Type 2 Diabetes Subtype Responsive to ACCORD Intensive Glycemia Treatment

Objective Current type 2 diabetes (T2D) management contraindicates intensive glycemia treatment in patients with high cardiovascular disease (CVD) risk, and is partially motivated by evidence of harms in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Heterogeneity in response to intensive glycemia treatment has been observed, suggesting potential benefit for some individuals. Research Design and Methods ACCORD was a randomized controlled trial that investigated whether intensively treating glycemia in individuals with T2D reduced CVD outcomes. Using a novel approach to cluster HbA1c trajectories, we identified groups in the intensive glycemia arm with modified CVD risk. Genome-wide analysis and polygenic score (PS) were developed to predict group membership. Mendelian randomization was performed to infer causality. Results We identified four clinical groupings in the intensive glycemia arm, and clinical group 4 (C4) displayed fewer CVD outcomes (HR=0.34, P=2.01x10-3) and microvascular outcomes (HR=0.86, P=.015) than standard treatment. A single nucleotide polymorphism, rs220721, in MAS1, reached suggestive significance with C4 (P=4.34x10-7). The PS predicted C4 with high accuracy (AUC=0.98), and predicted C4 displayed reduced CVD risk on intensive versus standard glycemia treatment (HR=0.53, P=4.02x10-6), but not for microvascular outcomes (P<.05). Mendelian randomization indicated causality between the PS, on-trial HbA1c, and reduction in CVD outcomes (P<.05). Conclusions We found evidence of a T2D clinical group in ACCORD that benefited from intensive glycemia treatment, and membership of this group can be predicted using genetic variants. This study generates new hypotheses with implications for precision medicine in T2D and represents an important development for this landmark clinical trial warranting further investigation.

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Type 2 Diabetes Subtype Responsive to ACCORD Intensive Glycemia Treatment

10.2337/figshare.14109806 ◽

2021 ◽

Author(s):

Arshiya Mariam ◽

Galen Miller-Atkins ◽

Kevin M. Pantalone ◽

Robert S. Zimmerman ◽

John Barnard ◽

...

Keyword(s):

Type 2 Diabetes ◽

Mendelian Randomization ◽

Controlled Trial ◽

Clinical Group ◽

Cvd Risk ◽

Group 4 ◽

Novel Approach ◽

Genome Wide ◽

Design And Methods

Objective Current type 2 diabetes (T2D) management contraindicates intensive glycemia treatment in patients with high cardiovascular disease (CVD) risk, and is partially motivated by evidence of harms in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Heterogeneity in response to intensive glycemia treatment has been observed, suggesting potential benefit for some individuals. Research Design and Methods ACCORD was a randomized controlled trial that investigated whether intensively treating glycemia in individuals with T2D reduced CVD outcomes. Using a novel approach to cluster HbA1c trajectories, we identified groups in the intensive glycemia arm with modified CVD risk. Genome-wide analysis and polygenic score (PS) were developed to predict group membership. Mendelian randomization was performed to infer causality. Results We identified four clinical groupings in the intensive glycemia arm, and clinical group 4 (C4) displayed fewer CVD outcomes (HR=0.34, P=2.01x10-3) and microvascular outcomes (HR=0.86, P=.015) than standard treatment. A single nucleotide polymorphism, rs220721, in MAS1, reached suggestive significance with C4 (P=4.34x10-7). The PS predicted C4 with high accuracy (AUC=0.98), and predicted C4 displayed reduced CVD risk on intensive versus standard glycemia treatment (HR=0.53, P=4.02x10-6), but not for microvascular outcomes (P<.05). Mendelian randomization indicated causality between the PS, on-trial HbA1c, and reduction in CVD outcomes (P<.05). Conclusions We found evidence of a T2D clinical group in ACCORD that benefited from intensive glycemia treatment, and membership of this group can be predicted using genetic variants. This study generates new hypotheses with implications for precision medicine in T2D and represents an important development for this landmark clinical trial warranting further investigation.

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Plasma vitamin C and type 2 diabetes: genome-wide association study and Mendelian randomization analysis in European populations

10.2337/figshare.13105559.v1 ◽

2020 ◽

Author(s):

Ju-Sheng Zheng ◽

Jian’an Luan ◽

Eleni Sofianopoulou ◽

Fumiaki Imamura ◽

Isobel D Stewart ◽

...

Keyword(s):

Type 2 Diabetes ◽

Vitamin C ◽

Mendelian Randomization ◽

Genome Wide Association ◽

European Ancestry ◽

Plasma Vitamin ◽

Genome Wide Association Studies ◽

Genome Wide ◽

European Populations

Objective Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes. Research Design and Methods We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted difference in plasma vitamin C with type 2 diabetes in up-to 80,983 cases and 842,909 non-cases. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 cases and 11,073 non-cases. Results We identified 11 genomic regions associated with plasma vitamin C (p<5×10-8), with the strongest signal at SLC23A1, and 10 novel genetic loci including SLC23A3, CHPT1, BCAS3, SNRPF, RER1, MAF, GSTA5, RGS14, AKT1 and FADS1. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per standard deviation, 0.88, 95%CI: 0.82, 0.94), <a>but there was no association between genetically predicted plasma vitamin C (excluding FADS1 variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03, 95%CI: 0.96, 1.10)</a>. Conclusions <a>These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of</a> vitamin C supplementation for type 2 diabetes prevention.

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Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations

Diabetes Care ◽

10.2337/dc20-1328 ◽

2020 ◽

Vol 44 (1) ◽

pp. 98-106

Author(s):

Ju-Sheng Zheng ◽

Jian’an Luan ◽

Eleni Sofianopoulou ◽

Fumiaki Imamura ◽

Isobel D. Stewart ◽

...

Keyword(s):

Type 2 Diabetes ◽

Vitamin C ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Genome Wide Association ◽

Plasma Vitamin ◽

Genome Wide ◽

Randomization Analysis ◽

European Populations

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Effect of psychotherapy for depression via home telehealth on glycemic control in adults with type 2 diabetes: Subgroup analysis of a randomized clinical trial

Journal of Telemedicine and Telecare ◽

10.1177/1357633x17730419 ◽

2017 ◽

Vol 24 (9) ◽

pp. 596-602 ◽

Cited By ~ 5

Author(s):

Leonard E Egede ◽

Rebekah J Walker ◽

Elizabeth H Payne ◽

Rebecca G Knapp ◽

Ronald Acierno ◽

...

Keyword(s):

Type 2 Diabetes ◽

Older Adults ◽

Glycemic Control ◽

Subgroup Analysis ◽

Repeated Measures ◽

Controlled Trial ◽

Treatment Groups ◽

Design And Methods ◽

The Impact

Objective We evaluated the impact of telemedicine-delivered behaviour activation treatment (BAT) on glycemic control in a subgroup of older adults with diabetes who participated in a randomized controlled trial for depression. Research design and methods We randomized older adults with major depression to same-room or telemedicine BAT. Each group received eight weekly sessions. For the subgroup analysis, we identified individuals with type 2 diabetes and obtained hemoglobin A1c at baseline and 12 months’ follow-up. We used mixed-effects models (MEM) for repeated measures analysis to compare the longitudinal mean A1c. We estimated model-derived mean A1c values and considered an adjusted model to account for baseline health status. Results We included 90 individuals with type 2 diabetes of the original 241 in the subgroup analysis (43 in telemedicine and 47 in same room). Treatment groups were not significantly different at baseline for demographics, depression, anxiety or A1c levels (telemedicine 6.9 vs. same room 7.3, p = 0.19). Baseline mean A1c for the telemedicine group remained at 6.9 (55 mmol/mol) at 12 months, whereas baseline mean A1c for the same-room group increased to 7.7 (61 mmol/mol). Longitudinal trajectories of model-derived mean A1c indicated a significant main effect of treatment group on mean A1c value at study end (difference = −0.82, 95% CI −1.41, −0.24). Adjusted analyses gave comparable results. Conclusions Telemedicine-delivered BAT was superior to same room in achieving lower mean A1c values in participants with type 2 diabetes, suggesting BAT-delivered via telemedicine is a viable treatment option for adults with diabetes.

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OpT2mise: A Randomized Controlled Trial to Compare Insulin Pump Therapy with Multiple Daily Injections in the Treatment of Type 2 Diabetes—Research Design and Methods

Diabetes Technology & Therapeutics ◽

10.1089/dia.2013.0363 ◽

2014 ◽

Vol 16 (7) ◽

pp. 414-420 ◽

Cited By ~ 13

Author(s):

Ronnie Aronson ◽

Ohad Cohen ◽

Ignacio Conget ◽

Sarah Runzis ◽

Javier Castaneda ◽

...

Keyword(s):

Type 2 Diabetes ◽

Randomized Controlled Trial ◽

Insulin Pump ◽

Controlled Trial ◽

Insulin Pump Therapy ◽

Diabetes Research ◽

Pump Therapy ◽

Randomized Controlled ◽

Design And Methods

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Efficacy and Safety of Dulaglutide 3.0 mg and 4.5 mg Versus Dulaglutide 1.5 mg in Metformin-Treated Patients With Type 2 Diabetes in a Randomized Controlled Trial (AWARD-11)

10.2337/figshare.13315403.v1 ◽

2021 ◽

Author(s):

Juan P. Frias ◽

Enzo Bonora ◽

Luis Nevarez Ruiz ◽

Ying G. Li ◽

Zhuoxin Yu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Body Weight ◽

Treatment Regimen ◽

Rescue Medication ◽

Controlled Trial ◽

Primary Objective ◽

Efficacy And Safety ◽

Relevant Dose ◽

Design And Methods

Objective: To compare efficacy and safety of dulaglutide at doses of 3.0 and 4.5 mg versus 1.5 mg in patients with type 2 diabetes inadequately controlled with metformin. Research Design and Methods: Patients were randomized to once weekly dulaglutide 1.5 mg, 3.0 mg, or 4.5 mg for 52 weeks. Primary objective was superiority of dulaglutide 3.0 mg and/or 4.5 mg over 1.5 mg in HbA1c reduction at 36 weeks. Secondary superiority objectives included change in body weight. Two estimands addressed efficacy objectives: treatment-regimen estimand (regardless of treatment discontinuation or rescue medication) and efficacy estimand (on treatment without rescue medication) in all randomized patients. Results: Mean baseline HbA1c and BMI in randomized patients (N=1842) was 8.6% (70 mmol/mol) and 34.2 kg/m2, respectively. At 36 weeks, dulaglutide 4.5 mg provided superior HbA1c reductions compared to 1.5 mg (treatment-regimen estimand: -1.77 vs ‑1.54% [-19.4 vs -16.8 mmol/mol], estimated treatment difference [ETD] -0.24% (-2.6 mmol/mol); P<0.001; efficacy estimand: -1.87 vs ‑1.53% [‑20.4 vs -16.7 mmol/mol], ETD -0.34% (-3.7 mmol/mol); P<0.001). Dulaglutide 3.0 mg was superior to 1.5 mg on HbA1c reduction using the efficacy estimand (ETD -0.17% [-1.9 mmol/mol]; P=0.003) but not the treatment-regimen estimand (ETD -0.10% [-1.1 mmol/mol ]; P=0.096). Dulaglutide 4.5 mg was superior to 1.5 mg for weight loss at 36 weeks for both estimands (treatment-regimen estimand: -4.6 vs -3.0 kg, ETD -1.6 kg; P<0.001; efficacy estimand: -4.7 vs -3.1 kg; ETD -1.6 kg; P<0.001). Common adverse events through 36 weeks included nausea (1.5 mg, 13.4%; 3 mg, 15.6%; 4.5 mg, 16.4%) and vomiting (1.5 mg, 5.6%; 3 mg, 8.3%; 4.5 mg, 9.3%). Conclusion: In patients with type 2 diabetes inadequately controlled on metformin, escalation from dulaglutide 1.5 mg to 3.0 mg or 4.5 mg provided clinically relevant, dose-related reductions in HbA1c and body weight with a similar safety profile.

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The putative causal effect of type 2 diabetes in risk of cataract: a Mendelian randomization study in East Asian

10.1101/2021.02.08.430342 ◽

2021 ◽

Author(s):

Haoyang Zhang ◽

Xuehao Xiu ◽

Angli Xue ◽

Yuedong Yang ◽

Yuanhao Yang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Genetic Correlation ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Population Based ◽

P Value ◽

Genome Wide Association Studies ◽

Genome Wide

AbstractBackgroundThe epidemiological association between type 2 diabetes and cataract has been well-established. However, it remains unclear whether the two diseases share a genetic basis, and if so, whether this reflects a causal relationship.MethodsWe utilized East Asian population-based genome-wide association studies (GWAS) summary statistics of type 2 diabetes (Ncase=36,614, Ncontrol=155,150) and cataract (Ncase=24,622, Ncontrol=187,831) to comprehensively investigate the shared genetics between the two diseases. We performed 1. linkage disequilibrium score regression (LDSC) and heritability estimation from summary statistics (ρ-HESS) to estimate the genetic correlation and local genetic correlation between type 2 diabetes and cataract; 2. multiple Mendelian randomization (MR) analyses to infer the putative causality between type 2 diabetes and cataract; and 3. Summary-data-based Mendelian randomization (SMR) to identify candidate risk genes underling the causality.ResultsWe observed a strong genetic correlation (rg=0.58; p-value=5.60×10−6) between type 2 diabetes and cataract. Both ρ-HESS and multiple MR methods consistently showed a putative causal effect of type 2 diabetes on cataract, with estimated liability-scale MR odds ratios (ORs) at around 1.10 (95% confidence interval [CI] ranging from 1.06 to 1.17). In contrast, no evidence supports a causal effect of cataract on type 2 diabetes. SMR analysis identified two novel genes MIR4453HG (βSMR=−0.34, p-value=6.41×10−8) and KCNK17 (βSMR=−0.07, p-value=2.49×10−10), whose expression levels were likely involved in the putative causality of type 2 diabetes on cataract.ConclusionsOur results provided robust evidence supporting a causal effect of type 2 diabetes on the risk of cataract in East Asians, and posed new paths on guiding prevention and early-stage diagnosis of cataract in type 2 diabetes patients.Key MessagesWe utilized genome-wide association studies of type 2 diabetes and cataract in a large Japanese population-based cohort and find a strong genetic overlap underlying the two diseases.We performed multiple Mendelian randomization models and consistently disclosed a putative causal effect of type 2 diabetes on the development of cataract.We revealed two candidate genes MIR4453HG and KCNK17 whose expression levelss are likely relevant to the causality between type 2 diabetes and cataract.Our study provided theoretical fundament at the genetic level for improving early diagnosis, prevention and treatment of cataract in type 2 diabetes patients in clinical practice

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Multiethnic Genome-wide Association Study of Subclinical Atherosclerosis in Individuals with Type 2 Diabetes

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.120.003258 ◽

2021 ◽

Author(s):

Yingchang Lu ◽

Latchezar Dimitrov ◽

Shyh-Huei Chen ◽

Lawrence F. Bielak ◽

Joshua C. Bis ◽

...

Keyword(s):

Type 2 Diabetes ◽

Coronary Artery ◽

Subclinical Atherosclerosis ◽

Genome Wide Association ◽

European Ancestry ◽

Potential Candidate ◽

Cvd Risk ◽

Genome Wide ◽

Meta Analyses

Background - Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease (CVD). Type 2 diabetes (T2D) is an independent CVD risk factor that accelerates atherosclerosis. Methods - We performed meta-analyses of genome-wide association studies (GWAS) in up to 2,500 T2D individuals of European ancestry (EA) and 1,590 T2D individuals of African ancestry (AA) with or without exclusion of prevalent CVD, for CAC measured by cardiac computed tomography, and 3,608 EA and 838 AA with T2D for cIMT measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Results - We replicated two loci (rs9369640 and rs9349379 near PHACTR1 and rs10757278 near CDKN2B ) for CAC and one locus for cIMT (rs7412 and rs445925 near APOE-APOC1 ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near CSNK1A1L/LINC00547/POSTN at 13q13.3) at P =2.0×10 -8 in EA. No additional loci were identified with the meta-analyses of EA and AA. The expression QTL analysis with nearby expressed genes derived from arterial wall and metabolic tissues from GTEx pinpoints POSTN , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations ( P <3.1×10 -4 ) for three previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near CDKN2B-AS1 and rs11170820 near FLJ12825 for CAC, and rs7412 near APOE for cIMT). Conclusions - Our results provide potential biological mechanisms that could link CAC and cIMT to increased CVD risk in individuals with T2D.

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Polygenic Prediction of Type 2 Diabetes in Africa

10.2337/figshare.17076419.v1 ◽

2022 ◽

Author(s):

Tinashe Chikowore ◽

Kenneth Ekoru ◽

Marijana Vujkovic ◽

Dipender Gill ◽

Fraser Pirie ◽

...

Keyword(s):

Type 2 Diabetes ◽

African American ◽

Association Studies ◽

Meta Analysis ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Data Set ◽

Genome Wide ◽

Design And Methods

Objective. Polygenic prediction of type 2 diabetes in continental Africans is adversely affected by the limited number of genome-wide association studies (GWAS) of type 2 diabetes from Africa and the poor transferability of European derived polygenic risk scores (PRS) in diverse ethnicities. We set out to evaluate if African American, European or multi-ethnic derived PRSs would improve polygenic prediction in continental Africans. Research Design and Methods. Using the PRSice software, ethnic-specific PRSs were computed with weights from the type 2 diabetes GWAS multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls. The South African Zulu study (1602 cases and 981 controls) was used as the target data set. Validation and assessment of the best predictive PRS association with age at diagnosis was done in the Africa America Diabetes Mellitus (AADM) study (2148 cases and 2161 controls). Results. The discriminatory ability of the African American and Multi-ethnic PRS were similar. However, the African American derived PRS was more transferable in all the countries represented in the AADM cohort, and predictive of type 2 diabetes in the country combined analysis compared to the European and multi-ethnic derived scores. Notably, participants in the 10th decile of this PRS had a 3.63-fold greater risk (OR 3.63; 95%CI (2.19 - 4.03), p = 2.79 x 10-17) per risk allele of developing diabetes and were diagnosed 2.6 years earlier compared to those in the first decile. Conclusions African American derived PRS enhances polygenic prediction of type 2 diabetes in continental Africans. Improved representation of non-European populations (including Africans) in GWAS promises to provide better tools for precision medicine interventions in type 2 diabetes.

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