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  • 1
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    Identical and Nonidentical Twins: Risk and Factors Involved in Development of Islet Autoimmunity and Type 1 Diabetes
    American Diabetes Association ; 2019
    In:  Diabetes Care Vol. 42, No. 2 ( 2019-02-01), p. 192-199
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 42, No. 2 ( 2019-02-01), p. 192-199
    Abstract: There are variable reports of risk of concordance for progression to islet autoantibodies and type 1 diabetes in identical twins after one twin is diagnosed. We examined development of positive autoantibodies and type 1 diabetes and the effects of genetic factors and common environment on autoantibody positivity in identical twins, nonidentical twins, and full siblings. RESEARCH DESIGN AND METHODS Subjects from the TrialNet Pathway to Prevention Study (N = 48,026) were screened from 2004 to 2015 for islet autoantibodies (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A] , and autoantibodies against insulin [IAA]). Of these subjects, 17,226 (157 identical twins, 283 nonidentical twins, and 16,786 full siblings) were followed for autoantibody positivity or type 1 diabetes for a median of 2.1 years. RESULTS At screening, identical twins were more likely to have positive GADA, IA-2A, and IAA than nonidentical twins or full siblings (all P & lt; 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more positive autoantibodies, and two or more positive autoantibodies (all P ≤ 0.03). Initially autoantibody-positive identical twins had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody-negative identical twins. In nonidentical twins, type 1 diabetes risk by 3 years was 72% for initially multiple autoantibody–positive, 13% for single autoantibody–positive, and 0% for initially autoantibody-negative nonidentical twins. Full siblings had a 3-year type 1 diabetes risk of 47% for multiple autoantibody–positive, 12% for single autoantibody–positive, and 0.5% for initially autoantibody-negative subjects. CONCLUSIONS Risk of type 1 diabetes at 3 years is high for initially multiple and single autoantibody–positive identical twins and multiple autoantibody–positive nonidentical twins. Genetic predisposition, age, and male sex are significant risk factors for development of positive autoantibodies in twins.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc18-0288
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 2
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    A Type 1 Diabetes Genetic Risk Score Predicts Progression of Islet Autoimmunity and Development of Type 1 Diabetes in Individuals at Risk
    American Diabetes Association ; 2018
    In:  Diabetes Care Vol. 41, No. 9 ( 2018-09-01), p. 1887-1894
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 41, No. 9 ( 2018-09-01), p. 1887-1894
    Abstract: We tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals. RESEARCH DESIGN AND METHODS We studied the 1,244 TrialNet Pathway to Prevention study participants (T1D patients’ relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median [range] age at initial autoantibody determination 11.1 years [1.2–51.8], 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic utility of T1D GRS, age, sex, Diabetes Prevention Trial–Type 1 (DPT-1) Risk Score, positive autoantibody number or type, HLA DR3/DR4-DQ8 status, and race/ethnicity. We used recursive partitioning analyses to identify cut points in continuous variables. RESULTS Higher T1D GRS significantly increased the rate of progression to T1D adjusting for DPT-1 Risk Score, age, number of positive autoantibodies, sex, and ethnicity (hazard ratio [HR] 1.29 for a 0.05 increase, 95% CI 1.06–1.6; P = 0.011). Progression to T1D was best predicted by a combined model with GRS, number of positive autoantibodies, DPT-1 Risk Score, and age (7-year time-integrated AUC = 0.79, 5-year AUC = 0.73). Higher GRS was significantly associated with increased progression rate from single to multiple positive autoantibodies after adjusting for age, autoantibody type, ethnicity, and sex (HR 2.27 for GRS & gt;0.295, 95% CI 1.47–3.51; P = 0.0002). CONCLUSIONS The T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc18-0087
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 3
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    Optimization of Metformin in the GRADE Cohort: Effect on Glycemia and Body Weight
    American Diabetes Association ; 2020
    In:  Diabetes Care Vol. 43, No. 5 ( 2020-05-01), p. 940-947
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 43, No. 5 ( 2020-05-01), p. 940-947
    Abstract: We evaluated the effect of optimizing metformin dosing on glycemia and body weight in type 2 diabetes. RESEARCH DESIGN AND METHODS This was a prespecified analysis of 6,823 participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) taking metformin as the sole glucose-lowering drug who completed a 4- to 14-week (mean ± SD 7.9 ± 2.4) run-in in which metformin was adjusted to 2,000 mg/day or a maximally tolerated lower dose. Participants had type 2 diabetes for & lt;10 years and an HbA1c ≥6.8% (51 mmol/mol) while taking ≥500 mg of metformin/day. Participants also received diet and exercise counseling. The primary outcome was the change in HbA1c during run-in. RESULTS Adjusted for duration of run-in, the mean ± SD change in HbA1c was −0.65 ± 0.02% (−7.1 ± 0.2 mmol/mol) when the dose was increased by ≥1,000 mg/day, −0.48 ± 0.02% (−5.2 ± 0.2 mmol/mol) when the dose was unchanged, and −0.23 ± 0.07% (−2.5 ± 0.8 mmol/mol) when the dose was decreased (n = 2,169, 3,548, and 192, respectively). Higher HbA1c at entry predicted greater reduction in HbA1c (P & lt; 0.001) in univariate and multivariate analyses. Weight loss adjusted for duration of run-in averaged 0.91 ± 0.05 kg in participants who increased metformin by ≥1,000 mg/day (n = 1,894). CONCLUSIONS Optimizing metformin to 2,000 mg/day or a maximally tolerated lower dose combined with emphasis on medication adherence and lifestyle can improve glycemia in type 2 diabetes and HbA1c values ≥6.8% (51 mmol/mol). These findings may help guide efforts to optimize metformin therapy among persons with type 2 diabetes and suboptimal glycemic control.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc19-1769
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 4
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    Baseline Characteristics of Randomized Participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE)
    American Diabetes Association ; 2019
    In:  Diabetes Care Vol. 42, No. 11 ( 2019-11-01), p. 2098-2107
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 42, No. 11 ( 2019-11-01), p. 2098-2107
    Abstract: GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) is a 36-center unmasked, parallel treatment group, randomized controlled trial evaluating four diabetes medications added to metformin in people with type 2 diabetes (T2DM). We report baseline characteristics and compare GRADE participants to a National Health and Nutrition Examination Survey (NHANES) cohort. RESEARCH DESIGN AND METHODS Participants were age ≥30 years at the time of diagnosis, with duration of T2DM & lt;10 years, HbA1c 6.8–8.5% (51–69 mmol/mol), prescribed metformin monotherapy, and randomized to glimepiride, sitagliptin, liraglutide, or insulin glargine. RESULTS At baseline, GRADE’s 5,047 randomized participants were 57.2 ± 10.0 years of age, 63.6% male, with racial/ethnic breakdown of 65.7% white, 19.8% African American, 3.6% Asian, 2.7% Native American, 7.6% other or unknown, and 18.4% Hispanic/Latino. Duration of diabetes was 4.2 ± 2.8 years, with mean HbA1c of 7.5 ± 0.5% (58 ± 5.3 mmol/mol), BMI of 34.3 ± 6.8 kg/m2, and metformin dose of 1,944 ± 204 mg/day. Among the cohort, 67% reported a history of hypertension, 72% a history of hyperlipidemia, and 6.5% a history of heart attack or stroke. Applying GRADE inclusion criteria to NHANES indicates enrollment of a representative cohort with T2DM on metformin monotherapy (NHANES cohort average age, 57.9 years; mean HbA1c, 7.4% [57 mmol/mol]; BMI, 33.2 kg/m2; duration, 4.2 ± 2.5 years; and 7.2% with a history of cardiovascular disease). CONCLUSIONS The GRADE cohort represents patients with T2DM treated with metformin requiring a second diabetes medication. GRADE will inform decisions about the clinical effectiveness of the addition of four classes of diabetes medications to metformin.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc19-0901
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 5
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    Association of Glycemia, Lipids, and Blood Pressure With Cognitive Performance in People With Type 2 Diabetes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE)
    American Diabetes Association ; 2021
    In:  Diabetes Care Vol. 44, No. 10 ( 2021-10-01), p. 2286-2292
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 44, No. 10 ( 2021-10-01), p. 2286-2292
    Abstract: Type 2 diabetes is a risk factor for cognitive impairment. We examined the relation of glycemia, lipids, blood pressure (BP), hypertension history, and statin use with cognition in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). RESEARCH DESIGN AND METHODS Cross-sectional analyses from GRADE at baseline examined the association of glycemia (hemoglobin A1c [HbA1c]), LDL, systolic BP (SBP) and diastolic BP (DBP), hypertension history, and statin use with cognition assessed by the Spanish English Verbal Learning Test, letter and animal fluency tests, and Digit Symbol Substitution Test (DSST). RESULTS Among 5,047 GRADE participants, 5,018 (99.4%) completed cognitive assessments. Their mean age was 56.7 ± 10.0 years, and 36.4% were women. Mean diabetes duration was 4.0 ± 2.7 years. HbA1c was not related to cognition. Higher LDL was related to modestly worse DSST scores, whereas statin use was related to modestly better DSST scores. SBP between 120 and 139 mmHg and DBP between 80 and 89 mmHg were related to modestly better DSST scores. Hypertension history was not related to cognition. CONCLUSIONS In people with type 2 diabetes of a mean duration of & lt;5 years, lower LDL and statin use were related to modestly better executive cognitive function. SBP levels in the range of 120–139 mmHg and DBP levels in the range of 80–89 mmHg, but not lower levels, were related to modestly better executive function. These differences may not be clinically significant.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc20-2858
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 6
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    Islet Autoimmunity Is Highly Prevalent and Associated With Diminished β-Cell Function in Patients With Type 2 Diabetes in the GRADE Study
    American Diabetes Association ; 2022
    In:  Diabetes Vol. 71, No. 6 ( 2022-06-01), p. 1261-1271
    Details
    In: Diabetes, American Diabetes Association, Vol. 71, No. 6 ( 2022-06-01), p. 1261-1271
    Abstract: Islet autoimmunity may contribute to β-cell dysfunction in type 2 diabetes (T2D). Its prevalence and clinical significance have not been rigorously determined. In this ancillary study to the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), we investigated the prevalence of cellular and humoral islet autoimmunity in patients with T2D duration of 4.0 ± 3.0 years (HbA1c 7.5 ± 0.5% on metformin alone). We measured T-cell autoreactivity against islet proteins, islet autoantibodies against 65-kDa GAD antigen, IA-2, and zinc transporter-8, and β-cell function. Cellular islet autoimmunity was present in 41.3%, humoral islet autoimmunity in 13.5%, and both in 5.3%. β-Cell function calculated as incremental area under the curve of glucose from 0–120 min (iAUC-CG) and ΔC-peptide(0–30)/Δglucose(0–30) from an oral glucose tolerance test was lower among T-cell–positive (T+) than T-cell–negative (T−) individuals using two different adjustments for insulin sensitivity (iAUC-CG: 13.2% [95% CI 0.3, 24.4] or 11.4% [95% CI 0.4, 21.2] lower; ΔC-peptide[0–30]/Δglucose[0–30] : 19% [95% CI 3.1, 32.3] or 17.7% [95% CI 2.6, 30.5%] lower). T+ patients had 17% higher HbA1c (95% CI 0.07, 0.28) and 7.7 mg/dL higher fasting plasma glucose levels (95% CI 0.2, 15.3) than T− patients. We conclude that islet autoimmunity is much more prevalent in patients with T2D than previously reported. T-cell–mediated autoimmunity is associated with diminished β-cell function and worse glycemic control.
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db21-0590
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 7
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    Association of Baseline Characteristics With Insulin Sensitivity and β-Cell Function in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study Cohort
    American Diabetes Association ; 2021
    In:  Diabetes Care Vol. 44, No. 2 ( 2021-02-01), p. 340-349
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 44, No. 2 ( 2021-02-01), p. 340-349
    Abstract: We investigated sex and racial differences in insulin sensitivity, β-cell function, and glycated hemoglobin (HbA1c) and the associations with selected phenotypic characteristics. RESEARCH DESIGN AND METHODS This is a cross-sectional analysis of baseline data from 3,108 GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) participants. All had type 2 diabetes diagnosed & lt;10 years earlier and were on metformin monotherapy. Insulin sensitivity and β-cell function were evaluated using the HOMA of insulin sensitivity and estimates from oral glucose tolerance tests, including the Matsuda Index, insulinogenic index, C-peptide index, and oral disposition index (DI). RESULTS The cohort was 56.6 ± 10 years of age (mean ± SD), 63.8% male, with BMI 34.2 ± 6.7 kg/m2, HbA1c 7.5 ± 0.5%, and type 2 diabetes duration 4.0 ± 2.8 years. Women had higher DI than men but similar insulin sensitivity. DI was the highest in Black/African Americans, followed by American Indians/Alaska Natives, Asians, and Whites in descending order. Compared with Whites, American Indians/Alaska Natives had significantly higher HbA1c, but Black/African Americans and Asians had lower HbA1c. However, when adjusted for glucose levels, Black/African Americans had higher HbA1c than Whites. Insulin sensitivity correlated inversely with BMI, waist-to-hip ratio, triglyceride-to-HDL-cholesterol ratio (TG/HDL-C), and the presence of metabolic syndrome, whereas DI was associated directly with age and inversely with BMI, HbA1c, and TG/HDL-C. CONCLUSIONS In the GRADE cohort, β-cell function differed by sex and race and was associated with the concurrent level of HbA1c. HbA1c also differed among the races, but not by sex. Age, BMI, and TG/HDL-C were associated with multiple measures of β-cell function and insulin sensitivity.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc20-1787
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 8
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    Clinical and Metabolic Characterization of Adults With Type 2 Diabetes by Age in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) Cohort
    American Diabetes Association ; 2022
    In:  Diabetes Care Vol. 45, No. 7 ( 2022-07-07), p. 1512-1521
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 45, No. 7 ( 2022-07-07), p. 1512-1521
    Abstract: Differences in type 2 diabetes phenotype by age are described, but it is not known whether these differences are seen in a more uniformly defined adult population at a common early stage of care. We sought to characterize age-related clinical and metabolic characteristics of adults with type 2 diabetes on metformin monotherapy, prior to treatment intensification. RESEARCH DESIGN AND METHODS In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), participants were enrolled who had type 2 diabetes duration & lt;10 years, had HbA1c 6.8–8.5%, and were on metformin monotherapy. Participants were randomly assigned to one of four additional glucose-lowering medications. We compared baseline clinical and metabolic characteristics across age categories ( & lt;45, 45 to & lt;55, 55 to & lt;65, and ≥65 years) using ANOVA and Pearson χ2 tests. RESULTS Within the GRADE cohort (n = 5,047), we observed significant differences by age, with younger adults having greater racial diversity, fewer medications for common comorbidities, lower prevalence of CVD, higher weight and BMI, and more pronounced hyperglycemia and diabetic dyslipidemia and with metabolic profile indicating lower insulin sensitivity (inverse fasting insulin [1/(fasting insulin)], HOMA of steady-state insulin sensitivity, Matsuda index) and inadequate β-cell response (oral disposition index) (P & lt; 0.05 across age categories). CONCLUSIONS Clinical and metabolic characteristics of type 2 diabetes differ by age within the GRADE cohort. Younger adults exhibit more prominent obesity-related characteristics, including higher obesity levels and lower insulin sensitivity and β-cell compensation. Given the increasing burden of type 2 diabetes and complications, particularly among younger populations, these age-related distinctions may inform risk factor management approaches and treatment priorities. Further study will determine whether age-related differences impact response to therapy.
    Type of Medium: Online Resource
    ISSN: 0149-5992
    URL: Article
    DOI: 10.2337/dc21-2659
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 9
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    The Use of Rescue Insulin in the Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study (GRADE)
    American Diabetes Association ; 2023
    In:  Diabetes Care ( 2023-09-26)
    Details
    In: Diabetes Care, American Diabetes Association, ( 2023-09-26)
    Abstract: To describe rescue insulin use and associated factors in the Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study (GRADE). RESEARCH DESIGN AND METHODS GRADE participants (type 2 diabetes duration & lt;10 years, baseline A1C 6.8%–8.5% on metformin monotherapy, N = 5,047) were randomly assigned to insulin glargine U-100, glimepiride, liraglutide, or sitagliptin and followed quarterly for a mean of 5 years. Rescue insulin (glargine or aspart) was to be started within 6 weeks of A1C & gt;7.5%, confirmed. Reasons for delaying rescue insulin were reported by staff-completed survey. RESULTS Nearly one-half of GRADE participants (N = 2,387 [47.3%]) met the threshold for rescue insulin. Among participants assigned to glimepiride, liraglutide, or sitagliptin, rescue glargine was added by 69% (39% within 6 weeks). Rescue aspart was added by 44% of glargine-assigned participants (19% within 6 weeks) and by 30% of non-glargine-assigned participants (14% within 6 weeks). Higher A1C values were associated with adding rescue insulin. Intention to change health behaviors (diet/lifestyle, adherence to current treatment) and not wanting to take insulin were among the most common reasons reported for not adding rescue insulin within 6 weeks. CONCLUSIONS Proportionately, rescue glargine, when required, was more often used than rescue aspart, and higher A1C values were associated with greater rescue insulin use. Wanting to use non-insulin strategies to improve glycemia was commonly reported, although multiple factors likely contributed to not using rescue insulin. These findings highlight the persistent challenge of intensifying type 2 diabetes treatment with insulin, even in a clinical trial.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc23-0516
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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