SAT-257 - Severe Refractory Hypertriglyceridemia Responding to Pioglitazone

Introduction
Severe hypertriglyceridemia (triglycerides >1000 mg/dL) is associated with recurrent abdominal pain, acute pancreatitis, and increased cardiovascular risk. Management is often challenging, particularly in the outpatient setting, as many patients fail to achieve adequate triglyceride control despite maximal standard-of-care therapy including fibrates, statins, omega-3 fatty acids, and insulin. We present a case of severe refractory hypertriglyceridemia that responded to escalating doses of pioglitazone.
Case Presentation
A 39-year-old male with type 2 diabetes mellitus presented for evaluation of persistently elevated triglycerides and recurrent acute pancreatitis, including a recent hospitalization for a second episode. He denied alcohol use. His medication regimen included empagliflozin, atorvastatin, metformin, fenofibrate, and omega-3 fatty acids. Despite adherence to this regimen and a strict low-fat diet, triglycerides fluctuated between 1,500–3,000 mg/dL over several years. By 2016, triglycerides had peaked at 2,443 mg/dL with a total cholesterol of 301 mg/dL and HbA1c of 7.0%.
In March 2021, with triglycerides at 3,292 mg/dL, pioglitazone 15 mg daily was initiated alongside his existing regimen. Within one month, triglycerides fell to 588 mg/dL; however, they rebounded to 1,575 mg/dL at two months. The dose was increased to 30 mg daily, achieving a reduction to 209 mg/dL. A GLP-1 receptor agonist was subsequently added without significant weight loss. Triglycerides again rose to 557 mg/dL despite full medication adherence and dietary compliance. Pioglitazone was escalated to 45 mg daily, after which triglycerides have remained persistently below 200 mg/dL. The patient has experienced no further episodes of pancreatitis since achieving triglyceride control on this regimen.
Discussion
A review of the literature identifies only two previously reported cases of severe hypertriglyceridemia exceeding 1,000 mg/dL that responded to pioglitazone after failing maximal standard-of-care therapy, including fibrates, statins, omega-3 fatty acids, insulin, and metformin. Familial chylomicronemia syndrome represents an important and underrecognized etiology of severe hypertriglyceridemia, for which two novel pharmacologic agents have recently received regulatory approval. However, insurance authorization for these therapies remains limited, and their broader real-world impact in this rare population is yet to be established. In the interim, escalation to maximal-dose pioglitazone represents a clinically reasonable and potentially effective strategy in patients with refractory severe hypertriglyceridemia who have exhausted conventional treatment options.

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