Proportion of participants with type 2 diabetes achieving a metabolic composite endpoint with once-weekly semaglutide treatment versus comparators: Post hoc pooled analysis from SUSTAIN 1-5, 7-10 and SUSTAIN China.

AIM: To compare the proportion of participants with type 2 diabetes (T2D) treated with once-weekly (OW) subcutaneous (SC) semaglutide versus comparators who achieved a composite metabolic endpoint. MATERIALS AND METHODS: SUSTAIN 1-5, 7-10 and SUSTAIN China trial data were pooled. Participants with T2D (aged ≥18 years) and glycated haemoglobin ≥7.0% (≥53 mmol/mol) who had been randomized to OW SC semaglutide (0.5 or 1.0 mg) or comparator in addition to background medication. Using patient-level data pooled by treatment, proportions of participants achieving the metabolic composite endpoint, defined as glycated haemoglobin <7% (<53 mmol/mol), blood pressure <140/90 mmHg and non-high-density lipoprotein cholesterol <130 mg/dl (<3.37 mmol/L), were evaluated following baseline adjustments. Endpoints were analysed per trial using a binomial logistic regression model with treatment, region/country and stratification factor as fixed effects and baseline value as covariate. Pooled analysis used logistic regression with treatment and trial as fixed effects and baseline value as covariate. RESULTS: This post hoc analysis included data from 7633 participants across 10 trials. The proportion of participants who achieved the metabolic composite endpoint was significantly higher with OW SC semaglutide 0.5 and 1.0 mg versus comparators (23.7% and 32.0% vs. 11.5%, respectively; p < .0001). Likewise, when the OW SC semaglutide doses were pooled, significantly higher proportions of patients receiving semaglutide achieved the composite metabolic endpoint versus comparators (29.1% vs. 11.4%, respectively; p < .0001). CONCLUSIONS: Treatment with OW SC semaglutide versus comparators was associated with increased proportions of participants with T2D meeting the composite metabolic endpoint.

Comparative efficacy, safety, and cardiovascular outcomes with once-weekly subcutaneous semaglutide in the treatment of type 2 diabetes: Insights from the SUSTAIN 1-7 trials.

In individuals with type 2 diabetes, glycaemic control and cardiovascular risk factor management reduces the likelihood of late-stage diabetic complications. Guidelines recommend treatment goals targeting HbA1c, body weight, blood pressure, and low-density lipoprotein cholesterol. Development of new treatments for type 2 diabetes requires an understanding of their mechanism and efficacy, as well as their relative effects compared to other treatment choices, plus demonstration of cardiovascular safety. Subcutaneous semaglutide is a glucagon-like peptide-1 receptor agonist currently approved in several countries for once-weekly treatment of type 2 diabetes. Semaglutide works via the incretin pathway, stimulating insulin and inhibiting glucagon secretion from the pancreatic islets, leading to lower blood glucose levels. Semaglutide also decreases energy intake by reducing appetite and food cravings, and lowering relative preference for fatty, energy-dense foods. Semaglutide was evaluated in the SUSTAIN clinical trial programme in over 8000 patients across the spectrum of type 2 diabetes. This review details the efficacy and safety profile of semaglutide in the SUSTAIN 1-5 and 7 trials, and its cardiovascular safety profile in the SUSTAIN 6 trial. Semaglutide consistently demonstrated superior and sustained glycemic control and weight loss vs. all comparators evaluated. In SUSTAIN 6, involving patients at high risk of cardiovascular disease, semaglutide significantly decreased the occurrence of cardiovascular events compared with placebo/standard of care (hazard ratio 0.74, P < 0.001 for non-inferiority). Through a comprehensive phase 3 clinical trial program, we have a detailed understanding of semaglutide's efficacy, safety, cardiovascular effects and comparative role in the treatment of type 2 diabetes.

Efficacy and safety of liraglutide versus placebo added to basal insulin analogues (with or without metformin) in patients with type 2 diabetes: a randomized, placebo-controlled trial.

AIM: To confirm the superiority, compared with placebo, of adding liraglutide to pre-existing basal insulin analogue ± metformin in adults with inadequately controlled type 2 diabetes [glycated haemoglobin (HbA1c) 7.0-10.0% (53-86 mmol/mol)]. METHODS: In this 26-week, double-blind, parallel-group study, conducted in clinics or hospitals, 451 subjects were randomized 1 : 1 to once-daily liraglutide 1.8 mg (dose escalated from 0.6 and 1.2 mg/day, respectively, for 1 week each; n = 226) or placebo (n = 225) added to their pre-existing basal insulin analogue (≥20 U/day) ± metformin (≥1500 mg/day). After randomization, insulin adjustments above the pre-study dose were not allowed. The primary endpoint was HbA1c change. RESULTS: After 26 weeks, HbA1c decreased more with liraglutide [-1.3% (-14.2 mmol/mol)] than with placebo [-0.1% (-1.2 mmol/mol); p < 0.0001]. More subjects on liraglutide reached HbA1c targets: <7.0% (59% vs 14%; p < 0.0001) and ≤6.5% (43% vs 4%; p < 0.0001) using slightly less insulin (35.8 IU vs 40.1 IU). Greater decreases from baseline (estimated treatment differences vs placebo; p < 0.0001) occurred in fasting plasma glucose (-1.3 mmol/l), seven-point glucose profiles (-1.6 mmol/l), body weight (-3.1 kg) and systolic blood pressure (-5.0 mmHg). Transient gastrointestinal adverse events (nausea: 22.2% vs 3.1%) and minor hypoglycaemia (18.2% vs 12.4%) were more frequent with liraglutide than placebo, and pulse increased (4.5 beats/min) compared with placebo. No severe hypoglycaemia or pancreatitis occurred. CONCLUSIONS: Adding liraglutide to a basal insulin analogue ± metformin significantly improved glycaemic control, body weight and systolic blood pressure compared with placebo. Typical gastrointestinal symptoms and minor hypoglycaemia were more frequent with liraglutide.

Effects of epidermal growth factor on thyroglobulin and adenosine 3',5'-monophosphate production by cultured human thyrocytes.

While several workers have identified epidermal growth factor (EGF) receptors on human thyroid membranes, very few reports have described EGF effects on intact human thyroid cells in primary culture, and these were short term studies indicating that EGF effects were primarily inhibitory [reduced iodide uptake and thyroglobulin (Tg), T4, and T3 release]. Paradoxically, in vivo EGF stimulates thyroid growth and increases colloid stores. In this study we examined the effects of EGF on cultured thyroid cells in regard to thymidine incorporation, Tg secretion, and cAMP production during a 12-day period. Addition of EGF (0-30 ng/mL) to medium for 6 or 12 days stimulated thymidine incorporation and enhanced Tg synthesis by thyroid cells. However, the profile of Tg release into medium was biphasic. Tg release was inhibited by EGF (0.1-10 ng/mL) during the first 3 days of culture, but the inhibitory effect disappeared by the sixth day, and EGF stimulated Tg release by day 12 and thereafter. EGF enhanced endogenous cAMP levels in thyroid cells, but did not augment TSH-stimulated increases in cAMP production. Our observations of EGF-stimulated growth and inhibited Tg secretion during short term culture are consistent with the findings of earlier studies with nonhuman thyrocytes. However, the later phase of enhanced cAMP levels with stimulation of Tg secretion indicates that EGF may have trophic effects on thyrocytes previously unrecognized because of the short term nature of the studies. These observations suggest an important role for EGF in maintenance of normal thyroid physiology.

[Molecular genetic detection of polyclonal immune response in autoimmune thyroiditis and inflammatory bowel diseases]. / Molekulargenetischer Nachweis einer polyklonalen Immunantwort bei Autoimmunthyreoiditis und entzündlichen Darmerkrankungen.

Southern blot hybridization techniques were used to analyze the arrangements of the immunoglobulin and the T cell antigen receptor genes in lymphocytes of patients with Graves disease and Hashimoto's thyroiditis as well as in patients with Crohn's disease, chronic ulcerative colitis, and with other gastrointestinal disease. The results indicate that the immune response of autoimmune thyroid disease and inflammatory bowel disease is of polyclonal origin.

Thyrotropin modulates receptors for atrial natriuretic peptide on intact human thyroid cells.

Interest in the mechanism of impaired salt and water metabolism in hypothyroidism has led to growing evidence of an interaction between atrial natriuretic peptide (ANP) and the thyroid, which includes reports of direct effects of thyroid hormone on ANP synthesis and circulating ANP levels, and of the presence of specific ANP receptors in human thyroid tissue, which may act to inhibit thyroglobulin (Tg) secretion. The authors questioned whether or not thyrotropin (TSH) has a role in this interaction. They used 125I-ANP to study the effect of TSH on ANP binding to human thyroid cells in primary culture. Binding competition by increasing concentrations of unlabeled ANP in the presence or absence of TSH was assessed by Scatchard analysis. At lower temperatures of 4 degrees C or 23 degrees C, TSH had no effect either on the ANP receptor equilibrium dissociation constant (Kd) or number of binding sites. However, at 37 degrees C, bovine TSH at 1 mU/ml reduced measurable binding sites by about 50% without affecting receptor affinity (Kd = 0.2 nM). Prolonged (6 days) coincubation of TSH with thyroid cells decreased the assayable ANP receptor. The effects of TSH appear to be specific because human luteinizing hormone, follicle-stimulatory hormone, growth hormone, human chorionic gonadotropin and iodide had no effect on ANP binding. Thus, human thyroid cells possess a single class of high-affinity, specific receptors for ANP with binding activity that is temperature dependent and modulated by TSH at physiologic temperature. TSH-mediated reduction of binding at 37 degrees C but not at 4 degrees C suggests an energy-dependent process that acts possibly by activating an ANP degradative enzyme or by changing the rate of receptor internalization and subsequent degradation.

Immunoglobulin and T cell antigen receptor gene arrangements indicate that the immune response in autoimmune thyroid disease is polyclonal.

To further define the degree of heterogeneity of the antibody and cellular immune responses in autoimmune thyroid disease, we used Southern blot hybridization techniques to analyze the arrangements of immunoglobulin and T cell antigen receptor genes in circulating lymphocytes and in those infiltrating the thyroid gland in nine patients with thyrotoxicosis due to Graves' disease and five patients with Hashimoto's thyroiditis. The sensitivity of these techniques was sufficient to detect a monoclonal population when there was as little as 1% clonal involvement in a mixed cell population. In the patients studied, DNA from non-T peripheral blood cells and non-T intrathyroid lymphocytes had only a germline gene pattern and no clonal nongermline rearrangements of immunoglobulin genes, as assessed using an immunoglobulin joining heavy chain (IgJH) gene probe. An analysis of the DNA from peripheral blood T cells or intrathyroidal lymphocytes revealed polyclonal gene rearrangement patterns and no clonal nongermline rearrangements of the T cell antigen receptor-beta and -gamma genes, as assessed using T constant-beta and T joining -gamma gene probes. These results indicate that the lymphocytes in peripheral blood and those infiltrating the thyroid gland in patients with autoimmune thyroid disease are of polyclonal origin.

The role of T lymphocytes in autoimmune thyroid disease.

Abnormalities in cellular mechanisms of immunoregulation are important factors in the initiation and/or propagation of autoimmune thyroid disease and Graves' ophthalmopathy. The primary immunologic lesion, however, remains elusive despite increasingly sophisticated investigations in the areas of antigen presentation and subsequent T-cell responses. Emphasis on functional evaluations of relevant cell populations and advances in lymphokine analysis, interpretation of DR antigen expression, and T-cell cloning offer promise for our future understanding of this complex process.

Antibodies to porcine eye muscle in patients with Graves' ophthalmopathy: identification of serum immunoglobulins directed against unique determinants by immunoblotting and enzyme-linked immunosorbent assay.

The immunological mechanisms involved in Graves' ophthalmopathy are not known. To explore the pathophysiology of this disorder, we used an enzyme-linked immunosorbent assay to detect antibodies that bound to the 100,000 X g sediment fraction of porcine eye muscle. Serum from patients with Graves' ophthalmopathy had enhanced immunoglobulin binding to porcine eye muscle compared to serum from control subjects (P less than 0.0001); however, several individual normal serum samples also had elevated binding activity. Incubation of serum from some Graves' patients with skeletal muscle or liver tissue resulted in reduction in immunoglobulin binding to porcine eye muscle. Thyroglobulin and TSH reduced binding only at high concentrations. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed some obvious differences in protein bands between porcine eye muscle and skeletal muscle. Serum from many normal subjects and patients with autoimmune thyroid disease formed bands with skeletal muscle protein fractions on immunoblotting, and no specific bands were found using serum from Graves' ophthalmopathy patients. Immunoblots of Graves' patients' serum after reaction with either porcine skeletal or eye muscle showed no reactivity with thyroglobulin (200K and 320K) or thyroid microsomal antigen (105K). Instead, immunoblots of eye muscle and serum from Graves' patients, with or without eye disease, showed two bands at 64K and 73K, which were shared by serum from normal subjects. In addition, several unique eye muscle determinants were detected in serum from 6 of 13 Graves' disease patients analyzed. These unique bands usually had mol wt of less than 50K, and 5 of the 6 patients whose serum reacted with these determinants had significant ophthalmopathy. Our findings support the presence of potential antigenic differences between eye muscle and skeletal muscle accounting for the immunological specificity of eye muscle as a target in Graves' ophthalmopathy.