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doi: 10.1007/s40265-015-0410-1pmid: 25985865
There is an urgent need for effective pharmacological therapies to help tackle the growing obesity epidemic and the healthcare crisis it poses. The past 3 years have seen approval of a number of novel anti-obesity drugs. The majority of these influence hypothalamic appetite pathways via dopaminergic or serotoninergic signalling. Some are combination therapies, allowing lower doses to minimize the potential for off-target effects. An alternative approach is to mimic endogenous satiety signals using long-lasting forms of peripheral appetite-suppressing hormones. There is also considerable interest in targeting thermogenesis by brown adipose tissue to increase resting energy expenditure. Obesity pharmacotherapy has seen several false dawns, but improved understanding of the pathways regulating energy balance, and better-designed trials, give many greater confidence that recently approved agents will be both efficacious and safe. Nevertheless, a number of issues from preclinical and clinical development continue to attract debate, and additional large-scale trials are still required to address areas of uncertainty.
doi: 10.1007/s40265-015-0411-0pmid: 26033077
In individuals with multiple sclerosis, physical and cognitive disability progression are clinical and pathophysiological hallmarks of the disease. Despite shortcomings, particularly in capturing cognitive deficits, the Expanded Disability Status Scale is the assessment of disability progression most widely used in clinical trials. Here, we review treatment effects on disability that have been reported in large clinical trials of disease-modifying treatment, both among patients with relapsing–remitting disease and among those with progressive disease. However, direct comparisons are confounded to some degree by the lack of consistency in assessment of disability progression across trials. Confirmed disability progression (CDP) is a more robust measure when performed over a 6-month than a 3-month interval, and reduction in the risk of 6-month CDP in phase III trials provides good evidence for the beneficial effects on disability of several high-efficacy treatments for relapsing–remitting disease. It is also becoming increasingly clear that therapies effective in relapsing–remitting disease have little impact on the course of progressive disease. Given that the pathophysiological mechanisms, which lead to the long-term accrual of physical and cognitive deficits, are evident at the earliest stages of disease, it remains a matter of debate whether the most effective therapies are administered early enough to afford patients the best long-term outcomes.
Kalabalik, Julie; Rattinger, Gail; Sullivan, Jesse; Slugocki, Malgorzata; Carbone, Antonia; Rivkin, Anastasia
doi: 10.1007/s40265-015-0405-ypmid: 25998374
Atrial fibrillation is a commonly encountered arrhythmia associated with increased risk for thromboembolic events. Anticoagulation is necessary to decrease the risk of ischemic stroke. Traditionally, warfarin has been the only oral pharmacotherapeutic option for long-term anticoagulation in patients with nonvalvular atrial fibrillation (NVAF). Recently, non-vitamin K antagonist oral anticoagulants (NOAC), including dabigatran, rivaroxaban, apixaban, and edoxaban, have become available as alternatives for warfarin in the prevention of stroke in patients with NVAF. Recently published atrial fibrillation guidelines contain new recommendations for risk stratification tools in determining the need for anticoagulant therapy and incorporate NOAC pharmacotherapy options for stroke prevention in patients with NVAF. NOACs offer several advantages over warfarin, including the elimination of routine laboratory monitoring, fewer drug and food interactions, and rapid therapeutic onset and offset. However, the lack of antidote in the case of serious bleeding and lack of data for long-term use in patient populations at risk for bleeding is problematic. Older adults are at high risk for thromboembolic and bleeding events as a result of anticoagulation and require special consideration when selecting anticoagulant therapy. The risk of drug accumulation and bleeding is concerning in the presence of renal impairment. The objective of this review is to provide the clinician with an update on the use of NOACs for NVAF, focusing on older adults and patients with renal impairment in light of recently published atrial fibrillation guidelines. Available data on using NOACs in coronary artery stenting, cardioversion, and ablation are also reviewed.
Beavers, Craig; Carris, Nicolas; Ruf, Kathryn
doi: 10.1007/s40265-015-0414-xpmid: 26056028
Clopidogrel is a cornerstone of dual antiplatelet therapy. Hypersensitivity reactions potentially limit the use of this treatment and present a significant clinical challenge. The authors have developed recommendations for the management of clopidogrel hypersensitivity with consideration for the etiology, pathophysiology, and critical evaluation of potential management strategies. The clopidogrel hypersensitivity reaction is complex in mechanism and presents generally around day 5 of treatment. Generalized reactions are most common, but the reaction may also be localized or systemic. Screening patients for hypersensitivity is not always possible because the type IV delayed reaction is not detected reliably by conventional skin prick, intradermal challenge, or patch testing. Proposed strategies for management of clopidogrel hypersensitivity include treatment of the reaction with corticosteroids, clopidogrel desensitization, substituting an alternative P2Y12 inhibitor, or clopidogrel avoidance. The safety, efficacy, and cost of each potential strategy must be considered when managing a patient with clopidogrel hypersensitivity.
Shirley, Matt; Keating, Gillian
doi: 10.1007/s40265-015-0406-xpmid: 25998375
Regorafenib (Stivarga®) is an orally administered small molecule inhibitor of multiple protein kinases, including kinases involved in oncogenesis and tumour angiogenesis. It was initially approved for use in patients with previously treated metastatic colorectal cancer. Based on the findings of the phase III GRID clinical trial, approval for regorafenib has been expanded to include the treatment of advanced gastrointestinal stromal tumours (GISTs) following the failure of imatinib and sunitinib. In the GRID trial, regorafenib significantly improved progression-free survival and was associated with a significantly higher disease control rate than placebo. No significant between-group difference was observed in overall survival (OS) in the trial; however, the high proportion of patients who crossed over from placebo to regorafenib likely impacted the OS analysis. Regorafenib has an acceptable tolerability profile, with most adverse events being manageable with dose modification and/or supportive measures. The most commonly reported drug-related adverse events among patients receiving regorafenib in the GRID trial were hand-foot skin reaction, hypertension, diarrhoea and fatigue. In conclusion, regorafenib presents a valuable new tool in the treatment of patients with advanced GISTs following the failure of imatinib and sunitinib.
doi: 10.1007/s40265-015-0407-9pmid: 26017303
A 91-day extended-cycle oral contraceptive (OC) consisting of levonorgestrel/ethinylestradiol 150/30 µg for 84 days and ethinylestradiol 10 µg for 7 days (Seasonique®) has recently been approved for the prevention of pregnancy in adult women in the EU. This regimen allows for a reduction in the number of withdrawal bleeding episodes to four per year, compared with 13 episodes per year with conventional 28-day regimens. Seasonique® was effective in preventing pregnancy in a large (n = 1006), noncomparative trial of healthy, sexually active women. In this trial, the overall Pearl index (pregnancies per 100 woman-years of use) in women aged 18−35 years (n = 621) was 0.76 and the Pearl index for method-failure (compliant use) was 0.26. Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over time, with a mean of 2 days of bleeding and 1 day of spotting per each 91-day cycle. Unscheduled bleeding and unscheduled spotting was highest during the first few cycles of use and decreased thereafter. Seasonique® was generally well tolerated, with a tolerability profile in line with that expected for OCs. Seasonique® extends the contraceptive options currently available to women, particularly in those who desire fewer withdrawal bleeding episodes.
doi: 10.1007/s40265-015-0412-zpmid: 26059288
A fixed-dose tablet comprising ombitasvir (an NS5A replication complex inhibitor), paritaprevir (an NS3/4A protease inhibitor) and ritonavir (a cytochrome P450 inhibitor) taken in combination with dasabuvir (an NS5B polymerase inhibitor) is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in several countries, including the USA (copackaged as Viekira Pak™) and those of the EU (Viekirax® and Exviera®). In phase II and III trials, this interferon-free regimen, taken ± ribavirin, provided high rates of sustained virological response 12 weeks post-treatment in adults with chronic HCV genotype 1a or 1b infection, including those with compensated cirrhosis, liver transplants or HIV-1 co-infection. The regimen was generally well tolerated, with nausea, insomnia, asthenia, pruritus, other skin reactions and fatigue being among the most common tolerability issues. Thus, ombitasvir/paritaprevir/ritonavir plus dasabuvir is an effective interferon-free, direct-acting antiviral regimen for use ± ribavirin in a broad range of adults chronically infected with HCV genotype 1.
doi: 10.1007/s40265-015-0413-ypmid: 26017304
Pasireotide (Signifor®, Signifor® LAR) is a somatostatin analogue recently approved for the treatment of acromegaly. Unlike the first-generation agents, octreotide and lanreotide, which bind preferentially to somatostatin receptor (SSTR)-2, pasireotide binds to multiple SSTRs. This article reviews the clinical use and summarizes the pharmacological properties of intramuscular pasireotide in the treatment of acromegaly. The efficacy of pasireotide 40 mg every 28 days was superior to that of intramuscular octreotide 20 mg every 28 days with regard to biochemical control in a 12-month, phase III trial in medically naive patients. Similarly, in a 6-month, phase III trial in patients with acromegaly inadequately controlled with somatostatin analogues for at least 6 months, the efficacy of pasireotide 40 or 60 mg was superior to that of continued octreotide 30 mg or lanreotide autogel 120 mg (each drug was administered once every 28 days) with regard to biochemical control. The tolerability profile of intramuscular pasireotide is generally similar to that of first-generation agents, except for a higher incidence of hyperglycaemia-related adverse events with pasireotide. In clinical trials, the risk of developing pasireotide-associated hyperglycaemia was numerically greater in patients categorized as diabetic or prediabetic at baseline than in those with normal glucose tolerance. Careful monitoring of glycaemic status is required prior to and during pasireotide treatment and antidiabetic therapy should be commenced as indicated. Thus, in the treatment of acromegaly, pasireotide may be a more effective somatostatin analogue than other approved agents of the same class; however, the increased risk of hyperglycaemia needs to be considered and proactively managed.
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