Diabetes, Obesity & Metabolism最新文献

Aim: The study aimed to assess the impact of varying degrees of initial serum sodium change among patients with type 2 diabetes (T2D) starting sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapy and their subsequent clinical outcome.

Methods: We used medical data from a multicentre health care provider in Taiwan and recruited 4400 patients with T2D with baseline normal serum sodium (135-145 mmol/L) and follow-up serum sodium measures available after 3 months of SGLT2i treatment from 1 June 2016 to 31 December 2021.

Results: After a median of 2.9 (2.4, 3.4) months of SGLT2i treatment, overall, there was a minimal change in serum sodium levels (from 139.6 ± 2.4 to 139.5 ± 3.7 mmol/L). Most patients (87.8%) maintained normal sodium levels, while 8.6% (n = 378) experienced hyponatraemia (<135 mmol/L) and 3.6% (n = 158) hypernatraemia (>145 mmol/L). Factors independently associated with hyponatraemia included cancer history, chronic lung disease, insulin use, higher glycated haemoglobin, impaired liver function, lower baseline sodium and greater initial decline in kidney function. Conversely, factors linked to hypernatraemia included older age, absence of cancer history, loop diuretic and non-steroidal anti-inflammatory drug use, higher baseline sodium and a lesser initial decline in kidney function. Over a median of 26.0 months of follow-up, hyponatraemia shortly after starting SGLT2i therapy was associated with significantly increased risks of major adverse cardiovascular events [hazard ratio (HR): 2.52; 95% confidence interval (CI): 1.83-3.48], heart failure for hospitalization (HR: 1.66; 95% CI: 1.16-2.37), major adverse renal events (HR: 2.27; 95% CI: 1.73-2.96) and all-cause death (HR: 2.98; 95% CI: 2.17-4.11) after adjusting for clinically relevant factors. Non-linear analysis indicated that a more pronounced initial decline in serum sodium levels correlated steeply with higher risks of these adverse events.

Conclusion: While most patients with T2D maintain stable serum sodium homeostasis on SGLT2i therapy, a subset may experience dysnatraemic events with potential worse clinical consequences. Physicians should be vigilant about monitoring sodium levels and considering the associated risks when initiating SGLT2i therapy in patients with risk.

Aims: Type 2 diabetes (T2D) and its complications disproportionally affect American Indian and Alaska Native (AI/AN) peoples. Prescribing decisions for anti-diabetic medications are complicated and require balancing medication benefits, costs and side effects. Little is known about trends in anti-diabetic medication use as well as acute diabetes complications among AI/AN adults. Here, we examined patterns and trends in anti-diabetic medication use and rates of hospital admissions or emergency department (ED) visits due to severe hypoglycaemia and hyperglycaemia among AI/AN adults with T2D.

Materials and methods: We conducted a retrospective analysis of Indian Health Service (IHS) Improving Health Care Delivery Data Project. A total of 39 183 AI/AN adults aged ≥18 years with T2D who used IHS or Tribal health services during any of the fiscal years (FYs) 2009-2013 were included. Utilization rates of each class of anti-diabetic medications and rates of severe hypoglycaemia and severe hyperglycaemia in emergency room and/or inpatient discharge diagnoses were calculated for each year. Longitudinal statistical models were fitted to examine time trends of anti-diabetic medication use and complications.

Results: During 2009-2013, use of metformin (56.0%-60.5%), insulin (31.4%-35.9%) and dipeptidyl peptidase-4 inhibitors (1.4%-9.0%) increased, whereas the use of sulfonylureas (40.3%-32.9%) and thiazolidinediones (TZDs, 31.6%-8.8%) decreased significantly. Trends in severe hypoglycaemia (1.6%-0.8%) and severe hyperglycaemia (2.0%-1.6%) declined gradually.

Conclusions: There were significant changes in the utilization of different anti-diabetic medication classes during 2009-2013 among AI/AN adults with T2D. Concurrently, there were significant reductions in severe hypoglycaemia and severe hyperglycaemia.

Aims: This study aims to determine whether postpartum body mass index (BMI) trajectories and its time in target range (TTR) are associated with long-term type 2 diabetes risk in women with a history of gestational diabetes mellitus (GDM).

Materials and methods: The present study included 1057 women with a history of GDM who participated in the Tianjin Gestational Diabetes Mellitus Prevention Program (TGDMPP). Oral glucose tolerance tests or physician-diagnosed information were used to diagnose type 2 diabetes after a median follow-up period of 8.47 years. Latent class modelling was applied to identify trajectories of BMI after delivery. TTR was defined as the proportion of time that BMI was within the standard range (18.5 ≤ BMI < 24.0 kg/m²). The associations of BMI trajectories and TTR with type 2 diabetes risk were analysed using multivariable Cox modelling.

Results: Five distinct trajectories of postpartum BMI were identified. Compared with low-stable class, the multivariable-adjusted hazard ratios of type 2 diabetes were 2.02 (95% confidence interval 0.99-4.10) for median-stable class, 3.01 (1.17-7.73) for high-stable class, 2.15 (0.63-7.38) for U-shape class and 7.15 (2.08-24.5) for inverse U-shape class (p for trend = 0.012), respectively. Multivariable-adjusted hazard ratios of type 2 diabetes associated with postpartum BMI TTR of 100%, >43.4%-<100%, >0%-≤43.4% and 0% were 1.00, 1.84 (0.72-4.73), 2.75 (1.23-6.15) and 2.31 (1.05-5.08) (p for trend = 0.039), respectively.

Conclusions: Postpartum BMI trajectories of high-stable and inverse U-shape class as well as lower TTR were associated with an increased risk of type 2 diabetes among women with a history of GDM. Reducing BMI to a normal range in the early postpartum period and maintaining stable over time could attenuate the development of long-term type 2 diabetes.

Aims: Life expectancy is reduced in people with obesity and is further reduced in those with concomitant type 2 diabetes. The aim of the study was to assess whether a 2-year delay in diabetes development influences life expectancy in people with obesity.

Materials and methods: Participants from the Swedish Obese Subjects study without diabetes at baseline and known diabetes status at the 2-year follow-up were included: bariatric surgery (n = 1471) and usual obesity care (n = 1392). Median follow-up was 26.1 years (interquartile range: 22.7-28.7 years). The Swedish Cause of Death Register, case sheets and autopsy reports were assessed to determine the direct cause of death. Analyses were adjusted for preselected risk factors: inclusion year, sex, baseline age, body mass index (BMI) and smoking.

Results: Across both study arms, 146 participants were newly diagnosed with type 2 diabetes at the 2-year examination, whereas 2717 remained diabetes-free. Most participants diagnosed with diabetes (n = 140) were from the usual care control group. During the follow-up, there were 18.3 deaths per 1000 person-years (95% confidence interval [CI]:14.1-23.9) in the group with diagnosed diabetes at the 2-year follow-up and 10.9 deaths per 1000 person-years (95% CI:10.2-11.8) in the group that remained diabetes-free (adjusted hazard ratio [HRadj] 1.60, 95% CI: 1.19-2.15, p = 0.002). The adjusted median life expectancy in the diabetes group was 3.7 years (95% CI: 1.4-6.0, p = 0.002) shorter than in the diabetes-free group. Specifically, cardiovascular mortality was higher in the group with diabetes (adj sub-hazard ratio [sub-HR] 1.74 [95% CI: 1.09-2.77], p = 0.021).

Conclusions: A 2-year delay in diabetes development may be linked to increased life expectancy, possibly due to a reduction in cardiovascular mortality. Future studies should confirm these findings.

Aim: We conducted a multicentre, randomized phase 3 trial in China to evaluate the efficacy and safety of cofrogliptin (HSK7653), a novel long-acting dipeptidyl peptidase-4 inhibitor, in patients with drug-naïve type 2 diabetes (T2D).

Materials and methods: Patients with inadequately controlled T2D were randomly assigned (1:1:1) to cofrogliptin 10 mg, cofrogliptin 25 mg or placebo, taken orally once every 2 weeks for a 24-week double-blind period. Eligible patients then received cofrogliptin 25 mg in a 28-week open-label extension. The primary endpoint was the change in glycated haemoglobin (HbA_1c) from baseline to week 24.

Results: In total, 475 patients (median age: 54.0 years) were randomized and received at least one dose of cofrogliptin 10 mg (n = 158), cofrogliptin 25 mg (n = 158) or placebo (n = 159); 401 patients entered the open-label extension. At week 24, the least-squares (LS) mean difference (95% confidence interval [CI]) in HbA_1c versus placebo was -0.63% (-0.81, -0.46) with cofrogliptin 10 mg and -0.59% (-0.77, -0.42) with cofrogliptin 25 mg (both p < 0.0001). The LS mean (standard error) change in HbA_1c from baseline was maintained at the end of the study in patients given open-label cofrogliptin 25 mg for an additional 28 weeks: cofrogliptin 10 mg: -0.86% (0.07); cofrogliptin 25 mg: -0.74% (0.07); placebo: -0.89% (0.07). Over the entire study, common adverse events were hyperuricaemia, hyperlipidaemia, hypertriglyceridaemia, increased lipase, upper respiratory tract infection and urinary tract infection. Hypoglycaemic events did not significantly differ between groups.

Conclusions: Cofrogliptin provided glycaemic control over 52 weeks and was generally well tolerated in patients with T2D.

Clinical trial registration: Registered on Clinicaltrials.gov with the registration number NCT04556851 (https://clinicaltrials.gov/study/NCT04556851).

Aim: To compare cardiorenal outcomes of dipeptidyl peptidase-4 inhibitors (DPP-4is) and sodium-glucose co-transporter-2 inhibitors (SGLT-2is) in a national diabetic kidney disease (DKD) population.

Methods: A cohort study was conducted using Taiwan's National Health Insurance Research Database and Laboratory Databases. Propensity score-matched prevalent new users of SGLT-2is (n = 1524) and DPP-4is (n = 6005) during 2017-2018 were selected from adults with DKD and an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73m². Composite renal outcomes included sustained eGFR decrease, renal failure and renal mortality. Composite cardiovascular (CV) outcomes included acute myocardial infarction, stroke, hospitalization for heart failure and CV death. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: Compared with DPP-4i users, SGLT-2i users had a reduced risk of composite renal endpoint (HR: 0.16; CI: 0.12-0.24), consistently for a prolonged time to 50% or higher eGFR decrease (HR 0.17; CI: 0.11-0.27), renal failure (HR: 0.14; CI: 0.08-0.23) and decreased renal death (HR: 0.10; CI: 0.01-0.70). SGLT-2i users had a better composite CV outcome than DPP-4i users (HR: 0.74; CI: 0.64-0.85), and lower risks of stroke (HR: 0.76; CI: 0.62-0.92) and hospitalization for heart failure (HR: 0.68; CI: 0.55-0.84). Findings were consistent in analyses stratified by concomitant antidiabetic agents or intervals between DKD diagnosis and study drug initiation.

Conclusions: This study shows the superior cardiorenal benefits of SGLT-2is compared with DPP-4is in the DKD population, regardless of concomitant antidiabetic agents or time from DKD onset to study drug initiation. SGLT-2is should be prioritized in adult patients with DKD.

Aim: To evaluate the effectiveness and safety of insulin glargine 300 U/mL (Gla-300) initiation according to diabetes duration (DD).

Materials and methods: We analysed patient-level data from 2381 insulin-naïve individuals with type 2 diabetes (T2D), of whom 2349 (98.7%) were treated with Gla-300 for 24 weeks. Of the 2381 participants, 1048 (44.0%) had a DD of less than 8 years and 1333 (56.0%) had a DD of 8 years or longer. We further analysed the subgroups of participants having a DD of less than 4 years (N = 450), 4-8 years (N = 598), 8-12 years (N = 627) and 12 years or longer (N = 706).

Results: Mean ± standard deviation age was 60.2 ± 9.0 years in participants with a DD less than 8 years and 64.2 ± 8.8 years in those with a DD of 8 years or longer. At 24 weeks of Gla-300 therapy, HbA1c improved with a least-squares (LS) mean change from baseline of -1.88% (95% confidence interval [CI], -1.95 to -1.80) and -1.71% (95% CI, -1.77 to -1.65), respectively, resulting in a LS mean difference between groups of 0.17% (95% CI, 0.07 to 0.26; P = .0005). In the subgroup analysis, LS mean HbA1c reduction from baseline to week 24 was highest in participants with a DD of less than 4 years and lowest in participants with a DD of 12 years or longer. Overall, incidences of symptomatic and severe hypoglycaemia were low, irrespective of DD, without body weight changes.

Conclusions: Gla-300 was effective and safe in insulin-naïve individuals with T2D, regardless of DD. Improvement in HbA1c was greater when Gla-300 was initiated in participants with a DD of less than 4 years, although the difference between the groups was modest.

Aim: The aim was to study the effect of two low-calorie, high-protein (HP) diets, with most of the protein coming from animal or plant sources, on glycaemic and other cardiometabolic outcomes in subjects with overweight or obesity and glucose metabolism disorders.

Materials and methods: A total of 117 participants aged >18 years with body mass index over 27.5 kg/m² and prediabetes or type 2 diabetes mellitus (T2DM) were randomized to one of two HP low-calorie diets (35% of total calories from protein), in which 75% of the protein was from either plant-based sources (HPP) or animal sources (HPA). For both diets, 30% and 35% of the total calories were from fat and carbohydrates, respectively. The dietary intervention lasted 6 months.

Results: Both diets improved body composition to a similar extent, including weight loss (-8.05 ± 5.12 kg for the HPA diet and -7.70 ± 5.47 kg for the HPP diet at 6 months) and fat mass, mainly visceral fat. Both diets had a similar beneficial effect on glucose metabolism, including fasting glucose, insulin, homeostasis model assessment of insulin resistance index and glycated haemoglobin. Other biochemical parameters, including lipid profiles, liver enzymes, adipokines and inflammatory biomarkers, similarly improved in both groups. Fasting incretins, mainly glucagon-like peptide 1, decreased significantly in both groups, and this effect correlated with weight loss.

Conclusions: Low-calorie HP diets improved body composition, glucose metabolism and other cardiometabolic outcomes, regardless of protein source (either animal or plant sources), in outpatients with prediabetes or T2DM.

Clinical trial registration: The clinical trial was registered in ClinicalTrials.gov (identifier: NCT05456347) https://clinicaltrials.gov/study/NCT05456347?term=NCT05456347&rank=1.

Aim: The aim was to investigate the effects of lotiglipron, a once-daily, oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist, in participants with type 2 diabetes (T2D) or obesity.

Materials and methods: A phase 2, randomized, double-blind, placebo-controlled, dose-ranging study investigated the efficacy and safety of lotiglipron. The study was terminated early for safety reasons after routine data and monitoring review. The planned analyses for the end points were modified prior to unblinding the study.

Results: In total, 901 participants were treated with at least one dose of the study drug (T2D cohort: n = 512, obesity cohort: n = 389). Although the majority of participants who were randomly assigned to higher doses did not reach their target maintenance dose, statistically significant changes in HbA1c and body weight were observed. In the T2D cohort, reductions in HbA1c were observed across all lotiglipron doses at week 16 (p < 0.0001), with least squares mean decreases up to -1.44% (90% confidence interval [CI]: -1.63, -1.26) (lotiglipron 80 mg), versus placebo, -0.07% (90% CI: -0.25, 0.11). In the obesity cohort, decreases in body weight were observed across all lotiglipron doses at week 20 (p < 0.01), up to -7.47% (90% CI: -8.50, -6.43) (lotiglipron 200 mg, five-step titration), versus placebo, -1.84% (90% CI: -2.85, -0.83). Across cohorts, the most frequently reported treatment-emergent adverse events were gastrointestinal related (most mild to moderate severity), with nausea being the most common (ranging from 4% [placebo] to 28.8% [80 mg] in the T2D cohort and 12.5% [placebo] to 60.6% [200 mg, four-step titration] in the obesity cohort). Transaminase elevations were observed in a subset of participants (6.6% and 6.0% of participants on lotiglipron in the T2D and obesity cohorts, respectively, compared with 1.6% on placebo in the obesity cohort).

Conclusions: The efficacy (HbA1c and/or body weight) of a range of lotiglipron doses was demonstrated in T2D and obesity cohorts. The safety profile was largely consistent with what has been previously known about the mechanism of action. Our results are unique in reporting elevations in liver transaminases in a subset of participants treated with lotiglipron, with attempts to identify the at-risk population unsuccessful and therefore clinical development of lotiglipron terminated.

Clinicaltrials: GOV: NCT05579977.