The Potential Role of SGLT2 Inhibitors in the Treatment of Type 1 Diabetes MellitusFattah, Hadi; Vallon, Volker
doi: 10.1007/s40265-018-0901-ypmid: 29663292
Type 1 diabetes mellitus is a difficult disease to treat due to the relative paucity of therapeutic options other than injectable insulin. The latter, however, can induce hypoglycemia, which has been linked to enhanced cardiovascular risk. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral anti-hyperglycemic medications that do not increase the hypoglycemia risk and are US Food and Drug Administration (FDA) approved in type 2 diabetes mellitus. SGLT2 inhibitors may also be of benefit in type 1 diabetic patients, in addition to insulin, although they have not yet been approved for this indication. By blocking SGLT2 in the early proximal tubules of the kidney, these drugs decrease renal glucose retention, which is enhanced in hyperglycemia, thereby improving blood glucose control, in type 1 and type 2 diabetic patents. Their low hypoglycemia risk is due to the compensating reabsorption capacity of another glucose transporter, SGLT1, in the downstream late proximal tubule and the body’s metabolic counter-regulation, which remains intact during SGLT2 inhibition. When insulin dosage is lowered too much, SGLT2 inhibitors can enhance ketogenesis to the extent that the risk of diabetic ketoacidosis increases, particularly in type 1 diabetic patients. SGLT2 inhibitors improve the renal and cardiovascular outcome in type 2 diabetic patients. The mechanisms likely include a reduction in glomerular hyperfiltration, blood pressure, volume overload, and body weight, as well as lowering blood glucose without increasing the hypoglycemia risk. The same mechanistic effects are induced in type 1 diabetic patients. More studies are needed with SGLT2 inhibitors in type 1 diabetic patients, including renal and cardiovascular clinical outcome trials, to fully evaluate their therapeutic potential in this specific population.
The Expanding Role of Ketamine in the Emergency DepartmentSheikh, Sophia; Hendry, Phyllis
doi: 10.1007/s40265-018-0904-8pmid: 29651740
Patients frequently come to the emergency department for pain. For decades, ketamine has been used in the emergency department for procedural sedation but is now receiving attention as a potential alternative to opioids because of its unique analgesic effects. Additionally, ketamine’s dissociative properties have made it a popular choice for sedating profoundly agitated patients. In this narrative review, these new roles for ketamine in the emergency department are discussed.
Chemotherapy-Induced Neutropenia as a Prognostic and Predictive Marker of Outcomes in Solid-Tumor PatientsKasi, Pashtoon; Grothey, Axel
doi: 10.1007/s40265-018-0909-3pmid: 29754293
Chemotherapy-induced neutropenia (CIN) is one of the most common side effects seen in cancer patients. As an adverse event, it is deemed undesirable since it often constitutes a dose-limiting toxicity for cytotoxic agents leading to treatment delays and/or dose reductions. It is also associated with a financial cost component from diagnostic work-up and treatment of patients with chemotherapy-induced febrile neutropenia (CIFN). Neutropenia is commonly accompanied by a decrease in other hematopoietic lineages (anemia and/or thrombocytopenia). Dosing of chemotherapeutic agents is based on the severity of adverse effects seen. Depending on the degree of neutropenia, chemotherapeutic agents may be put on hold until count recovery and growth factor support might be added to allow for dosing as scheduled. However, neutropenia appears to be more than just an adverse event. While CIFN by itself constitutes an adverse event, the appearance of just CIN is not necessarily a marker of poor outcome. In fact, it rather appears to be a surrogate marker of response and/or survival in patients treated with cytotoxic regimens. Here we present evidence in different tumor types treated with different regimens on the role CIN plays as a marker for improved outcomes. If CIN is a surrogate prognostic and/or potentially predictive marker of response, chemotherapy doses may need to be escalated to achieve neutropenia. In addition, instead of reducing treatment doses for safety concerns, the addition of growth factor support and alternative dosing schemes may be strategies to consider.
Apatinib: A Review in Advanced Gastric Cancer and Other Advanced CancersScott, Lesley
doi: 10.1007/s40265-018-0903-9pmid: 29663291
Apatinib [Aitan® (brand name in China)], also known as rivoceranib, is a novel, small molecule, selective vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor and is the second anti-angiogenic drug to be approved in China for the treatment of advanced or metastatic gastric cancer. This article summarizes the pharmacological properties of apatinib and reviews its clinical use in chemotherapy-experienced patients with advanced gastric adenocarcinoma, including gastroesophageal adenocarcinoma (GEA), or with other advanced cancers such as non-small cell lung cancer (NSCLC), breast cancer, gynaecological cancers, hepatocellular carcinoma (HCC), thyroid cancer and sarcomas. As third- or subsequent-line therapy, oral apatinib significantly prolonged median progression-free survival (PFS) and overall survival (OS) compared with placebo and had a manageable safety profile in Chinese patients with advanced or metastatic gastric cancer or GEA participating in randomized, double-blind, multicentre, phase 2 and 3 trials. More limited evidence also supports it use as subsequent-line treatment in Chinese patients with other advanced or metastatic solid tumours, including NSCLC, breast cancer and HCC. Further clinical experience and long-term pharmacovigilance data are required to more definitively establish the efficacy and safety profile of apatinib, including its use in combination with other chemotherapy agents and its role in the management of other types of advanced or metastatic solid tumours. In the meantime, given its convenient administration regimen and the limited treatment options and poor prognosis for patients with advanced or metastatic solid tumours, apatinib is an important, emerging treatment option for adult patients with advanced gastric adenocarcinoma or GEA who have progressed or relapsed after chemotherapy.
Baricitinib: A Review in Rheumatoid ArthritisAl-Salama, Zaina; Scott, Lesley
doi: 10.1007/s40265-018-0908-4pmid: 29687421
Baricitinib (Olumiant®) is an oral, targeted synthetic DMARD that inhibits JAK1 and JAK2, which are implicated in the pathogenesis of rheumatoid arthritis (RA). This novel, small molecule is approved for use as monotherapy, or in combination with methotrexate, for the treatment of adults with moderate to severe active RA who responded inadequately to or were intolerant of ≥ 1 DMARD. In pivotal multinational trials, once-daily baricitinib 4 mg, with/without methotrexate (± another csDMARD), improved the signs and symptoms of RA, disease activity and physical function in DMARD-naive patients and in patients with an inadequate response to methotrexate, csDMARDs or TNF inhibitors; baricitinib treatment also slowed structural joint damage in DMARD-naive patients and in those with an inadequate response to methotrexate and csDMARDs. Baricitinib plus methotrexate was more effective than adalimumab plus methotrexate in patients with an inadequate response to methotrexate. The onset of these benefits was generally rapid and sustained over time. Baricitinib was generally well tolerated during up to 5.5 years’ treatment; the most commonly reported adverse drug reactions were upper respiratory tract infections, increased LDL cholesterol, nausea and thrombocytosis. Thus, once-daily baricitinib, as monotherapy or in combination with methotrexate, is an effective and generally well tolerated emerging treatment for patients with moderate to severe active RA who have responded inadequately to or are intolerant of ≥ 1 DMARD, and extends the options available for this population.
Latanoprostene Bunod Ophthalmic Solution 0.024%: A Review in Open-Angle Glaucoma and Ocular HypertensionHoy, Sheridan
doi: 10.1007/s40265-018-0914-6pmid: 29761382
Latanoprostene bunod ophthalmic solution 0.024% (hereafter referred to as latanoprostene bunod 0.024%) [Vyzulta™] is a nitric oxide (NO)-donating prostaglandin F2α analogue approved in the USA for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma (OAG) or ocular hypertension. It is thought to lower IOP by increasing aqueous humour outflow through the uveoscleral pathway (mediated by latanoprost acid) and increasing the facility of aqueous humour outflow through the trabecular meshwork pathway (mediated by NO). Results from two multinational, phase III studies (APOLLO and LUNAR) and a pooled analysis of these studies demonstrated the noninferiority of latanoprostene bunod 0.024% to timolol ophthalmic solution 0.5% (hereafter referred to as timolol 0.5%) in terms of IOP-lowering efficacy over 3 months in patients with OAG or ocular hypertension, with the superiority of latanoprostene bunod 0.024% over timolol 0.5% subsequently demonstrated in APOLLO and the pooled analysis. Moreover, there was no apparent loss of IOP-lowering effect in subsequent safety extension periods of up to 9 months. The IOP-lowering efficacy seen in APOLLO and LUNAR was confirmed in a phase III study (JUPITER) in Japanese patients, with IOP reductions observed early (week 4) and maintained over the longer-term (12 months). Latanoprostene bunod 0.024% was well tolerated over up to 12 months in these studies, with most ocular treatment-emergent adverse events (TEAEs) being mild to moderate in severity. Thus, current evidence indicates once-daily latanoprostene bunod 0.024% is an effective and well tolerated treatment option for the reduction of IOP in adults with OAG or ocular hypertension.
Ibalizumab: First Global ApprovalMarkham, Anthony
doi: 10.1007/s40265-018-0907-5pmid: 29675744
TaiMed Biologics is developing ibalizumab (Trogarzo™, ibalizumab-uiyk)—a humanised IgG4 monoclonal antibody—as a treatment for HIV-1 infection. Ibalizumab blocks HIV entry into CD4 cells while preserving normal immunological function and is the first CD4-directed post-attachment HIV-1 inhibitor and the first humanised monoclonal antibody for the treatment of HIV/AIDS. This article summarizes the milestones in the development of ibalizumab leading to this first approval in HIV-1 treatment.