Diabetes Drug Pioglitazone Helpful for Lupus [Suggests NIH study]
Lupus Research Article
Peroxisome proliferator-activated receptor-γ agonist pioglitazone improves vascular and metabolic dysfunction in systemic lupus erythematosus
This NIH research study suggests that pioglitazone is helpful for lupus patients
Hasni S, Temesgen-Oyelakin Y, Davis M, Chu J, Poncio E, Naqi M, Gupta S, Wang X, Oliveira C, Claybaugh D, Dey A, Lu S, Carlucci P, Purmalek M, Manna ZG, Shi Y, Ochoa-Navas I, Chen J, Mukherjee A, Han KL, Cheung F, Koroleva G, Belkaid Y, Tsang JS, Apps R, Thomas DE, Heller T, Gadina M, Playford MP, Li X, Mehta NN, Kaplan MJ. Ann Rheum Dis. 2022 Aug 1:annrheumdis-2022-222658. doi: 10.1136/ard-2022-222658. Epub ahead of print. PMID: 35914929.
– Pioglitazone (Actos) 45 mg a day taken for 3 months by systemic lupus erythematosus (SLE) patients improves cardiovascular (CV) measurements (decreased stiffness of artery walls)
– Pioglitazone also improved insulin resistance and cholesterol
– It also improved part of the lupus immune system (reduced NETosis, see below)
– A small number of patients developed ankle swelling (edema) and elevated liver enzymes. These were mild and not common.
– Some of my patients participated in this study. Thank you so much for adding this valuable information to our growing knowledge about lupus!
What we already know about cardiovascular disease in lupus
– SLE patients are at high risk of CV events (heart attacks, strokes, blood clots)
– CV events are one of the top two causes of death in SLE patients in countries such as the U.S., Canada, UK, and Australia
– These tend to occur sooner and at younger ages than the healthy population. This includes our young patients (such as in their 20s)
– We need to find ways of preventing CV events in SLE patients
-Patients take pioglitazone to help type 2 diabetes and fatty liver. However, we do not know how helpful pioglitazone is for lupus patients.
What this study adds to our knowledge about pioglitazone being helpful for lupus
– Most SLE patients in this study tolerated pioglitazone well
– If lupus patients take pioglitazone, it could potentially help reduce CV events (however, further studies are needed), showing it to be helpful for lupus patients
– There is a glimmer of hope that maybe pioglitazone could help lupus disease activity (but this is only theoretical)
How the pioglitazone lupus study was done (in brief)
Location: National Institutes of Health, Bethesda, Maryland
Patients: 72 SLE patients finished the study.
21% of the patients had African ancestry (a higher number than usual), which is good since SLE is more common in this population, and they are typically underrepresented in research studies.
- Placebo-Controlled: Each patient received either placebo (fake pills) or pioglitazone daily for 3 months.
- Cross-over design with a washout period: The researchers tested numerous CV measurements and immune system tests before and after treatment. They then stopped treatment for 2 months, after which they took the other treatment for 3 months. In other words, if they first took pioglitazone, they then took a placebo. The researchers repeated the baseline and final CV and lupus disease measurements like during the 1st three months.
- Double-blinded: Neither the doctors nor the patients knew if they were taking a placebo or pioglitazone.
Additional key points about pioglitazone and lupus
One of the tests measured neutrophil NETosis, as mentioned above. Neutrophils are a type of white blood cell of the immune system. NETosis is the process where neutrophils produce “neutrophil extracellular traps,” or NETs for short. When neutrophils are damaged, they can spew their inner contents outside the cell. This spewed-out structure, filled with cellular debris, looks like a fishing net. However, instead of fish, the spewed-out, net-like structure contains the inner cell contents.
The researchers point out that unusual NET formation adds to the CV problems that we see in SLE. Therefore, calming down this process with pioglitazone could possibly help lupus patients by reduced hardening of the arteries.
How NETs work in lupus
However, these NETs also contain DNA and other cell proteins (antigens) recognized by the lupus immune system. Anti-DNA, antinuclear antibody, anti-Smith, anti-RNP, anti-SSA, anti-SSB, anti-chromatin are some of these antibodies. They identify and attach to their corresponding proteins in the NETs and in turn, cause higher lupus immune system activity. Active lupus has more NETosis activity. Therefore, this becomes a vicious circle of greater immune system activity and inflammation throughout the body.
If something, like pioglitazone, can reduce NETs from forming (reduce NETosis as in this study), theoretically, it could potentially decrease lupus disease activity. Yet, the study did not prove this.
However, C4 complement levels did increase (this can occur with reduced lupus disease activity). This is a sign that it could possibly help lupus disease.
The research study design was such that it would have been hard to prove that pioglitazone improves lupus disease activity.
- Overall, patients had mild disease activity (it is easier to show if a treatment works or not in patients who have more active disease).
- If a patient’s doctor raised their immunosuppressant dose (or add a new drug), the researchers had to exclude that patient from the final study results. Therefore, this removes patients who are flaring. If these were to mainly happen in the placebo group, and patients were kept in the study, then we could see if the treatment (pioglitazone) helps lupus or not.
- And lastly, patients took each treatment for only 3 months. This is too short a time to look for an active lupus therapy for most medications. Three months may be long enough for fast-working drugs, such as prednisone and anifrolumab (Saphnelo), but not for most, which take longer to work.
What should be studied in the future regarding pioglitazone and lupus
– Repeat this study in a larger number of and sicker SLE patients over a longer length of time to see if these results are reproduced
– Also, see if treated patients end up with fewer heart attacks, strokes, and blood clots
– Also, see if lupus disease activity improves in treated patients and see if they have fewer lupus flares
-Another reason to have a research study for a longer length of time is that pioglitazone may increase the risk of getting bladder cancer, broken bones, and heart failure. We need to ensure these are not long-term side effects in lupus patients