OBJECTIVE To evaluate the association between acute-to-chronic (A/C) glycemic ratio and mortality and severity outcomes for patients with type 2 diabetes (T2D) hospitalized with coronavirus disease 2019 (COVID-19). RESEARCH DESIGN AND METHODS A total of 91 patients were included. We measured glycemia at admission and estimated the average chronic glucose levels to calculate the A/C glycemic ratio. The primary outcome was a composite of in-hospital mortality, intensive care unit admission, and mechanical ventilation. RESULTS Thirty-five patients had a primary outcome event, presenting a significant association with the A/C glycemic ratio (hazard ratio [HR] 1.57 [95% CI 1.14–2.15], P = 0.005). In comparisons with the 2nd tertile, the 3rd tertile of the A/C glycemic ratio was associated with the primary outcome (HR 3.39 [95% CI 1.31–8.75], P = 0.012). In the multivariate analysis, after additional adjustment for age, sex, comorbidities, inflammatory markers, and corticosteroid therapy, the association for the 3rd tertile (HR 3.96 [95% CI 1.35–11.59], P = 0.012) remained significant. CONCLUSIONS In patients with T2D hospitalized with COVID-19, the imbalance between acute glycemia at admission and chronic metabolic control is associated with worse prognosis.

OBJECTIVE The deletion (D) allele of the ACE insertion/deletion (I/D) polymorphism is a risk factor for diabetic kidney disease. We assessed its contribution to long-term kidney outcomes and all-cause death in patients with long-standing type 1 diabetes. RESEARCH DESIGN AND METHODS A total of 1,155 participants from three French and Belgian cohorts were monitored for a median duration of 14 (interquartile range 13) years. The primary outcome was the occurrence of end-stage kidney disease (ESKD) or a 40% drop in the estimated glomerular filtration rate (eGFR). Secondary outcomes were the individual components of the primary outcome, rapid decline in eGFR (steeper than –3 mL/min/1.73 m² per year), incident albuminuria, all-cause death, and a composite ESKD or all-cause death. Hazard ratios (HRs) for XD versus II genotype and for baseline plasma ACE levels were computed by Cox analysis. Genotype performance in stratifying the primary outcome was tested. RESULTS Genotype distribution was 954 XD and 201 II. The primary outcome occurred in 20% of XD and 13% of II carriers: adjusted HR 2.07 (95% CI 1.32–3.40; P = 0.001). Significant associations were also observed for rapid decline in eGFR, incident albuminuria, ESKD, all-cause death, and ESKD or all-cause death. Baseline plasma ACE levels were higher in XD carriers and significantly associated with an increased risk of the primary outcome. The ACE genotype enhanced net reclassification improvement (0.154, 95% CI 0.007–0.279; P = 0.04) and integrated discrimination improvement (0.012, 95%CI 0.001–0.021; P = 0.02) for primary outcome stratification. CONCLUSIONS The D-allele of the ACE I/D polymorphism was associated with an increased risk of major kidney events and all-cause death in patients with long-standing type 1 diabetes.

OBJECTIVE Better preconception metabolic and nutritional health are hypothesized to promote gestational normoglycemia and reduce preterm birth, but evidence supporting improved outcomes with nutritional supplementation starting preconception is limited. RESEARCH DESIGN AND METHODS This double-blind randomized controlled trial recruited from the community 1,729 U.K., Singapore, and New Zealand women aged 18–38 years planning conception. We investigated whether a nutritional formulation containing myo-inositol, probiotics, and multiple micronutrients (intervention), compared with a standard micronutrient supplement (control), taken preconception and throughout pregnancy could improve pregnancy outcomes. The primary outcome was combined fasting, 1-h, and 2-h postload glycemia (28 weeks gestation oral glucose tolerance test). RESULTS Between 2015 and 2017, participants were randomized to control (n = 859) or intervention (n = 870); 585 conceived within 1 year and completed the primary outcome (295 intervention, 290 control). In an intention-to-treat analysis adjusting for site, ethnicity, and preconception glycemia with prespecified P < 0.017 for multiplicity, there were no differences in gestational fasting, 1-h, and 2-h glycemia between groups (β [95% CI] log_e mmol/L intervention vs. control −0.004 [−0.018 to 0.011], 0.025 [−0.014 to 0.064], 0.040 [0.004–0.077], respectively). Between the intervention and control groups there were no significant differences in gestational diabetes mellitus (24.8% vs. 22.6%, adjusted risk ratio [aRR] 1.22 [0.92–1.62]), birth weight (adjusted β = 0.05 kg [−0.03 to 0.13]), or gestational age at birth (mean 39.3 vs. 39.2 weeks, adjusted β = 0.20 [−0.06 to 0.46]), but there were fewer preterm births (5.8% vs. 9.2%, aRR 0.43 [0.22–0.82]), adjusting for prespecified covariates. CONCLUSIONS Supplementation with myo-inositol, probiotics, and micronutrients preconception and in pregnancy did not lower gestational glycemia but did reduce preterm birth.

OBJECTIVE SMART-GDM examined whether Habits-GDM, a smartphone application (app) coaching program, can prevent excessive gestational weight gain (EGWG) and improve glycemic control and maternal and neonatal outcomes in gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS In this randomized controlled trial, women diagnosed with GDM between 12 and 30 weeks were randomly assigned to usual care (control) or to additional support from Habits-GDM that integrated dietary, physical activity, weight, and glucose monitoring (intervention). The primary outcome was the proportion of participants with EGWG. Secondary outcomes included absolute gestational weight gain (GWG), glycemic control, and maternal, delivery, and neonatal outcomes. RESULTS In total, 340 women were randomized (170 intervention, 170 control; mean ± SD age 32.0 ± 4.2 years; mean BMI 25.6 ± 5.6 kg/m²). There were no statistically significant differences in the proportions of women with EGWG, absolute GWG, or maternal and delivery outcomes between experimental groups. Average glucose readings were lower in the intervention group (mean difference −0.15 mmol/L [95% CI −0.26; −0.03], P = 0.011) as were the proportions of glucose above targets (premeal: 17.9% vs. 23.3%, odds ratio 0.68 [95% CI 0.53; 0.87], P = 0.003; 2-h postmeal: 19.9% vs. 50%, 0.54 [0.42; 0.70], P < 0.001). When regarded as a composite (although not prespecified), the overall neonatal complications (including birth trauma, neonatal hypoglycemia, hyperbilirubinemia, respiratory distress, neonatal intensive care unit admission, and perinatal death) were significantly lower in the intervention group (38.1% vs. 53.7%, 0.53 [0.34; 0.84], P = 0.006). CONCLUSIONS When added to usual care, Habits-GDM resulted in better maternal glycemic control and composite neonatal outcomes (nonprespecified) but did not reduce EGWG among women with GDM.

OBJECTIVE The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial demonstrated that glycemic failure rates were significantly lower in youth randomized to metformin plus rosiglitazone treatment than in youth randomized to metformin alone or metformin plus intensive lifestyle intervention. At the end of the study, rosiglitazone was permanently discontinued, and routine diabetes care resumed. Herein, we report postintervention glycemic failure rates in TODAY participants over an additional 36 months of follow-up for the three original treatment arms and describe insulin sensitivity and β-cell function outcomes. RESEARCH DESIGN AND METHODS A total of 699 participants were randomized during TODAY, of whom 572 enrolled in the TODAY2 observational follow-up. Glycemic failure was defined as HbA_1c ≥8% over a 6-month period, inability to wean from temporary insulin therapy within 3 months after acute metabolic decompensation during TODAY, or sustained HbA_1c ≥8% over two consecutive visits during TODAY2. Oral glucose tolerance tests were conducted, and insulin sensitivity, insulinogenic index, and oral disposition index were calculated. RESULTS During the 36 months of TODAY2, glycemic failure rates did not differ among participants by original treatment group assignment. Insulin sensitivity and β-cell function deteriorated rapidly during the 36 months of TODAY2 routine diabetes care but did not differ by treatment group assignment. CONCLUSIONS The added benefit of preventing glycemic failure by using rosiglitazone as a second agent in youth-onset type 2 diabetes did not persist after its discontinuation. More work is needed to address this rapid progression to avoid long-term diabetes complications.

OBJECTIVE Limited information is available about glycemic outcomes with a closed-loop control (CLC) system compared with a predictive low-glucose suspend (PLGS) system. RESEARCH DESIGN AND METHODS After 6 months of use of a CLC system in a randomized trial, 109 participants with type 1 diabetes (age range, 14–72 years; mean HbA_1c, 7.1% [54 mmol/mol]) were randomly assigned to CLC (N = 54, Control-IQ) or PLGS (N = 55, Basal-IQ) groups for 3 months. The primary outcome was continuous glucose monitor (CGM)-measured time in range (TIR) for 70–180 mg/dL. Baseline CGM metrics were computed from the last 3 months of the preceding study. RESULTS All 109 participants completed the study. Mean ± SD TIR was 71.1 ± 11.2% at baseline and 67.6 ± 12.6% using intention-to-treat analysis (69.1 ± 12.2% using per-protocol analysis excluding periods of study-wide suspension of device use) over 13 weeks on CLC vs. 70.0 ± 13.6% and 60.4 ± 17.1% on PLGS (difference = 5.9%; 95% CI 3.6%, 8.3%; P < 0.001). Time >180 mg/dL was lower in the CLC group than PLGS group (difference = −6.0%; 95% CI −8.4%, −3.7%; P < 0.001) while time <54 mg/dL was similar (0.04%; 95% CI −0.05%, 0.13%; P = 0.41). HbA_1c after 13 weeks was lower on CLC than PLGS (7.2% [55 mmol/mol] vs. 7.5% [56 mmol/mol], difference −0.34% [−3.7 mmol/mol]; 95% CI −0.57% [−6.2 mmol/mol], −0.11% [1.2 mmol/mol]; P = 0.0035). CONCLUSIONS Following 6 months of CLC, switching to PLGS reduced TIR and increased HbA_1c toward their pre-CLC values, while hypoglycemia remained similarly reduced with both CLC and PLGS.

OBJECTIVE To investigate the relationship between lifestyle counseling in primary care settings and clinical outcomes in patients with diabetes. RESEARCH DESIGN AND METHODS We retrospectively studied hyperglycemic adults with diabetes treated at primary care practices between 2000 and 2014. We analyzed the relationship between frequency of lifestyle counseling (identified using natural language processing of electronic notes) and a composite outcome of death and cardiovascular events during subsequent follow-up. RESULTS Among patients with monthly counseling or more, 10-year cumulative incidence of the primary outcome was 33.0% compared with 38.1% for less than monthly counseling (P = 0.0005). In multivariable analysis, higher frequency of lifestyle counseling was associated with lower incidence of the primary outcome (hazard ratio 0.88 [95% CI 0.82–0.94]; P < 0.001). CONCLUSIONS More frequent lifestyle counseling was associated with a lower incidence of cardiovascular events and death among patients with diabetes.

OBJECTIVE Pediatric hepatic steatosis is highly prevalent and closely related to type 2 diabetes. This study aimed to determine whether the addition of supervised exercise to a family-based lifestyle and psycho-educational intervention results in greater reduction of percentage of hepatic fat (HF), adiposity, and cardiometabolic risk factors in children with overweight/obesity. RESEARCH DESIGN AND METHODS The study subjects of this nonrandomized, two-arm, parallel design clinical trial were 116 overweight/obese children (10.6 ± 1.1 years of age, 53.4% girls) living in Vitoria-Gasteiz (Spain). For 22 weeks, they followed either a lifestyle and psycho-education program (control intervention [CInt], N = 57), consisting of two family-based education sessions/month, or the same plus supervised exercise (intensive intervention [II], N = 59) focused mainly on high-intensity aerobic workouts (3 sessions/week, 90 min/session). The primary outcome was the change in percentage of HF (as measured by MRI) between baseline and the end of the intervention period. Secondary outcomes included changes in BMI, fat mass index (FMI), abdominal fat (measured by DEXA), blood pressure, triglycerides, HDL, LDL, γ-glutamyl transferase, glucose, and insulin concentrations. RESULTS A total of 102 children completed the trial (N = 53 and N = 49 in the CInt and II groups, respectively). Percentage of HF decreased only in the II group (−1.20 ± 0.31% vs. 0.04 ± 0.30%, II and CInt groups, respectively), regardless of baseline value and any change in adiposity (P < 0.01). BMI, FMI, abdominal fat (P ≤ 0.001), and insulin (P < 0.05) were reduced in both groups. CONCLUSIONS Multicomponent intervention programs that include exercise training may help to reduce adiposity, insulin resistance, and hepatic steatosis in overweight/obese children.

OBJECTIVE While vitamin E has shown to improve nonalcoholic steatohepatitis (NASH) in patients without diabetes, information on patients with type 2 diabetes mellitus (T2DM) is lacking. The aim of this study was to determine whether vitamin E, alone or combined with pioglitazone, improves histology in patients with T2DM and NASH. RESEARCH DESIGN AND METHODS This was a proof-of-concept, randomized, double-blind, placebo-controlled trial conducted from 2010 to 2016. Patients with T2DM and biopsy-proven NASH (n = 105) were randomized to vitamin E 400 IU b.i.d., vitamin E 400 IU b.i.d. plus pioglitazone 45 mg/day, or placebo. Eighty-six patients completed the 18-month study. The primary end point was a two-point reduction in the nonalcoholic fatty liver disease activity score from two different parameters, without worsening of fibrosis. Secondary outcomes were resolution of NASH without worsening of fibrosis, individual histological scores, and metabolic parameters. RESULTS More patients on combination therapy achieved the primary outcome versus placebo (54% vs. 19%, P = 0.003) but not with vitamin E alone (31% vs. 19%, P = 0.26). Both groups showed improvements in resolution of NASH compared with placebo (combination group: 43% vs. 12%, P = 0.005; vitamin E alone: 33% vs. 12%, P = 0.04). While steatosis assessed by histology improved with combination therapy (P < 0.001) and vitamin E alone (P = 0.018), inflammation (P = 0.018) and ballooning (P = 0.022) only improved with combination therapy. No improvement in fibrosis was observed in any group. CONCLUSIONS In this proof-of-concept study, combination therapy was better than placebo in improving liver histology in patients with NASH and T2DM. Vitamin E alone did not significantly change the primary histological outcome.

OBJECTIVE To determine if a structured transition program for young adults with type 1 diabetes improves clinic attendance, glycemic control, diabetes-related distress, quality of life, and satisfaction with care. RESEARCH DESIGN AND METHODS In this multicenter randomized controlled trial, young adults (17–20 years) with type 1 diabetes were randomly assigned to a transition program with a transition coordinator or to standard care. The intervention lasted 18 months (6 in pediatric and 12 in adult care). The primary outcome was the proportion of participants who failed to attend at least one adult diabetes clinic visit during the 12-month follow-up after completion of the intervention. RESULTS We randomized 205 participants, 104 to the transition program and 101 to standard care. Clinic attendance was improved in the transition program (mean [SD] number of visits 4.1 [1.1] vs. 3.6 [1.2], P = 0.002), and there was greater satisfaction with care (mean [SD] score 29.0 [2.7] vs. 27.9 [3.4], P = 0.032) and less diabetes-related distress (mean [SD] score 1.9 [0.8] vs. 2.1 [0.8], P = 0.049) reported than in standard care. There was a trend toward improvement in mean HbA_1c (8.33% [68 mmol/mol] vs. 8.80% [73 mmol/mol], P = 0.057). During the 12-month follow-up, there was no difference in those failing to attend at least one clinic visit (P = 0.846), and the mean change in HbA_1c did not differ between the groups (P = 0.073). At completion of follow-up, the groups did not differ with respect to satisfaction with care or diabetes-related distress and quality of life. CONCLUSIONS Transition support during this 18-month intervention was associated with increased clinic attendance, improved satisfaction with care, and decreased diabetes-related distress, but these benefits were not sustained 12 months after completion of the intervention.

OBJECTIVE Marshallese adults experience high rates of type 2 diabetes. Previous diabetes self-management education (DSME) interventions among Marshallese were unsuccessful. This study compared the extent to which two DSME interventions improved glycemic control, measured on the basis of change in glycated hemoglobin (HbA_1c). RESEARCH DESIGN AND METHODS A two-arm randomized controlled trial compared a standard-model DSME (standard DSME) with a culturally adapted family-model DSME (adapted DSME). Marshallese adults with type 2 diabetes (n = 221) received either standard DSME in a community setting (n = 111) or adapted DSME in a home setting (n = 110). Outcome measures were assessed at baseline, immediately after the intervention, and at 6 and 12 months after the intervention and were examined with adjusted linear mixed-effects regression models. RESULTS Participants in the adapted DSME arm showed significantly greater declines in mean HbA_1c immediately (−0.61% [95% CI −1.19, −0.03]; P = 0.038) and 12 months (−0.77% [95% CI −1.38, −0.17]; P = 0.013) after the intervention than those in the standard DSME arm. Within the adapted DSME arm, participants had significant reductions in mean HbA_1c from baseline to immediately after the intervention (−1.18% [95% CI −1.55, −0.81]), to 6 months (−0.67% [95% CI −1.06, −0.28]), and to 12 months (−0.87% [95% CI −1.28, −0.46]) (P < 0.001 for all). Participants in the standard DSME arm had significant reductions in mean HbA_1c from baseline to immediately after the intervention (−0.55% [95% CI −0.93, −0.17]; P = 0.005). CONCLUSIONS Participants receiving the adapted DSME showed significantly greater reductions in mean HbA_1c immediately after and 12 months after the intervention than the reductions among those receiving standard DSME. This study adds to the body of research that shows the potential effectiveness of culturally adapted DSME that includes participants’ family members.

OBJECTIVE Continuous subcutaneous insulin infusion (CSII) is the most advanced form of insulin delivery, but it requires structured education to provide users with the necessary knowledge/skills and to support their motivation. Currently, no structured education program designed to provide this training has been evaluated. We developed a CSII-specific, structured education program (Insulin Pump Treatment [INPUT]) and evaluated its impact on glycemic control, behavior, and psychosocial status. RESEARCH DESIGN AND METHODS This was a multicenter, randomized, parallel trial with a 6-month follow-up. Eligible participants (age 16–75 years) currently were treated with insulin pump therapy. Participants were randomly assigned (1:1) to the INPUT program or to usual care using a computer-generated algorithm, with study center as the stratification factor. The primary outcome was HbA_1c change from baseline to 6 months. Secondary outcomes were incidence of severe hypoglycemia and changes in behavioral and psychosocial measures. RESULTS Between 1 April 2016 and 26 April 2016, 268 people with diabetes and a mean duration of CSII therapy of 9.5 years were randomly assigned to the INPUT group (n = 135) or control group (n = 133). At 6 months, HbA_1c improved in the INPUT group (8.33 ± 0.8 vs. 8.04 ± 0.9; P < 0.0001) but not in the control group (8.33 ± 1.0 vs. 8.27 ± 1.0; P = 0.11). The between-group difference in HbA_1c reduction was significant, favoring INPUT (−0.28% vs. −0.06%, Δ −0.22%, 95% CI −0.38 to −0.06; P = 0.0029). The incidence rate ratio of severe hypoglycemia was 3.55 times higher for participants in the control group than for those in the INPUT group (95% CI 1.50–8.43; P = 0.0041). CONCLUSIONS The INPUT education program led to a significant improvement in glycemic control and incidence of severe hypoglycemia in insulin pump users.

OBJECTIVE Type 2 diabetes (T2D) results from progressive loss of β-cell function. The BetaFat study compared gastric banding and metformin for their impact on β-cell function in adults with moderate obesity and impaired glucose tolerance (IGT) or recently diagnosed, mild T2D. RESEARCH DESIGN AND METHODS Eighty-eight people aged 21–65 years, BMI 30–40 kg/m², with IGT or diabetes known for <1 year, were randomized to gastric banding or metformin for 2 years. Hyperglycemic clamps (11.1 mmol/L) followed by arginine injection at maximally potentiating glycemia (>25 mmol/L) were performed at baseline, 12 months, and 24 months to measure steady-state C-peptide (SSCP) and acute C-peptide response to arginine at maximum glycemic potentiation (ACPRmax) and insulin sensitivity (M/I). RESULTS At 24 months, the band group lost 10.7 kg; the metformin group lost 1.7 kg (P < 0.01). Insulin sensitivity increased 45% in the band group and 25% in the metformin group (P = 0.30 between groups). SSCP adjusted for insulin sensitivity fell slightly but not significantly in each group (P = 0.34 between groups). ACPRmax adjusted for insulin sensitivity fell significantly in the metformin group (P = 0.002) but not in the band group (P = 0.25 between groups). HbA_1c fell at 12 and 24 months in the band group (P < 0.004) but only at 12 months (P < 0.01) in the metformin group (P > 0.14 between groups). Normoglycemia was present in 22% and 15% of band and metformin groups, respectively, at 24 months (P = 0.66 between groups). CONCLUSIONS Gastric banding and metformin had similar effects to preserve β-cell function and stabilize or improve glycemia over a 2-year period in moderately obese adults with IGT or recently diagnosed, mild T2D.

OBJECTIVE Rigorous evidence is lacking whether online games can improve patients’ longer-term health outcomes. We investigated whether an online team-based game delivering diabetes self-management education (DSME) to patients via e-mail or mobile application (app) can generate longer-term improvements in hemoglobin A_1c (HbA_1c). RESEARCH DESIGN AND METHODS Patients (n = 456) on oral diabetes medications with HbA_1c ≥58 mmol/mol were randomly assigned between a DSME game (with a civics booklet) and a civics game (with a DSME booklet). The 6-month games sent two questions twice weekly via e-mail or mobile app. Participants accrued points based on performance, with scores posted on leaderboards. Winning teams and individuals received modest financial rewards. Our primary outcome measure was HbA_1c change over 12 months. RESULTS DSME game patients had significantly greater HbA_1c reductions over 12 months than civics game patients (−8 mmol/mol [95% CI −10 to −7] and −5 mmol/mol [95% CI −7 to −3], respectively; P = 0.048). HbA_1c reductions were greater among patients with baseline HbA_1c >75 mmol/mol: −16 mmol/mol [95% CI −21 to −12] and −9 mmol/mol [95% CI −14 to −5] for DSME and civics game patients, respectively; P = 0.031. CONCLUSIONS Patients with diabetes who were randomized to an online game delivering DSME demonstrated sustained and meaningful HbA_1c improvements. Among patients with poorly controlled diabetes, the DSME game reduced HbA_1c by a magnitude comparable to starting a new diabetes medication. Online games may be a scalable approach to improve outcomes among geographically dispersed patients with diabetes and other chronic diseases.

OBJECTIVE In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, ∼4 years of intensive versus standard glycemic control in participants with type 2 diabetes and other cardiovascular risk factors had a neutral effect on the composite cardiovascular outcome, increased cardiovascular and total mortality, and reduced nonfatal myocardial infarction. Effects of the intervention during prolonged follow-up were analyzed. RESEARCH DESIGN AND METHODS All surviving ACCORD participants were invited to participate in the ACCORD Follow-on (ACCORDION) study, during which participants were treated according to their health care provider’s judgment. Cardiovascular and other health-related outcomes were prospectively collected and analyzed using an intention-to-treat approach according to the group to which participants were originally allocated. RESULTS A total of 8,601 people, representing 98% of those who did not suffer a primary outcome or death during the ACCORD trial, were monitored for a median of 8.8 years and a mean of 7.7 years from randomization. Intensive glucose lowering for a mean of 3.7 years had a neutral long-term effect on the primary composite outcome (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death), death from any cause, and an expanded composite outcome that included all-cause death. Moreover, the risk of cardiovascular mortality noted during the active phase (hazard ratio 1.49; 95% CI 1.19, 1.87; P < 0.0001) decreased (HR 1.20; 95% CI 1.03, 1.39; P = 0.02). CONCLUSIONS In high-risk people with type 2 diabetes monitored for 9 years, a mean of 3.7 years of intensive glycemic control had a neutral effect on death and nonfatal cardiovascular events but increased cardiovascular-related death.

The development of artificial pancreas systems has evolved to the point that pivotal studies designed to assess efficacy and safety are in progress or soon to be initiated. These pivotal studies are intended to provide the necessary data to gain clearance from the U.S. Food and Drug Administration, coverage by payers, and adoption by patients and clinicians. Although there will not be one design that is appropriate for every system, there are certain aspects of protocol design that will be considerations in all pivotal studies designed to assess efficacy and safety. One key aspect of study design is the intervention to be used by the control group. A case can be made that the control group should use the currently available best technology, which is sensor-augmented pump therapy. However, an equally, if not more, compelling case can be made that the control intervention should be usual care. In this Perspective, we elaborate on this issue and provide a pragmatic approach to the design of clinical trials of artificial pancreas systems.

OBJECTIVE Glycemic variability may contribute to adverse medical outcomes of type 2 diabetes, but prior therapies have had limited success in controlling glycemic fluctuations, and the hypothesis has not been adequately tested. RESEARCH DESIGN AND METHODS People with insulin-requiring type 2 diabetes and high cardiovascular risk were enrolled during a run-in period on basal-bolus insulin (BBI), and 102 were randomized to continued BBI or to basal insulin with a prandial GLP-1 receptor agonist (GLIPULIN) group, each seeking to maintain HbA_1c levels between 6.7% and 7.3% (50–56 mmol/mol) for 6 months. The primary outcome measure was glycemic variability assessed by continuous glucose monitoring; other measures were HbA_1c, weight, circulating markers of inflammation and cardiovascular risk, albuminuria, and electrocardiographic patterns assessed by Holter monitoring. RESULTS At randomization, the mean age of the population was 62 years, median duration of diabetes 15 years, mean BMI 34 kg/m², and mean HbA_1c 7.9% (63 mmol/mol). Thirty-three percent had a prior cardiovascular event, 18% had microalbuminuria, and 3% had macroalbuminuria. At baseline, the continuous glucose monitoring coefficient of variation for glucose levels was similar in both groups. CONCLUSIONS FLAT-SUGAR is a proof-of-concept study testing whether, in a population of individuals with type 2 diabetes and high cardiovascular risk, the GLIPULIN regimen can limit glycemic variability more effectively than BBI, reduce levels of cardiovascular risk markers, and favorably alter albuminuria and electrocardiographic patterns. We successfully randomized a population that has sufficient power to answer the primary question, address several secondary ones, and complete the protocol as designed.

Over the past three decades there have been a number of clinical trials directed at interdicting the type 1 diabetes (T1D) disease process in an attempt to prevent the development of the disease in those at increased risk or to stabilize—potentially even reverse—the disease in people with T1D, usually of recent onset. Unfortunately, to date there has been no prevention trial that has resulted in delay or prevention of T1D. And, trials in people with T1D have had mixed results with some showing promise with at least transient improvement in β-cell function compared with randomized control groups, while others have failed to slow the decline in β-cell function when compared with placebo. This Perspective will assess the past and present challenges in this effort and provide an outline for potential future opportunities.

OBJECTIVE This study tested the hypothesis that intensive treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial disproportionately produced adverse outcomes in patients with diabetes with a high hemoglobin glycation index (HGI = observed HbA_1c − predicted HbA_1c). RESEARCH DESIGN AND METHODS ACCORD was a randomized controlled trial of 10,251 patients with type 2 diabetes assigned to standard or intensive treatment with HbA_1c goals of 7.0% to 7.9% (53 to 63 mmol/mol) and less than 6% (42 mmol/mol), respectively. In this ancillary study, a linear regression equation (HbA_1c = 0.009 × fasting plasma glucose [FPG] [mg/dL] + 6.8) was derived from 1,000 randomly extracted participants at baseline. Baseline FPG values were used to calculate predicted HbA_1c and HGI for the remaining 9,125 participants. Kaplan-Meier and Cox regression were used to assess the effects of intensive treatment on outcomes in patients with a low, moderate, or high HGI. RESULTS Intensive treatment was associated with improved primary outcomes (composite of cardiovascular events) in the low (hazard ratio [HR] 0.75 [95% CI 0.59–0.95]) and moderate (HR 0.77 [95% CI 0.61–0.97]) HGI subgroups but not in the high HGI subgroup (HR 1.14 [95% CI 0.93–1.40]). Higher total mortality in intensively treated patients was confined to the high HGI subgroup (HR 1.41 [95% CI 1.10–1.80]). A high HGI was associated with a greater risk for hypoglycemia in the standard and intensive treatment groups. CONCLUSIONS HGI calculated at baseline identified subpopulations in ACCORD with harms or benefits from intensive glycemic control. HbA_1c is not a one-size-fits-all indicator of blood glucose control, and taking this into account when making management decisions could improve diabetes care.

OBJECTIVE Depression is a common comorbidity of diabetes, undesirably affecting patients’ physical and mental functioning. Psychological interventions are effective treatments for depression in the general population as well as in patients with a chronic disease. The aim of this study was to assess the efficacy of individual mindfulness-based cognitive therapy (MBCT) and individual cognitive behavior therapy (CBT) in comparison with a waiting-list control condition for treating depressive symptoms in adults with type 1 or type 2 diabetes. RESEARCH DESIGN AND METHODS In this randomized controlled trial, 94 outpatients with diabetes and comorbid depressive symptoms (i.e., Beck Depression Inventory-II [BDI-II] ≥14) were randomized to MBCT (n = 31), CBT (n = 32), or waiting list (n = 31). All participants completed written questionnaires and interviews at pre- and postmeasurement (3 months later). Primary outcome measure was severity of depressive symptoms (BDI-II and Toronto Hamilton Depression Rating Scale). Anxiety (Generalized Anxiety Disorder 7), well-being (Well-Being Index), diabetes-related distress (Problem Areas In Diabetes), and HbA_1c levels were assessed as secondary outcomes. RESULTS Results showed that participants receiving MBCT and CBT reported significantly greater reductions in depressive symptoms compared with patients in the waiting-list control condition (respectively, P = 0.004 and P < 0.001; d = 0.80 and 1.00; clinically relevant improvement 26% and 29% vs. 4%). Both interventions also had significant positive effects on anxiety, well-being, and diabetes-related distress. No significant effect was found on HbA_1c values. CONCLUSIONS Both individual MBCT and CBT are effective in improving a range of psychological symptoms in individuals with type 1 and type 2 diabetes.