Levels of circulating semaglutide determine reductions in HbA1c and body weight in people with type 2 diabetes.
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SUBMITTER: Overgaard RV
PROVIDER: S-EPMC8484505 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AimsSemaglutide is a glucagon-like peptide-1 (GLP-1) analogue approved for the treatment of type 2 diabetes. The impact of switching treatment from another GLP-1 receptor agonist (GLP-1RA) to semaglutide was investigated by analyses of exposure-response models.MethodsHbA1c and body weight time-course models were developed, using up to 30 weeks of observations from four trials in the semaglutide phase 3 programme. Given the recommended dosing for each GLP-1RA, pharmacokinetic profiles were simulated based on published population pharmacokinetic models and exposure was adjusted by the relative potencies to ensure that model predictions matched the effects observed in clinical trials. After 26 weeks of simulated treatment with liraglutide, dulaglutide or exenatide extended-release, simulated semaglutide treatment was initiated 1 day after the last once-daily dose of liraglutide and 1 week after the last once-weekly doses of dulaglutide or exenatide extended-release.ResultsThe potency-adjusted total effective GLP-1RA concentration increased after switching from another GLP-1RA to semaglutide and was associated with reductions ranging from ~0.3% to ~0.8%-points for HbA1c and from ~2% to ~4% for body weight with semaglutide 1.0 mg. Temporary slight deteriorations in HbA1c were observed after switching to semaglutide 0.25 mg from liraglutide 1.2/1.8 mg or dulaglutide 1.5 mg.ConclusionsExposure-response modelling suggests that switching to semaglutide from liraglutide, dulaglutide or exenatide extended-release results in further reductions in HbA1c and body weight. Initial slight deterioration in outcome values when switching to semaglutide 0.25 mg could be avoided by initiating semaglutide treatment at a higher dose.
| S-EPMC6585654 | biostudies-literature
Project description:INTRODUCTION:Despite treatment with oral antidiabetic drugs (OADs), achieving effective glycaemic control in type 2 diabetes (T2D) remains a challenge. The objective of this post hoc analysis of data from the SUSTAIN 2, 3, 4 and 10 active-controlled trials was to assess the efficacy and safety of the once-weekly glucagon-like peptide 1 receptor agonist (GLP-1RA) semaglutide in patients on background treatment with metformin (MET), with or without a sulphonylurea (SU). METHODS:Data from the randomised phase 3 trials SUSTAIN 2, 3, 4 and 10 for subjects who received background MET alone or MET?+?SU were analysed. Change from baseline in HbA1c and body weight at the end of treatment visit (week 30 in SUSTAIN 4 and 10, week 56 in SUSTAIN 2 and 3), and rates of hypoglycaemia and adverse events leading to premature treatment discontinuation were assessed. RESULTS:In total, 3411 subjects were included in the full analysis set (3410 in the safety analysis set). Across the four trials, semaglutide significantly reduced HbA1c (estimated treatment difference [ETD] -?0.32 to -?0.79%-points for semaglutide 0.5 mg, and -?0.38 to -?1.07%-points for semaglutide 1.0 mg vs comparators; p?<?0.01) in subjects receiving both MET and MET?+?SU. Regardless of background OAD, semaglutide significantly reduced body weight (ETD -?2.35 to -?4.72 kg for semaglutide 0.5 mg, and -?2.96 to -?6.76 kg for semaglutide 1.0 mg vs comparators; p?<?0.0001). Across the trials, hypoglycaemic events were more common with background MET?+?SU than MET alone, in subjects receiving either semaglutide or a comparator. The rate of adverse events (AEs) leading to premature treatment discontinuations in subjects treated with semaglutide were generally consistent regardless of background therapy. CONCLUSION:Semaglutide 0.5 mg and 1.0 mg significantly improve glycaemic control (HbA1c) and body weight in subjects with T2D, with a similar tolerability profile, regardless of whether they receive background MET or MET?+?SU. TRIAL REGISTRATION:Clinicaltrials.gov: NCT01930188 (SUSTAIN 2), NCT01885208 (SUSTAIN 3), NCT02128932 (SUSTAIN 4) and NCT03191396 (SUSTAIN 10).
| S-EPMC7193006 | biostudies-literature
Project description:IntroductionA post hoc analysis of the PIONEER 1-5 and 8 trials assessed the clinically relevant composite endpoints of HbA1c (glycated haemoglobin) reduction ≥ 1% and body weight loss of ≥ 5% or ≥ 10% with orally administered semaglutide versus comparators.MethodsIn the PIONEER trials, people with type 2 diabetes were randomised to orally administered semaglutide versus placebo (PIONEER 1, 4, 5 and 8), empagliflozin (PIONEER 2), sitagliptin (PIONEER 3) and liraglutide (PIONEER 4) for 26-78 weeks. This analysis assessed the proportion of people achieving an HbA1c reduction of ≥ 1% and body weight loss of ≥ 5% at week 26 and at end of treatment, and the proportion of people achieving an HbA1c reduction of ≥ 1% and body weight loss of ≥ 10% at end of treatment.ResultsOverall, 3506 people in PIONEER 1-5 and 8 were included. At week 26 and at end of treatment, odds of achieving the composite endpoint of an HbA1c reduction of ≥ 1% and body weight loss of ≥ 5% were significantly greater with orally administered semaglutide 14 mg than with placebo (PIONEER 1, 4, 5 and 8; all p < 0.0001), empagliflozin 25 mg (PIONEER 2, p < 0.0001), sitagliptin 100 mg (PIONEER 3, p < 0.0001) and liraglutide 1.8 mg (PIONEER 4, p < 0.0001). Odds of achieving the composite endpoint of HbA1c reduction of ≥ 1% and body weight loss of ≥ 10% at end of treatment were also significantly greater with orally administered semaglutide versus comparators.ConclusionIn PIONEER 1-5 and 8, odds of achieving clinically relevant reductions in both HbA1c and body weight were significantly greater with orally administered semaglutide versus comparators.
| S-EPMC10299987 | biostudies-literature
Project description:INTRODUCTION:Dapagliflozin is an orally active inhibitor of sodium-glucose co-transporter 2 (SGLT2) that is indicated for use in adults with type 1 diabetes (T1DM) (with a body mass index (BMI) of at least 27 kg/m2 in Europe, no such BMI limit in Japan), when insulin alone does not provide adequate glycaemic control. The aim of this study was to evaluate changes in glycated haemoglobin (HbA1c), body weight and insulin dose following discontinuation of dapagliflozin for the management of T1DM in the DEPICT clinical trial programme. METHODS:The interrelationship between treatment discontinuation, insulin requirement and outcomes post-discontinuation was evaluated using descriptive summary statistics and linear regression modelling. Data were analysed from individuals with T1DM discontinuing dapagliflozin in DEPICT-1 or DEPICT-2 (unplanned or end of study). HbA1c and body weight were measured over the 56-week study period (consisting of a 52-week treatment period and a 4-week follow-up period) at 4-8 weekly intervals. Following discontinuation of dapagliflozin, 1-year change in HbA1c (%) and weight (kg) following discontinuation of dapagliflozin was estimated; total daily insulin doses were descriptively summarised. RESULTS:Of the 1059 individuals that received dapagliflozin during the DEPICT trials 91 met the eligibility criteria and were included in the analyses of HbA1c and body weight. The mean duration of follow-up was 209 days in both analyses. Following dapagliflozin discontinuation, estimated annualised changes in HbA1c and body weight were + 0.99% (95% CI 0.39, 1.59) and + 3.75 kg (1.65, 5.86), respectively. An increase in insulin dose was observed around the time of discontinuation; insulin dose in the 2-week post-discontinuation was + 3.6 IU and + 4.4 IU higher with dapagliflozin 5 mg and 10 mg than 2 weeks pre-discontinuation, respectively. CONCLUSION:Discontinuation of dapagliflozin is predicted to lead to clinically meaningful increases in HbA1c and body weight, in addition to higher insulin doses. These findings are important in the management of people with T1DM among whom insulin is the only existing pharmacological treatment option.
| S-EPMC7192983 | biostudies-literature
Project description:Semaglutide, a glucagon-like peptide 1 (GLP-1) analog, induces weight loss, lowers glucose levels, and reduces cardiovascular risk in patients with diabetes. Mechanistic preclinical studies suggest weight loss is mediated through GLP-1 receptors (GLP-1Rs) in the brain. The findings presented here show that semaglutide modulated food preference, reduced food intake, and caused weight loss without decreasing energy expenditure. Semaglutide directly accessed the brainstem, septal nucleus, and hypothalamus but did not cross the blood-brain barrier; it interacted with the brain through the circumventricular organs and several select sites adjacent to the ventricles. Semaglutide induced central c-Fos activation in 10 brain areas, including hindbrain areas directly targeted by semaglutide, and secondary areas without direct GLP-1R interaction, such as the lateral parabrachial nucleus. Automated analysis of semaglutide access, c-Fos activity, GLP-1R distribution, and brain connectivity revealed that activation may involve meal termination controlled by neurons in the lateral parabrachial nucleus. Transcriptomic analysis of microdissected brain areas from semaglutide-treated rats showed upregulation of prolactin-releasing hormone and tyrosine hydroxylase in the area postrema. We suggest semaglutide lowers body weight by direct interaction with diverse GLP-1R populations and by directly and indirectly affecting the activity of neural pathways involved in food intake, reward, and energy expenditure.
| S-EPMC7213778 | biostudies-literature
Project description:PurposeType 1 diabetes is an autoimmune disease that often develops during childhood. Complications such as retinopathy often occur during the course of the disease. Studies to identify possible predictors of complications in type 1 diabetes are needed; in particular markers able to identify risk of complications long before they occur. The first aim of this study was to investigate plasma levels of sCD163, sST2 and Gal-3 at diagnosis of type 1 diabetes in children and adolescents. The second aim was to study their correlation to HbA1c in this study cohort.MethodsPatients (n = 242, 0-18 years) with type 1 diabetes, at Helsingborg's Hospital were included in this study and circulating levels of sCD163, sST2 and Gal-3 were investigated in plasma using commercially available DuoSet ELISA and supplementary ancillary kit.ResultsCirculating sCD163 was significantly higher at diagnosis compared to after diagnosis (666 ± 318ng/ml and 505 ± 223ng/ml respectively; p < 0.001). Also sST2 was significantly higher (18.2 [12.7-25.6] ng/ml respectively 9.1 [6.3-13.5] ng/ml (p < 0.001), but Gal-3 levels did not differ from onset of diabetes to after diagnosis. HbA1c was shown to correlate to sCD163 (rs=0.36; p < 0.001), sST2 (rs=0.22; p = 0.016) and Gal-3 (rs=0.2; p = 0.020) in patients with a diabetes duration < 5 years.ConclusionssCD163 levels increased in patients with recent-onset type 1 diabetes and the levels increased with higher HbA1c. Patients included in this study will be followed annually until the eventual development of diabetic complications, while continuously studying circulating levels of inflammatory proteins such as sCD163.
| S-EPMC9672210 | biostudies-literature
Project description:Improving diabetes self-management (DSM) is facing real-world challenges among people with type 2 diabetes mellitus (T2DM) who have a low education level in resource-limited areas. This study aimed to investigate whether diabetes knowledge could predict glycemic levels in people with T2DM in rural China. This analytical cross-sectional study recruited 321 people with T2DM from eight villages by purposive sampling at baseline. After 10 months, 206 patients completed the follow-up survey and HbA1c tests, with a response rate of 64.17% (206/321). Multiple regression analysis was employed to explore the correlation between diabetes knowledge and HbA1c levels. The patient's diabetes knowledge was significantly negatively correlated with HbA1c levels before and after controlling for covariates in both hierarchical multiple regression and multiple logistic regression (p < 0.01). In addition, other influencing factors, including sex, age, marital status, employment status, income, and HbA1c levels at baseline, were also identified. Diabetes knowledge could predict HbA1c levels significantly among patients with low education levels in rural China. Therefore, interventions on improving diabetes knowledge need to be strengthened for patients in rural China so that they can improve their health outcomes and reduce the disease burden.
| S-EPMC10600128 | biostudies-literature
Project description:BackgroundThis study was aimed to determine whether incident dementia and HbA1c levels are associated with increased rates of potentially preventable hospitalizations (PPHs) in persons with diabetes.MethodA total of 565 adults aged 65+ ever treated for diabetes were enrolled from Adult Changes in Thought study. PPHs were from principal discharge diagnoses and included diabetes PPH (dPPH), respiratory PPH (rPPH), urinovolemic PPH (uPPH), cardiovascular PPH, and other PPH. Poisson generalized estimating equations estimated rate ratios (RRs) and 95% confidence intervals (CIs) for the associations between dementia or HbA1c measures and rate of PPHs.ResultsA total of 562 individuals contributed 3 602 dementia-free years, and 132 individuals contributed 511 dementia follow-up years. One hundred twenty-eight (23%) dementia-free individuals had 210 PPH admissions and a crude rate of 58 per 1 000 person-years, while 55 (42%) individuals with dementia had 93 PPH admissions and a crude rate of 182 per 1 000 person-years. The adjusted RR (95% CI) comparing rates between dementia and dementia-free groups were 2.27 (1.60, 3.21) for overall PPH; 5.90 (2.70, 12.88) for dPPH; 5.17 (2.49, 10.73) for uPPH; and 2.01 (1.06, 3.83) for rPPH. Compared with HbA1c of 7%-8% and adjusted for dementia, the RR (95% CI) for overall PPH was 1.43 (1.00, 2.06) for >8% HbA1c and 1.18 (0.85, 1.65) for <7% HbA1c. The uPPH RR was also increased, comparing >8% and <7% HbA1c levels.ConclusionIncident dementia is associated with higher rates of PPHs among people with diabetes, especially PPHs due to diabetes, urinary tract infection (UTI), and dehydration. Potential evidence suggested that HbA1c levels of >8% versus lower levels are associated with higher rates of overall PPHs and UTI- and dehydration-related PPHs.
| S-EPMC8514059 | biostudies-literature
Project description:Objective:To evaluate variables associated with hemoglobin A1c (HbA1c) and weight reduction when adding liraglutide to persons with type 2 diabetes treated with multiple daily insulin injections (MDI). Research design and methods:This was a reanalysis of a previous trial where 124 patients were enrolled in a double-blind, placebo-controlled, multicenter randomized trial carried out over 24 weeks. Predictors for effect on change in HbA1c and weight were analyzed within the treatment group and with concurrent interaction analyses. Correlation analyses for change in HbA1c and weight from baseline to week 24 were made. Results:The mean age at baseline was 63.7 years, 64.8% were men, the mean number of insulin injections was 4.4 per day, the mean daily insulin dose was 105 units and the mean HbA1c was 74.5?mmol/mol (9.0%). The mean HbA1c and weight reductions were 12.3?mmol/mol (1.13%; P<0.001) and 3.8?kg (P<0.001) greater in liraglutide than placebo-treated persons. There was no significant predictor for greater effect on HbA1c that existed in all analyses (univariate, multivariate and interaction analyses against controls). For a greater weight reduction when adding liraglutide, a lower HbA1c level at baseline was a predictor (liraglutide group P=0.002, P=0.020 for liraglutide group vs placebo). During follow-up in the liraglutide group, no significant correlation was found between change in weight and change in HbA1c (r=0.09, P=0.46), whereas a correlation existed between weight and insulin dose reduction (r=0.44, P<0.001). Conclusion:Weight reduction becomes greater when adding liraglutide in patients with type 2 diabetes treated with MDI who had a lower HbA1c level compared with those with a higher HbA1c level. There was no correlation between reductions in HbA1c and weight when liraglutide was added, that is, different patient groups responded with HbA1c and weight reductions. Trial registration number:EudraCT nr: 2012-001941-42.
| S-EPMC5841497 | biostudies-literature
Project description:Canagliflozin, a sodium glucose co-transporter 2 inhibitor, reduces HbA1c, body weight and systolic BP (SBP) in patients with type 2 diabetes. As weight loss is known to reduce both HbA1c and SBP, these analyses were performed to evaluate the contribution of weight loss resulting from treatment with canagliflozin to HbA1c and SBP reductions in patients with type 2 diabetes.Pooled data from four placebo-controlled Phase 3 studies (N?=?2,250) in patients with type 2 diabetes were used in the analyses. In each study, patients were treated with placebo, canagliflozin 100 mg or canagliflozin 300 mg, once daily for 26 weeks. Changes from baseline in body weight, HbA1c and SBP were measured at week 26, and the contribution of weight loss to the lowering of HbA1c and SBP was obtained using ANCOVA.Canagliflozin 100 and 300 mg reduced mean body weight, HbA1c and SBP compared with placebo (p?<?0.001 for each), and more patients had body-weight reductions >0%, ?5% and ?10% with canagliflozin treatment than with placebo. Weight-loss-independent and weight-loss-associated mechanisms contributed to HbA1c and SBP lowering with canagliflozin: ~85% of HbA1c lowering and ~60% of SBP lowering was independent of weight loss.In patients with type 2 diabetes, canagliflozin provided clinically meaningful body-weight reductions, and the weight loss contributed to reductions in HbA1c and SBP.
| S-EPMC4800739 | biostudies-literature