Hypertriglyceridemia in equines with refractory hyperinsulinemia treated with SGLT2 inhibitors.

Background: Sodium-Glucose CoTransporter-2 (SGLT2) inhibitors, the -flozin group of drugs, which block glucose reuptake in the renal proximal tubule, are being increasingly used off-label to treat horses with refractory hyperinsulinemia. After 2 years of use by animals in our group, a horse on canagliflozin was incidentally noted to be hyperlipemic. Case Description: We have been following a cohort of equines (n = 20) treated with SGLT2 inhibitors due to refractory hyperinsulinemia. The animals are owned by members of the Equine Cushing's and Insulin Resistance Group and treated by their attending veterinarians. The index case was a 23 years old gelding with a 2 years history of recurring laminitis that began canagliflozin therapy to control hyperinsulinemia which was no longer responsive to metformin. Between 6 and 10 weeks post start of therapy, significant weight loss was noticed. Two days later he was hospitalized with colic symptoms and hyperlipemia but was bright, alert, and eating well throughout. Canagliflozin was discontinued and triglycerides returned to normal reference values within 10 days. A subsequent study of 19 other horses on SGLT2 inhibitors revealed varying degrees of hypertriglyceridemia, all asymptomatic. Conclusion: While this class of drugs holds great promise for cases of refractory hyperinsulinemia and laminitis that do not respond to diet or metformin therapy, hypertriglyceridemia is a potential side effect. In our experience, animals remained asymptomatic and eating well. Further study of hypertriglyceridemia in horses on SGLT2 inhibitors and the possible mitigating effect of diet is indicated. To our knowledge, this is the first report of hypertriglyceridemia with canagliflozin treatment in equines.

Use of the SGLT2 inhibitor canagliflozin for control of refractory equine hyperinsulinemia and laminitis.

Background: Hyperinsulinemia associated with pituitary pars intermedia dysfunction (PPID) and/or equine metabolic syndrome is well documented to put horses at high risk of laminitis. While dietary control of simple sugars and starch is the most effective therapy to control hyperinsulinemia, some horses fail to respond. Case Descriptions: Ten horses with hyperinsulinemia refractory to diet control, metformin, levothyroxine, and pergolide (if diagnosed with PPID) were treated with sodium-glucose cotransporter-2 inhibitor canagliflozin (Invokana®). Nine horses were hyperglycemic (>5.5 mmol/l) or had a history of hyperglycemia. Before instituting therapy, renal function was assessed by determining serum creatinine and blood urea nitrogen concentrations. Canagliflozin was administered orally once a day, with food. Dipstick urinalysis was performed every 2 weeks to confirm glucosuria and screen for proteinuria. Owners were also instructed regarding clinical signs consistent with urinary tract infection. All horses responded with a substantial decrease in serum insulin concentrations to normal or near normal values. Laminitis pain resolved in all cases, with regression of fat deposits. Owner satisfaction with outcomes was 100%. Conclusion: Once daily administration of the SGLT2 inhibitor canagliflozin corrected hyperglycemia, reduced insulin to normal or near normal levels, and was 100% effective in reversing or reducing abnormal fat pads and eliminating laminitis pain in horses with refractory hyperinsulinemia and laminitis. The core aspects of therapy-diet control, exercise when possible, and adequate treatment of PPID-must also be maintained if using canagliflozin. Canagliflozin should be reserved for refractory cases. Further controlled trials to investigate canagliflozin pharmacokinetics, pharmacodynamics, efficacy, and safety are needed.

Possible dysmetabolic hyperferritinemia in hyperinsulinemic horses.

Background: Hyperinsulinemia associated with equine metabolic syndrome and pituitary pars intermedia dysfunction is a risk factor for laminitis. Research in other species has shown elevated body iron levels as both a predictor and consequence of insulin resistance. In humans, this is known as dysmetabolic hyperferritinemia. Aim: To explore the relationship between equine hyperinsulinemia and body iron levels. Methods: We reviewed case histories and laboratory results from an open access database maintained by the Equine Cushing's and Insulin Resistance Group Inc. (ECIR). We identified 33 horses with confirmed hyperinsulinemia and laboratory results for serum iron, total iron binding capacity, and ferritin. Pearson correlation was used to test the relationship between insulin and iron indices. Additionally, we performed a secondary analysis of a previously reported controlled trial that was originally designed to test the correlation between iron status and the insulin response in horses. Here, we used a t-test to compare the mean values of insulin and ferritin between horses we categorized as normal or hyperinsulinemic based on their response to an oral challenge. Results: Serum ferritin exceeded published reference range in 100% of the horses identified from the ECIR database. There were no statistically significant associations between insulin indices (RISQI, log insulin) and iron indices (log serum iron, log TSI%, log ferritin). There were trends for a negative association between RISQI and log iron [r(31) = -0.33, p = 0.058] and a positive association between age and ferritin [r(30) = 0.34, p = 0.054]. From the secondary data analysis of published data, we found significantly elevated ferritin (p = 0.05) in horses considered hyperinsulinemic by dynamic insulin testing compared to horses with a normal response. Conclusion: These results suggest the potential for iron overload in hyperinsulinemic horses, a feature documented in other species and should stimulate further study into the relationship between insulin and iron dysregulation in the horse.