Diabetes, Obesity & Metabolism最新文献

Aims: Most type 2 diabetes (T2D) studies have predominantly enrolled White people aged <65 years. This retrospective study evaluated outcomes for iGlarLixi (fixed-ratio combination [FRC] of insulin glargine 100 U/mL and lixisenatide) versus basal-bolus or premixed insulin in African American, Asian and Hispanic adults with T2D aged ≥65 years.

Methods: Medicare claims data were assessed from beneficiaries receiving basal insulin who newly initiated iGlarLixi, basal-bolus insulin, or premixed insulin between 7/1/2019 and 12/30/2021. Groups were propensity score matched at baseline and followed for up to 12 months. Endpoints (primary: treatment persistence; secondary: treatment adherence, hypoglycaemia event rates, healthcare resource utilisation) were assessed using multivariable regression.

Results: Treatment persistence was higher for iGlarLixi versus basal-bolus or premixed insulin in the overall population (26.9%, 7.6%, 18.9%; adjusted p < 0.0001) and numerically higher in all ethnic subgroups. Treatment adherence was numerically higher for iGlarLixi versus basal-bolus or premixed insulin in the overall population (28.0%, 8.0%, 19.0%) and in all subgroups. Hypoglycaemia event rates were numerically lower for iGlarLixi versus basal-bolus insulin or premixed insulin in the overall population (2.5, 3.8, 7.5/100 person-years' follow-up) and in all subgroups except Asians receiving basal-bolus insulin. All-cause and diabetes-related hospitalisation and emergency department visit event rates were lower with iGlarLixi versus basal-bolus insulin or premixed insulin in the overall population, and in all subgroups except for hospitalisations in Hispanics.

Conclusion: FRC therapies such as iGlarLixi represent an appropriate treatment option when intensifying basal insulin therapy in ethnic minority older adults with T2D.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-Like peptide-1 receptor agonists (GLP-1 RA) are recommended in people with type 2 diabetes (T2D) for glycaemic control and for people with high cardiovascular risk. However, current guidelines do not specifically address the role of initial early combination therapy with SGLT2i and GLP-1 RA or dual gastric inhibitory polypeptide (GIP)/GLP-1 RA, but rather sequential initiation with either in T2D. This review synthesizes the available evidence on the use of SGLT2i and GLP-1-based therapies for T2D and provides a rationale for their combination. The combination of SGLT2i with GLP-1-based therapies addresses complementary pathophysiological mechanisms and enhances efficacy in achieving target haemoglobin A1C (HbA1c) levels. SGLT2i and GLP-1 RA also have been shown to prevent complications of T2D. While both classes reduce adverse cardiorenal events, SGLT2i has a predominant effect on prevention of kidney dysfunction and heart failure, whereas GLP-1 RA has a more marked effect on the risk of atherosclerotic cardiovascular disease. Both drug classes have favourable safety profiles. Finally, weight loss with combination therapy may have disease-modifying effects that may reverse T2D progression. We propose that the combination of SGLT2i with GLP-1 RA or dual GIP/GLP-1 RA should be considered for most patients with T2D who do not have contraindications.

Aims: The SURMOUNT-1 trial investigated effects of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, on body weight in participants with obesity or overweight. This analysis evaluated changes in patient-reported outcomes (PROs) assessing physical function, psychosocial well-being, and overall health aspects of participants' health-related quality of life (HRQoL) in SURMOUNT-1.

Methods: PRO instruments included the Impact of Weight on Quality of Life-Lite Clinical Trials version (IWQOL-Lite-CT), Short Form Survey-36 version 2 (SF-36v2) and EQ-5D-5L. Scores were analysed by treatment group and by categorical degree of weight reduction group: >0 to <5%, ≥5 to <10%, ≥10 to <20% and ≥20%. Relevant PROs were evaluated for participants with or without physical or psychosocial limitations at baseline, as measured by Patient Global Impression of Status for physical activity (PGIS) and Patient Health Questionnaire-2 (PHQ-2), respectively.

Results: All tirzepatide groups demonstrated significant improvements in PRO scores versus placebo. There was a consistent trend of incremental PRO improvement with greater degrees of weight reduction, starting from ≥5% weight reduction. Participants achieving ≥20% weight reduction demonstrated the greatest changes from baseline to week 72 (SF-36v2 Physical Component Summary, 4.60; SF-36v2 Mental Component Summary, 0.80; IWQOL-Lite CT Total score, 24.7). Those with baseline physical and psychosocial limitations experienced greater improvements than those without.

Conclusions: Tirzepatide treatment was associated with improved HRQoL compared to placebo in people with overweight or obesity. Higher percentages of weight reduction were associated with greater improvements. Clinical trial registration number for SURMOUNT-1: NCT04184622.

Background: The presence of low-grade inflammation has been reported in people with type 2 diabetes and related to the development of (macro)vascular complications. Whether systemic inflammation is present in type 1 diabetes and linked to long-term complications remains unknown. We used a targeted proteomics approach to compare inflammation in people with type 1 diabetes and type 2 diabetes with control subjects and linked these proteins to diabetes related characteristics and complications.

Methods: We included 233 participants with type 1 diabetes, 387 participants with type 2 diabetes and 150 healthy controls. Plasma was collected and used to determine high sensitive C-reactive proteins (hs-CRP) and an additional 92 inflammatory proteins using the Olink proteomics platform.

Results: Compared to healthy controls, 41 circulating inflammatory proteins were higher in type 1 diabetes (FDR < 0.05) and 64 inflammatory proteins in type 2 diabetes (FDR < 0.05) (including CXCL5, IL-15RA, MCP-4 and AXIN1 for both groups). HbA_1c levels were positively associated with 21 inflammatory proteins (including CDCP1, FGF-21, HGF and IL-18R1) in type 1 diabetes (FDR < 0.05), whereas a positive association existed between body mass index (BMI) and 26 inflammatory proteins (including IL6, IL17C, FGF-23 and CSF-1) in type 2 diabetes. Inflammatory proteins associated with the presences, of complications, particularly nephropathy, were similar in both type 1 and type 2 diabetes. FlT3L and EN-RAGE were associated with the development of cardiovascular disease (CVD) in type 2 diabetes.

Conclusions: Both type 1 diabetes and type 2 diabetes are associated with increased circulating inflammatory protein concentrations, but the increase is more pronounced in type 2 diabetes. These results suggest both differences in drivers of inflammation between type 1 diabetes and type 2 diabetes as well as potential similarities in pathways involved in the development of diabetes-associated complications.

Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity increases risk of cardiovascular disease. This cohort study examines the prognostic value of MASLD, across body weight categories, in a secondary preventative acute myocardial infarction (AMI) cohort.

Methods: Patients with AMI were stratified into four phenotypes-obesity MASLD, non-obesity MASLD, obesity non-MASLD, non-obesity non-MASLD. The primary outcome was all-cause mortality. Cox regression analysis was performed to investigate determinants of long-term all-cause mortality.

Results: Of 5702 patients, majority were in the non-obesity non-MASLD group (66.7%), followed by obesity MASLD (16.1%), non-obesity MASLD (11.2%) and non-obesity MASLD (6.0%). Across the four phenotypes, obesity MASLD had the highest cardiometabolic burden, followed by non-obesity MASLD. Non-obesity MASLD had the highest risk of heart failure (p = 0.034), cardiogenic shock (p < 0.001), and all-cause long-term mortality (p = 0.019). The non-obesity MASLD (HR 1.400, 95%CI 1.077-1.820, p = 0.012) and obesity MASLD phenotypes (HR 1.222, 95%CI 1.005-1.485, p = 0.044) were independently associated with long-term all-cause mortality.

Conclusions: Obesity and non-obesity MASLD phenotypes were predictors of all-cause mortality following AMI, with an even larger magnitude of mortality risk in the non-obesity MASLD group. The recognition of MASLD and its body weight phenotypes will be beneficial in the prognostication following AMI.

Background: Chronic inflammation is a key factor in type 2 diabetes mellitus (T2DM) development. The cholinergic anti-inflammatory pathway (CAP) reduces inflammation by activating α7 nicotinic acetylcholine receptors (α7nAChRs) on macrophages, suppressing proinflammatory cytokines. Acetylcholinesterase inhibitors (AChEis), primarily used for Alzheimer's disease (AD), may exert anti-inflammatory effects through the CAP. One AChEi, galantamine, also directly agonizes α7nAChRs, potentially enhancing its anti-inflammatory properties.

Objective: This study aimed to investigate the association between AChEi use, particularly galantamine, and T2DM risk in AD patients.

Methods: We conducted a retrospective analysis of Veterans Health Administration (VA) data, examining early- and late-onset AD patients receiving galantamine or other AD medications. Propensity score matching was used to balance groups and minimize confounding. Cox proportional hazard models assessed T2DM risk for galantamine, other AChEis and memantine.

Results: A total of 40 065 AD patients were included in the study. Among early-onset AD patients, galantamine use significantly reduced T2DM risk (hazard ratio [HR] = 0.80, 95% confidence interval [CI]: 0.66-0.98). Memantine also showed a protective effect (HR = 0.82, 95% CI: 0.69-1) in this group. Neither galantamine nor memantine influenced T2DM risk in late-onset AD. Other AD medications showed no association with T2DM risk.

Conclusion: Galantamine use was associated with a lower risk of T2DM in early-onset AD patients, potentially due to enhanced anti-inflammatory effects through both AChE inhibition and direct α7nAChR agonism. Memantine also demonstrated a protective effect. These findings suggest potential new applications for existing AD medications in T2DM prevention, particularly in early-onset AD patients. Further research, including randomized controlled trials with diverse populations, is needed to confirm these results and the underlying mechanisms.

Aims: Imeglimin is a new oral anti-diabetic drug with a similar structure to that of metformin; however, unlike metformin, clinical trials indicate that imeglimin elicits its glucose-lowering effect mainly by enhancement of insulin secretion. The comparative effects of the two drugs on incretin secretion remains to be elucidated.

Materials and methods: A single-center, open-label, randomized controlled trial was conducted in patients with type 2 diabetes who were drug-naïve or were on a single oral hypoglycaemic agent (OHA). For patients taking a single OHA, an 8-week washout period was employed before randomization. Participants were randomized to the imeglimin group (IME, 2000 mg/day) or the metformin group (MET, 1000 mg/day), and OGTT was performed before treatment and after 12 and 24 weeks of treatment.

Results: The reduction in HbA1c at 24 weeks was similar in IME and MET. OGTT revealed a comparable decrease in post-challenge blood glucose excursion in both groups, but insulin levels were increased only in IME. Total and active glucagon-like peptide-1 (GLP-1) levels were increased in both IME and MET; however, total and active glucose-dependent insulinotropic peptide (GIP) levels were increased only in IME. Interestingly, while an increase in insulin levels in IME was positively correlated with an increase in GLP-1 at 12 weeks, it was correlated only with an increase in GIP at 24 weeks.

Conclusions: Unlike metformin, imeglimin enhances GIP secretion as well as GLP-1 secretion, in addition to its direct insulinotropic mechanism of glucose control, emphasizing its potential as a therapeutic option in the treatment of patients with diabetes.

Aims: Weight loss mediated by glucagon-like peptide-1 (GLP-1) analogues is lower in patients with type 2 diabetes versus those without. Type 2 diabetes and obesity are risk factors for metabolic dysfunction-associated steatotic liver disease (MASLD) and associated steatohepatitis (MASH). We evaluated weight changes in adults with MASLD/MASH with or without type 2 diabetes receiving the GLP-1 analogue semaglutide.

Materials and methods: This was a post hoc analysis of data from three 48-72-week randomised trials investigating the effect of semaglutide versus placebo in adults with MASLD (NCT03357380) or biopsy-confirmed MASH (NCT02970942 and NCT03987451). Pooled data for semaglutide (0.4 mg once daily and 2.4 mg once weekly [n = 163]) and placebo (n = 137) were analysed at 1 year. Weight changes were analysed by type 2 diabetes status (type 2 diabetes [n = 209], pre-type 2 diabetes [n = 51] and no diabetes [n = 40]) and by other cardiometabolic risk parameters using analysis of covariance and Spearman's rank correlations.

Results: The overall mean weight change was -11.1 kg (-11.7%) and -0.7 kg (-0.6%) with semaglutide and placebo, respectively. While numerically higher for people without type 2 diabetes, estimated treatment differences with semaglutide versus placebo were similar overall for people with type 2 diabetes (-10.2 kg; -10.8%), pre-type 2 diabetes (-9.8 kg; -10.2%) and no diabetes (-11.6 kg; -13.1%). Differences between groups were not statistically significant (p > 0.50 for all). Baseline fasting plasma glucose, glycated haemoglobin, insulin levels, insulin resistance and lipids did not correlate with weight change.

Conclusions: People with MASLD/MASH had similar semaglutide-mediated weight loss regardless of type 2 diabetes status and other cardiometabolic risk parameters.

Aims: Fibroblast growth factor 21 (FGF21) decreases hepatic lipogenesis in animal models, and FGF21 analogues decrease serum triglycerides (TG) in adults in phase-2 trials. On the other hand, serum FGF21 is associated with higher TG in observational studies of people with obesity, raising a sort of paradox. We tested the hypothesis that FGF21 is induced by TG in youth with obesity, as a compensatory mechanism.

Materials and methods: We recruited 159 children/adolescents with obesity (80 males, 12.7 ± 2.1 years). Besides serum FGF21 and lipid dosages, we genotyped the Pro446Leu variant at glucokinase regulator (GCKR) as a known marker of genetically increased hepatic de novo lipogenesis, and we used it as an instrumental variable to establish a cause-and-effect relationship between FGF21 and TG, according to a Mendelian randomization analysis.

Results: The Pro446Leu variant increased circulating TG (β = +0.35, p < 0.001), which was positively associated with circulating FGF21 (β = +0.42, p < 0.001). The Pro446Leu variant increased FGF-21 (β = +0.14, p = 0.031) with the expected slope (β-coefficient) in case of association entirely mediated by TG: 0.35 (slope between Pro446Ala and TG) × 0.42 (slope between TG and FGF21) = 0.14.

Conclusions: Hepatic lipogenesis, marked by GCKR-modulated triglycerides, is significantly associated with increased serum FGF-21 in children/adolescents with obesity.