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OBJECTIVE: To compare the long-term effects of glucose-lowering medications (insulin glargine U-100, glimepiride, liraglutide, and sitagliptin) when added to metformin on insulin sensitivity and β-cell function. RESEARCH DESIGN AND METHODS: In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) cohort with type 2 diabetes (n = 4,801), HOMA2 was used to estimate insulin sensitivity (HOMA2-%S) and fasting β-cell function (HOMA2-%B) at baseline and 1, 3, and 5 years on treatment. Oral glucose tolerance test β-cell responses (C-peptide index [CPI] and total C-peptide response [incremental C-peptide/incremental glucose over 120 min]) were evaluated at the same time points. These responses adjusted for HOMA2-%S in regression analysis provided estimates of β-cell function. RESULTS: HOMA2-%S increased from baseline to year 1 with glargine and remained stable thereafter, while it did not change from baseline in the other treatment groups. HOMA2-%B and C-peptide responses were increased to variable degrees at year 1 in all groups but then declined progressively over time. At year 5, CPI was similar between liraglutide and sitagliptin, and higher for both than for glargine and glimepiride [0.80, 0.87, 0.74, and 0.64 (nmol/L)/(mg/dL) * 100, respectively; P < 0.001], while the total C-peptide response was greatest with liraglutide, followed in descending order by sitagliptin, glargine, and glimepiride [1.54, 1.25, 1.02, and 0.87 (nmol/L)/(mg/dL) * 100, respectively, P < 0.001]. After adjustment for HOMA2-%S to obtain an estimate of β-cell function, the nature of the change in β-cell responses reflected those in β-cell function. CONCLUSIONS: The differential long-term effects on insulin sensitivity and β-cell function of four different glucose-lowering medications when added to metformin highlight the importance of the loss of β-cell function in the progression of type 2 diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We evaluated whether adding basal insulin to metformin in adults with early type 2 diabetes mellitus (T2DM) would increase emotional distress relative to other treatments. RESEARCH DESIGN AND METHODS: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) of adults with T2DM of <10 years' duration, HbA1c 6.8–8.5%, and taking metformin monotherapy randomly assigned participants to add insulin glargine U-100, sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or the dipeptidyl peptidase 4 inhibitor sitagliptin. The Emotional Distress Substudy enrolled 1,739 GRADE participants (mean [SD] age 58.0 [10.2] years, 32% female, 56% non-Hispanic White, 18% non-Hispanic Black, 17% Hispanic) and assessed diabetes distress and depressive symptoms every 6 months. Analyses examined differences at 1 year and over the 3-year follow-up. RESULTS: Across treatments, diabetes distress (−0.24, P < 0.0001) and depressive symptoms (−0.67, P < 0.0001) decreased over 1 year. Diabetes distress was lower at 1 year for the glargine group than for the other groups combined (−0.10, P = 0.002). Diabetes distress was also lower for liraglutide than for glimepiride or sitagliptin (−0.10, P = 0.008). Over the 3-year follow-up, there were no significant group differences in total diabetes distress; interpersonal diabetes distress remained lower for those assigned to liraglutide. No significant differences were observed for depressive symptoms. CONCLUSIONS: Contrary to expectations, this randomized trial found no evidence for a deleterious effect of basal insulin on emotional distress. Glargine lowered diabetes distress modestly at 1 year rather than increasing it. Liraglutide also reduced diabetes distress at 1 year. Results can inform treatment decisions for adults with early T2DM. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Diabetes is associated with reduced health-related quality of life (HRQoL). Information on the relationship between HRQoL and glucose-lowering medications in recently diagnosed type 2 diabetes (T2D) is limited. We assessed changes in HRQoL in participants with T2D receiving metformin plus one of four glucose-lowering medications in Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). RESEARCH DESIGN AND METHODS: A total of 5,047 participants, baseline mean age 57 years, with <10 years T2D duration and glycated hemoglobin level 6.8–8.5% and taking metformin monotherapy, were randomly assigned to glargine, glimepiride, liraglutide, or sitagliptin. HRQoL was evaluated at baseline for 4,885 participants, and at years 1, 2, and 3, with use of the self-administered version of the Quality of Well-being Scale (QWB-SA) and SF-36 physical (PCS) and mental (MCS) component summary scales. Linear models were used to analyze changes in HRQoL over time in intention-to-treat analyses. RESULTS: None of the medications worsened HRQoL. There were no differences in QWB-SA or MCS by treatment group at any time point. PCS scores improved with liraglutide versus other groups at year 1 only. Greater weight loss during year 1 explained half the improvement in PCS scores with liraglutide versus glargine and glimepiride. Liraglutide participants in the upper tertile of baseline BMI showed the greatest improvement in PCS scores at year 1. CONCLUSIONS: Adding liraglutide to metformin in participants within 10 years of T2D diagnosis showed improvement in the SF-36 PCS in comparisons with the other medications at 1 year, which was no longer significant at years 2 and 3. Improvement was related to weight loss and baseline BMI. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We examined longitudinal associations between emotional distress (specifically, depressive symptoms and diabetes distress) and medication adherence in Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), a large randomized controlled trial comparing four glucose-lowering medications added to metformin in adults with relatively recent-onset type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: The Emotional Distress Substudy assessed medication adherence, depressive symptoms, and diabetes distress in 1,739 GRADE participants via self-completed questionnaires administered biannually up to 3 years. We examined baseline depressive symptoms and diabetes distress as predictors of medication adherence over 36 months. Bidirectional visit-to-visit relationships were also examined. Treatment satisfaction, beliefs about medication, diabetes care self-efficacy, and perceived control over diabetes were evaluated as mediators of longitudinal associations. RESULTS: At baseline, mean ± SD age of participants (56% of whom were White, 17% Hispanic/Latino, 18% Black, and 66% male) was 58.0 ± 10.2 years, diabetes duration 4.2 ± 2.8 years, HbA1c 7.5% ± 0.5%, and medication adherence 89.9% ± 11.1%. Higher baseline depressive symptoms and diabetes distress were independently associated with lower adherence over 36 months (P < 0.001). Higher depressive symptoms and diabetes distress at one visit predicted lower adherence at the subsequent 6-month visit (P < 0.0001) but not vice versa. Treatment assignment did not moderate relationships. Patient-reported concerns about diabetes medications mediated the largest percentage (11.9%–15.5%) of the longitudinal link between emotional distress and adherence. CONCLUSIONS: Depressive symptoms and diabetes distress both predict lower adherence to glucose-lowering medications over time among adults with T2DM. Addressing emotional distress and concerns about anticipated negative effects of taking these treatments may be important to support diabetes treatment adherence. [ABSTRACT FROM AUTHOR]

OBJECTIVE: In Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) (5,047 participants, mean follow-up 5.0 years), differences in glycemic control were demonstrated over time among four randomized therapies added to metformin. Weight gain and hypoglycemia are also important outcomes for people with type 2 diabetes. We compared the effects of the four randomized GRADE medications on a composite outcome incorporating glycemic deterioration, weight gain, and hypoglycemia. RESEARCH DESIGN AND METHODS: The composite outcome was time to first occurrence of any of the following: HbA1c >7.5%, confirmed; ≥5% weight gain; or severe or recurrent nonsevere hypoglycemia. Secondary analyses included examination of individual components of the composite outcome, subgroup effects and potential mediators, and treatment satisfaction. Cumulative incidence was estimated with the Kaplan-Meier estimator. Cox proportional hazards models were used to assess pairwise group differences in risk of an outcome. RESULTS: Risk of reaching the composite outcome (events per 100 participants per treatment year [PTYs]) was lowest with liraglutide (19 per 100 PTYs) followed by sitagliptin (26 per 100 PTYs), glargine (29 per 100 PTYs), and glimepiride (40 per 100 PTYs); all pairwise comparisons were statistically significant. The order was the same for risk of weight gain and hypoglycemia, but risk of glycemic deterioration was lowest with glargine, followed by liraglutide, glimepiride, and sitagliptin. No significant heterogeneity in risk of composite outcome was detected across prespecified covariates. Participants who reached the composite outcome had modestly but significantly lower treatment satisfaction. CONCLUSIONS: Among participants treated with common second-line drug classes for type 2 diabetes, the liraglutide group had the lowest and glimepiride the highest risk of reaching a composite outcome encompassing glycemic deterioration, weight gain, and hypoglycemia. These findings may inform decision-making regarding type 2 diabetes therapy. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We report mortality outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) among people with type 2 diabetes diagnosed within 10 years and no recent history of cardiovascular events or cancer. RESEARCH DESIGN AND METHODS: Overall mortality rates and major causes of death were assessed over an average of 5 years of follow-up. Cause of death was adjudicated centrally by a committee masked to treatment assignment. We examined baseline covariates and the 10-year Framingham Risk Score for associations. RESULTS: Mortality rate was low (0.59 per 100 participant-years). Participants who died during follow-up were likely to be older, be male, have a history of hypertension, have a history of smoking, and have moderate albuminuria. The two most common underlying causes of death were "cardiovascular-cause" (a composite of underlying causes) (38.6%) and cancer (26.8%). There were no differences by treatment group. CONCLUSIONS: Among people with diabetes of relatively short duration, cause of death was varied. Attention to health risks beyond cardiovascular diseases is warranted. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate whether baseline levels of depressive symptoms and diabetes-specific distress are associated with glycemic control in Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), a large randomized controlled trial comparing the metabolic effects of four common glucose-lowering medications when combined with metformin in individuals with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: The primary and secondary outcomes were defined as an HbA1c value ≥7%, subsequently confirmed, and an HbA1c value >7.5%, subsequently confirmed, respectively. Separate Cox proportional hazards models assessed the association between baseline levels of each exposure of interest (depressive symptoms measured with the eight-item Patient Health Questionnaire and diabetes distress measured with the Diabetes Distress Scale) and the subsequent risk of metabolic outcomes. RESULTS: This substudy included 1,739 participants (56% of whom were non-Hispanic White, 18% non-Hispanic Black, 17% Hispanic, and 68% male; mean [SD] age 58.0 [10.2] years, diabetes duration 4.2 [2.8] years, and HbA1c 7.5% [0.48%]). A total of 1,157 participants reached the primary outcome, with time to event of 2.1 years on average, while 738 participants reached the secondary outcome at 3 years on average. With adjustment for sex, race/ethnicity, treatment group, baseline age, duration of T2DM, BMI, and HbA1c, there were no significant associations between the depressive symptoms or diabetes distress and the subsequent risk of the primary or secondary outcomes. CONCLUSIONS: The current findings suggest that, at least for individuals with diabetes of relatively short duration, baseline levels of emotional distress are not associated with glycemic control over time. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To compare the effects of insulin sensitivity and β-cell function over time on HbA1c and durability of glycemic control in response to dual therapy. RESEARCH DESIGN AND METHODS: GRADE participants were randomized to glimepiride (n = 1,254), liraglutide (n = 1,262), or sitagliptin (n = 1,268) added to baseline metformin and followed for mean ± SD 5.0 ± 1.3 years, with HbA1c assessed quarterly and oral glucose tolerance tests at baseline, 1, 3, and 5 years. We related time-varying insulin sensitivity (HOMA 2 of insulin sensitivity [HOMA2-%S]) and early (0–30 min) and total (0–120 min) C-peptide (CP) responses to changes in HbA1c and glycemic failure (primary outcome HbA1c ≥7% [53 mmol/mol] and secondary outcome HbA1c >7.5% [58 mmol/mol]) and examined differential treatment responses. RESULTS: Higher HOMA2-%S was associated with greater initial HbA1c lowering (3 months) but not subsequent HbA1c rise. Greater CP responses were associated with a greater initial treatment response and slower subsequent HbA1c rise. Higher HOMA2-%S and CP responses were each associated with lower risk of primary and secondary outcomes. These associations differed by treatment. In the sitagliptin group, HOMA2-%S and CP responses had greater impact on initial HbA1c reduction (test of heterogeneity, P = 0.009 HOMA2-%S, P = 0.018 early CP, P = 0.001 total CP) and risk of primary outcome (P = 0.005 HOMA2-%S, P = 0.11 early CP, P = 0.025 total CP) but lesser impact on HbA1c rise (P = 0.175 HOMA2-%S, P = 0.006 early CP, P < 0.001 total CP) in comparisons with the glimepiride and liraglutide groups. There were no differential treatment effects on secondary outcome. CONCLUSIONS: Insulin sensitivity and β-cell function affected treatment outcomes irrespective of drug assignment, with greater impact in the sitagliptin group on initial (short-term) HbA1c response in comparison with the glimepiride and liraglutide groups. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]