Efficacy of beta-blockers on blood pressure control and morbidity and mortality endpoints in hypertensives of African ancestry: an individual patient data meta-analysis.

Introduction: Compared with first-line antihypertensives, beta-blockers (BB) have been reported to lower the central aortic blood pressure suboptimally and are associated with increased stroke risk. This observation has not been investigated in hypertensives of African ancestry. We hypothesised that an individual patient data meta-analysis (IPD-MA) on the efficacy of second- or third-generation beta-blockers (STGBBs) in hypertensives of African descent may provide new insights. Methods: A single-stage IPD-MA analysed the efficacy of STGBB in lowering the mean arterial blood pressure and reducing the composite outcomes: cardiovascular death, stroke, and myocardial infarction. Results: A total of 11,860 participants from four randomised control trials were included in the analysis. Second- or third-generation beta-blockers reduced the mean arterial pressure by 1.75 mmHg [95% confidence interval (CI):1.16-2.33; P < 0.001] in all participants included in the analysis, and by 1.93 mmHg (95% CI: 0.86-3.00; P < 0.001) in hypertensive Africans. In patients with established cardiovascular disease, where the benefits of BB therapy are well established, STGBBs were associated with an adjusted odds ratio of 1.33 (95% CI: 1.06-1.65; P = 0.015) of the composite outcome, most likely due to confounding. Similarly, the risk of total myocardial infarction was 1.76 times higher (95% CI: 1.15-2.68; P = 0.008) in hypertensives of African ancestry on STGBBs. Conclusion: The STGBBs reduced the mean arterial pressure comparably to other antihypertensives, and they were not associated with an increased risk of stroke.

Therapeutic Properties of Highly Selective ß-blockers With or Without Additional Vasodilator Properties: Focus on Bisoprolol and Nebivolol in Patients With Cardiovascular Disease.

Bisoprolol and nebivolol are highly selective ß1-adrenoceptor antagonists, with clinical indications in many countries within the management of heart failure with reduced left ventricular ejection fraction (HFrEF), ischaemic heart disease (IHD), and hypertension. Nebivolol has additional vasodilator actions, related to enhanced release of NO in the vascular wall. In principle, this additional mechanism compared with bisoprolol might lead to more potent vasodilatation, which in turn might influence the effectiveness of nebivolol in the management of HFrEF, IHD and hypertension. In this article, we review the therapeutic properties of bisoprolol and nebivolol, as representatives of "second generation" and "third generation" ß-blockers, respectively. Although head-to-head trials are largely lacking, there is no clear indication from published studies of an additional effect of nebivolol on clinical outcomes in patients with HFrEF or the magnitude of reductions of BP in patients with hypertension.

ß-Blockade for Patients with Hypertension, Ischemic Heart Disease or Heart Failure: Where are We Now?

ß-blockers are a heterogeneous class of drugs, with varying selectivity/specificity for ß1 vs ß2 receptors, intrinsic sympathomimetic activity (ISA), and vasodilatory properties (through ß2 stimulation, α receptor blockade or nitric oxide release). These drugs are indicated for the management of arterial hypertension, heart failure or ischemic heart disease (IHD; eg angina pectoris or prior myocardial infarction). Most of the benefit of ß-blockade in these conditions arises from blockade of the ß1 receptor, and, in practice, the addition of ISA appears to reduce the potential for improved clinical outcomes in people with heart failure or IHD. Aspects of the benefit/risk balance of ß-blockers remain controversial, and recent meta-analyses have shed new light on this issue. We have reviewed the current place of cardioselective ß-blockade in hypertension, IHD and heart failure, with special reference to the therapeutic profile of a highly selective ß1-adrenoceptor blocker, bisoprolol.

Managing symptoms in hypothyroid patients on adequate levothyroxine: a narrative review.

The current standard of care for hypothyroidism is levothyroxine (LT4) monotherapy to reduce levels of thyrotropin (thyroid-stimulating hormone, TSH) within its reference range and amelioration of any symptoms. A substantial minority continues to report hypothyroid-like symptoms despite optimized TSH, however. These symptoms are not specific to thyroid dysfunction and are frequent among the euthyroid population, creating a therapeutic dilemma for the treating clinician as well as the patient. We present a concise, narrative review of the clinical research and evidence-based guidance on the management of this challenging population. The clinician may endeavor to ensure that the serum TSH is within the target range. However, the symptomatic patient may turn to alternative non-evidence-based therapies in the hope of obtaining relief. Accordingly, it is important for the clinician to check for conditions unrelated to the thyroid that could account for the ongoing symptoms such as other autoimmune conditions, anemia or mental health disorders. Systematic and thorough investigation of the potential causes of persistent symptoms while receiving LT4 therapy will resolve the problem for most patients. There may be some patients that may benefit from additional treatment with liothyronine (LT3), although it is unclear as yet as to which patient group may benefit the most from combined LT4 + LT3 therapy. In the future, personalized treatment with LT4 + LT3 may be of benefit for some patients with persistent symptoms of hypothyroidism such as those with polymorphisms in the deiodinase enzyme 2 (DIO2). For now, this remains a subject for research.

Challenges in Interpreting Thyroid Stimulating Hormone Results in the Diagnosis of Thyroid Dysfunction.

The pituitary hormone, thyrotropin (TSH), is regarded as the primary biomarker for evaluating thyroid function and is useful in guiding treatment with levothyroxine for patients with hypothyroidism. The amplified response of TSH to slight changes in thyroid hormone levels provides a large and easily measured signal in the routine care setting. Laboratories provide reference ranges with upper and lower cutoffs for TSH to define normal thyroid function. The upper limit of the range, used to diagnose subclinical (mild) hypothyroidism, is itself a matter for debate, with authoritative guidelines recommending treatment to within the lower half of the range. Concomitant diseases, medications, supplements, age, gender, ethnicity, iodine status, time of day, time of year, autoantibodies, heterophilic antibodies, smoking, and other factors influence the level of TSH, or the performance of current TSH assays. The long-term prognostic implications of small deviations of TSH from the reference range are unclear. Correction of TSH to within the reference range does not always bring thyroid and other biomarkers into range and will not always resolve the patient's symptoms. Overt hypothyroidism requires intervention with levothyroxine. It remains important that physicians managing a patient with symptoms suggestive of thyroid disease consider all of the patient's relevant disease, lifestyle, and other factors before intervening on the basis of a marginally raised TSH level alone. Finally, these limitations of TSH testing mitigate against screening the population for the undoubtedly substantial prevalence of undiagnosed thyroid disease, until appropriately designed randomised trials have quantified the benefits and harms from this approach.

Mechanisms of action of metformin with special reference to cardiovascular protection.

Management guidelines continue to identify metformin as initial pharmacologic antidiabetic therapy of choice for people with type 2 diabetes without contraindications, despite recent randomized trials that have demonstrated significant improvements in cardiovascular outcomes with newer classes of antidiabetic therapies. The purpose of this review is to summarize the current state of knowledge of metformin's therapeutic actions on blood glucose and cardiovascular clinical evidence and to consider the mechanisms that underlie them. The effects of metformin on glycaemia occur mainly in the liver, but metformin-stimulated glucose disposal by the gut has emerged as an increasingly import site of action of metformin. Additionally, metformin induces increased secretion of GLP-1 from intestinal L-cells. Clinical cardiovascular protection with metformin is supported by three randomized outcomes trials (in newly diagnosed and late stage insulin-treated type 2 diabetes patients) and a wealth of observational data. Initial evidence suggests that cotreatment with metformin may enhance the impact of newer incretin-based therapies on cardiovascular outcomes, an important observation as metformin can be combined with any other antidiabetic agent. Multiple potential mechanisms support the concept of cardiovascular protection with metformin beyond those provided by reduced blood glucose, including weight loss, improvements in haemostatic function, reduced inflammation, and oxidative stress, and inhibition of key steps in the process of atherosclerosis. Accordingly, metformin remains well placed to support improvements in cardiovascular outcomes, from diagnosis and throughout the course of type 2 diabetes, even in this new age of improved outcomes in type 2 diabetes.

Prediabetes management in the Middle East, Africa and Russia: Current status and call for action.

Most data on the burden of diabetes and prediabetes are from countries where local infrastructure can support reliable estimates of the burden of non-communicable diseases. Countries in the Middle East and Africa, together with Russia, have a total population of almost 2 billion, but have been relatively overlooked by authors in this field. We reviewed the prevalence and drivers of prediabetes and diabetes across this large region. A large, and variable, burden of dysglycaemia exists, especially in Middle Eastern and North African countries, associated with high levels of obesity and sedentariness, with a generally lower prevalence in most other parts of Africa. The design and size of studies are highly variable, and more research to quantify the scale of the problem is needed. Local barriers to care relating to issues concerned with gender, consanguinity, lack of understanding of diabetes, lack of understanding of obesity as a health issue, and limited resource at a national level for tracking and intervention for diabetes and other non-communicable diseases. Lifestyle interventions with proven local cost-effectiveness, enhanced access to pharmacologic intervention, and societal interventions to promote better diet and more activity will be an important element in strategies to combat these adverse trends.