Use of Premixed Insulin, Metformin, and a Glucagon-Like Peptide 1 Receptor Agonist as a Therapeutic Approach for Uncontrolled Type 2 Diabetes.

OBJECTIVE | To explore the use of premixed insulin, a glucagon-like peptide 1 (GLP-1) receptor agonist, and metformin as combination therapy for type 2 diabetes. DESIGN AND METHODS | All adult patients with type 2 diabetes who had been prescribed premixed insulin and a GLP-1 receptor agonist simultaneously at our outpatient clinic were selected for retrospective review. We reviewed A1C, weight, cumulative daily insulin dose, and adverse events over 12 months. RESULTS | A total of 72 patients received premixed insulin and a GLP-1 receptor agonist, of which 32 met inclusion criteria. The average duration of type 2 diabetes for these patients was 14.2 ± 7.1 years. Mean A1C at baseline was 10.5 ± 2.1%. At 12 months, mean A1C was 8.3 ± 1.9%. The change in mean A1C after 12 months was -2.2% (95% CI -3.433 to -1.014, P <0.0001). At 12 months, the mean cumulative insulin dose was 33.3 units less than before the therapy change (95% CI -57.13 to -9.46, P = 0.0030). Average weight change at 12 months was -2.2 kg (95% CI -27.6 to 37.6, P = NS). After 12 months, 61% of included patients (19 of 31) had an A1C ≤8%. Six additional patients were not included in analysis because they stopped the regimen after <3 months because of adverse events. CONCLUSION | Despite a decreased cumulative daily dose of insulin, patients with historically uncontrolled type 2 diabetes using metformin, premixed insulin, and a GLP-1 receptor agonist in combination experienced improved glycemic control over 12 months. Prospective randomized trials are needed to better assess the potential benefit of this combination therapy.

Antiangiogenic therapies for pheochromocytoma and paraganglioma.

Metastatic pheochromocytomas and paragangliomas are rare, highly vascular tumors that spread primarily to the lymph nodes, skeletal tissue, lungs, and liver. Tumor morbidity is related to their size, location, hormonal activity, vascular nature, and rate of progression. Systemic therapies for this indication are limited. Only high-specific-activity iodine-131 metaiodobenzylguanidine is approved in the Unites States for treatment of these patients, and not all patients are candidates for this radiopharmaceutical. Antiangiogenic medications are currently being evaluated in prospective clinical trials for patients with metastatic pheochromocytomas and paragangliomas, and preliminary results have been encouraging. Antiangiogenic medications frequently offer antineoplastic effects with sometimes durable responses. However, cardiovascular toxicity and the development of tumor resistance may limit their efficacy. Experience derived from clinical trials is being used to identify mechanisms to effectively improve drug toxicity and possibly prevent the emergence of resistance. Therefore, antiangiogenic medications represent a therapeutic option for patients with metastatic pheochromocytomas and paragangliomas. Furthermore, in the world of oncology, there is strong scientific interest in the development of clinical trials that combine antiangiogenic medications with other modalities such as immunotherapy, radiopharmaceuticals, and hypoxia inhibitors since these combinations may substantially enhance clinical outcomes, including survivorship. In this review, we examine the progress made to date on antiangiogenic treatments for patients with metastatic pheochromocytomas and paragangliomas.

Salutary Response to Targeted Therapy in Anaplastic Thyroid Cancer.

Context. Anaplastic thyroid cancer (ATC) is an aggressive tumor with a median survival of 3 to 9 months, a 1-year survival of less than 10% and without definitive therapies. Recently, in BRAF V600E mutated ATCs, new targeted therapy using a combination of a BRAF inhibitor, dabrafenib (Dab), with a mitogen-activated extracellular protein kinase (MEK) inhibitor, trametinib (Tram), has shown significant promise. Case Description. We report a case of aggressive ATC with 5 sequence mutations: BRAF V600E (mutation fraction [MF] 34%), TERT E441del (MF 37%), RET N579K (MF 55%), EZH2 D154E (MF 60%), and CDK4 S259L (MF 48%). The patient had a dramatic response to the Dab/Tram combination with near complete resolution of his lung, bone, hepatic, and splenic lesions soon after starting therapy. Unfortunately, intolerable side effects (grade 2-3) on this regimen required tapering and discontinuation of the treatment. He had a quick resurgence of disease after stopping the combination therapy. The patient died approximately 3 months after discontinuing Dab/Tram. Autopsy revealed an atrophic thyroid gland with microscopic subcapsular focus of well-differentiated papillary thyroid carcinoma. There was extensive lymphatic spread of the tumor throughout bilateral lungs with fibrosis. No other metastatic site was identified. Conclusion. We report a unique case of ATC with 2 new mutations of EZH2 D154E and CDK S529L. This case exemplifies the significant promise Dab/Tram therapy holds, the potential side effects that limit their use, and autopsy findings status post use of this combination therapy.