Efficacy and safety of visepegenatide, a long-acting weekly GLP-1 receptor agonist as monotherapy in type 2 diabetes mellitus: a randomised, double-blind, parallel, placebo-controlled phase 3 trial.

Background: Type 2 diabetes (T2DM) remains a challenge to treat despite the expansion of various therapeutic classes. Visepegenatide (PB-119) is a once a week, subcutaneous, glucagon-like peptide-1 receptor agonist (GLP-1 RA) injection without the requirement of dose titration that has shown glycaemic control and safety profile in two phase 2 studies conducted in China and the United States, respectively. The aim of this study was to evaluate the efficacy and safety of visepegenatide as a monotherapy in treatment-naïve patients with T2DM. Methods: This was a multicentre, double-blind, parallel, placebo-controlled, phase 3 trial conducted in 30 centres in China. Adult participants (aged 18-75 years) with T2DM, glycated haemoglobin (HbA1c) of 7.5%-11.0% [58.47-96.73 mmol/mol], body mass index (BMI) of 18-40 kg/m2, and who had been treated with diet and exercise alone for at least 8 weeks before the screening visit were eligible for enrolment. After a 4-week placebo injection run-in period, participants with HbA1c of 7.0%-10.5% [53.0-91.3 mmol/mol] and fasting plasma glucose (FPG) < 15 mmol/L were randomised in a ratio of 1:1 to receive visepegenatide (150 µg) or placebo subcutaneous injections once a week for 24 weeks. The treatment was extended to another 28 weeks during which all participants received visepegenatide. The primary outcome was a change in HbA1c from baseline to week 24. This study was registered with ClinicalTrials.gov, as NCT04504370. Findings: Between November 2, 2020, and November 2, 2022, we randomly assigned 273 adult participants to the visepegenatide (n = 137) and placebo (n = 136) groups. In total, 257 (94.12%) participants, 131 (95.6%) on visepegenatide, and 126 (92.6%) on placebo, completed the double-blinded treatment period. At baseline, the mean (SD) HbA1c was 8.47% (0.81) [69.07 [8.81] mmol/mol], which rapidly decreased to 7.63% (0.80) [59.94 [8.70] mmol/mol] with visepegenatide by week 4 of treatment, and the change from baseline was significantly greater than that in the placebo group (-0.82% [-0.90 to -0.74]; [-8.99 [-9.89 to -8.10] mmol/mol] vs -0.30% [-0.41 to -0.19]; [-3.30 [-4.50 to -2.09] mmol/mol]). At week 24, when evaluating the effects of treatment with treatment policy estimand, the least square mean (LSM change in HbA1c from baseline was -1.36 (95% confidence interval [CI] -1.52 to -1.20) [-14.84 [-16.60 to -13.08] mmol/mol] in the visepegenatide group vs -0.63 (-0.79 to -0.46) [-6.84 [-8.61 to -5.07] mmol/mol] in the placebo group. The reduction in HbA1c was significantly greater with visepegenatide than placebo (LSM difference -0.73, 95% CI -0.96 to -0.50; p < 0.001). When evaluating the treatment estimand with hypothetic policy, the LSM change in HbA1c from baseline in the visepegenatide group (-1.37 [-1.53 to -1.20]) [-14.95 [-16.76 to -13.14] mmol/mol] was significantly greater than the placebo group (-0.63 [-0.81 to -0.45]) [6.90 (-8.89 to -4.90) mmol/mol]. The LSM difference was (-0.74, 95% CI -0.98 to -0.49; [-8.00 [-10.50 to -5.50] mmol/mol]; p < 0.001]. A significantly greater proportion of the visepegenatide group achieved a target HbA1c level of <7% (<53 mmol/mol) than the placebo (50.4% vs 14.2%; p < 0.05) and stringent HbA1c level of ≤6.5% (≤48 mmol/mol) (26.7% vs 7.9%), respectively. There was also a significantly greater improvement in FPG, 2-h postprandial glucose, homeostasis model assessment (HOMA) of beta cell function, post-prandial insulin, fasting, and post-prandial C-peptide level (p < 0.05) with visepegenatide treatment. The number (3 [2.2%]) of participants who received rescue therapy in the visepegenatide group was remarkably lower compared with those (17 [12.5%]) in the placebo group (p < 0.05). During the extended treatment period, visepegenatide consistently maintained the efficacy till week 52 confirmed by all the above endpoints. The reduction in HbA1c at week 52 was -1.39% (-1.58 to -1.19) [-15.14 [-17.28 to -13.01] mmol/mol], which was even greater than that at week 24. There was also a significant improvement in HOMA-insulin resistance (p = 0.004) at week 52 compared with the baseline value. For the placebo→visepegenatide group, which received visepegenatide in the extended treatment period, a notable decrease in HbA1c at week 52 compared to baseline was observed. The change from baseline in HbA1c was -1.49% (-1.68 to -1.30) [-16.27 [-18.37 to -14.16] mmol/mol]. The outcome was in the same direction as the visepegenatide group from the double-blind treatment period. Comprehensive benefits of visepegenatide including weight loss, improvement in lipid profile, and reduction in blood pressure have been demonstrated in this study. Visepegenatide reduced the body weight in a BMI-dependent manner that was prominent in BMI ˃32 kg/m2 with a mean (SD) reduction of -4.77 (13.94) kg at week 52 (p < 0.05). Incidences of gastrointestinal adverse events were less common than other weekly GLP-1 RA in the market, and most of the adverse events were mild and moderate in nature, occurring in the first weeks of the treatment, and were transient. No serious hypoglycaemia or grade 2 hypoglycaemia (blood glucose: ≤3 mmol/L) was reported during the study. Interpretation: As a monotherapy, visepegenatide provided rapid without the risk of hypoglycaemia, significant, and sustainable glycaemic control by improving islet ß-cell function and insulin resistance. Treatment with visepegenatide induced early treatment response in reducing HbA1c and maintaining glycaemic control for 52 weeks. Meanwhile, visepegenatide provided a comprehensive benefit in body weight loss, lipids, and blood pressure reduction. Visepegenatide had a better safety profile than other weekly GLP-1 RA in participants with T2DM even without the requirement of dose titration. Visepegenatide would provide an optimal treatment approach with its high benefit and low-risk balance. Funding: PegBio Co., Ltd.

Metabolic outcomes in patients with type 2 diabetes mellitus after metabolic management center.

The Chinese Medical Doctor Association has initiated metabolic management center (MMC) program for 6 years since 2016 nationwide. It is worth investigating the level of control metabolic outcomes in patients with type2 diabetes (T2DM) after MMC model in Yan'an, northwest China. Patients with T2DM was admitted to MMC in Yan'an University Affiliated Hospital from November 2018 to July 2021. They were asked to revisit hospital every 3 months. Blood glucose, blood pressure and blood lipids at baseline were compared to its counterparts after 1 year MMC management. Glycosylated hemoglobin and low density lipoprotein cholesterol (LDL-C) level in T2DM patients after 1 year management were lower than their baseline level (glycosylated hemoglobin 7.74 ±â€…1.94% vs 8.63 ±â€…2.26%, P < .001; LDL-C 1.81 ±â€…0.73mmol/L vs 2.18 ±â€…1.49mmol/L, P < .001). Mean HOMA-ß increased after management (65.89 ±â€…90.81% vs 128.38 ±â€…293.93%, P < .05). After 1 year of management, patients in high school or above group achieved higher control rate of body mass index than those in middle school or below group (71.82% vs 28.18%, P = .043). high density lipoprotein cholesterol control rate was higher in high income group (42.86% vs 34.97%, 16.28%, P = .012), while LDL-C control rate was higher in low-income group (97.67% vs 78.57%, 84.51%, P = .018). fasting plasma glucose control rate in new diagnosis group was higher than that of the middle and long course groups (71.43% vs 52.38%, 42.44%, P = .002). The comprehensive control rate increased from 9.83% at baseline to 26.15% after 1 year MMC management. The metabolic outcomes and their control rate in T2DM patients were improved after 1 year MMC management. It indicated that patients may achieve more benefits with MMC management.

Effectiveness and safety of Bifidobacterium and berberine in human hyperglycemia and their regulatory effect on the gut microbiota: a multi-center, double-blind, randomized, parallel-controlled study.

BACKGROUND: Berberine and Bifidobacterium have been reported to improve glucose tolerance in people with hyperglycemia or other metabolic disorders. This study aimed to assess the hypoglycemic effect and the regulation of the gut microbiota caused by berberine and Bifidobacterium and the possible additive benefits of their combination. METHODS: This was an 18-week, multi-center, randomized, double-blind, parallel-controlled study of patients newly diagnosed with hyperglycemia. After a 2-week run-in period, 300 participants were randomly assigned to the following four groups for 16 weeks of treatment: berberine (Be), Bifidobacterium (Bi), berberine and Bifidobacterium (BB), and placebo group. The primary efficacy endpoint was the absolute value of fasting plasma glucose (FPG) compared with baseline after 16 weeks of treatment. RESULTS: Between October 2015 and April 2018, a total of 297 participants were included in the primary analysis. Significant reductions of FPG were observed in the Be and BB groups compared with the placebo group, with a least square (LS) mean difference of - 0.50, 95% CI [- 0.85, - 0.15] mmol/L, and - 0.55, 95% CI [- 0.91, - 0.20] mmol/L, respectively. The Be and BB groups also showed significant reductions in 2-h postprandial plasma glucose. A pronounced decrease in HbA1c occurred in the BB group compared to the placebo group. Moreover, compared with the Bi and placebo groups, the Be and BB groups had more changes in the gut microbiota from the baseline. CONCLUSIONS: Berberine could regulate the structure and function of the human gut microbiota, and Bifidobacterium has the potential to enhance the hypoglycemic effect of berberine. These findings provide new insights into the hypoglycemic potential of berberine and Bifidobacterium. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03330184. Retrospectively registered on 18 October 2017.

Associations between CD160 polymorphisms and autoimmune thyroid disease: a case-control study.

BACKGROUND: Recent researches suggest that the CD160/HVEM/LIGHT/BTLA signaling pathway may contribute to the pathogeneses of autoimmune diseases, but the relationship between CD160 polymorphisms and autoimmune thyroid disease (AITD) has not been reported yet. This study aimed to evaluate the associations between CD160 polymorphisms and AITD. METHODS: A total of 1017 patients with AITD (634 Graves' disease and 383 Hashimoto's thyroiditis) and 856 unrelated healthy controls were recruited into our study. Odds ratios (ORs) with 95% confidence interval (95%CI) were calculated through logistic regression analyses. The CD160 SNPs were detected using Hi-SNP high-throughput genotyping. RESULTS: There was a statistically significant difference between Graves' disease patients and the control group with respect to both the genotype distribution (P = 0.014) and allele frequency of rs744877 (P = 0.034). A significant association of CD160 rs744877 with AITD was observed before adjusted age and gender under a dominant model (OR = 0.79, 95%CI 0.66-0.95; P = 0.013) and an additive model (OR = 0.77, 95%CI 0.64-0.94, P = 0.008), and was also observed after adjusted age and gender under a dominant model (OR = 0.78, 95%CI 0.65-0.95; P = 0.011) and an additive model (OR = 0.76, 95%CI 0.63-0.93, P = 0.007). A significant association of rs744877 with Graves' disease was observed under an allele model (OR = 0.84, 95%CI 0.71-0.98, P = 0.027), a dominant model (OR = 0.74, 95%CI 0.60-0.91; P = 0.005), and an additive model (OR = 0.72, 95%CI 0.58-0.90, P = 0.004). Multivariate logistic regression analyses suggested that the association remained significant after adjustment for age and gender. However, rs744877 was not related to Hashimoto's thyroiditis. Furthermore, CD160 rs3766526 was not significantly related to either Graves' disease or Hashimoto's thyroiditis. CONCLUSION: This is the first identification of the association of CD160 rs744877 with Graves' disease. Our findings add new data to the genetic contribution to Graves' disease susceptibility and support the crucial role of the CD160/HVEM/LIGHT/BTLA pathway in the pathogenesis of Graves' disease.

Associations between NLRC4 Gene Polymorphisms and Autoimmune Thyroid Disease.

BACKGROUND: Many studies have shown that NLRC4 inflammasome polymorphisms are associated with a variety of autoimmune diseases, but the associations between NLRC4 polymorphisms and autoimmune thyroid diseases (AITDs) are unclear. Our research was aimed at identifying the correlations between NLRC4 polymorphisms and AITDs. METHODS: Hi-SNP high-throughput genotyping technology was used for detecting four single-nucleotide polymorphisms (SNPs) of NLRC4 in 1005 AITDs patients (including 629 Graves' disease and 376 Hashimoto's thyroiditis) and 781 healthy controls. RESULTS: Compared with healthy controls, the allele frequencies and genotype distribution of rs385076 were statistically related to AITDs (P = 0.016 and P = 0.048, respectively) and Hashimoto's thyroiditis (P = 0.022 and P = 0.046, respectively). Before adjusting for age and gender, rs385076 and AITDs had a significant association in three models of allele model, dominant model, and homozygous model. After adjusting for age and gender, in the above three models, there is still a clear relationship between them. Before adjusting for age and gender, there were prominent discrepancy between rs385076 and Hashimoto's thyroiditis in the allele model (OR = 0.81, 95% CI 0.67-0.97; P = 0.021) and the dominant model (OR = 0.73, 95% CI 0.57-0.94; P = 0.014), after adjusting for age and gender, rs385076 and Hashimoto's thyroiditis were significantly related to allele model, dominant model, and homozygous model. However, rs455060, rs212704, and rs675712 were not related to AITDs in our study. CONCLUSION: NLRC4 rs385076 was found to have a significant association with Hashimoto's thyroiditis for the first time. It laid a foundation for the disclosure of the pathogenesis of AITDs, and provided a possible treatment prospect for HT.

Aberrant Expressions of Co-stimulatory and Co-inhibitory Molecules in Autoimmune Diseases.

Co-signaling molecules include co-stimulatory and co-inhibitory molecules and play important roles in modulating immune responses. The roles of co-signaling molecules in autoimmune diseases have not been clearly defined. We assessed the expressions of co-stimulatory and co-inhibitory molecules in autoimmune diseases through a bioinformatics-based study. By using datasets of whole-genome transcriptome, the expressions of 54 co-stimulatory or co-inhibitory genes in common autoimmune diseases were analyzed using Robust rank aggregation (RRA) method. Nineteen array datasets and 6 RNA-seq datasets were included in the RRA discovery study and RRA validation study, respectively. Significant genes were further validated in several autoimmune diseases including Graves' disease (GD). RRA discovery study suggested that CD160 was the most significant gene aberrantly expressed in autoimmune diseases (Adjusted P = 5.9E-12), followed by CD58 (Adjusted P = 5.7E-06) and CD244 (Adjusted P = 9.5E-05). RRA validation study also identified CD160 as the most significant gene aberrantly expressed in autoimmune diseases (Adjusted P = 5.9E-09). We further found that the aberrant expression of CD160 was statistically significant in multiple autoimmune diseases including GD (P < 0.05), and CD160 had a moderate role in diagnosing those autoimmune diseases. Flow cytometry confirmed that CD160 was differentially expressed on the surface of CD8+ T cells between GD patients and healthy controls (P = 0.002), which proved the aberrant expression of CD160 in GD at the protein level. This study suggests that CD160 is the most significant co-signaling gene aberrantly expressed in autoimmune diseases. Treatment strategy targeting CD160-related pathway may be promising for the therapy of autoimmune diseases.

Association of single-nucleotide polymorphisms in the IL27 gene with autoimmune thyroid diseases.

Background Accumulating data have shown that interleukin-27 (IL27) polymorphisms are linked to the susceptibility of some autoimmune diseases. We assessed whether there was an association between three single-nucleotide polymorphisms (SNPs) of IL27 gene and autoimmune thyroid diseases (AITDs). Methods Three SNPs (rs153109, rs17855750 and rs181206) of IL27 gene were genotyped by Hi-SNP high-throughput genotyping in 843 patients with AITDs (516 Graves' disease (GD) and 327 Hashimoto's thyroiditis (HT)) and 677 healthy controls in Chinese Han population. Results Compared with controls, rs153109 displayed significant associations with GD in allele and genotype frequencies (P = 0.002 and P = 0.008, respectively) and rs17855750 displayed significant associations with HT in allele frequencies (P = 0.02), whereas no differences in genotype or allele frequencies were found between AITD patients and controls at rs181206. Conclusion Our study, for the first time, showed the significant association of the IL27 gene SNPs with AITD.

Dose-response relationship between thyroid stimulating hormone and hypertension risk in euthyroid individuals.

BACKGROUND: The adverse impact of thyroid dysfunction on cardiovascular system is well established, but the relationship between the level of thyroid stimulating hormone (TSH) and the risk of hypertension in euthyroid individuals is still inconclusive. METHODS: We carried out a population-based, cross-sectional study to evaluate the relationship between TSH and hypertension risk in euthyroid individuals, and logistic regression analysis was utilized. In addition, a dose-response meta-analysis of relevant cohort or cross-sectional studies was carried out to further assess the impact of TSH on hypertension risk among euthyroid individuals. RESULTS: A total of 2289 euthyroid individuals without thyroid diseases were recruited in our cross-sectional study. Serum TSH level within the upper reference range was associated with higher risk of hypertension [odds ratio (OR) = 1.29, 95% confidence interval (CI) 1.04-1.61, P = 0.023], and the OR for hypertension was still statistically significant after adjustment for confounding factors (OR = 1.32, 95% CI 1.01-1.72, P = 0.041). Moreover, meta-analysis suggested an obvious dose-response relationship between TSH and hypertension risk in euthyroid individuals, and the OR for hypertension associated with per 1 mIU/l increase in TSH level was 1.09 (95% CI 1.04-1.14, P < 0.001). Meta-analysis also showed that the ß-coefficients of SBP and DBP associated with per 1 mIU/l increase in TSH level were 0.78 (95% CI 0.37-1.18, P < 0.001) and 0.45 (95% CI 0.15-0.76, P = 0.004), respectively. CONCLUSION: The current study provides strong evidence for the dose-response relationship between serum TSH level and hypertension risk in euthyroid individuals. Euthyroid individuals with higher normal TSH level are at higher risk of developing hypertension than those with lower normal TSH level.

Effect of Levothyroxine on Blood Pressure in Patients With Subclinical Hypothyroidism: A Systematic Review and Meta-Analysis.

Background: Patients with subclinical hypothyroidism (SCH) have elevated blood pressure, but the effect of levothyroxine (LT4) therapy on blood pressure among those patients is still unclear. This study aimed to assess whether LT4 therapy could reduce blood pressure in SCH patients through a systematic review and meta-analysis. Methods: PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science were searched. Randomized controlled trials (RCTs) assessing the effect of LT4 therapy on blood pressure or prospective follow-up studies comparing the blood pressure level before and after LT4 treatment were included, and the mean difference of systolic blood pressure (SBP) or diastolic blood pressure (DBP) was pooled using random-effect meta-analysis. Results: Twenty-nine studies including 10 RCTs and 19 prospective follow-up studies were eligible for the analysis. Meta-analysis of 10 RCTs suggested that LT4 therapy could significantly reduce SBP in SCH patients by 2.48 mmHg (95% CI -4.63 to -0.33, P = 0.024). No heterogeneity was observed among these 10 RCTs (I2 = 0%). Meta-analysis of the 19 prospective follow-up studies found that LT4 therapy significantly decreased SBP and DBP by 4.80 mmHg (95%CI -6.50 to -3.09, P < 0.001) and 2.74 mmHg (95%CI -4.06 to -1.43, P < 0.001), respectively. Conclusion: The findings suggest that LT4 replacement therapy can reduce blood pressure in SCH patients, which needs to be validated in more clinical trials with larger samples.

Association between serum chemerin concentrations and clinical indices in obesity or metabolic syndrome: a meta-analysis.

OBJECTIVE: Chemerin is a novel adipokine. Previous research has investigated the association between chemerin and clinical indices in patients with obesity or metabolic syndrome (MS), although the results obtained have been inconsistent. We conducted a meta-analysis to investigate the association between chemerin and clinical indicators of diabetes, MS and obesity with obesity or MS subjects. DESIGN AND METHODS: Studies were identified by searching the PubMed, the Cochrane Library, EMBASE and CNKI, databases beginning with the original report in July 2007 until the end of May 2013. For each variable, summary correlation coefficients were estimated using random-effects or fixed-effect meta-analysis with 95% confidence interval (CI) performed by STATA software. RESULTS: A total of eight studies with 20 clinical variables (total n = 1787) met the inclusion criteria. The meta-analyse of diabetes markers showed that FSI (rs = 0.26; 95% CI = 0.21-0.31; P = 0.000), 2HPG (rs = 0.06; 95% CI = 0.01-0.12; P = 0.030) and HOMA-IR (rs = 0.178; 95% CI = 0.019-0.337; P = 0.028) were positively correlated with chemerin, however, FPG (rs = 0.03, 95% CI = -0.02 to 0.08, P = 0.240) and HbA1c (rs = -0.05; 95% CI = -0.24-0.15; P = 0.641) were not significantly correlated with chemerin. The meta-analyses of MS and obesity markers indicated that TG, TC, CRP BMI, TBF%, WC, WHR and Leptin were positively correlated with chemerin, nevertheless, SBP, DBP, LDL-C, HDL-C, ALT and r-GT were not significantly correlated, adiponectin was negatively correlated. Sensitivity analysis was performed and the summary results did not change significantly. CONCLUSIONS: The results suggest that chemerin in patients with obesity or MS may be associated with obesity, imbalances in lipid and diabetes metabolism and insulin resistance. Chemerin played an important role in the pathophysiology of obesity and MS.

Calcitonin is expressed in the submaxillary glands of rats.

Calcitonin is usually produced by the parafollicular cells of the thyroid. However in an immunohistochemistry experiment we observed that the cells of the serous acini of rat submaxillary gland tissue were stained positive with calcitonin antibodies. We further used immunocytochemistry and nucleic acid hybridization to localize the distribution of calcitonin protein and calcitonin mRNA respectively in cultivated cells of rat submaxillary glands. The results showed that the cytoplasm of the epithelial cells of the submaxillary glands had positive staining in immunocytochemistry using calcitonin monoclonal antibody and positive reaction in nucleic acid hybridization using calcitonin mRNA complementary DNA probe. For the first time we found that the cells of the submaxillary glands of rats can produce the hormone calcitonin.