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AIMS/HYPOTHESIS: This study compares the efficacy and safety of a tubeless, on-body automated insulin delivery (AID) system with that of a tubeless, on-body sensor-augmented pump (SAP). METHODS: This multicentre, parallel-group, RCT was conducted at 13 tertiary medical centres in South Korea. Adults aged 19-69 years with type 1 diabetes who had HbA1c levels of <85.8 mmol/mol (<10.0%) were eligible. The participants were assigned at a 1:1 ratio to receive a tubeless, on-body AID system (intervention group) or a tubeless, on-body SAP (control group) for 12 weeks. Stratified block randomisation was conducted by an independent statistician. Blinding was not possible due to the nature of the intervention. The primary outcome was the percentage of time in range (TIR), blood glucose between 3.9 and 10.0 mmol/l, as measured by continuous glucose monitoring. ANCOVAs were conducted with baseline values and study centres as covariates. RESULTS: A total of 104 participants underwent randomisation, with 53 in the intervention group and 51 in the control group. The mean (±SD) age of the participants was 40±11 years. The mean (±SD) TIR increased from 62.1±17.1% at baseline to 71.5±10.7% over the 12 week trial period in the intervention group and from 64.7±17.0% to 66.9±15.0% in the control group (difference between the adjusted means: 6.5% [95% CI 3.6%, 9.4%], p<0.001). Time below range, time above range, CV and mean glucose levels were also significantly better in the intervention group compared with the control group. HbA1c decreased from 50.9±9.9 mmol/mol (6.8±0.9%) at baseline to 45.9±7.4 mmol/mol (6.4±0.7%) after 12 weeks in the intervention group and from 48.7±9.1 mmol/mol (6.6±0.8%) to 45.7±7.5 mmol/mol (6.3±0.7%) in the control group (difference between the adjusted means: -0.7 mmol/mol [95% CI -2.0, 0.8 mmol/mol] (-0.1% [95% CI -0.2%, 0.1%]), p=0.366). No diabetic ketoacidosis or severe hypoglycaemia events occurred in either group. CONCLUSIONS/INTERPRETATION: The use of a tubeless, on-body AID system was safe and associated with superior glycaemic profiles, including TIR, time below range, time above range and CV, than the use of a tubeless, on-body SAP. TRIAL REGISTRATION: Clinical Research Information Service (CRIS) KCT0008398 FUNDING: The study was funded by a grant from the Korea Medical Device Development Fund supported by the Ministry of Science and ICT; the Ministry of Trade, Industry and Energy; the Ministry of Health and Welfare; and the Ministry of Food and Drug Safety (grant number: RS-2020-KD000056).
Subject(s)
Blood Glucose , Diabetes Mellitus, Type 1 , Hypoglycemic Agents , Insulin Infusion Systems , Insulin , Humans , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/blood , Male , Middle Aged , Adult , Female , Insulin/administration & dosage , Insulin/therapeutic use , Blood Glucose/drug effects , Blood Glucose/metabolism , Blood Glucose/analysis , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/therapeutic use , Aged , Glycated Hemoglobin/metabolism , Glycated Hemoglobin/analysis , Republic of Korea , Blood Glucose Self-Monitoring/methods , Young AdultABSTRACT
AIM: To evaluate the efficacy and tolerability of an initial triple combination therapy (TCT) compared with conventional stepwise add-on therapy (SAT) in patients with newly diagnosed type 2 diabetes (T2D). MATERIALS AND METHODS: This multicentre, randomized, 104-week, open-label trial randomized 105 patients with drug-naïve T2D (with HbA1c level ≥ 8.0%, < 11.0%) to the TCT (1000 mg of metformin, 10 mg of dapagliflozin and 5 mg of saxagliptin once daily) or SAT (initiated with metformin, followed by glimepiride and sitagliptin) groups. The primary outcome was the proportion of patients who achieved an HbA1c level of less than 6.5% without hypoglycaemia, weight gain of 5% or higher, or discontinuation of drugs because of adverse events at week 104. RESULTS: HbA1c reduction from baseline at week 104 was similar between the groups (the least squares mean change was -2.56% in the TCT group vs. -2.75% in the SAT group). The primary outcome was achieved in 39.0% and 17.1% of the TCT and SAT groups, respectively, with a risk difference of 22.0 (95% confidence interval 3.0, 40.8; P = .027). HbA1c level less than 6.5% at week 104 was 46.3% in both the TCT and SAT groups, whereas the incidence of hypoglycaemia, weight gain, or discontinuation of drugs was 16.7% and 62.0% in the TCT and SAT groups, respectively (P < .001). TCT was well-tolerated and had fewer adverse events than SAT. CONCLUSIONS: Among newly diagnosed patients with T2D, initial TCT effectively lowered HbA1c levels with higher tolerability and safety than SAT for 104 weeks, suggesting a novel strategy for initial combination therapy in T2D patients.
Subject(s)
Adamantane , Benzhydryl Compounds , Diabetes Mellitus, Type 2 , Dipeptides , Drug Therapy, Combination , Glucosides , Glycated Hemoglobin , Hypoglycemic Agents , Metformin , Humans , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/blood , Metformin/therapeutic use , Metformin/administration & dosage , Metformin/adverse effects , Glucosides/administration & dosage , Glucosides/adverse effects , Glucosides/therapeutic use , Male , Female , Benzhydryl Compounds/therapeutic use , Benzhydryl Compounds/administration & dosage , Benzhydryl Compounds/adverse effects , Middle Aged , Dipeptides/adverse effects , Dipeptides/administration & dosage , Dipeptides/therapeutic use , Adamantane/analogs & derivatives , Adamantane/administration & dosage , Adamantane/adverse effects , Adamantane/therapeutic use , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/therapeutic use , Hypoglycemic Agents/adverse effects , Glycated Hemoglobin/analysis , Glycated Hemoglobin/metabolism , Aged , Treatment Outcome , Hypoglycemia/chemically induced , Sulfonylurea Compounds/therapeutic use , Sulfonylurea Compounds/administration & dosage , Sulfonylurea Compounds/adverse effects , Blood Glucose/drug effects , Blood Glucose/metabolism , Adult , Weight Gain/drug effects , Sitagliptin Phosphate/therapeutic use , Sitagliptin Phosphate/administration & dosage , Sitagliptin Phosphate/adverse effectsABSTRACT
AIMS: To evaluate the long-term safety and efficacy of enavogliflozin monotherapy (0.3 mg/day) in individuals with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Following a 24-week randomized, double-blind treatment period with enavogliflozin 0.3 mg/day (n = 77) or placebo (n = 69), consenting participants received enavogliflozin 0.3 mg/day for an additional 28 weeks during an open-label extension (OLE) period. The safety and efficacy of enavogliflozin were assessed at Week 52. RESULTS: A total of 37 participants continued enavogliflozin (maintenance group), and 26 participants switched from placebo to enavogliflozin (switch group). No additional adverse drug reactions related to enavogliflozin were observed during the OLE period. At Week 52, glycated haemoglobin (HbA1c) and fasting plasma glucose were significantly lower than at the baseline, by 0.9% and 24.9 mg/dL, respectively, in the maintenance group (p < 0.0001 for both), and by 0.7% and 18.0 mg/dL, respectively, in the switch group (p < 0.0001 and p = 0.002). The proportions of participants reaching HbA1c 7.0% (53 mmol/mol) at Week 52 were 69.4% in the maintenance group and 65.4% in the switch group. A significant increase in urine glucose-to-creatinine ratio was observed at Week 52, by 84.9 g/g and 67.1 g/g in the maintenance and switch groups, respectively (p < 0.0001 for both). Body weight in both groups decreased significantly (p < 0.0001) from baseline to Week 52, by 3.5 kg and 3.8 kg in the maintenance and switch groups, respectively. CONCLUSIONS: Enavogliflozin 0.3 mg monotherapy provides long-term glycaemic control in T2DM and is safe and well tolerated during a 52-week treatment period.
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BACKGROUND: The predictive relationship between mild-to-moderate alcohol consumption and the risk of incident atrial fibrillation (AF) remains controversial. OBJECTIVE: We investigated whether the relationship between alcohol consumption and the risk of incident AF could be associated with the genetic predisposition to alcohol metabolism. METHODS: A total of 399,329 subjects with genetic data from the UK Biobank database, enrolled between 2006 and 2010, were identified and followed for incident AF until 2021. Genetic predisposition to alcohol metabolism was stratified according to the polygenic risk score (PRS) tertiles. Alcohol consumption was categorized as non-drinkers, mild-to-moderate drinkers (< 30 g/day), and heavy drinkers (≥ 30 g/day). RESULTS: During the follow-up (median 12.2 years), 19,237 cases of AF occurred. When stratified by PRS tertiles, there was a significant relationship between genetic predisposition to alcohol metabolism and actual alcohol consumption habits (P < 0.001). Mild-to-moderate drinkers showed a decreased risk of AF (HR 0.96, 95% CI 0.92-0.99), and heavy drinkers showed an increased risk of AF (HR 1.06, 95% CI 1.02-1.10) compared to non-drinkers. When stratified according to PRS tertiles for genetic predisposition to alcohol metabolism, mild-to-moderate drinkers had equivalent AF risks, and heavy drinkers showed increased AF risk in the low PRS tertile group. However, mild-to-moderate drinkers had decreased AF risks and heavy drinkers showed similar risks of AF in the middle/high PRS tertile groups. CONCLUSIONS: Differential associations between alcohol consumption habits and incident AF across genetic predisposition to alcohol metabolism were observed; individuals with genetic predisposition to low alcohol metabolism were more susceptible to AF.
Subject(s)
Atrial Fibrillation , Humans , Atrial Fibrillation/epidemiology , Atrial Fibrillation/genetics , Cohort Studies , Risk Factors , UK Biobank , Biological Specimen Banks , Alcohol Drinking/adverse effects , Alcohol Drinking/epidemiology , Alcohol Drinking/genetics , Genetic Predisposition to DiseaseABSTRACT
Joint modelling of genetic and environmental risk factors can provide important information to predict the risk of type 2 diabetes (T2D). Therefore, to predict the genetic risk of T2D, we constructed a polygenic risk score (PRS) using genotype data of one Korean cohort, KARE (745 cases and 2549 controls), and the genome-wide association study summary statistics of Biobank Japan. We evaluated the performance of PRS in an independent Korean cohort, HEXA (5684 cases and 35,703 controls). Individuals with T2D had a significantly higher mean PRS than controls (0.492 vs. - 0.078, p ≈ 0 ). PRS predicted the risk of T2D with an AUC of 0.658 (95% CI 0.651-0.666). We also evaluated interaction between PRS and waist circumference (WC) in the HEXA cohort. PRS exhibited a significant sub-multiplicative interaction with WC (ORinteraction 0.991, 95% CI 0.987-0.995, pinteraction = 4.93 × 10-6) in T2D. The effect of WC on T2D decreased as PRS increased. The sex-specific analyses produced similar interaction results, revealing a decreased WC effect on T2D as the PRS increased. In conclusion, the risk of WC for T2D may differ depending on PRS and those with a high PRS might develop T2D with a lower WC threshold. Our findings are expected to improve risk prediction for T2D and facilitate the identification of individuals at an increased risk of T2D.
Subject(s)
Diabetes Mellitus, Type 2 , Male , Female , Humans , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/genetics , Genetic Risk Score , Genome-Wide Association Study , Risk Factors , Republic of Korea/epidemiology , Genetic Predisposition to DiseaseABSTRACT
Background: Identifying risk factors for postpartum type 2 diabetes in women with gestational diabetes mellitus (GDM) is crucial for effective interventions. We examined whether changes in insulin sensitivity after delivery affects the risk of type 2 diabetes in women with GDM. Methods: This prospective cohort study included 347 women with GDM or gestational impaired glucose tolerance, who attended the follow-up visits at 2 months postpartum and annually thereafter. Changes in insulin sensitivity were calculated using the Matsuda index at GDM diagnosis and at 2 months postpartum (ΔMatsuda index). After excluding women with pregestational diabetes or those followed up only once, we analyzed the risk of postpartum type 2 diabetes based on the ΔMatsuda index tertiles. Results: The incidence of type 2 diabetes at the two-month postpartum visit decreased with increasing ΔMatsuda index tertiles (16.4%, 9.5%, and 1.8%, P=0.001). During a 4.1-year follow-up, 26 out of 230 women who attended more than two follow-up visits (11.3%) developed type 2 diabetes. Compared to the lowest tertile, subjects in the highest ΔMatsuda index tertile showed a significantly reduced risk of type 2 diabetes (hazard ratio, 0.33; 95% confidence interval, 0.12 to 0.93; P=0.036) after adjusting for confounders. Conclusion: Improvement in insulin sensitivity after delivery is associated with a reduced risk of postpartum type 2 diabetes in women with GDM. Postpartum changes in insulin sensitivity could be a useful prediction for future type 2 diabetes development in women with GDM.
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OBJECTIVE: Obesity is a key predictor of type 2 diabetes (T2D). However, metabolic complications are not solely due to increased BMI. We hypothesized that differences between genetically predicted BMI and observed BMI (BMI-diff) could reflect deviation from individual set point and may predict incident T2D. RESEARCH DESIGN AND METHODS: From the UK Biobank cohort, we selected participants of European ancestry without T2D (n = 332,154). The polygenic risk score for BMI was calculated via Bayesian regression and continuous shrinkage priors (PRS-CS). According to the BMI-diff, the 10-year risk of T2D was assessed using multivariable Cox proportional hazards model. Independent data from the Korean Genome and Epidemiology Study (KoGES) cohort from South Korea (n = 7,430) were used for replication. RESULTS: Participants from the UK Biobank were divided into train (n = 268,041) and test set (n = 115,119) to establish genetically predicted BMI. In the test set, the genetically predicted BMI explained 7.1% of the variance of BMI, and there were 3,599 T2D cases (3.1%) during a 10-year follow-up. Participants in the higher quintiles of BMI-diff (more obese than genetically predicted) had significantly higher risk of T2D than those in the lowest quintile after adjusting for observed BMI: the adjusted hazard ratio of the 1st quintile (vs. 5th quintile) was 1.61 (95% CI, 1.26-2.05, P < 0.001). Results were consistent among individuals in the KoGES study. Moreover, higher BMI than predicted was associated with impaired insulin sensitivity. CONCLUSIONS: Having a higher BMI than genetically predicted is associated with an increased risk of T2D. These findings underscore the potential to reassess T2D risk based on individual levels of obesity using genetic thresholds for BMI.
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The clinical utility of a type 2 diabetes mellitus (T2DM) polygenic risk score (PRS) in the East Asian population remains underexplored. We aimed to examine the potential prognostic value of a T2DM PRS and assess its viability as a clinical instrument. We first established a T2DM PRS for 5490 Korean individuals using East Asian Biobank data (269,487 samples). Subsequently, we assessed the predictive capability of this T2DM PRS in a prospective longitudinal study with baseline data and data from seven additional follow-ups. Our analysis showed that the T2DM PRS could predict the transition of glucose tolerance stages from normal glucose tolerance to prediabetes and from prediabetes to T2DM. Moreover, T2DM patients in the top-decile PRS group were more likely to be treated with insulin (hazard ratio = 1.69, p value = 2.31E-02) than were those in the remaining PRS groups. T2DM PRS values were significantly high in the severe diabetes subgroup, characterized by insulin resistance and ß -cell dysfunction (p value = 0.0012). The prediction models with the T2DM PRS had significantly greater Harrel's C-indices than did corresponding models without it. By utilizing prospective longitudinal study data and extensive clinical risk factor information, our analysis provides valuable insights into the multifaceted clinical utility of the T2DM PRS.
Subject(s)
Diabetes Mellitus, Type 2 , Prediabetic State , Humans , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/genetics , Prediabetic State/epidemiology , Prediabetic State/genetics , Prospective Studies , Genetic Risk Score , Clinical Relevance , Longitudinal Studies , Blood Glucose/analysis , Risk Factors , Republic of Korea/epidemiologyABSTRACT
OBJECTIVE: While most genetic variants of type 2 diabetes (T2D) are suggested to be associated with ß-cell dysfunction cross sectionally, their association with the longitudinal change of ß-cell function remains largely unknown. RESEARCH DESIGN AND METHODS: We analyzed data from 6,311 participants without T2D at baseline (mean [SD] age 51.6 [8.7] years) from a community-based prospective cohort in Korea. Participants underwent biennial 2-h 75-g oral glucose tolerance tests (OGTTs) during 14 years of follow-up, and the OGTT-derived disposition index (DI) was used as a marker for ß-cell function. Genetic risk was quantified using the genome-wide polygenic risk score (PRS) and was stratified into low (1st quintile), intermediate (2nd-4th quintiles), and high (5th quintile) genetic risk. Lifestyle was assessed according to Life's Essential 8. RESULTS: During a mean follow-up of 10.9 years, 374 (29.6%), 851 (22.5%), and 188 (14.9%) participants developed T2D in the high, intermediate, and low genetic risk groups, respectively. Compared with the low genetic risk group, participants in the high genetic risk group had a 25% lower DI at baseline. Furthermore, in longitudinal analysis, we observed a 1.83-fold faster decline in log2-transformed DI per year (-0.034 vs. -0.019, P = 2.1 × 10-3; per 1-SD increase in T2D PRS, P = 1.2 × 10-4). Healthy lifestyle attenuated the rate of decline in DI across all genetic risk groups. CONCLUSIONS: Individuals with a higher genetic risk for T2D exhibited not only a lower OGTT-derived ß-cell function at baseline but also a notably more rapid decline during follow-up. This information could be used to enable a focused precision prevention with lifestyle intervention.
Subject(s)
Diabetes Mellitus, Type 2 , Insulin-Secreting Cells , Humans , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/epidemiology , Insulin-Secreting Cells/physiology , Middle Aged , Male , Female , Adult , Glucose Tolerance Test , Asian People/genetics , Genetic Predisposition to Disease , Prospective Studies , Risk Factors , East Asian PeopleABSTRACT
Maternally inherited diabetes and deafness (MIDD) is a rare mitochondrial disorder primarily resulting from m.3243A>G mutation. The clinical characteristics of MIDD exhibit significant heterogeneity. Our study aims to delineate these characteristics and determine the potential correlation with m.3243A>G heteroplasmy levels. This retrospective, descriptive study encompassed patients with confirmed m.3243A>G mutation and diabetes mellitus at Seoul National University Hospital. Our cohort comprises 40 patients with MIDD, with a mean age at study enrollment of 33.3±12.9 years and an average % of heteroplasmy of 30.0%± 14.6% in the peripheral blood. The most prevalent comorbidity was hearing loss (90%), followed by albuminuria (61%), seizure (38%), and stroke (33%). We observed a significant negative correlation between % of heteroplasmy and age at diabetes diagnosis. These clinical features can aid in the suspicion of MIDD and further consideration of genetic testing for m.3243A>G mutation.
Subject(s)
DNA, Mitochondrial , Deafness , Mitochondrial Diseases , Mutation , Humans , Female , Male , DNA, Mitochondrial/genetics , Retrospective Studies , Adult , Republic of Korea/epidemiology , Mitochondrial Diseases/genetics , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/epidemiology , Middle Aged , Deafness/genetics , Young Adult , Diabetes Mellitus/genetics , Diabetes Mellitus/epidemiology , Adolescent , Heteroplasmy , Hearing Loss/genetics , Diabetes Mellitus, Type 2ABSTRACT
OBJECTIVE: Women with a history of gestational diabetes mellitus (GDM) are at increased risk of developing type 2 diabetes (T2D). It remains unclear whether genetic information improves prediction of incident T2D in these women. RESEARCH DESIGN AND METHODS: Using five independent cohorts representing four different ancestries (n = 1,895), we investigated whether a genome-wide T2D polygenic risk score (PRS) is associated with increased risk of incident T2D. We also calculated the area under the receiver operating characteristics curve (AUROC) and continuous net reclassification improvement (NRI) following the incorporation of T2D PRS into clinical risk models to assess the diagnostic utility. RESULTS: Among 1,895 women with previous history of GDM, 363 (19.2%) developed T2D in a range of 2 to 30 years. T2D PRS was higher in those who developed T2D (-0.08 vs. 0.31, P = 2.3 × 10-11) and was associated with an increased risk of incident T2D (odds ratio 1.52 per 1-SD increase, 95% CI 1.05-2.21, P = 0.03). In a model that includes age, family history of diabetes, systolic blood pressure, and BMI, the incorporation of PRS led to an increase in AUROC for T2D from 0.71 to 0.74 and an intermediate improvement of NRI (0.32, 95% CI 0.15-0.49, P = 3.0 × 10-4). Although there was variation, a similar trend was observed across study cohorts. CONCLUSIONS: In cohorts of GDM women with diverse ancestry, T2D PRS was significantly associated with future development of T2D. A significant but small improvement was observed in AUROC when T2D PRS was integrated into clinical risk models to predict incident T2D.
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BACKGROUND: The association between alcohol consumption and the risk of sudden cardiac death and/or fatal ventricular arrhythmia remains controversial. OBJECTIVE: We analyzed the association between alcohol consumption, genetic traits for alcohol metabolism, and the risk of sudden cardiac death and/or fatal ventricular arrhythmia. METHODS: We identified 397,164 individuals enrolled between 2006 and 2010 from the UK Biobank database and followed them until 2021. Alcohol consumption was categorized as current nondrinkers (nondrinkers and ex-drinkers), mild drinkers, moderate drinkers, or heavy drinkers. Genetic traits of alcohol metabolism were stratified according to the polygenic risk score tertiles. The primary and secondary outcomes were a composite of sudden cardiac death and fatal ventricular arrhythmia as well as their individual components. RESULTS: During follow-up (median 12.5 years), 3543 cases (0.89%) of clinical outcomes occurred. Although mild, moderate, and heavy drinkers showed deceased risks of outcomes compared with current nondrinkers, there was no prognostic difference among nondrinkers, mild drinkers, moderate drinkers, and heavy drinkers. Ex-drinkers showed an increased risk in univariate analysis, but the significance was attenuated after adjusting covariates (hazard ratio 1.19; 95% confidence interval 0.94-1.50). As a continuous variable, alcohol consumption was not associated with clinical outcomes (hazard ratio 1.01; 95% confidence interval 0.99-1.02). Consistent with these findings, there was no association between genetic traits for alcohol metabolism and the risk of clinical outcomes. CONCLUSION: Alcohol consumption was neither a protective factor nor a risk factor for sudden cardiac death or fatal ventricular arrhythmia. Genetic traits of alcohol metabolism were not associated with the clinical prognosis.
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PURPOSE: The purpose of this study was to determine the efficacy and safety profile of pioglitazone compared with placebo (PBO) in patients with type 2 diabetes (T2D) inadequately controlled with metformin and dapagliflozin. METHODS: In this prospective, multicenter, randomized, double-blind, PBO-controlled trial, 366 patients with T2D who did not meet glycemic targets (7.0% ≤ glycosylated hemoglobin [HbA1c] ≤ 10.5%), despite treatment with metformin ≥1000 mg and dapagliflozin 10 mg, received either a PBO, 15 mg of pioglitazone daily (PIO15), or 30 mg of pioglitazone daily (PIO30). The primary end point was the mean change in HbA1c from baseline at 24 weeks across the groups. FINDINGS: For the 366 participants (PBO, n = 124; PIO15, n = 118; PIO30, n = 124), the mean age was 55.6 years and mean duration of diabetes was 8.7 years, with a baseline HbA1c of 7.9%. After 24 weeks, HbA1c reduced significantly in the PIO15 and PIO30 groups from baseline, with intergroup differences of -0.38% and -0.83%, respectively, compared with the PBO group. The proportion of patients with HbA1c levels <7% was significantly higher in the PIO15 and PIO30 groups than in the PBO group. The adverse event rates did not significantly differ across the groups, indicating favorable safety profiles for triple combination therapy using metformin, dapagliflozin, and pioglitazone. IMPLICATIONS: The addition of pioglitazone as a third oral antidiabetic medication is an appropriate option for patients with T2D inadequately controlled with metformin and dapagliflozin based on the resulting significant efficacy in glycemic control and favorable safety profile. CLINICALTRIALS: gov identifier: NCT04885712.
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The prevalence of youth-onset type 2 diabetes (T2D) and childhood obesity has been rising steadily1, producing a growing public health concern1 that disproportionately affects minority groups2. The genetic basis of youth-onset T2D and its relationship to other forms of diabetes are unclear3. Here we report a detailed genetic characterization of youth-onset T2D by analysing exome sequences and common variant associations for 3,005 individuals with youth-onset T2D and 9,777 adult control participants matched for ancestry, including both males and females. We identify monogenic diabetes variants in 2.4% of individuals and three exome-wide significant (P < 2.6 × 10-6) gene-level associations (HNF1A, MC4R, ATXN2L). Furthermore, we report rare variant association enrichments within 25 gene sets related to obesity, monogenic diabetes and ß-cell function. Many youth-onset T2D associations are shared with adult-onset T2D, but genetic risk factors of all frequencies-and rare variants in particular-are enriched within youth-onset T2D cases (5.0-fold increase in the rare variant and 3.4-fold increase in common variant genetic liability relative to adult-onset cases). The clinical presentation of participants with youth-onset T2D is influenced in part by the frequency of genetic risk factors within each individual. These findings portray youth-onset T2D as a heterogeneous disease situated on a spectrum between monogenic diabetes and adult-onset T2D.
Subject(s)
Diabetes Mellitus, Type 2 , Pediatric Obesity , Male , Adult , Female , Humans , Adolescent , Child , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/genetics , Exome , Genome-Wide Association Study , BiologyABSTRACT
OBJECTIVE: To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD. RESULTS: Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, hazard ratio [HR] 1.23, P = 3.6 × 10-9), rs77142250 (near HS3ST1, HR 1.89, P = 9.9 × 10-9), and rs335407 (near TFB1M/NOX3, HR 1.25, P = 1.5 × 10-8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison-adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P = 1.0 × 10-16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Genome-Wide Association Study , Humans , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/complications , Cardiovascular Diseases/genetics , Cardiovascular Diseases/epidemiology , Female , Male , Middle Aged , Aged , Polymorphism, Single NucleotideABSTRACT
Background: Atherogenic dyslipidemia, which is frequently associated with type 2 diabetes (T2D) and insulin resistance, contributes to the development of vascular complications. Statin therapy is the primary approach to dyslipidemia management in T2D, however, the role of non-statin therapy remains unclear. Ezetimibe reduces cholesterol burden by inhibiting intestinal cholesterol absorption. Fibrates lower triglyceride levels and increase high-density lipoprotein cholesterol (HDL-C) levels via peroxisome proliferator- activated receptor alpha agonism. Therefore, when combined, these drugs effectively lower non-HDL-C levels. Despite this, few clinical trials have specifically targeted non-HDL-C, and the efficacy of triple combination therapies, including statins, ezetimibe, and fibrates, has yet to be determined. Methods: This is a multicenter, prospective, randomized, open-label, active-comparator controlled trial involving 3,958 eligible participants with T2D, cardiovascular risk factors, and elevated non-HDL-C (≥100 mg/dL). Participants, already on moderate-intensity statins, will be randomly assigned to either Ezefeno (ezetimibe/fenofibrate) addition or statin dose-escalation. The primary end point is the development of a composite of major adverse cardiovascular and diabetic microvascular events over 48 months. Conclusion: This trial aims to assess whether combining statins, ezetimibe, and fenofibrate is as effective as, or possibly superior to, statin monotherapy intensification in lowering cardiovascular and microvascular disease risk for patients with T2D. This could propose a novel therapeutic approach for managing dyslipidemia in T2D.
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BACKGROUND: Perinatal outcomes vary for women with gestational diabetes mellitus (GDM). The precise factors beyond glycemic status that may refine GDM diagnosis remain unclear. We conducted a systematic review and meta-analysis of potential precision markers for GDM. METHODS: Systematic literature searches were performed in PubMed and EMBASE from inception to March 2022 for studies comparing perinatal outcomes among women with GDM. We searched for precision markers in the following categories: maternal anthropometrics, clinical/sociocultural factors, non-glycemic biochemical markers, genetics/genomics or other -omics, and fetal biometry. We conducted post-hoc meta-analyses of a subset of studies with data on the association of maternal body mass index (BMI, kg/m2) with offspring macrosomia or large-for-gestational age (LGA). RESULTS: A total of 5905 titles/abstracts were screened, 775 full-texts reviewed, and 137 studies synthesized. Maternal anthropometrics were the most frequent risk marker. Meta-analysis demonstrated that women with GDM and overweight/obesity vs. GDM with normal range BMI are at higher risk of offspring macrosomia (13 studies [n = 28,763]; odds ratio [OR] 2.65; 95% Confidence Interval [CI] 1.91, 3.68), and LGA (10 studies [n = 20,070]; OR 2.23; 95% CI 2.00, 2.49). Lipids and insulin resistance/secretion indices were the most studied non-glycemic biochemical markers, with increased triglycerides and insulin resistance generally associated with greater risk of offspring macrosomia or LGA. Studies evaluating other markers had inconsistent findings as to whether they could be used as precision markers. CONCLUSIONS: Maternal overweight/obesity is associated with greater risk of offspring macrosomia or LGA in women with GDM. Pregnancy insulin resistance or hypertriglyceridemia may be useful in GDM risk stratification. Future studies examining non-glycemic biochemical, genetic, other -omic, or sociocultural precision markers among women with GDM are warranted.
Gestational Diabetes (GDM) is high blood sugar that develops during pregnancy and may cause complications. GDM diagnosis is centered on blood sugar levels. Despite everyone receiving standard treatment, the clinical outcomes may vary from one individual to another. This indicates a need to identify factors that may help GDM diagnosis and result in improved classification of those at greatest risk for complications. Here, we systematically analyzed all published evidence for potential markers that could identify those with GDM who have greater risk of complications. We find that high maternal weight is a risk factor for offspring born larger for their gestational age. Other promising markers were identified, but further analysis is needed before they can be applied in the clinic.