A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

The long-term effects of type 1 diabetes treatment and complications on health-related quality of life: A 23-year follow-up of the diabetes control and complications/ epidemiology of diabetes interventions and complications cohort

OBJECTIVE To examine the long-term effects of type 1 diabetes treatment, metabolic control, and complications on health-related quality of life (HRQOL). RESEARCH DESIGN AND METHODSdA total of 1,441 participants, initially 13-39 years of age, were followed for an average of 23.5 years as part of the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study. The Diabetes Quality-of-Life questionnaire (DQOL) was administered annually during DCCT and every other year during EDIC. Biomedical data, including HbA1c levels, exposure to severe hypoglycemia, intercurrent psychiatric events, and development of diabetes complications were collected at regular intervals throughout the follow-up. RESULTSdMean total DQOL scores were not significantly different between the former DCCT intensive and conventional treatment groups (DCCT baseline, 78±8 vs. 78±9; EDIC year 17, 75±11 vs. 74±11). Over the course of the study, a drop of ≥5 points in DQOL score from DCCT baseline maintained on two successive visits occurred in 755 individuals and was associated with increased HbA1c, albumin excretion rate, mean blood pressure, BMI, and occurrence of hypoglycemic events requiring assistance. LowerDQOL scores after 23.5 years of followup were associated with prior development of retinopathy (P = 0.0196), nephropathy (P = 0.0019), and neuropathy (P\u3c0.0001) as well as self-reported chest pain (P = 0.0004), decreased vision in both eyes (P = 0.0005), painful paresthesias (P\u3c 0.0001), recurrent urinary incontinence (P = 0.0001), erectile dysfunction (P \u3c0.0001), and history of psychiatric events (P \u3c0.0001). CONCLUSIONSdAmong DCCT/EDIC participants, worsening metabolic control, serious diabetes complications and their associated symptoms, and development of psychiatric conditions led to decreased HRQOL. © 2013 by the American Diabetes Association

Cardiometabolic Risk Factors and Incident Cardiovascular Disease Events in Women vs Men With Type 1 Diabetes

Importance: The lower risk of cardiovascular disease (CVD) among women compared with men in the general population may be diminished among those with diabetes. Objective: To evaluate cardiometabolic risk factors and their management in association with CVD events in women vs men with type 1 diabetes enrolled in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Design, Setting, and Participants: This cohort study used data obtained during the combined DCCT (randomized clinical trial, conducted 1983-1993) and EDIC (observational study, conducted 1994 to present) studies through April 30, 2018 (mean [SD] follow-up, 28.8 [5.8] years), at 27 clinical centers in the US and Canada. Data analyses were performed between July 2021 and April 2022. Exposure: During the DCCT phase, patients were randomized to intensive vs conventional diabetes therapy. Main Outcomes and Measures: Cardiometabolic risk factors and CVD events were assessed via detailed medical history and focused physical examinations. Blood and urine samples were assayed centrally. CVD events were adjudicated by a review committee. Linear mixed models and Cox proportional hazards models evaluated sex differences in cardiometabolic risk factors and CVD risk over follow-up. Results: A total of 1441 participants with type 1 diabetes (mean [SD] age at DCCT baseline, 26.8 [7.1] years; 761 [52.8%] men; 1390 [96.5%] non-Hispanic White) were included. Over the duration of the study, compared with men, women had significantly lower body mass index (BMI, calculated as weight in kilograms divided by height in meters squared; β = -0.43 [SE, 0.16]; P = .006), waist circumference (β = -10.56 cm [SE, 0.52 cm]; P \u3c .001), blood pressure (systolic: β = -5.77 mm Hg [SE, 0.35 mm Hg]; P \u3c .001; diastolic: β = -3.23 mm Hg [SE, 0.26 mm Hg]; P \u3c .001), and triglyceride levels (β = -10.10 mg/dL [SE, 1.98 mg/dL]; P \u3c .001); higher HDL cholesterol levels (β = 9.36 mg/dL [SE, 0.57 mg/dL]; P \u3c .001); and similar LDL cholesterol levels (β = -0.76 mg/dL [SE, 1.22 mg/dL]; P = .53). Women, compared with men, achieved recommended targets more frequently for blood pressure (ie, \u3c130/80 mm Hg: 90.0% vs 77.4%; P \u3c .001) and triglycerides (ie, \u3c150 mg/dL: 97.3% vs 90.5%; P \u3c .001). However, sex-specific HDL cholesterol targets (ie, ≥50 mg/dL for women, ≥40 mg/dL for men) were achieved less often (74.3% vs 86.6%; P \u3c .001) and cardioprotective medications were used less frequently in women than men (ie, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker: 29.6% [95% CI, 25.7%-33.9%] vs 40.0% [95% CI, 36.1%-44.0%]; P = .001; lipid-lowering medication: 25.3% [95% CI, 22.1%-28.7%] vs 39.6% [95% CI, 36.1%-43.2%]; P \u3c .001). Women also had significantly higher pulse rates (mean [SD], 75.2 [6.8] beats per minute vs 71.8 [6.9] beats per minute; P \u3c .001) and hemoglobin A1c levels (mean [SD], 8.3% [1.0%] vs 8.1% [1.0%]; P = .01) and achieved targets for tighter glycemic control less often than men (ie, hemoglobin A1c \u3c7%: 11.2% [95% CI, 9.3%-13.3%] vs 14.0% [95% CI, 12.0%-16.3%]; P = .03). Conclusions and Relevance: These findings suggest that despite a more favorable cardiometabolic risk factor profile, women with type 1 diabetes did not have a significantly lower CVD event burden than men, suggesting a greater clinical impact of cardiometabolic risk factors in women vs men with diabetes. These findings call for conscientious optimization of the control of CVD risk factors in women with type 1 diabetes

RISK FACTORS FOR HEARING IMPAIRMENT IN TYPE 1 DIABETES

Objective: Studies have demonstrated that glycated hemoglobin (HbA1c) is a significant predictor of hearing impairment in type 1 diabetes. We identified additional factors associated with hearing impairment in participants with type 1 diabetes from the Diabetes Control and Complications Trial and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Methods: A total of 1,150 DCCT/EDIC participants were recruited for the Hearing Study. A medical history, physical measurements, and a self-administered hearing questionnaire were obtained. Audiometry was performed by study-certified personnel and assessed centrally. Logistic regression models assessed the association of risk factors and comorbidities with speech- and high-frequency hearing impairment. Results: Mean age was 55 ± 7 years, duration of diabetes 34 ± 5 years, and DCCT/EDIC HbA1c 7.9 ± 0.9% (63 mmol/mol). In multivariable models, higher odds of speech-frequency impairment were significantly associated with older age, higher HbA1c, history of noise exposure, male sex, and higher triglycerides. Higher odds of high-frequency impairment were associated with older age, male sex, history of noise exposure, higher skin intrinsic florescence (SIF) as a marker of tissue glycation, higher HbA1c, nonprofessional/nontechnical occupations, sedentary activity, and lower low-density-lipoprotein cholesterol. Among participants who previously completed computed tomography and carotid ultrasonography, coronary artery calcification (CAC) \u3e0 and carotid intima-medial thickness were significantly associated with high-but not speech-frequency impairment. Conclusion: Consistent with previous reports, male sex, age, several metabolic factors, and noise exposure are independently associated with hearing impairment. The association with SIF further emphasizes the importance of glycemia-as a modifiable risk factor-over time. In addition, the macrovascular contribution of CAC is novel and important. Abbreviations: AER = albumin excretion rate; CAC = coronary artery calcification; CVD = cardiovascular disease; DCCT/EDIC = Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications; eGFR = estimated glomerular filtration rate; ETDRS = Early Treatment Diabetic Retinopathy Study; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; IMT = intima-media thickness; LDL = low-density lipoprotein; NHANES = National Health and Nutrition Examination Survey; OR = odds ratio; SIF = skin intrinsic fluorescence; T1D = type 1 diabetes

Continuous Glucose Monitoring in Adults With Type 1 Diabetes With 35 Years Duration From the DCCT/EDIC Study

OBJECTIVE: We evaluated blinded continuous glucose monitoring (CGM) profiles in a subset of adults with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study to characterize the frequency of glycemic excursions and contributing factors. RESEARCH DESIGN AND METHODS: CGM-derived metrics were compared for daytime and nighttime periods using blinded CGM for a minimum of 6.5 days (average 11.9 days) and correlated with HbA1c levels, routine use of diabetes devices, and other characteristics in 765 participants. RESULTS: Participants were 58.9 ± 6.5 years of age with diabetes duration 36.8 ± 4.9 years and HbA1c 7.8 ± 1.2%; 58% used insulin pumps, and 27% used personal, unblinded CGM. Compared with daytime, nighttime mean sensor glucose was lower, percent time in range 70-180 mg/dL (TIR) was similar, and hypoglycemia was more common. Over the entire recording period, only 9% of the 765 participants achieved \u3e70% TIR and only 28% achieved \u3c1% of observations of \u3c54 mg/dL. Indeed, participants with the highest percentage of hypoglycemia had the lowest HbA1c levels. However, use of insulin pumps and CGM decreased the percent time at \u3c54 mg/dL. CONCLUSIONS: In adults with long-standing type 1 diabetes, short-term blinded CGM profiles revealed frequent clinically significant hypoglycemia (\u3c54 mg/dL) during the night and more time in hyperglycemia during the day. The small subset of participants using routine CGM and insulin pumps had fewer hypoglycemic and hyperglycemic excursions and lower HbA1c levels. Thus, strategies to lower meal-stimulated hyperglycemia during the day and prevent hypoglycemia at night are relevant clinical goals in older patients with type 1 diabetes