 10 years. At the start, mean scores were 15.38 and 15.25 in the two TOGETHER-PsO groups and 17.46 and 18.25 in the TOGETHER-PsA groups. By week 36, predicted risk was about 30% lower with the combination than with ixekizumab alone, with hazard ratios of 0.70 in TOGETHER-PsO and 0.69 in TOGETHER-PsA. Results were similar with the American Heart Association's PREVENT equation, Healio reported. More of the combination patients also brought their waist to height ratio below 0.6, a marker of central body fat.
| Measure at week 36 | TOGETHER-PsO | TOGETHER-PsA |
|---|---|---|
| Weight change, combination | minus 16.5 kg | minus 18.5 kg |
| Weight change, ixekizumab alone | minus 1.1 kg | minus 1.1 kg |
| HbA1c change, combination | minus 0.5 points | minus 0.6 points |
| Predicted 10 year risk, hazard ratio | 0.70 | 0.69 |
Why psoriatic disease raises cardiovascular risk
Psoriasis and psoriatic arthritis are chronic inflammatory diseases, and the abstract authors wrote that this inflammation raises cardiovascular risk beyond the usual risk factors. They estimated that 60% to 82% of patients also have overweight or obesity, which adds to that risk through blood pressure, lipids and further inflammation. Lilly has said that about 61% of people with psoriasis and 65% of people with psoriatic arthritis in the United States have obesity or overweight with a related condition. Mean body mass index at baseline was 39.2 in TOGETHER-PsO and 37.6 in TOGETHER-PsA. Treating the skin or joints alone does little for blood pressure, blood sugar or weight, which is the gap the combination was designed to test.
"This finding is an important reminder that treating psoriasis alone does not modify traditional cardiovascular risk factors," said Joel Gelfand of the University of Pennsylvania, one of the study investigators, who is also chief medical editor of Healio Dermatology. The trials add to a run of results for tirzepatide beyond weight loss, including its approval for sleep apnea. A small study has also linked it with lower pulmonary artery pressure in heart failure. Ixekizumab is an antibody, not a peptide. The tirzepatide arm is what brings these trials onto the peptide medicine beat. The presenters argued that the tirzepatide psoriasis pairing works on inflammation and metabolism together, which may lower long term risk.
What the 30 percent figure does not show
A lower predicted risk is not the same as fewer heart attacks. Risk scores translate blood pressure, cholesterol, blood sugar and other inputs into an estimate, and they were built in general populations rather than in people with psoriatic disease. The TOGETHER trials were not designed or powered to count cardiovascular events, and they lasted one year, while the scores look ten years ahead. The comparison also mixes two effects, since the combination group lost far more weight, so the analysis cannot separate the benefit of weight loss from any direct effect of tirzepatide. The open label design adds a further caution. Our guide to reading weight loss headlines sets out similar questions.
The data so far come from a congress abstract and company releases. A full peer reviewed paper has not yet been published, BioPharm International noted, and the week 52 results remain exploratory. A trial that counts actual cardiovascular events in people with psoriatic disease would be needed to show that the risk score change turns into fewer heart attacks and strokes. Lilly is also running two phase 4 TOGETHER AMPLIFY studies that test adding tirzepatide after starting ixekizumab in routine practice, according to their registry listings. Both medicines are already approved separately in the United States, and any decision to combine them rests with prescribers.
Conclusion
The tirzepatide psoriasis analysis adds a cardiovascular angle to the TOGETHER program. Adding tirzepatide to ixekizumab produced large weight loss and better blood pressure, sugar and lipid readings, which together lowered predicted 10 year cardiovascular risk by about 30% at week 36. The result rests on risk scores, an open label design and an unpublished abstract. Only an outcomes trial could show whether people with psoriatic disease actually have fewer heart attacks and strokes on the combination.
