Association of Baseline Factors With Glycemic Outcomes in GRADE: A Comparative Effectiveness Randomized Clinical Trial.

OBJECTIVE: To describe the individual and joint associations of baseline factors with glycemia, and also with differential effectiveness of medications added to metformin. RESEARCH DESIGN AND METHODS: Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) participants (with type 2 diabetes diagnosed for <10 years, on metformin, and with HbA1c 6.8-8.5%; N = 5,047) were randomly assigned to a basal insulin (glargine), sulfonylurea (glimepiride), glucagon-like peptide 1 agonist (liraglutide), or dipeptidyl peptidase 4 inhibitor (sitagliptin). The glycemic outcome was HbA1c ≥7.0%, subsequently confirmed. Univariate and multivariate regression and classification and regression tree (CART) analyses were used to assess the association of baseline factors with the glycemic outcome at years 1 and 4. RESULTS: In univariate analyses at baseline, younger age (<58 years), Hispanic ethnicity, higher HbA1c, fasting glucose, and triglyceride levels, lower insulin secretion, and relatively greater insulin resistance were associated with the glycemic outcome at years 1 and/or 4. No factors were associated with differential effectiveness of the medications by year 4. In multivariate analyses, treatment group, younger age, and higher baseline HbA1c and fasting glucose were jointly associated with the glycemic outcome by year 4. The superiority of glargine and liraglutide at year 4 persisted after multiple baseline factors were controlled for. CART analyses indicated that failure to maintain HbA1c <7% by year 4 was more likely for younger participants and those with baseline HbA1c ≥7.4%. CONCLUSIONS: Several baseline factors were associated with the glycemic outcome but not with differential effectiveness of the four medications. Failure to maintain HbA1c <7% was largely driven by younger age and higher HbA1c at baseline. Factors that predict earlier glycemic deterioration could help in targeting patients for more aggressive management.

The Use of Rescue Insulin in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

OBJECTIVE: To describe rescue insulin use and associated factors in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). RESEARCH DESIGN AND METHODS: GRADE participants (type 2 diabetes duration <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 >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 noninsulin 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.

BMI, insulin sensitivity, and cognition in early type 2 diabetes: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study.

OBJECTIVE: This study explored the association of BMI and insulin sensitivity with cognitive performance in type 2 diabetes. METHODS: A cross-sectional analysis of data from the baseline assessment of the Glycemia Reduction Approaches in Diabetes: a Comparative Effectiveness Study (GRADE) was conducted. BMI was used as a surrogate of adiposity and the Matsuda index as the measure of insulin sensitivity. Cognitive tests included the Spanish English Verbal Learning Test, the Digit Symbol Substitution Test, and the letter and animal fluency tests. RESULTS: Cognitive assessments were completed by 5018 (99.4%) of 5047 participants aged 56.7 ± 10.0 years, of whom 36.4% were female. Higher BMI and lower insulin sensitivity were related to better performance on memory and verbal fluency tests. In models including BMI and insulin sensitivity simultaneously, only higher BMI was related to better cognitive performance. CONCLUSIONS: In this study, higher BMI and lower insulin sensitivity in type 2 diabetes were cross-sectionally associated with better cognitive performance. However, only higher BMI was related to cognitive performance when both BMI and insulin sensitivity were considered simultaneously. The causality and mechanisms for this association need to be determined in future studies.