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Introduction: In 2008, the Federal Drug Administration (FDA) required all new glucose-lowering therapies to show cardiovascular safety, and this applies to the dipeptidyl peptidase (DPP)-4 inhibitors (‘gliptins’). At present, there is contradictory evidence on whether the gliptins increase hospitalizations for heart failure. Areas covered: This is an evaluation of the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) in high risk cardiovascular subjects with type 2 diabetes [1]. TECOS demonstrated non-inferiority for sitagliptin over placebo for the primary outcome, which was cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. There was no difference in the rate of hospitalization for heart failure between sitagliptin and placebo. Expert Opinion: Despite the results of TECOS, debate over the effects of sitagliptin on the rates of hospitalizations for heart failure continues with some recent studies suggesting increased rate...

Statins alone often do not reduce LDL cholesterol levels sufficiently to given maximum cardiovascular benefit. Thus, additional drugs are required to reduce the levels of LDL cholesterol. Monoclonal antibodies to PCSK9 have recently been shown to decrease LDL cholesterol, but it is not known whether they improve cardiovascular outcomes.We evaluated two clinical trials reporting cardiovascular outcomes with antibodies to PCSK9, the OSLER extension with evolocumab, and the ODYSSEY LONG TERM trial with alirocumab.In OSLER and ODYSSEY LONG TERM, there were very few cardiovascular outcomes, but the trials do suggest that evolocumab and alirocumab may reduce these outcomes. However, there are also some safety concerns with both of these antibodies. Large clinical outcome trials are underway with both evolocumab and alirocumab, which will probably clarify both the safety concerns and any cardiovascular benefits with these antibodies. In our opinion, these antibodies may be suitable for use in subjects with familial hypercholesterolemia, who are uncontrolled with their present medications, provided intensive safety and cardiovascular monitoring is being undertaken. However, evolocumab and alirocumab should be used with caution in other subjects, until outcome studies in higher numbers of subjects have shown acceptable safety and cardiovascular profiles.

Several new medicines are in development for the treatment of type 2 diabetes, and cardiovascular outcome trials are the gold standard for these medicines. This editorial demonstrates that despite being available for over 10 years, there are no cardiovascular outcome studies for any of the glucagon-like peptide-1 receptor agonists, which demonstrate cardiovascular safety or benefit in subjects with high cardiovascular risk. The author argues that the FDA should be ensuring that clinical outcome studies for subjects with type 2 diabetes and high cardiovascular risk be undertaken in a timelier manner.

INTRODUCTION: Inhibitors of the sodium-glucose co-transporter 2 (SGLT2) promote the excretion of glucose to reduce glycated hemoglobin (HbA1c) levels. Canagliflozin was the first SGLT2 inhibitor to be approved by the US FDA for use in the treatment of type 2 diabetes, and recently dapagliflozin has also been approved. AREAS COVERED: We evaluated a recent Phase III clinical trial with dapagliflozin. EXPERT OPINION: Dapagliflozin was studied as add-on therapy to sitagliptin with or without metformin, and was shown to lower HbA1c levels and body weight. The incidence of hypoglycaemia was low with dapagliflozin, but it did increase the incidence of urogenital infections. As no clear benefits have been identified for dapagliflozin over canagliflozin, which was the first gliflozin registered by the FDA, we do not fully understand why it was necessary to register dapagliflozin. Given that there are no completed cardiovascular/clinical outcome studies with dapagliflozin, and therefore no evidence of beneficial effect, it also seems premature to be using it extensively or considering it as an alternative to the clinically proven metformin.

Introduction: In 2008, the US FDA required all new glucose-lowering therapies to show cardiovascular safety, and this applies to the dipeptidyl peptidase-4 inhibitors (‘gliptins’). Areas covered: The cardiovascular safety trials of saxagliptin and alogliptin have recently been published and are the subject of this evaluation. Expert opinion: The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction 53 trial and Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care were both multicentre, randomised, double-blind, placebo-controlled, Phase IV clinical trials. These trials showed that saxagliptin and alogliptin did not increase the primary end point, which was a composite of cardiovascular outcomes that did not include hospitalisations for heart failure. However, saxagliptin significantly increased hospitalisation for heart failure, which was a component of the secondary end point. The effect of alogliptin on h...

There is a debate as to whether percutaneous coronary intervention (PCI) with drug-eluting stents or coronary artery bypass surgery (CABG) is the best procedure for subjects with type 2 diabetes and coronary artery disease requiring revascularization. There is some evidence that by following these procedures, there is less further revascularization with CABG than PCI in subjects with diabetes. Two recent studies, namely, the FREEDOM (Future Revascularization Evaluation in patients with Diabetes mellitus: Optimal Management of Multivessel Disease) trial and a trial using a real-world diabetic population from a Registry have shown that the benefits of CABG over PCI in subjects with type 2 diabetes extend to lower rates of death and myocardial infarction, in addition to lower rates of revascularization. However, the rates of stroke may be higher with CABG than PCI with drug-eluting stents in this population. Thus, if CABG is going to be preferred to PCI in subjects with type 2 diabetes and multivessel coronary disease, consideration should be given as to how to reduce the rates of stroke with CABG.

Introduction Ondansetron is a 5-HT₃ receptor antagonist commonly used as an antiemetic to prevent nausea and vomiting associated with anti-cancer drugs, cancer radiotherapy or postoperatively. Recently, the US Food and Drug Administration (FDA) issued a warning for ondansetron due to a potential for prolongation of the QT interval of the electrocardiogram (ECG), a phenomenon that is associated with an increased risk of the potentially fatal arrhythmia torsade de pointes. Areas covered The authors undertook a review of the cardiac safety of ondansetron. Their primary sources of information were PubMed (with downloading of full articles) and the Internet. Expert opinion The dose of ondansetron that the FDA has concerns about is 32 mg i.v. (or several doses that are equivalent to this), which is only used in preventing nausea and vomiting associated with cancer chemotherapy. This suggests that ondansetron may be safe in lower doses used to prevent nausea and vomiting in radiation treatment or postoperatively. However, as there is a report that a lower dose of ondansetron prolonged the QT interval in healthy volunteers, this needs to be clarified by the FDA. More research needs to be undertaken on the relationship between QT prolongation and torsades in order that the FDA can produce clear-cut evidence of proarrhythmic risk when introducing warnings for this.

The primary target in the treatment of hypercholesterolemia is often to lower low-density lipoprotein (LDL) cholesterol, rather than improve clinical outcomes. Despite the wide use of lipid-modifying drugs, considerable cardiovascular mortality and morbidity remains with this disease. Hypercholesterolemia plays a key role in the development and progression of atherosclerosis and can lead to cardiac heart disease.The purpose of this review is to determine whether ezetimibe has proven clinical benefits; it discusses the clinical trials of simvastatin and ezetimibe alone and in combination.Simvastatin has been clearly shown to decrease LDL-cholesterol, which is associated with the slowing of atherosclerosis and a reduction in cardiovascular morbidity and mortality. Ezetimibe alone or in the presence of simvastatin lowers LDL-cholesterol. However, ezetimibe alone or in the presence of simvastatin has not been shown to have any irrefutable beneficial effects on atherosclerosis or cardiovascular morbidity and mortality. Thus, until/unless the use of ezetimibe is clearly shown to improve clinical outcomes, its use should be largely restricted to clinical trials investigating clinical outcomes and should not be used routinely in everyday practice.

Introduction: Subjects with atrial fibrillation are at risk of thromboembolic events. The vitamin K antagonists (e.g., warfarin) are useful at preventing coagulation in atrial fibrillation, but are difficult to use. One of the FXa inhibitors, oral apixaban, has been tested as an anticoagulant in atrial fibrillation. Areas covered: In ARISTOTLE (Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation) apixaban was compared to warfarin in subjects with atrial fibrillation, and shown to cause a lower rate of stroke or systemic embolism and of major bleeding, than warfarin. In the AVERROES (Apixaban versus acetylsalicylic acid [ASA] to prevent stroke in atrial fibrillations patients who have failed or are unsuitable for vitamin K antagonist treatment) trial, stroke or systemic embolism occurred less often with apixaban than aspirin, whereas the occurrence of major bleeding was similar in the groups. Expert opinion: Apixaban is much easier for subjects with atrial fibrillation t...

Atrial fibrillation increases the risk of stroke. Dronedarone has been shown to reduce the composite of hospitalizations due to cardiovascular events or death, in subjects with intermittent atrial fibrillation or flutter. Recently, dronedarone has been tested in subjects with permanent atrial fibrillation in the PALLAS (permanent atrial fibrillation outcome study using dronedarone on top of standard therapy) trial, and this clinical trial is evaluated in this paper. PALLAS was stopped early as there was an increased incidence of cardiovascular events in the dronedarone group. Dronedarone also increased the rate of hospitalizations in PALLAS. As a result of PALLAS, dronedarone has been contraindicated in permanent atrial fibrillation. The outcomes of PALLAS highlight a discontinuity between dronedarone actions in permanent and intermittent atrial fibrillation. The mechanism(s) underlying the detrimental effects of dronedarone in permanent atrial fibrillation are unknown at present and need to be investigated.

Background: As low HDL cholesterol levels are a risk factor for cardiovascular disease, raising HDL cholesterol substantially by inhibiting or modulating cholesteryl ester transfer protein (CETP) may be useful in coronary artery disease. The first CETP inhibitor that went into clinical trial, torcetrapib, was shown to increase the levels of HDL cholesterol, but it also increased cardiovascular outcomes, probably due to an increase in blood pressure and aldosterone secretion, by an off-target mechanism/s. Objective/methods: Dalcetrapib is a new CETP modulator that increases the levels of HDL cholesterol, but does not increase blood pressure or aldosterone secretion. The objective was to evaluate a paper describing the effects of dalcetrapib on carotid and aortic wall thickness in subjects with, or at high risk of, coronary artery disease, the dal-PLAQUE study. Results: dal-PLAQUE showed that dalcetrapib reduced the progression of atherosclerosis and may also reduce the vascular inflammation associated with...

Oestrogen receptor positive (ER+) breast cancers are susceptible to endocrine treatments, such as tamoxifen. However, resistance is a major problem when treating breast cancer with these agents. ERα phosphorylation is implicated in this resistance to tamoxifen, and kinases are the enzymes that catalyse phosphorylation. A kinome search in human breast cancer cells identified lemur tyrosine kinase 3 (LMTK3). In primary breast cancer samples, high nuclear LMTK3 expression was associated with a shorter disease-free survival time. In tamoxifen-resistant cell lines, the addition of LMTK3 siRNA, increased the inhibitory effect of tamoxifen. In nude mice, with established human MCF-7 breast cancer tumours, LMTK3 siRNA decreased tumour growth. In conclusion, LMKT3 is a possible target and marker of breast cancer.

Introduction: There is a need for new and improved treatments for type 2 diabetes. Glucagon-like peptide 1 (GLP-1) is a gut hormone that stimulates insulin secretion and the levels of GLP-1 can be increased by inhibiting DPP-4. Sitagliptin is one of the DDP-4 inhibitors used to increase the levels of GLP-1. Exenatide is an agonist at the GLP-1 receptors, which is resistant to breakdown and has a longer action than GLP-1. Areas covered: This review compares the clinical trials of sitagliptin and exenatide once weekly in the treatment of type 2 diabetes. Only peer-reviewed trials listed on PubMed were included. Expert opinion: Both sitagliptin and exenatide once weekly are capable of reducing HbA1c and plasma glucose levels, but exenatide once weekly is more potent than sitagliptin and this may lead to different roles for these agents in the treatment of type 2 diabetes.

Despite the present treatments for asthma (β2-adrenoceptor agonists, glucocorticoids, leukotriene receptor antagonists), many subjects with asthma have difficulty controlling it. Bitter taste receptors have recently been identified on human lung. The paper evaluated considers these receptors as a target for bronchodilation, by characterizing the effects of agonists in cultured human airway smooth muscle cells, isolated human bronchial smooth muscle and a mouse model of allergic asthma. The study confirmed that a bitter taste receptor (TAS2R) is a viable target for bronchodilation. Many diverse chemicals are known to stimulate the bitter taste receptors to produce the bitter taste, and many of these have more than one mechanism of action. Thus, it is not known whether any of these have clinical potential in asthma. It may be necessary to design and develop selective agonists for TAS2R, before the clinical potential of this target can be thoroughly investigated.

The prognosis for those with relapsed Hodgkin lymphoma is poor. This evaluation is of two new approaches to the treatment of relapsed Hodgkin lymphoma. First, is a refinement of the chemotherapy for the relapsed condition, which showed that adding SHDCT (sequential high-dose chemotherapy of cyclophosphamine, uromitexane, granulocyte colony-stimulating factor, methotrexate, vincristine, etoposide) did not improve outcome. Second, is new targeted treatment for relapsed Hodgkin disease – brentuximab vedotin, which has an antitubulin agent (monomethylauristatin E) attached to a CD30-specific antibody. This agent gave promising results in a Phase I clinical trial in subjects with relapsed Hodgkin lymphoma. Brentuximab vedotin has produced good initial findings in the treatment of Hodgkin lymphoma and needs to be tested more widely.

Background: Genetic studies have shown that mutations in several genes may be linked to Parkinson's disease including leucine-rich repeat kinase-2 (LRRK2). The most common of the LRRK2 mutants is the Gly2019Ser mutant. Objective/methods: A paper suggesting that inhibitors of Gly2019Ser mutant may be useful in the treatment of Parkinson's disease associated with this mutant is evaluated. Results: Overexpression of the wild-type LRRK2 or the Gly2019Ser LRRK2 mutant type produced cortical neuron injury in cell culture, and the mutant also caused cell death; this was reduced by GW5074. Administered intraperitoneally to mice, GW5074 prevented the loss of neurons induced by the Gly2019Ser LRRK2 mutant. Conclusions: Selective Gly2019Ser LRRK2 mutant inhibitors may have potential in the treatment of Parkinsonism associated with mutations of this gene and GW5074 is a lead compound for this.

The Bcr-Abl kinase inhibitor imatinib is the standard treatment for chronic myeloid leukaemia (CML). Some subjects with CML do not respond to, or are intolerant of, imatinib. Nilotinib and dasatinib were initially developed to treat these subjects, and were shown to be effective. They are now being trialled as initial 'inib' treatment for CML. The objective was to evaluate the recent Phase III clinical trials comparing nilotinib or dasatinib with imatinib in newly diagnosed CML. Nilotinib and dasatinib were shown to give a higher rate of complete cytogenic and major molecular responses than imatinib over 1 year. They should be considered as first choice in the treatment of subjects who develop CML. However, there are still major limitations to the populations with which these 'inib' drugs can be used, and how they can be used.

Background: Inflammation and pain coexist in conditions such as arthritis, inflammatory bowel disease and lower back pain. The drugs currently used to treat the combination of inflammation and pain all have disadvantages. Thus, new drugs and new approaches are needed to treat inflammation with pain. Resolvins are considered to be part of the natural resolving mechanism for inflammation and have been shown to prevent inflammation in animal models. Objectives/methods: To evaluate a paper suggesting that the resolvins RvE1 and RvD1 attenuate inflammatory pain in animal models. Results: RvE1 has been shown to attenuate inflammation and, to a lesser extent, pain in animal models. Limited results are presented of the effectiveness of RvD1 against inflammatory pain. Conclusion: Drugs that mimic or potentiate the effects of the resolvins may be useful for the treatment of some inflammation with pain.

Methotrexate alone or in combination with other agents is the standard treatment for moderate-to-severe rheumatoid arthritis. As biological agents are expensive, they are not usually used until methotrexate has failed to give a good response. Thus, there is scope for the development of cheaper drugs that can be used instead of methotrexate or in addition to methotrexate. Pamapimod is a p38α inhibitor being developed for use in the treatment of rheumatoid arthritis. The objective of this review was to evaluate the recent clinical trials of pamapimod in subjects with rheumatoid arthritis. There is no clear-cut evidence that pamapimod alone or in the presence of methotrexate is efficacious in subjects with rheumatoid arthritis but it does cause adverse effects. It is unlikely that pamapimod will be useful in the treatment of rheumatoid arthritis.

Most people with multiple sclerosis (MS) have the relapsing-remitting type. The objective was to evaluate two clinical trials of fingolimod in relapsing MS. FREEDOMS (FTY720 Research Evaluation Effects of Daily Oral therapy in Multiple Sclerosis), a Phase III placebo-controlled trial, showed that fingolimod (0.5 or 1.25 mg) reduced the relapse rate and disability in MS, compared with placebo. Fingolimod (0.5 or 1.25 mg) has been compared to interferon-beta-1a in a Phase III clinical trial (TRANSFORMS; Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis) and shown to be more efficacious than interferon-beta-1a in reducing relapse rates. However, fingolimod did increase the risk of infections and skin cancers. Only the lower dose of fingolimod (0.5 mg), which possibly has less toxicity, should be considered for prevention of relapses in relapsing-remitting MS.

The first sign of developing multiple sclerosis is a clinically isolated syndrome that resembles a multiple sclerosis relapse. Objective/methods: The objective was to review the clinical trials of two medicines in clinically isolated syndromes (interferon β and glatiramer acetate) to determine whether they prevent progression to definite multiple sclerosis. In the BENEFIT trial, after 2 years, 45% of subjects in the placebo group developed clinically definite multiple sclerosis; the rate was lower in the interferon β-1b group. All subjects were then offered interferon β-1b, and the original interferon β-1b group became the early-treatment group and the placebo group became the delayed-treatment group. After 5 years, the number of subjects with clinical definite multiple sclerosis remained lower in the early-treatment than in the late-treatment group. In the PreCISe trial, after 2 years, the time for 25% of the subjects to convert to definite multiple sclerosis was prolonged in the glatiramer group. Interf...

Acute coronary syndromes are a major cause of mortality and morbidity. The objective of this evaluation is to review the clinical trials of two new drugs being developed for the treatment of acute coronary syndromes. The first drug is the anticoagulant otamixaban, and the trial compared otamixaban with unfractionated heparin and eptifibatide in acute coronary syndromes. The second drug is the antiplatelet ticagrelor, and the trial compared ticagrelor with clopidogrel in acute coronary syndromes. In the SEPIA-ACS1 TIMI 42 trial, the primary efficacy endpoint occurred in 6.2% of subjects treated with unfractionated heparin and eptifibatide, and to a significantly lesser extent with otamixaban. In the PLATO trial, the primary efficacy endpoint had occurred less in the ticagrelor group (9.8%) than in the clopidogrel group (11.7%) at 12 months. Two new drugs for acute coronary syndromes, otamixaban and ticagrelor, have recently been shown to have benefits in subjects undergoing percutaneous interventions compa...

Background: The hedgehog signalling pathway is vital in early development, but then becomes dormant, except in some cancer tumours. Hedgehog inhibitors are being developed for potential use in cancer.Objectives/methods: The objective of this evaluation is to review the initial clinical studies of the hedgehog inhibitor, GDC-0449, in subjects with cancer.Results: Phase I trials have shown that GDC-0449 has benefits in subjects with metastatic or locally advanced basal-cell carcinoma and in one subject with medulloblastoma. GDC-0449 was well tolerated.Conclusions: Long-term efficacy and safety studies of GDC-0449 in these conditions and other solid cancers are now underway. These clinical trials with GDC-0449, and trials with other hedgehog inhibitors, will reveal whether it is beneficial and safe to inhibit the hedgehog pathway in a wide range of solid tumours or not.

Background: Bone loss associated with low oestrogen levels in postmenopausal women, and with androgen deprivation therapy in men with hormone-sensitive prostate cancer, result in an increased incidence of fractures. Denosumab has been shown to increase bone mineral density in these two conditions. Objectives/methods: The objective of this evaluation is to review the clinical trials that have studied clinical endpoints in these conditions. Results: FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) was an International Phase III clinical trial that measured the clinical endpoints with denosumab in postmenopausal women with osteoporosis. At 36 months, new vertebral fractures had occurred in 7.2% of subjects in the placebo group and this was lowered to 2.3% of subjects treated with denosumab. HALT (Denosumab Hormone Ablation Bone Loss Trial) studied the clinical endpoints in men with non-metastatic prostate cancer receiving androgen-deprivation therapy. The incidence of vertebral fractures was significantly lower in the denosumab group (1.5%) than in the placebo group (3.9%). The incidence of adverse effects with denosumab in both clinical trials was low. Conclusions: Denosumab reduces the incidence of fractures in postmenopausal women with osteoporosis and in men with non-metastatic prostate cancer receiving androgen-deprivation therapy. Denosumab is well tolerated.

Background: Subjects with type 2 diabetes have high circulating levels of glucose. Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that has a major role in glucose homeostasis. Exenatide and liraglutide are both agonists at the GLP-1 receptor, and are effective at reducing circulating glucose levels (measured as HbA1c levels), but they have not been compared. Objectives/methods: This evaluation is of a clinical trial comparing liraglutide once a day with exenatide twice a day in subjects with type 2 diabetes. Results: In the Liraglutide Effect and Action in Diabetes (LEAD)-6 trial, subcutaneous liraglutide 1.8 mg once a day was compared with exenatide 10 μg twice a day. The primary efficacy outcome was change in HbA1c levels, and this was significantly greater with liraglutide (1.12%) than with exenatide (0.79%). Liraglutide and exenatide had similar small abilities to reduce body weight, blood pressure and LDL-cholesterol. Conclusions: Liraglutide was more effective than exenatide for overall gl...

Background: Migraine is a common cause of disability. Many subjects (30 – 40%) do not respond to the 5-HT1B/1D agonists (the triptans) commonly used in the treatment of migraine attacks. Calcitonin gene-related protein (CGRP) receptor antagonism is a new approach to the treatment of migraine attacks. Objectives/methods: This evaluation is of a Phase III clinical trial comparing telcagepant, an orally active CGRP receptor antagonist, with zolmitriptan in subjects during an attack of migraine. Results: Telcagepant 300 mg has a similar efficacy to zolmitriptan in relieving pain, phonophobia, photophobia, and nausea. Telcagepant was better tolerated than zolmitriptan. Conclusions: The initial Phase III clinical trial results with telcagepant are promising but several further clinical trials are needed to determine the place of telcagepant in the treatment of migraine attacks.

Background : Postmenopausal osteoporosis is common and is associated with stooped posture, loss of height, back pain and fractures. Objectives/methods : This evaluation is of clinical outcome trials with tibolone (Long-Term Intervention of Fractures with Tibolone) and strontium ranelate (Spinal Osteoporosis Therapeutic Intervention) in postmenopausal osteoporosis. Results : Although the Long-Term Intervention of Fractures with Tibolone trial established that tibolone decreased the incidence of vertebral and non-vertebral fractures in postmenopausal osteoporosis, it also showed that tibolone caused a small increase in the incidence of stoke. The Spinal Osteoporosis Therapeutic Intervention trial established that strontium ranelate decreased the incidence of vertebral fractures, but had little effect on the incidence of non-vertebral fractures. Conclusions : As some of the bisphosphonates (alendronate, risedronate, zoledronic acid) have been shown to prevent hip fractures without increasing the incidence of stroke, they should be preferred to tibolone and strontium in the treatment of postmenopausal osteoporosis.

Background: Tamoxifen is the established adjuvant treatment for postmenopausal women with hormone-sensitive breast cancer. Objective: To determine whether the aromatase inhibitor anastrozole should replace tamoxifen as the adjuvant treatment in this cancer. Methods: Two recent trials of anastrozole and tamoxifen as adjuvant treatment were evaluated. Results/conclusion: The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial showed that 5 years of adjuvant therapy with anastrozole reduced recurrence of breast cancer to a greater extent than did tamoxifen. The Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 6a showed that after 5 years of adjuvant treatment with tamoxifen more benefit was achieved by continuing with adjuvant anastrozole for 3 years than no further treatment. Although the long-term adjuvant treatment of hormone receptor positive breast cancer with anastrozole is indicated, questions remain as to how long the adjuvant treatment with anastrozole should continue.

Background: Topiramate was originally developed as an anti-epileptic but has recently been tested in motivated subjects with alcohol dependency and with binge-eating disorder (BED). Method: Evaluation of recent clinical trials. Results: In the trial with subjects with alcohol dependency, the primary efficacy outcome was the percentage of heavy drinking days, which fell to a greater extent with topiramate (from 82 to 40%). In the trial with subjects with BED, the primary efficacy measure was weight change. Weight decreased from 98.4 to 97.5 kg in the placebo group, and from 96.6 to 89.8 kg in the topiramate group over 21 weeks. Conclusion: Topiramate may be indicated in alcohol dependency and BED. However, it is not known whether benefits with topiramate are retained in the long term, nor whether topiramate will be effective in subjects with less resolve.

Nearly 2 million hip fractures occur each year in the US as a result of osteoporosis. After hip fracture, people are at an increased risk of a further fracture. The HORIZON-PFT (Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial), investigated the effect of zoledronic acid on fractures in women with osteoporosis, whereas the HORIZON-RFT (Recurrent Fracture Trial), studied the effect of zoledronic acid after hip fracture. In the HORIZON-PFT, after 3 years the incidence of new vertebral fractures in postmenopausal women, who were not taking any medication for osteoporosis at randomisation, was 10.9% in the placebo group and this was significantly lower in the once-yearly intravenous zoledronic acid group (3.3%). In the second of the HORIZON trials, the RFT, the effect of a single intravenous injection of zoledronic acid within 90 days of fracture on the recurrence of fracture was tested. The primary endpoint was a new clinical fracture, and after a median follow-up...

Rosiglitazone is commonly used in the treatment of Type 2 diabetes. However, the cardiovascular outcomes with rosiglitazone have only been evaluated recently. Firstly, they were evaluated by meta-analysis. A total of 42 short-term trials, not designed to determine cardiovascular outcomes, were included in the meta-analysis. There were 72 myocardial infarctions in the control group of 12283 subjects (0.59%) and 86 in the rosiglitazone group of 15560 subjects (0.55%). This gave an odds ratio of 1.43 and a p-value of 0.03. As a consequence of this meta-analysis, the safety of this widely used medicine in subjects with Type 2 diabetes is being questioned. Interim analysis of the long-term RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes) trial, which was designed to determine cardiovascular outcomes, showed that these occurred in 9.1% of control subjects and 9.8% of the rosiglitazone subjects, and these values were not significantly different. Both the meta-analysis and the interim analysis of RECORD have many limitations. In conclusion, it seems that it is possible that rosiglitazone may have a small harmful effect on cardiovascular outcomes. As the effect (if any) is small, this should not be cause for alarm, but rather for further review of how rosiglitazone should be used and for a larger trial to determine the unequivocal effect of rosiglitazone on cardiovascular outcomes.

Previous clinical trials have established that clopidogrel is beneficial when used with coronary artery stenting. However, questions remain as to when the clopidogrel treatment should be started and how long treatment should be continued for. In a Clopidogrel Registry, it was shown that when subjects received a loading dose of clopidogrel 300 mg, 6 – 24 h before the intervention and clopidogrel maintenance for 1 month, the primary end point at 30 days (acute myocardial infarction, all cause death and revascularisation) was lower than in subjects who were just given clopidogrel maintenance. An observational study has shown that there are no additional benefits from continuing to use clopidogrel after 6 months from bare-metal stenting. In contrast, long-term treatment with clopidogrel is beneficial in subjects given drug-eluting stents, when long-term stent thrombosis can be a rare complication. Thus, in subjects given drug-eluting stents, there was an incidence of death and non-fatal myocardial infarction ...

Thiazolidinediones are known to increase insulin sensitivity and to be useful in the treatment of Type 2 diabetes. Recently, other important benefits of the thiazolidinediones have emerged. One of the thiazolidinediones (rosiglitazone) has been shown to prevent the progression from a pre-diabetic state to diabetes. In subjects with impaired fasting glucose or impaired glucose tolerance, the diabetic rate over 3 years was 25.0% in the placebo group and 11.6% in the rosiglitazone group. Another recent clinical trial with rosiglitazone has shown that it reduced microalbuminuria and blood pressure independently of glycaemia in subjects with Type 2 diabetes and microalbuminuria. After 32 weeks, there was a 22.7% reduction in the urine albumin:creatinine ratio with rosiglitazone.

Cigarette smoking is the leading preventable cause of death. Varenicline is a partial agonist at nicotinic α4β2 receptors being tested for smoking cessation. During a trial in which the drugs were administered for 12 weeks, the continuous abstinence rate was 17.7% in the placebo group, which improved to 29.5% with bupropion SR and to 44.0% with varenicline 1 mg b.i.d. Abstinence rates for weeks 9 through 52 were 8.4, 16.1 and 21.9% for placebo, bupropion and varenicline, respectively. Prolonging the treatment with varenicline may give better quit rates. In this trial, after 12 weeks of open-label varenicline, the abstainers received either another 12 weeks of varenicline or placebo. At week 24, more of the participants in the varenicline group (70.5%) were abstinent than in the placebo group (49.6%). The most common adverse effect in both these trials with varenicline was nausea. This prompted a trial comparing the efficacy and safety of four varenicline dosing regimens, to determine whether a lower dose ...

In adolescents, there is an epidemic of being overweight or obese. Sibutramine has been shown to cause sustained loss of weight in adults. In a study based in Mexico City, adolescents with a BMI of 35/36 kg/m2, who were put on a hypocaloric diet and undertook physical activity, lost 4.3 kg in 6 months, and this loss was increased to 7.3 kg by sibutramine. Similarly, in a study based in the US, there was a loss of 1.9 kg in the placebo group of obese adolescents with a hypocaloric diet and increased physical activity at the end of 12 months, and this was increased to 6.5 kg in the sibutramine group. Sibutramine has a slight tendency to increase blood pressure and heart rate, and seems to be more effective than orlistat in causing weight loss in adolescents. However, orlistat does not have negative effects on blood pressure. Long-term follow-up studies of sibutramine in adolescents are needed to determine whether the weight loss is maintained, and whether the weight loss translates into better clinical outc...

Alcoholism is the third leading cause of preventable mortality and morbidity in the US. In the COMBINE (Combined Pharmacotherapies and Behavioural Interventions) study, the co-primary end points were the percentage of days abstinent and the time to first heavy drinking day after 16 weeks, and 1 year. The biggest difference observed in COMBINE was that seen between combined behavioural intervention (CBI; percentage of abstinent days = 66.6%) and CBI and medical management with placebos (79.8%). This illustrated a major effect of the medical management of nine sessions and/or the placebo pills. Acamprosate had no effect alone or in combination with naltrexone. At 16 weeks with medical management, there were 75.1% of the patients who were abstinent for placebos, and this was improved by naltrexone, CBI, and naltrexone with CBI (80.6, 78.2 and 77.1%, respectively). There was a follow up after 1 year, which showed that, with medical management, the amount of those who were abstinent for placebos was 61.4%, and this was improved by naltrexone, CBI, and naltrexone with CBI (66.2, 66.6 and 67.3%, respectively), but this improvement no longer reached statistical significance. After 1 year, there was no difference between groups in the overall frequency of hospitalisation, emergency treatment for alcohol problems, use of medication for drinking or emotional problems and detoxification. Being part of a study for alcohol dependence is known to increase the percentage of abstinent days. In COMBINE, this percentage was high in the group having medical management and placebo pills, and naltrexone or additional behavioural therapy only had modest additional effects.

Exenatide has been shown to improve glycaemic control (over 30 weeks) in subjects with Type 2 diabetes. A recent extension study has shown that, in metformin-treated subjects with Type 2 diabetes, exenatide remained beneficial at 82 weeks. For those subjects who completed the study, in addition to the 1% fall in glycosylated haemoglobin (HbA1c) at 30 weeks, there was another 0.2% fall in HbA1c by 82 weeks. The weight loss achieved was a mean of 3 kg after 30 weeks, and this increased to 5.3 kg after 82 weeks in the completer cohort. In another extension study, continued benefit with exenatide was shown in subjects treated with metformin and/or sulfonylureas. For those subjects who completed the study, in addition to the 0.9% fall in HbA1c at 30 weeks, there was another 0.2% fall in HbA1c by 82 weeks. The weight loss achieved was a mean of 1.6 kg after 30 weeks, and this increased to 2.1 kg after 82 weeks in the completer cohort. The subjects taking exenatide with metformin had a greater weight loss (5.3 k...

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the CNS. In a Phase II clinical trial, natalizumab was shown to reduce the relapses in patients with relapsing MS, without improving the disability score. After 1-year of Phase III clinical trials, natalizumab was approved by the FDA for use in relapsing MS but was withdrawn 3 months later, due to two reported cases of progressive multifocal leukoencephalopathy (PML). The completed clinical trials with natalizumab for relapsing MS have recently been reported. In a trial of 1171 subjects with relapsing MS, natalizumab alone was shown to reduce the relapse rate and lesions, without causing PML. Although natalizumab was also shown to reduce the relapse rates and lesions in patients taking IFN-β, two cases of PML with natalizumab occurred in these patients. An assessment of patients who had taken natalizumab for 1 – 2 years (∼ 3000), showed the incidence of PML to be 1/1000. A drug that is useful in relapsing MS will be used as a l...

The choice of treatment after failure of selective serotonin re-uptake inhibitors in the treatment of depression largely depends on the preferences of the physician. The STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trials set out to rationalise the treatment of depression after the failure of citalopram. When subjects who were unresponsive or intolerant to citalopram were switched to sustained-release bupropion, sertaline or extended-release venlafaxine, remission rates were similar (21, 18 and 25%, respectively). When subjects who were unresponsive to citalopram had sustained-release bupropion or buspirone added to citalopram, there were similar remission rates of 29.7 and 30.1%, respectively. The interpretation of this data are complicated by the lack of placebo groups. One interpretation is that sustained-release bupropion, sertaline or extended-release venlafaxine are equally effective in subjects with major depression after the failure of citalopram, and that sustained-release bupropion or buspirone are equally effective when added to citalopram in subjects with major depression after the failure of citalopram. An alternative explanation is that none of the drugs are effective in citalopram failure, and the responses are the placebo effect.

Rheumatoid arthritis and systemic lupus erythematosus are autoimmune diseases, which may involve phosphoinositide 3-kinase gamma (PI3Kγ). AS605240 is a new and selective PI3Kγ inhibitor. The direct administration of collagen II-specific antibodies produced the features of rheumatoid arthritis in mice, and when AS605240 was administered orally after the collagen antibodies, it reduced the clinical and histological signs of joint inflammation. Collagen can also be used to induce the clinical and histopathological symptoms similar to rheumatoid arthritis in mice and this can be prevented or reduced by treatment with AS605240. MRL-lpr mice develop lupus-like disease and AS605240 prolonged the life of these mice. MRL-lpr mice also develop kidney disease and this can be reversed with AS605240 treatment. These results suggest that PI3Kγ is a therapeutic target in chronic inflammation and that the PI3Kγ inhibitor AS605240 may have potential in the treatment of chronic inflammatory conditions.

Hyperglycaemia in Type 2 diabetes has a major role in the development of microvascular complications, whereas the dyslipidaemia is the major cause of macrovascular complications. In patients with Type 2 diabetes, activation of PPAR-alpha and PPAR-gamma with the fibrates and glitazones improves dyslipidaemia and increases insulin sensitivity, respectively. Muraglitazar is an agonist at both of these receptors and has been shown to increase high-density lipoprotein cholesterol, decrease triglycerides and improve insulin sensitivity. However, there is also some evidence that muraglitazar has detrimental effects on the cardiovascular system. Before muraglitazar is widely used in the treatment of Type 2 diabetes, more safety testing needs to be undertaken.

Osteoporosis affects > 10 million people in the US. Although there are a range of drugs available to treat osteoporosis, adherence to these agents is poor, leaving patients at risk of fracture. Receptor activator of nuclear-κB ligand (RANKL) is essential for the function of the bone-resorbing osteoclasts. Denosumab is a humanised monoclonal antibody to RANKL that can be administered subcutaneously every 3 or 6 months. With this protocol, denosumab increased bone mineral density in the lumbar spine and total hip of postmenopausal women with osteoporosis over 1 year. This confirms that inhibition of RANKL is a new and potentially useful approach to the treatment of osteoporosis. The long-term safety of denosumab, and the effect of denosumab on the incidence of fractures, needs to be evaluated, especially as there is, as yet, no indication that denosumab decreases the incidence of fractures. Comparative studies with denosumab, once-weekly alendronate and once-yearly zoledronate, evaluating their effects on b...

The only pharmacological treatment for acute ischaemic stroke used at present is tissue plasminogen activator. The nitrone NXY-049 has been shown to be neuroprotective in a variety of animal models. The SAINT (Stoke Acute Ischemic NXY-059 Treatment) I trial has shown that, on the modified Rankin scale at 90 days, there were slightly more patients with no symptoms in the NXY-059 group than the placebo group. Conversely, there were slightly fewer patients with a score of 4 (moderately-severe disability) in the NXY-059 group than placebo group. NXY-059 was well tolerated. These data suggest that NXY-059 may be a modest advancement for the treatment of acute ischaemic stroke.

Hypertension is the principle cause of stroke, and leads to coronary artery disease with myocardial infarction and sudden cardiac death. The ASCOT–BPLA (Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm) trial has recently shown that an amlodipine-based regimen (with perindopril and doxazosin added as required) has greater benefits than an atenolol-based regimen (with bendroflumethiazide and doxazosin). Thus, with the amlodipine-based regimen there was less nonfatal myocardial infarction and fatal heart disease, total cardiovascular events and procedures, cardiovascular mortality, fatal and nonfatal stroke, unstable angina, peripheral arterial disease, development of diabetes and renal impairment. Thus, the amlodipine-based regimen used in ASCOT–BPLA should be preferred to the atenolol-based regimen.

Human epidermal growth factor receptor-2 (HER-2)-positive metastatic breast cancer is a more aggressive disease than HER-2-negative metastatic breast cancer. The initial Phase III trial with the HER-2 antibody, trastuzumab, in this cancer suggested that, although trastuzumab was beneficial, cardiac adverse events would prevent it from being widely used. Recently trials suggest that, with close monitoring of left ventricular ejection fraction, trastuzumab can be used concurrently or sequentially with the standard adjuvant treatment of HER-2-positive metastatic breast cancer with good benefit. Therefore, with appropriate regimens, trastuzumab will be able to be used routinely in the treatment of HER-2-positive metastatic breast cancer.

Asthma is a very common condition that can be managed well pharmacologically. In contrast, the presently available management of chronic obstructive pulmonary disease (COPD) is poor. The phosphodiesterase 4 inhibitor roflumilast has an anti-inflammatory effect, and has recently been shown to reduce the early and late responses in mild allergic asthma. Roflumilast may become a steroid-free option for those patients who do not tolerate or want to take long-term corticosteroids to prevent asthma. In COPD, roflumilast improved measures of pulmonary function, quality of life and well being. As the inflammation of COPD is resistant to corticosteroids, roflumilast has potential as an anti-inflammatory agent in the treatment of COPD. Roflumilast is generally well tolerated.

A feature of emphysema is the destruction of the walls of the airspaces in the bronchioles. Ceramide is a membrane sphingolipid that induces apoptosis. In lung samples from human emphysema, ceramide levels were much higher than in lungs from patients without emphysema. Emphysema can be induced in rats or mice with the vascular endothelial growth factor receptor antagonist SU5416, and this is associated with increased levels of ceramide. Fumonisin B1 is a specific inhibitor of dihydroceramide synthase. Fumonisin B1 inhibited the production of ceramide in response to SU5416, and reduced the SU5418-induced increase in alveolar diameter and number of severely damaged distal airspaces. A synthetic short-chain ceramide, C12 ceramide instilled into the trachea of mice increased lung ceramide levels, and induced alveolar cell apoptosis and septal destruction. These results suggest that ceramide is a target in emphysema, and ways of reducing the effects of ceramide in the lung need to be investigated.

In coronary artery disease treatment, the rate of restenosis has been reduced by the introduction of sirolimus- and paclitaxel-eluting stents. Recently, two clinical trials have directly compared these stents. The first study enrolled 1012 patients with either stable angina, or an acute coronary syndrome with a stenotic lesion of ≥ 50% in a vessel. The primary end point was the composite of major adverse events by 9 months, and occurred in fewer patients with sirolimus than paclitaxel stents (6.2 and 10.8%, respectively), due to a lower rate of target-lesion revascularisation with sirolimus- than paclitaxel-eluting stents (4.8 and 8.3%, respectively). The second study enrolled 250 patients with diabetes, angina pectoris and/or a positive stress test, and clinically significant angiographic stenosis in a native coronary artery. The primary end point was in-segmental luminal loss on follow-up angiography, and showed a late luminal in-stent loss of 0.46 and 0.19 mm in the paclitaxel and sirolimus groups, rep...

Glucagon-like peptide 1 is an intestinal peptide hormone that is secreted in response to food to regulate the postprandial blood glucose concentration. Exendin-4 is a 39-amino acid peptide that acts as an agonist at the glucagon-like peptide 1 receptor. Synthetic exendin-4 (exenatide) has recently been trialled in patients with Type 2 diabetes taking either metformin alone or a combination of metformin and a sulfonylurea. In both trials, exenatide 5 and 10 µg s.c. was shown to improve glycaemic control, with few adverse events. Exenatide represents a new and useful addition to the medicines used to treat Type 2 diabetes.

Breast cancer is the most common cancer affecting women. A comparison of docetaxel and 5-fluorouracil in women with operable node-positive breast cancer, also taking doxorubicin and cyclophosphamide, was started in 1997. The primary end point was disease-free survival; the time from randomisation to clinical relapse, a second cancer, or death. In a median follow up of 55 months, fewer events had occurred in the docetaxel (172/745) than the 5-fluorouracil group (227/746). This suggests that docetaxel should replace 5-fluorouracil, and that docetaxel, doxorubicin and cyclophosphamide should become the standard treatment of operable node-positive breast cancer. Paclitaxel and docetaxel are approved for use in patients with metastatic breast cancer. In a head-to-head trial of paclitaxel with docetaxel in patients with metastatic breast cancer, despite previous chemotherapy including anthracycline, an overall response (complete and partial) was observed in more docetaxel than paclitaxel patients. This suggests...