Search

Mortality from heart failure remains high. Many subjects who have been hospitalized with acute decompensated heart failure leave hospital with residual congestion, despite treatment with loop diuretics. In an attempt to improve this, the Acetazolamide in Decompensated heart failure with Volume OveRload (ADVOR) trial was undertaken, where acetazolamide was added to the loop diuretic bumetanide.This article discusses ADVOR. The primary endpoint of ADVOR was the reversal of congestion, which was increased by adding acetazolamide to bumetanide. However, acetazolamide did not shorten hospital stay or the composite of rehospitalisation and death after three months.The limitations of ADVOR include that acetazolamide did not improve quality of life and that the testing was in white subjects only. During the hospital stay for decompensation, medicines that inhibit the angiotensin and mineralocorticoid systems were increased, which suggests that the treatment for heart failure was not ideal on hospitalization. As the death rates in ADVOR were lower than in previous studies, this suggests that the overall treatment of decompensated/heart failure is improving. However, in the author's opinion, although the addition of acetazolamide is a small improvement in the treatment of acute decompensated heart failure with volume overload, more options need to be considered.

The involvement of B-cells in multiple sclerosis has only recently emerged. Ublituximab is a monoclonal antibody that binds to the B-cell antigen CD20 with enhanced B-cell targeting.This evaluation is of the identical ULTIMATE (UbLiTuximab In Multiple Sclerosis Treatment Effects) I and II trials comparing ublituximab (TG-1101) and teriflunomide in relapsing multiple sclerosis. The primary efficacy end point was the annualized relapse rate and was lower in the ublituximab than the teriflunomide group.The continuation rates to oral teriflunomide in ULTIMATE were higher than in other trials, possibly because of the supervised double-dummy protocol used with intravenous ublituximab. This may have contributed to the higher efficacy with teriflunomide in this trial than previously reported. Nevertheless, ublituximab was more effective than teriflunomide at reducing the annualized relapse rates and MRI endpoints, but not for no evidence of disease activity (NEDA). Subsequently, a meta-analysis of the ULTIMATE trials did show that ublituximab was superior to teriflunomide in NEDA. Long-term studies of the adverse effects of ublituximab are required. Despite the positive results from ULTIMATE for ublituximab, it is still under the scrutiny of the Food and Drug Administration (FDA), and conclusions should await their findings.

Obesity is a major risk factor for cardiovascular disease, diabetes, osteoarthritis, and some cancers. Weight loss is an obvious management for this, but a major problem is that after weight loss, many people regain weight.In the following evaluation of S-LITE (NCT04122716, Combined effects of GLP-1 analogue and exercise on maintenance of weight loss after very-low calorie diet), the author gives emphasis to the prevention of weight regain by liraglutide, not the effects of exercise. In S-LITE, liraglutide (with or without exercise) was effective in reducing weight regain in subjects with obesity.The subjects with obesity in S-LITE were limited by the enrollment criteria, and the findings of S-LITE cannot be generalized. The increased heart rate with liraglutide did not occur when liraglutide was combined with exercise, and this suggests that liraglutide should probably not be used alone, but only with exercise to maintain weight loss. As the only presently available medicine to have been shown to be effective against weight regain, liraglutide should probably be preferred to other weight-loss medicines in this circumstance. However, without clear evidence that liraglutide treatment for obesity prevents diabetes and/or reduces cardiovascular risk, it is difficult to justify using it.

Since the availability of lecture recordings, there have been limited studies of any associations between face-to-face lecture attendance and academic outcomes. The aims of the study, in an introductory pathophysiology course, where lecture recordings were available, were 1) to quantify lecture attendance and any associations between academic outcomes and lecture attendance, and 2) to determine why students do or do not attend lectures. Data were analyzed for the whole cohort before separating the nursing (∼60%) and nonnursing students. Of 288 enrolled students, 205 consented to sign the attendance register, and 139 to undertake the online survey. Lecture attendance was higher (41%) before the midsemester exam than afterwards (24%), P < 0.001, due to higher attendance by the nursing than nonnursing students. Students who attended ≥50% of lectures consistently got higher academic outcomes than those that attended

Introduction Treatments for subjects with Covid-19 are required. One approach is neutralizing monoclonal antibodies. Bamlanivimab and etesevimab are monoclonal antibodies to SARS-CoV-2. Areas Covered This evaluation is of the phase 3 BLAZE-1 clinical trial, which was of bamlanivimab plus etesevimab in adult ambulatory participants with a risk factor for, and mild to moderate, Covid-19 illness. The primary outcome was Covid 19 related hospitalization of ≥ 24 hours or death from any cause by day 29, and this occurred in 2.1% subjects in the bamlanivimab/etesevimab group, compared to 7.0% in the placebo group. Expert Opinion In the pandemic, the attempts by the FDA to shorten approval processes for medicines and by journals to make information available in a timely manner are admirable. However, these shortened processes made negotiating the details of BLAZE-1 and producing accurate and critical appraisals difficult. It seems to me that if there are any benefits of bamlanivimab alone in Covid-19, they are not clear-cut. Bamlanivimab has limited effects against the beta and gamma variants and is not effective against the delta variant. Thus, the benefits of bamlanivimab/etesevimab in the phase 3 of the BLAZE-1 may be solely due to etesevimab, and this needs to be tested.

Many factors predict academic performance at university but accessing lecture recordings has not been established as one. Our aims were to quantify how and why biochemistry students accessed lecture recordings and to determine any association between accessing lecture recordings and academic outcomes. Lecture recording access data was collected and related to academic outcomes. On average, students accessed 46% of lecture recordings and each recording was accessed 2.3 times, but not to completion. After lecture delivery, students were slow to access lecture recordings, and the number of accesses was still increasing prior to the examinations. For the entire cohort, there were weak positive associations between accessing lecture recordings and academic outcomes for the semester, and between the access to lecture recordings in weeks 1-5 and 6-11 with the mid-semester and final examination, respectively. For programs, the weak association for the semester was only apparent for the pharmacy and biomedical science students, and not for the medical laboratory or nutrition students. The most common reason for accessing lecture recording was to "Revise lecture concepts for assessment purposes." For students, who did not attend lectures, lecture recordings were accessed predominantly as "I prefer the flexibility of online recordings." Flexibility was also the theme of the positive additional feedback on accessing lecture recordings. In conclusion, consideration needs to be given on how to persuade students to access lecture recordings in a timelier way. As accessing lecture recordings is weakly associated with positive academic outcomes for some program cohorts, this supports their continued availability.

Anemia is common in CKD and increases the risk of developing heart disease. Although ESAs relieve the symptoms of anemia, they have adverse effects and do not reduce the adverse outcomes associated with anemia. This evaluation is of the phase 3 ASCEND clinical trials of the hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor daprodustat versus ESAs in subjects with CKD undergoing dialysis or not. Daprodustat was non-inferior to ESAs in increasing hemoglobin, and in the incidence of cardiovascular events and adverse effects. Daprodustat is effective in subjects who are hyporesponsive to ESAs, and this is one circumstance when daprodustat may be preferred to ESAs. However, to become a widely used medicine in subjects with CKD responsive to ESAs, daprodustat needs to be well tolerated, used by a high percentage of subjects over a long time, and be superior to ESAs in improving clinical outcomes. As this may not be the case, there is not a strong basis for recommending daprodustat over ESAs. The other 'dustats' (roxadustat, vadadustat) have also not been shown to be superior to the ESAs, and none have been approved by the FDA to date.

Introduction: Homozygous Familial Hypercholesterolemia (HoFH) is a very severe genetic form of hypercholesterolemia. Lacking LDL receptors in the liver, subjects with HoFH have raised plasma levels...

Introduction: The amyloid-beta (Aβ) cascade hypothesis is that reducing Aβ levels in the brain will be beneficial in treating Alzheimer's disease. Aβ is formed by the cleavage of amyloid precursor protein by β-site amyloid precure protein cleaving enzyme (BACE1) and the BACE1 inhibitor verubecestat was developed to lower the brain levels of Aβ. However, in the EPOCH trial of verubecestat in mild-to-moderate Alzheimer's disease, it was not beneficial and increased adverse effects.Areas covered: Prior to completing EPOCH, APECS, which trialled verubecestat in prodromal Alzheimer's disease, was commenced. Like EPOCH, APECS was terminated early. In APECS, verubecestat 40 mg worsened cognition and increased adverse effects.Expert opinion: In recruiting subjects to clinical trials in Alzheimer's disease, a clinical diagnosis involving the measurement of Aβ should be undertaken for all subjects, as this may help to clarify the findings. In my opinion, the failure of verubecestat in EPOCH and APECS probably could have been avoided if a safety and potential efficacy trial (phase 2) had been completed prior to starting phase 3. It seems to me that, as we have a poor understanding of the underlying mechanisms/cause of Alzheimer's disease, this is where the research emphasis should be, not phase 3 clinical trials.

Introduction Alzheimer's disease is the leading cause of disability and poor health, takes a huge emotional and financial burden on family caregivers, and is costly. Donanemab (LY3002813) is a new monoclonal antibody that uniquely targets Aβ(p3-42), a pyroglutamate form of Amyloid-β (Aβ) exclusively found in plaques. Areas covered The phase 2 trial of donanemab in participants with early symptomatic Alzheimer's disease, TRAILBLAZER-ALZ. Donanemab reduced cerebral plaque but not tau load and only marginally improved the primary outcome of cognition and activities of daily living (p = 0.04) without altering individual measures of these. Expert opinion In TRAILBLAZER-ALZ, anticholinesterase use was given at the beginning but not the end of the trial, and thus, it is not known whether changes in this or other medicines were involved in the outcome with donanemab. Tau load (measured with flortuacipir PET) may be a biomarker of cognition but was not altered by donanemab. As there is no clear evidence that removing cerebral amyloid plaques with Aβ antibodies, such as donanemab, improves cognition and the activities of daily living in Alzheimer's disease, clinical trials with these agents should be abandoned, and more time and money should spend on further investigating the underlying cause of Alzheimer's disease.

Introduction: Chronic kidney disease occurs in 40% of subjects with diabetes and increases the risk of cardiovascular death three-fold, compared to having diabetes alone. The non-steroidal mineralocorticoid receptor antagonist finerenone protects against chronic kidney disease in animal models.Areas covered: This evaluation is of a phase 3 trial of finerenone; Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD). In FIDELIO-DKD, finerenone reduced the primary composite outcome of kidney failure, a sustained decrease of at least 40% in eGFR over four weeks, or death from renal causes, from 21.1% to 17.8%, with a good safety profile.Expert opinion: Finerenone is an effective mineralocorticoid receptor antagonist for the treatment of diabetic chronic kidney disease. Recently, glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporters 2 (SGLT-2) inhibitors have been added to the list of medicines for use in subjects with this condition. Although finerenone has a different mechanism of action to these medicines, it will need to be tested and shown to be effective in presence of these medicines in diabetic kidney disease, prior to widespread use.

Historically, lecture attendance was considered a predictor of better academic outcomes. However, it is not known whether this is true for the human biosciences or whether it still applies with the introduction of lecture recordings. The aims were to determine (i) any association between lecture attendance and academic outcomes for students studying the human biosciences, and (ii) whether this was altered by the availability of lecture recordings. There were 27 studies of the association between lecture attendance and academic outcomes in 32 courses, and for 24 courses (75%) there was a positive association. The positive association occurred in a similar percentage of undergraduate courses for allied health students and science students (72%) and courses for dental and medical students (82%), who are predominantly postgraduate students. Eleven studies reported the use of lecture recordings with a positive association between lecture attendance and academic outcomes being reported for 11 of the 16 courses (69%). From 16 studies/courses not reporting the availability of lecture recordings, 13 did show (82%) a positive association, and three did not show (18%) an association between lecture attendance and academic outcomes. In conclusion, as most studies show a positive relationship between lecture attendance and academic outcomes, it seems reasonable to continue to provide face-to-face lectures, and encourage students to attend. To date, there is no definitive evidence that the availability of lecture recordings alters the positive relationship between lecture attendance and academic outcomes.

Background In programs with higher proportions of marks allocated to ongoing assessment, the students have higher overall marks than those with a lower proportion allocated to assessment. Little or no attention has been made to how the allocation affects the academic success of students in individual courses. The purpose of this study was to determine how the allocation of marks to examinations, tutorials and an assignment affects the performance of nursing students in a pharmacology course. Methods For students who passed a pharmacology course (i) the marks for examinations and ongoing assessment (tutorials and/or an assignment) were compared, and (ii) regression line and correlation analysis was undertaken to determine any association between these marks. In addition, for completing students, modelling was undertaken to determine the effects of changing the allocation of marks on passing and failing rates. Results Nursing students who passed a pharmacology course obtained significantly lower marks in examinations than ongoing assessment, and for the ongoing assessment, lower marks in the assignment than tutorials. Regression line analysis showed that the marks in ongoing assessment (tutorials and/or the assignment) versus examination marks were a poor line-fit. The correlation coefficients between ongoing assessment and examinations were weak to moderate. A high percentage of students passed the course (> 90%) and, modelling for completing students, showed that decreasing the marks for examination would have led to slightly more students passing the pharmacology course with higher grades. In contrast, increasing the marks for examination would have dramatically decreased the number of students passing the course, and their grades. Conclusions The allocation of marks can have a major effect on student performance. As ongoing assessment is only a weak or moderate indicator of performance in examination this has implications for students who rely on passing examinations for their advancement. For instance, nursing students in some countries (e.g. USA) are required to pass examinations prior to registration, whereas in others (e.g. Australia) they are not. Consideration needs to be given as to whether it is appropriate for nursing students who fail examinations to pass courses/programs.

Introduction: If statins are unsuccessful at achieving the LDL cholesterol level goal in subjects with hypercholesterolemia, non-statin therapy should be added to reduce cardiovascular morbidity and mortality. The first inhibitors of proprotein convertase substilisin-kexin type 9 (PCSK9) were human monoclonal antibodies and these reduced LDL cholesterol and cardiovascular events. Inclisiran is a small interfering RNA molecule (siRNAs) directed against PCSK9. Areas covered: This key paper evaluation focuses on Phase 3 trials that assess inclisiran in the treatment of hypercholesterolemia and heterozygous familial hypercholesterolemia. Expert opinion: To date, the findings with inclisiran have been very promising as it causes large decreases in LDL cholesterol with few adverse effects. However, there are some limitations to its widespread use. Firstly, cardiovascular outcomes trials have not been completed, so we do not know how inclisiran compares to the PCSK9 monoclonal antibodies, which, seem to me, to only have a modest effect on cardiovascular outcomes. Secondly, a major problem with the PCSK9 monoclonal antibodies is that they are expensive, and their use is often discontinued or not pursued, which can leave the subjects intended for treatment at high cardiovascular risk. At present, it is not clear whether similar problems around cost will apply to inclisiran.

Introduction Lopinavir in combination with ritonavir is approved for the treatment of HIV and has recently been subject to a clinical trial in severe COVID-19. Areas covered This evaluation is of LOTUS China (the Lopinavir Trial for Suppression of SARS-Cov-2 in China), which was a randomized trial in hospitalized subjects with COVID-9 in a respiratory sample and pneumonia. As, in severe COVID-19, lopinavir/ritonavir had no beneficial effects but increased gastrointestinal adverse effects, this combination should not be used at this stage of COVID-19. Expert opinion In my opinion, the rationale for undertaking a trial of lopinavir/ritonavir in COVID-19 was poor. The analysis of a modified intention to treat group analysis in LOTUS China may have introduced bias. After LOTUS China, there is probably no future for lopinavir in the treatment of severe COVID-19, but some clinical trials for prevention or in various stages of COVID-19 have recently started or are ongoing. The major limitation of these trials is that as lopinavir does not inhibit COVID-19, it is unlikely to prevent infection, reduce viral load, or reduce the severity. However, these trials may be worthwhile in finally determining whether lopinavir has any role in preventing or treating COVID-19.

Introduction: The ‘glutides,’ which stimulate the glucagon-like peptide 1 (GLP-1) receptor to stimulate insulin secretion, are used in the treatment of type 2 diabetes. Semaglutide is the first glu...

Introduction: The amyloid-beta (Aβ) cascade hypothesis is that reducing Aβ levels in the brain will be beneficial in the treatment of Alzheimer’s disease. Solanezumab is a humanized analog of a mur...

Glucagon-like peptide-1 (GLP-1) is produced by the gut, and in a glucose-dependent manner stimulates insulin secretion while inhibiting glucagon secretion, reduces appetite and energy intake, and delays gastric emptying. The GLP-1R agonist semaglutide has recently been registered to treat type 2 diabetes. Area covered: This review is of semaglutide in type 2 diabetes, and considers which properties of this GLP-1R agonist, may be responsible for its clinical outcome benefits . Expert opinion: The pharmacokinetics of semaglutide make it ideal for once-weekly dosing. SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) showed that semaglutide 0.5 or 1 mg subcutaneously once-weekly reduced cardiovascular outcomes in subjects with type 2 diabetes and cardiovascular disease or risk, mean age 65 years, baseline HbA1c 8.7% and mean body weight of 92 kg. Although, semaglutide may be a useful drug in this population, it increased retinopathy to a small extent and this needs further investigation. Also, it is not known whether semaglutide will improve cardiovascular outcomes in other populations including those with lower ages, HbA1c values, and body weights similar to those included in the unsuccessful clinical outcome trials with the GLP-1R agonists, lixisenatide and exenatide.

Background The older-aged living in a low socioeconomic, rental, retirement village have a low adherence to medicines and a poor understanding of their illnesses. MedsChecks are commonly used in Australian pharmacies in an attempt to improve the management of medicines. There is no published evidence that MedsChecks, or similar brief/single, interventions improve the management of medicines in the older-aged. Objective The objective of our study was to determine the effect of an AdherenceCheck, which is similar to a MedsCheck, but is performed in the home of the older-aged, had on the ongoing management of medicines by the older-aged living independently. Both a MedsCheck and an AdherenceCheck involves forming an individual Action Plan. Setting Rental retirement village. Method After interviewing the older-aged in the village about their management of medicines, they were given an AdherenceCheck and an Action Plan. Six months later their management of medicines and the Action Plan were (re-)evaluated. Main outcome measure Present and ongoing adherence to medicines. Results Only 15 of the original 23 participants completed the study. The AdherenceCheck with Action Plan did not significantly change the adherence to medicines of these older-aged living in the rental retirement village. Pre- to post-AdherenceCheck, there was a reduction in the percentage of participants with a good knowledge of their illnesses, and thus a corresponding significant increase in the percentage with no knowledge of their illnesses, and this may have been age related. Only 11 of the 15 participants remembered receiving an Action Plan, as part of the AdherenceCheck, and 7 of these considered that the Action Plan helped them manage their medicines. Conclusion An AdherenceCheck may not improve the management of medicines by the older-aged living in a rental retirement village. As there are no peer-reviewed publications as to whether the commonly used MedsChecks, which have some similarities to the AdherenceCheck, improve the management of medicines, it is suggested that these MedsChecks should also be formally evaluated.

Introduction: Hypertriglyceridemia is common and increases cardiovascular risk. Fish oil decreases triglyceride levels, but also increases low-density lipoprotein (LDL) cholesterol, which may negate any cardiovascular benefits. EPA, a component of fish oil, reduces triglyceride levels without increasing LDL cholesterol. Areas covered: Two forms of purified EPA ethyl ester are available on prescription. This review considers the clinical trials of these purified esters to treat hypertriglyceridemia and shows that the EPA ethyl esters reduce triglyceride levels and reduce cardiovascular events. Expert opinion: To date, the effects of the purified EPA ethyl esters on cardiovascular events have only been tested in subjects taking statins. With statin treatment, if hypertriglyceridemia persists, it may be worthwhile considering adding an EPA ethyl ester. However, as the fibrates reduce the triglyceride levels by similar amounts to the EPA ethyl esters, while increasing the levels of HDL cholesterol, they are an alternative to EPA ethyl esters in combination with statins. As the proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors reduce triglycerides to a similar extent to the EPA ethyl ester, while reducing LDL cholesterol levels to a greater extent than the statins, they should be considered as an alternative to the statin/EPA ethyl ester combination.

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...

Glucagon-like peptide-1 (GLP-1) is produced by the gut, stimulates insulin secretion from the pancreatic β-cells, and inhibits glucagon secretion from the α-cells. The GLP-1 receptor (GLP-1R) agonists are used in the treatment of type 2 diabetes (T2DM).This review covers the clinical trials of the GLP-1R agonists (exenatide and liraglutide) and their potential as adjunct treatment in type 1 diabetes mellitus (T1DM).GLP-1R agonists are unable to increase insulin secretion, in subjects with T1DM, who are C-peptide negative. Also, the GLP-1R agonists either have no effect or cause a small inhibition of glucagon secretion in subjects with T1DM. There is no evidence that the GLP-1R agonists cause a major reduction in HbA1c, or have a major effect on hypo- or hyperglycemia in subjects with TD1M. The main beneficial effect of the GLP-1R agonists is probably the modest weight loss, which may underlie the reduction in dose of insulin used. Given that the GLP-1R agonists cause gastrointestinal adverse effects, and with reduced insulin doses, increase the risk of ketosis, it seems to me that the risk with these agents may outweigh any benefit in T1DM, and that they have little potential as adjuncts in the treatment of T1DM.

Introduction : The actions of the cholesteryl ester transfer protein (CETP) inhibitors (torcetrapib, dalcetrapib and evacetrapib) include increasing high-density lipoprotein (HDL) cholesterol, but they do not reduce cardiovascular outcomes in subjects with high cardiovascular risk. Anacetrapib also inhibits CETP, increases HDL cholesterol and lowers low-density lipoprotein (LDL) cholesterol. Areas covered : This evaluation is of the REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification) trial, which was a cardiovascular outcomes trial with anacetrapib in subjects with high cardiovascular risk. Consideration is given as to whether increasing HDL cholesterol, lowering LDL cholesterol or other mechanisms/factors underlying the positive outcome with this CETP inhibitor. Expert opinion : After three years, the REVEAL trial with anacetrapib, demonstrated cardiovascular benefits, but not a reduction in coronary artery deaths. The reductions were not significant in years one and two. Thus, in my opinion, the benefits of anacetrapib were not major, and may not apply in ‘real’ world populations where adherence to medicines is lower than in REVEAL. Also, lowering LDL cholesterol and off-target mechanisms of anacetrapib may have contributed to any beneficial and/or toxic effects. Anacetrapib has a good safety profile.

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.

Background In a low socioeconomic status, small, rental retirement village, we have shown the older-aged managed their medicines poorly (Doggrell and Kairuz in J Pharm Pract Res 42:208–212, 2012). Objective As the number of participants was only 25, and the population in the rental retirement village turns over regularly; our objective was to determine whether the findings were consistent and ongoing. Methods We returned to the rental retirement villages after 1 and 2 years, and reassessed the management of medicines, using the same semi-structured interview method. Main outcome measure The perception of present and ongoing adherence. Results Although similar numbers (23–25) participated in the studies in 2011–2013, the actual participants changed with only three being interviewed on three occasions. Nevertheless, the findings over the 3 years were similar

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.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors (the 'gliflozins') promote the excretion of glucose from the kidney to lower HbA1c. Empagliflozin was the first gliflozin shown to improve cardiovascular and renal outcomes in subjects with type 2 diabetes and cardiovascular disease. Areas covered: In the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program, there were improvements in the primary cardiovascular and exploratory renal outcomes with canagliflozin, compared to placebo. The safety outcome finding, which was of most interest, was that there was a higher risk of amputation of toes, feet, or legs with canagliflozin than in the placebo group. This program is the subject of this evaluation. Expert opinion: As canagliflozin has small beneficial effects in the treatment of type 2 diabetes in subjects with cardiovascular disease, it is not on the canvas. However, there are still several questions about canagliflozin that need to be answered before it is widely used, especially in comparison with other gliflozins; As amputations have only been reported with canagliflozin in CANVAS, should other gliflozins be preferred? As canagliflozin has not been shown to be beneficial in subjects not taking diuretics, should other gliflozins be preferred in this population? Clarification is also needed as to whether canagliflozin increases the risk of non-fatal stroke, or not.

Introduction: Increasing high-density lipoprotein(HDL) cholesterol levels predict improved cardiovascular outcomes. However, inhibiting cholesteryl ester transfer protein (CETP) to increase HDL cholesterol, with the ‘cetrapibs’ (torcetrapib and dalcetrapib), did not improve cardiovascular clinical outcomes. Despite these findings, the clinical outcomes trial with evacetrapib continued. Areas covered: Treatment with evacetrapib increased the levels of HDL by ~130%, and decreased low-density lipoprotein (LDL) cholesterol by ~37%. However, The Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial did not show reduced cardiovascular outcomes with this cetrapib. Evacetrapib may have failed because increasing HDL cholesterol may not be beneficial in the presence of coronary artery disease and/or it is possible that evacetrapib has toxic effects that counter any beneficial effects. Expert opinion: In addition to our understanding of the relationships between CETP, HDL cholesterol and cardiovascular disease being incomplete, recent meta-analysis evidence suggests that increasing HDL cholesterol does not improve cardiovascular outcomes in subjects taking statins, and this may explain the failure of evacetrapib. Also, the preclinical characteristics of the cetrapibs, especially off-target mechanisms, were not explored prior to clinical trial, and may have contributed to the failure of cetrapibs, including evacetrapib.

Introduction: Chemotherapy-induced nausea and vomiting (CINV) has a negative impact on the lives of subjects receiving chemotherapy. In 2009, the second generation 5-HT3-receptor antagonist, palonosetron, which is longer-acting than granisetron, was shown, as part of dual therapy with dexamethasone, to be superior to intravenous granisetron in the delayed phase of CINV.Area covered: In an attempt to maintain plasma levels of granisetron during the delayed phase of CINV, longer-acting preparations of granisetron have been manufactured. In addition to comparing intravenous/oral granisetron with palonosetron, this review considers the new longer-acting preparations of granisetron (transdermal and subcutanous) with emphasis on whether they are effective in the delayed phase of CINV.Expert opinion: Comparison of intravenous/oral granisetron and palonosetron, as part of triple therapy against the delayed phase of CINV, do not give clear-cut results as to non-inferiority or superiority of either agent. S...

Background Nonadherence to cardiovascular medicines occurs in 60% of subjects with chronic cardiovascular disease and leads to poor outcomes. In an attempt to improve adherence and cardiovascular outcomes, interventions are often used. Interventions may involve a pharmacist, but it is not always clear whether these are effective. Objectives The primary objective of this review is to determine whether interventions by pharmacists, alone, discussing adherence to medicines, improve adherence to medicines for cardiovascular disease. Subsequently, the review links the characteristics of the individual studies with effectiveness or lack of effect. The second objective of this review is to consider whether any improvement in adherence with interventions by pharmacist is associated with better clinical outcomes. Methods A literature search of PubMed and CINAHL for ‘pharmacist’, ‘medicine’ with ‘adherence’ or ‘compliance’ or ‘persistence’ was undertaken. To be included in this review, papers had to be of a pharmacist working alone and in person in an intervention of subjects with hypertension, hyperlipidemia (prior to or after a coronary artery event) or heart failure. The paper had to be published in a peer review journal, with a measure of adherence to medicines. The effectiveness of the intervention had to be evaluated after ≥ 6 months. Results Only 3 out of 8 interventions by pharmacists in hypertension, and 5 out of 12 interventions in subjects with hyperlipidemia led to improved adherence to medicines. In contrast, all 6 interventions by a pharmacist in subjects with heart failure were successful in improving adherence. One characteristic of successful interventions by pharmacists to improve adherence to cardiovascular medicines is that they must be more than brief/single interventions. A second characteristic is that the intervention should not involve subjects who are already highly adherent, as it is unlikely adherence can be improved in this population. Only 2 of 3 successful interventions in hypertension were associated with small reductions in blood pressure, and only one intervention in hyperlipidemia was shown to decrease LDL- cholesterol to a small extent. In subjects with heart failure, 5 of the 6 successful studies of the successful interventions by pharmacists to increase adherence also showed improved clinical outcomes. Conclusions When planning an intervention to improve adherence to medicines and cardiovascular outcomes in subjects with hypertension or hyperlipidemic, by a pharmacist alone, or as part of a multi-faceted interventions, it is essential to use an intervention that has been shown to be effective, as most interventions are not effective at improving adherence or only improve adherence and clinical outcomes to a small extent. In heart failure, there is well documented evidence of interventions by pharmacists that do improve clinical outcomes, which should be adopted widely.

Evaluation of: Ahrén B, Johnson SL, Stewart M et al. HARMONY 3: 104-Week randomized, double-blind, placebo- and active-controlled trial assessing the efficacy and safety of albiglutide compared with placebo, sitagliptin, and glimepiride in patients with type 3 diabetes taking metformin. Diabetes Care 2014;37:2141-8 and Rosenstock J, Fonseca VA, Grass JL et al. Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care 2014;37:2317-25. Agonists of glucagon-like peptide-1 (GLP-1) receptors are used in the treatment of Type 2 diabetes. Albiglutide is a new long-acting GLP-1 receptor agonist being developed for once weekly use. This is an evaluation of two clinical trials in the HARMONY clinical trials series. HARMONY 3 compares albiglutide with sitagliptin and glimepiride in subjects with Type 2 diabetes poorly controlled with metformin, and HARMONY 6 compares albiglutide with insulin lispro in subjects poorly controlled with slow/medium release preparations of insulin. Both studies showed that albiglutide lowered HbA1c and had advantages over its comparator drugs. However, questions remain about the safety of albiglutide. Albiglutide is not being used in subjects with a history of thyroid cancer because it is not known whether this is a rare adverse effect with albiglutide. Also, the safety of albiglutide in subjects with Type 2 diabetes and high cardiovascular risk is unknown.

Insulin is used in all subjects with Type 1 diabetes, and when Type 2 diabetes is not controlled by oral anti-diabetic medicines, insulin is also used in Type 2 diabetes. However, despite this use, there is still increased mortality and morbidity in subjects with diabetes, compared to subjects without diabetes. One of the factors, which may be involved in this increased mortality and morbidity in subjects with diabetes, is nonadherence to insulin. Nonadherence rates to insulin are in the range of 20-38%, and many factors contribute to the nonadherence. The major aim of the review was to determine whether interventions to improve adherence to insulin do actually improve adherence to insulin. Most studies have shown that adherence to insulin was improved by changing from the vial-and-syringe approach to prefilled insulin pens, but not all studies have shown that this translated into better glycemic control and clinical outcomes. The results of studies using automatic telephone messages to improve adherence to insulin to date are inconclusive. There is limited and variable evidence that an intervention by a nurse/educator, which discusses adherence to medicines, does improve adherence to insulin. In contrast, there is little or no evidence that an extra intervention by a doctor or an intervention by a pharmacist, which discusses adherence to insulin, does actually improve the measured adherence to insulin. In conclusion, rather than assuming that an intervention by a health professional discussing adherence to insulin actually improves adherence to insulin, long-term studies investigating this are required.

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.

Type 2 diabetes remains an escalating problem worldwide, despite a range of treatments being available. The revelation that insulin secretion is under the control of a gut hormone, glucagon-like peptide 1, has led to a new paradigm in the management of type 2 diabetes, ie, use of medicines that directly stimulate or prolong the actions of endogenous glucagon-like peptide 1 at its receptors. Exenatide is an agonist at the glucagon-like peptide 1 receptor, and was initially developed as a subcutaneous medication twice daily (ExBID). Clinical trials with ExBID established a role for exenatide in the treatment of type 2 diabetes. Subsequently, exenatide once weekly (ExQW) was shown to have advantages over ExBID, and there is now more emphasis on the development of ExQW. ExQW alone reduces glycosylated hemoglobin (HbA(1c)) and body weight, and is well tolerated. ExQW has been compared with sitagliptin, pioglitazone, and metformin, and been shown to have a greater ability to reduce HbA(1c) than these other medicines. The only preparation of insulin with which ExQW has been compared is insulin glargine, and ExQW had some favorable properties in this comparison, notably causing weight loss compared with the weight gain on insulin glargine. ExQW has been compared with another glucagon-like peptide 1 receptor agonist, liraglutide, and was noninferior to liraglutide in reducing HbA(1c). The small amount of evidence available shows that subjects with type 2 diabetes prefer ExQW to ExBID, and that adherence is high in the clinical trial setting. Health care and economic modeling suggests that ExQW will reduce diabetic complications and be cost-effective, compared with other medications, in long-term use. Little is known about whether subjects with type 2 diabetes prefer ExQW to other medicines, and whether adherence is good with ExQW in practice. These important topics require further study.

Diet and medical treatment are the standard treatment for type 2 diabetes. In obese subjects with type 2 diabetes, bariatric surgery is effective in resolving diabetes. Two clinical trials comparing bariatric surgery to medical treatment were evaluated. Both the Surgical Treatment And Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial (laparoscopic Roux-En Y gastric bypass and sleeve gastrectomy) and the DIet and medical therapy versus BAriatric SurgerY in type 2 diabetes (DIBASY) trial (laparoscopic gastric bypass and biliopancreatic-diversion) showed that surgery was more effective than medical care in resolving or managing type 2 diabetes. Larger studies, or a compilation of studies, are needed to determine whether one of these procedures is better, or if they are all similarly effective, and this should also be weighed against the risk of the operations.

Background: Resources to assist the older-aged manage their medicines should target those in greatest need. Little is known about whether socioeconomic status (SES) influences medicines management by the older-aged. Aim: To explore whether there is a difference in medicines management by the older-aged living independently in different types of retirement villages. Method: Semi-structured interviews were conducted with 56 older-aged residents living in 5 different types of retirement villages. A purposefully designed instrument was used to inform the researchers’ perceptions of medication adherence. Results: 92% of residents from the freehold retirement village (metropolitan city, high SES) were perceived to be adherent to their medicines and not likely to have problems with adherence within the next 6 to 12 months. While in the 2 rental retirement villages (low SES), 50% or fewer residents were in this category. Participants from the freehold retirement village had a good understanding of about 80% of their illnesses, which was significantly lower in the 2 rental villages (10% to 20%). More medicines per person were prescribed in the 2 rental retirement villages than in the freehold village. Cardiovascular drugs were the most commonly prescribed in all of the retirement villages, but prescribing of psychotropic drugs was greater in rental than freehold villages. Pooled data showed that lack of knowledge about medicines and illness was associated with a medication organiser dispensed by a pharmacy. Conclusion: The older-aged living in low SES rental retirement villages may need assistance and resources to manage their medicines.

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...

The anticoagulant effect of apixaban is due to direct inhibition of FXa in the coagulation cascade. The main advantages apixaban has over the current anti-coagulant drugs is that it is active after oral administration, and its coagulation effect does not require monitoring. Apixaban has been compared to enoxaparin in the prevention of venous thromboembolism associated with knee and hip replacement, where it is as efficacious as enoxaparin, but causes less bleeding. However, apixaban is not the only FXa inhibitor that could replace enoxaparin for this indication, as the FXa inhibitor rivaroxaban is as efficacious and safe as enoxaparin in preventing thromboembolism associated with these surgical procedures. Until the results of the AMPLIFY Phase III trial are known, it is too early to consider apixaban as an alternative to enoxaparin in symptomatic thromboembolism. Apixaban should not be used to prevent thromboembolism in medical immobilised subjects or acute coronary syndromes, as it causes excess bleeding in these conditions without benefit.