Metformin For Warts?

Hello Summarians!

Non-traditional uses for older medications—an interesting concept. The more we learn about the mechanisms of action, the more able we are to theorize new potential uses.

Here are a couple of studies that look at new uses for older meds.

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Metformin For Papillomas

Cutaneous papilloma (CP) in dogs, caused by canine papillomavirus, is generally self-limiting due to a cell-mediated immune response, but in some cases, lesions persist, multiply, or progress to squamous cell carcinoma. Recent research has shown persistent activation of the mammalian target of rapamycin (mTOR) signaling pathway in CP, providing a rationale for targeted treatments. Metformin, a drug commonly used to treat type II diabetes, has been shown in mice to reduce CP size by inhibiting mTOR signaling, an effect dependent on the presence of the metformin uptake transporter OCT3 (SLC22A3). High OCT3 expression, combined with phosphorylated ribosomal protein S6 (pS6)—a marker of mTOR activation—predicts sensitivity to metformin. 

This study investigated OCT3 expression in canine CPs already known to exhibit mTOR activation to assess whether these lesions could be sensitive to metformin. Immunohistochemical analysis revealed consistent OCT3 expression in both normal canine epidermis and CPs, similar to findings in human head and neck squamous cell carcinomas, regardless of papillomavirus status. Furthermore, OCT3 was expressed in all epidermal cells displaying mTOR pathway activation. These findings suggest that canine CPs possess the molecular characteristics necessary for metformin uptake and action at the lesion site. Since normal canine epidermis exhibits limited mTOR activation restricted to upper layers, metformin use is unlikely to interfere with normal epidermal functions. Evidence from other animal models also supports metformin’s ability to selectively inhibit mTOR activity within dysplastic epithelial cells. 

Overall, the findings indicate that metformin, known for its safety and low toxicity, could offer a mechanism-based therapeutic option for dogs with persistent or multiple CPs by exerting antiproliferative effects directly at the lesion site. This provides a rationale for future clinical assessment of metformin as a treatment for canine CP. 

Sanz Ressel BL, Gomez Castro G, Mórtola EC, Massone AR, Barbeito CG. Characterising the expression of the organic cation transporter OCT3 in cutaneous papillomas of dogs. Vet Dermatol. 2025; 36: 385–391. https://doi.org/10.1111/vde.13302 

Bottom line — Potentially effective, low-cost, and safe treatment.

New Insulin Treatment for Horses?

Endocrinopathic laminitis accounts for the majority of laminitis cases in horses, with most affected animals exhibiting hyperinsulinemia. Previous pharmaceutical treatments for insulin dysregulation, including levothyroxine, metformin, and resveratrol, have shown variable success. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have recently demonstrated strong effects on insulin regulation but are costly and often cause hypertriglyceridemia. Pioglitazone, a thiazolidinedione and PPAR-γ agonist, is of interest due to its insulin-sensitizing effects, promotion of smaller, more sensitive adipocytes, and its ability to increase circulating adiponectin, which has anti-inflammatory and metabolic benefits. 

This study evaluated pioglitazone administered orally at 2 mg/kg once or twice daily over 70 days in horses and ponies with severe hyperinsulinemia. The treatment was well tolerated, with minimal adverse effects limited to mild ventral edema in two horses, and no liver toxicity was observed. However, pioglitazone produced only minor improvements in basal insulin concentrations and did not reduce the insulin response to oral sugar testing, in contrast to earlier studies in less severely affected animals. The response to treatment was variable, with many horses remaining severely hyperinsulinemic at the end of the trial and few achieving normal basal insulin levels. 

Notably, twice-daily dosing significantly increased both total and high-molecular-weight adiponectin, whereas once-daily dosing produced a slower and smaller effect. Increased adiponectin may have potential metabolic and anti-inflammatory benefits, possibly contributing to improved laminitis comfort scores observed in both groups despite persistent hyperinsulinemia. Twice-daily dosing also reduced serum triglycerides, an effect opposite to that seen with SGLT-2 inhibitors, suggesting possible complementary use of the two drug classes. 

Although pioglitazone alone was not effective as a primary therapy for severe insulin dysregulation, its ability to increase adiponectin and reduce triglycerides suggests potential as an adjunct to more potent insulin-lowering drugs. Future studies should explore its combined use with SGLT-2 inhibitors, the long-term role of adiponectin in laminitis risk, and effects in less severely affected or newly diagnosed horses. Overall, pioglitazone at the tested doses is safe but provides limited benefit for controlling severe hyperinsulinemia as a standalone treatment. 

Lowndes, C. R., Boyle, A. G., Kulp, J., Stefanovski, D., Davis, J. L., & van Eps, A. (2025). Pioglitazone does not adequately control hyperinsulinemia but does increase serum adiponectin concentrations in equids with severe insulin dysregulation. Journal of the American Veterinary Medical Association https://doi.org/10.2460/javma.25.04.0269 

Bottom line — Limited effectiveness as a stand-alone therapy.

Links Between Cruciate and MPLs in Dogs

Cranial cruciate ligament deficiency (CCLD) and medial patellar luxation (MPL) are among the most common canine stifle disorders, yet their pathogenesis is multifactorial and not fully understood. Contributing factors to CCLD include genetics, conformation, obesity, lack of fitness, abnormal tibial plateau angle, internal rotational instability, concurrent MPL, and osteoarthritis. MPL is similarly complex, involving congenital and developmental abnormalities such as femoral and tibial deformities, trochlear groove malformation, and altered quadriceps alignment. Both conditions are linked to internal rotational instability, which may worsen when CCL failure or patellar maltracking is present. Although tibial osteotomies have been developed to address cranial tibial thrust, they do not correct internal rotation, leading to persistent pivot shift and meniscal damage. Likewise, recurrent MPL is often linked to incomplete correction of bony or soft tissue abnormalities, and the role of rotational instability has not been thoroughly explored. 

Rotational instability differs from laxity, as the former describes abnormal dynamic joint motion while the latter reflects the normal passive range of motion. Exaggerated laxity (hyperlaxity) can predispose to instability under load. However, understanding rotational instability has been limited by a lack of baseline data for normal stifle rotation and difficulty separating it from tibial torsion, which is a fixed anatomical feature. The presence of bilateral MPL or contralateral CCLD complicates the use of the opposite limb as a normal reference, highlighting the need for standard measures of stifle rotation. Previous methods for quantifying knee rotation in humans and dogs have included advanced imaging and three-dimensional kinematics, but these techniques are impractical for routine clinical use. Goniometry, a simple, reliable tool already used for measuring joint angles in humans and dogs, offers a practical alternative. 

This study used goniometry to compare stifle rotation in breeds predisposed to CCLD (PCCLD) or MPL (PMPL), and in dogs already affected by these conditions, with that of Greyhounds, a breed at low risk for stifle disease. The results showed greater internal rotation in predisposed and affected breeds compared with Greyhounds, supporting the hypothesis that rotational hyperlaxity is associated with stifle disease. Stifles affected by CCLD had a median internal rotation angle of 32°, consistent with experimental findings following CCL transection. MPL-affected limbs showed even greater rotation (39°), likely due to chronic quadriceps misalignment and soft tissue strain. Interestingly, even clinically normal stifles in predisposed breeds showed greater rotation than Greyhounds, suggesting inherent rotational hyperlaxity may be a risk factor for these diseases. Greyhounds had the lowest and most consistent rotation values, likely reflecting their unique conformation. 

Additional findings included decreased flexion and increased extension in predisposed and affected limbs compared with Greyhounds, consistent with altered stifle biomechanics and CCL dysfunction. Hyperextension has been proposed as a risk factor for CCLD due to increased ligament strain. The range of motion values obtained were broadly comparable to those reported in previous studies of various breeds, indicating measurement reliability despite breed differences and variable conformation. 

Study limitations included difficulties with dog positioning in some cases, reliance on manual restraint for measurements, and demographic variation between groups. The control group consisted mostly of intact Greyhounds, whereas most other dogs were neutered, which may influence ligament properties. Breed variability and the lack of advanced imaging to rule out subtle bony deviations were also constraints, but these did not diminish the observed differences in rotational laxity. 

In conclusion, internal rotation and extension of the stifle were greater in breeds predisposed to or affected by CCLD and MPL compared with Greyhounds, supporting an association between rotational hyperlaxity and stifle disease risk. These findings suggest that inherent rotational laxity may contribute to disease development and highlight the potential value of incorporating antirotational strategies in prevention and surgical repair. Future studies should expand these findings to additional breeds and explore methods to address rotational instability as part of comprehensive stifle management. 

Faulkner, E., Griffon, D. J., Dong, F., Morris, Z., Nucci, D., & Schaeffer, D. J. (2025). Internal rotational laxity of the stifle is increased in dogs predisposed to or affected by medial patellar luxation or cranial cruciate ligament disease. Journal of the American Veterinary Medical Association https://doi.org/10.2460/javma.25.03.0154 

Bottom line — Anti-rotational strategies may be needed in these dogs.

Just putting things in perspective …