Subclinical hypothyroidism and metabolic syndrome: reasons for drug intervention

The high prevalence of metabolic syndrome (MS) and subclinical hypothyroidism (SHypo) creates danger of integral cardio-metabolic risk (CMR). A concept is being developed to increase thyroid-stimulating hormone (TSH) levels as a component of MS with the key role of insulin resistance (IR). To identify groups of active intervention, the definitions of SHypo with age and gender characteristics are analyzed. The results of randomized clinical trials showed a higher incidence of prediabetes and type 2 diabetes mellitus (T2DM) in SHypo, as well as positive associations of autoimmune thyroiditis (AIT) with components of MS, especially in postmenopausal women. The association of SHypo with a systemic inflammatory response is analyzed, which can determine an increase in cardio-metabolic risk. At the same time, most of the thyroid dysfunction and the components of MS are associated with insulin resistance. The feasibility of SHypo treating with levothyroxine is discussed: the threshold parameters of thyroid-stimulating hormone (TSH) are not determined for initiating treatment; in old age, due to a decrease in the need for thyroid hormones, an increase in the upper reference range of TSH is discussed; there is no evidence of a decrease in cardiovascular risk and mortality. In parallel, data have been accumulated on a decrease in TSH levels in overt and subclinical hypothyroidism in patients with MS and T2DM with metformin therapy. The gender effect of metformin on the activity of the hypothalamus-pituitary-thyroid axis was suggested, its new antihyperglycemic mechanism of action, including the activation of the AMP protein kinase (adenosine monophosphate (AMP) -activated protein kinase) in the pituitary gland, was revealed. It is possible that metformin is a promising therapeutic agent not only for patients with type 2 diabetes and thyroid disease, but also for MS and obesity. The multifaceted capabilities of metformin, including the correction of peripheral and central insulin resistance and a decrease in TSH levels in patients with SHypo, emphasizes an integrated approach to the prevention of CMR. The prolonged release form of metformin has several advantages: better tolerance, greater efficiency in the correction of IR, lipid and carbohydrate metabolism, additional indication - treatment of prediabetes, the possibility of prescribing for creatinine clearance up to 30 ml/min

Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial

Background: Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. Methods: The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. Findings: Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60-0·87 for MACE; 0·79, 0·64-0·98 for the heart failure composite endpoint; 0·76, 0·59-0·97 for cardiovascular death; and 0·81, 0·66-1·00 for all-cause death; all pinteraction>0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49-0·87 for MACE; 0·79, 0·58-1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51-0·91 for MACE; 0·75, 0·52-1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. Interpretation: In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. Funding: Novo Nordisk

Multidimensional effects of metformin in patients with type 2 diabetes

In modern algorithms for the treatment of type 2 diabetes, metformin is positioned as a first-line drug, which, when the disease progresses, is universally combined with other groups of hypoglycemic drugs, including insulin. Review of literature demonstrates the multifaceted effects of metformin with its efficacy and extensive safety range, allowing the drug to be used not only for glycemic control but also for the management of cardiovascular risk factors. Here we present a retrospective study of whether cardiovascular safety of hypoglycemic drugs should be assessed, on the basis of which the idea of a vulnerable patient in the presence of diabetes can be formulated, and the necessity of joint management of such patients by an endocrinologist and cardiologist can be postulated. The mechanisms of macrovascular protection by the drug demonstrated in the UKPDS with the phenomenon of metabolic memory are analysed along with a discussion regarding their lipid-lowering and antisclerotic effects using modern analytical reviews. The features of the action of long form of the drug (Glucophage Long) are considered. The pleiotropic possibilities of metformin, the expansion of the present indications and the prospects of application as well as new hypotheses about its mechanism of action are discussed. The possible effects of the drug on the components of the gastrointestinal tractbrainliver axis are discussed, and the effects of metformin on homeostasis due to the effect on the microbiota are presented

Associations of functional and biochemical parameters of endothelial dysfunction in postmenopausal women with a different state of carbohydrate metabolism

Most of the questions regarding vascular and rheological regulation related to normal health and disorders of carbohydrate metabolism remain unclear, which is important in the pathogenesis of angiopathy. Consequently, in the literature, there is no information about the function of endothelial vasomotion during occlusion. The present study investigated early postmenopausal women, when clinical, metabolic, and hemodynamic disturbances often manifest. Aim. To study the association between clinical and biochemical indicators of endothelial microcirculation in naturally postmenopausal women with different carbohydrate metabolism statuses. Materials and methods. We surveyed 94 postmenopausal women who were divided into three groups based on their carbohydrate metabolism status: group 1, type 2 diabetes mellitus (n = 52); group 2, prediabetes (n = 16); group 3, normoglycemia (n = 26). The following indicators were assessed: lipid profiles and anthropometric fasting plasma glucose, glycated hemoglobin, vascular endothelial growth factor (VEGF), and endothelin-1 levels. Microcirculation was evaluated by laser Doppler flowmetry (LDF). Statistical analysis was performed using SPSS software (version 17.0). Results. LDF parameters in group 3 were significantly different from group 1 during occlusion and reperfusion and also from group 2 in basal blood flow. During occlusion, the frequency of microcirculation oscillation was higher in group 1, whereas the amplitude of oxygen saturation oscillation was lower in group 3 than those in group 2. VraEr and Vra/mEr indicators during reperfusion in group 1 and VrfEf during basal blood flow in group 2 were higher than those in group 3; Vr parameters reflect the contribution of fluctuations in the relative erythrocyte volume in the probed area of skin to the modulation of vascular tone. In group 1, occlusal LDF indicators correlated with waist circumference, whereas VEGF, lipid profile parameters, and reperfusion parameters, VraEr correlated with systolic blood pressure and lipid profile. In group 2, VrfEf inversely correlated with VEGF levels, and in group 3, the frequency of microcirculation oscillation inversely correlated with endothelin-1 levels. Conclusions. We revealed the associations of metabolic, anthropometric, and hemodynamic factors as well as biochemical markers of endothelial dysfunction with microcirculation parameters in various modes of endothelial activity (basal, occlusion, and reperfusion) in postmenopausal women according to their carbohydrate metabolism status; we also describe the effect of age on microvasculature vasomotion