OBJECTIVE: The overall aim of the Alliance of Randomized Trials of Medicine versus Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D) consortium is to assess the durability and longer-term effectiveness of metabolic surgery compared to medical/lifestyle management in patients with type 2 diabetes (NCT02328599). RESEARCH DESIGN AND METHODS: 316 patients with type 2 diabetes previously randomized to surgery (N=195) or medical/lifestyle therapy (N=121) in the STAMPEDE, TRIABETES, SLIMM-T2D and CROSSROADS trials were enrolled into this prospective observational cohort. The primary outcome was the rate of diabetes remission (hemoglobin A1c (HbA1c) ≤6.5% for 3 months without usual glucose-lowering therapy) at three years. Secondary outcomes included glycemic control, body weight, biomarkers, and comorbidity reduction. RESULTS: Three-year data were available for 256 patients with mean age 50±8.3 years, BMI 36.5±3.6 kg/m2 and duration of diabetes 8.8±5.7 years. Diabetes remission was achieved in more participants following surgery than medical/lifestyle intervention (60/160 (37.5%) vs. 2/76 (2.6%), respectively, p<0.001). Reductions in HbA1c (Δ = -1.9±2.0 vs. -0.1±2.0%, p<0.001), fasting plasma glucose (Δ = -52[-105, -5] vs. -12[-48, 26] mg/dL, p<0.001) and BMI (Δ = -8.0±3.6 vs. -1.8±2.9 kg/m2, p<0.001) were also greater after surgery. The percentage of patients using medications to control diabetes, hypertension, and dyslipidemia were all lower after surgery (p<0.001). CONCLUSIONS: Three-year follow-up of the largest cohort of randomized patients followed to date demonstrates that metabolic/bariatric surgery is more effective and durable than medical/lifestyle intervention in remission of type 2 diabetes, including among individuals with class 1 obesity, for whom surgery is not widely used.

Aims To evaluate the efficacy and safety of dapagliflozin (DAPA) + saxagliptin (SAXA) compared with glimepiride (GLIM) in patients with type 2 diabetes who were inadequately controlled [glycated haemoglobin (HbA1c) 7.5-10.5% (58-91 mmol/mol)] on metformin monotherapy. Materials and methods This 52-week, multicentre, double-blind, active-controlled study (NCT02419612) randomized (1:1) patients on metformin to add-on DAPA 10 mg + SAXA 5 mg (n =227) or GLIM 1-6 mg (titrated;n =217). The primary efficacy endpoint was change in HbA1c from baseline to week 52. Results Baseline mean +/- standard deviation of age, duration of diabetes and HbA1c were 56.1 +/- 9.7 years, 7.8 +/- 6.4 years and 8.5% +/- 0.8% (69 +/- 9.0 mmol/mol), respectively. Adjusted mean change from baseline in HbA1c was -1.35% (-14.8 mmol/mol) with DAPA + SAXA versus -0.98% (-10.7 mmol/mol) with GLIM (P <0.001). Changes from baseline in body weight and systolic blood pressure were -3.1 kg and -2.6 mmHg with DAPA + SAXA versus +1.0 kg (P <0.001) and +1.0 mmHg (P =0.007) with GLIM. More patients achieved HbA1c <7.0% (53 mmol/mol) (44.3% vs. 34.3%;P =0.044), and fewer patients required treatment intensification (1.3% vs. 8.8%;P =0.002) with DAPA + SAXA than with GLIM. Conclusions Compared with GLIM, concurrent addition of DAPA + SAXA significantly improved glycaemic control, body weight and other metabolic parameters in patients inadequately controlled on metformin. Trial: NCT02419612, ClinicalTrials.gov.

The brain mechanisms underlying the association of hyperglycemia with depressive symptoms are unknown. We hypothesized that disrupted glutamate metabolism in pregenual anterior cingulate cortex (ACC) in type 1 diabetes (T1D) without depression affects emotional processing. Using proton magnetic resonance spectroscopy (MRS), we measured glutamate concentrations in ACC and occipital cortex (OCC) in 13 T1D without major depression (HbA1c=7.1±0.7% [54±7mmol/mol]) and 11 healthy non-diabetic controls (HbA1c=5.5±0.2% [37±3mmol/mol]) during fasting euglycemia (EU) followed by a 60-minute +5.5mmol/l hyperglycemic clamp (HG). Intrinsic neuronal activity was assessed using resting-state blood oxygen level dependent functional MRI to measure the fractional amplitude of low frequency fluctuations in slow-band 4 (fALFF4). Emotional processing and depressive symptoms were assessed using emotional tasks (Emotional-Stroop, Self-Referent-Encoding-Task SRET) and clinical ratings (HAM-D, SCL-90-R), respectively. During HG, ACC glutamate increased (1.2mmol/kg, +10%, p=0.014) while ACC fALFF4 was unchanged (-0.007, -2%, p=0.449) in T1D; in contrast, glutamate was unchanged (-0.2mmol/kg, -2%, p=0.578) while fALFF4 decreased (-0.05, -13%, p=0.002) in controls. OCC glutamate and fALFF4 were unchanged in both groups. T1D had longer SRET negative-word response-times (p=0.017) and higher depression-rating scores (HAM-D p=0.020; SCL-90-R-depression p=0.008). Higher glutamate change tended to associate with longer Emotional-Stroop response-times in T1D only. Brain glutamate must be tightly controlled during hyperglycemia due to the risk for neurotoxicity with excessive levels. Results suggest that ACC glutamate control mechanisms are disrupted in T1D, which affects glutamatergic neurotransmission related to emotional or cognitive processing. Increased prefrontal glutamate during acute hyperglycemic episodes could explain our previous findings of associations between chronic hyperglycemia, cortical thinning and depressive symptoms in T1D.

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.

Patients with T2D inadequately controlled by metformin require additional oral antidiabetes agent(s), injected GLP-1 or basal insulin. Although insulin has greater effect on A1C than a DPP-4 or SGLT2 inhibitor, its higher rates of hypoglycemia, weight gain and regimen burden might decrease satisfaction and quality of life. We analyzed patient-reported outcomes (PRO) from patients with T2D inadequately controlled by metformin ± sulfonylurea during an international, randomized, 24-week, open-label, non-inferiority trial (NCT02551874) of dapagliflozin plus saxagliptin add-on (DAPA + SAXA, n = 324) compared to titrated insulin glargine add-on (INS, n = 319). A1C and PRO questionnaires were obtained at baseline and weeks 12 and 24. Baseline data were: 54.0% male; 80.4% white; 60.7% working ≥3 days/week; age 55.5 ± 9.6 years; A1C 9.0 ± 1.0%; BMI 32.2 ± 5.3 kg/m2; diabetes duration 9.4 ± 6.3 years. Overall Satisfaction, Regimen Acceptance and its eight subscales, Net Benefit and Preference subscale, and Weight Concern all favored DAPA + SAXA at week 24 (Table). Quality of life scales favored DAPA + SAXA at week 12, but were not different at week 24. Compared to INS, DAPA + SAXA had greater treatment satisfaction and acceptance, better short-term quality of life, and less burden and concern about weight gain, hypoglycemia and pain despite comparable A1C. Change from baseline in HbA1c and PRO at Wk 24 [LS Mean (SE)]: Higher value denotes better outcomeWk-24 EndpointDAPA + SAXA + MetforminINS + MetforminP-valueWk-24 EndpointDAPA + SAXA + MetforminINS + MetforminP-valueHbA1c (%)−1.67 (0.06)−1.54 (0.06)0.118-- Interference6.45 (0.98)2.75 (1.00)0.009Overall Satisfaction10.14 (0.63)6.19 (0.64)<0.0001-- Social4.32 (0.83)0.62 (0.85)0.002- Regimen Acceptance7.00 (0.72)2.28 (0.73)<0.0001-- Pain4.41 (0.94)−1.93 (0.96)<0.0001-- Burden7.70 (0.85)2.48 (0.86)<0.0001-- Side Effects6.(0.99)0.17 (1.00)<0.0001-- Convenience8.01 (0.89)2.95 (0.91)<0.0001- Net Benefit17.36 (0.67)15.34 (0.68)0.035-- Flexibility9.91 (1.01)4.69 (1.02)<0.001-- Preference30.69 (1.24)26.26 (1.26)0.012-- Hassle5.92 (0.94)1.83 (0.95)0.002Weight Concern17.68 (2.46)10.38 (2.50)0.038 Disclosure M.A. Testa: Stock/Shareholder; Spouse/Partner; GI Windows, Inc.. Stock/Shareholder; Self; Phase V Technologies, Inc. D.C. Simonson: Advisory Panel; Self; GI Windows, Inc.. Stock/Shareholder; Self; GI Windows, Inc.. Stock/Shareholder; Spouse/Partner; Phase V Technologies, Inc. E. Ekholm: None. M. Su: None. E.K. Johnsson: Employee; Self; AstraZeneca.

Glycemic excursions, variability, and hypoglycemia may impact therapeutic effectiveness even when A1C reduction is comparable between therapies. We analyzed masked continuous glucose monitoring (CGM) data from patients with type 2 diabetes (T2D) inadequately controlled on metformin ± sulfonylurea during an international randomized, 24-week, open-label, non-inferiority trial of dapagliflozin plus saxagliptin add-on (DAPA + SAXA, n = 141) compared to titrated insulin glargine add-on (INS, n = 142). Six-day CGM (288 readings/day), A1C and patient-reported outcomes (PRO) were measured at baseline and Weeks 2, 12 and 24. At baseline, patients had mean ± SD age = 55.2 ± 9.4 years; A1C = 9.1 ± 1.1%; diabetes duration = 9.8 ± 6.1 years; 54.1% male. Using linear mixed models, mean ± SE changes in A1C for DAPA + SAXA vs. INS at Week 24 were comparable (−1.75 ± 0.09% vs. −1.63 ± 0.09%, P = 0.33). However, CGM summary analytics were more favorable for DAPA + SAXA: more time in glycemic range, lower glucose variability and less time with nocturnal hypoglycemia (Table 1a). Improvements in CGM at Week 24 correlated with better patient satisfaction and quality of life (n = 225, Table 1b). This analysis of CGM data showed superior diurnal glycemic profiles associated with better PRO for add-on DAPA + SAXA vs. INS in patients with T2D, even though A1C changes were comparable.Table 1a: Treatment Differences in CGM Summary Analytics --- Table 1b: Correlations of CGM with PROTable 1a. CGM Change from Baseline [Mean (SE)]DAPA + SAXA + MetforminINS + MetforminDifferenceP-valueTable 1b. Correlation of Change in CGM with Change in PRO at Week 24 P-valueMean 24-hr glucose mg/dL - Week 2−48.53 (2.51)−28.54 (2.51)−19.99 (3.55)< 0.0001Mean 24-hr glucose mg/dLSatisfaction<0.0001% time glucose ≤ 70 mg/dL - Week 120.52 (0.38)2.29 (0.39)−1.77 (0.54)0.001% time > 70 & ≤ 180 mg/dLSatisfaction<0.0001% time glucose ≤ 70 mg/dL 12 to 6 am - Week 240.60 (0.53)2.66 (0.53)−2.(0.75)0.007Glycemic Risk Assessment Diabetes Equation (GRADE)Satisfaction<0.0001% time glucose > 70 and ≤ 180 mg/dL - Week 2434.28 (1.89)28.50 (1.91)5.78 (2.69)0.033AUC > 180 mg/dLSatisfaction0.001Mean Amplitude Glycemic Excursion (MAGE) mg/dL - Week 24−12.73 (2.26)−5.01 (2.28)−7.72 (3.21)0.017High Blood Glucose Index (HBGI)Satisfaction0.001Within-Day SD (mg/dL) - Week 24−5.93 (0.85)−0.50 (0.86)−5.43 (1.21)< 0.0001Within-Day SD (mg/dL)QOL Weight Interference0.001Low Blood Glucose Index (LBGI) - Week 240.20 (0.05)0.41 (0.05)−0.20 (0.08)0.008Within-Day SD (mg/dL)QOL Composite0.020 Disclosure D.C. Simonson: Advisory Panel; Self; GI Windows, Inc.. Stock/Shareholder; Self; GI Windows, Inc.. Stock/Shareholder; Spouse/Partner; Phase V Technologies, Inc. T. Vilsbøll: None. E. Ekholm: None. E.K. Johnsson: Employee; Self; AstraZeneca. M.A. Testa: Stock/Shareholder; Spouse/Partner; GI Windows, Inc.. Stock/Shareholder; Self; Phase V Technologies, Inc.. S. Jabbour: None. M. Lind: Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Eli Lilly and Company. Research Support; Self; Dexcom, Inc.. Consultant; Self; Eli Lilly and Company. Advisory Panel; Self; MSD K.K.. Research Support; Self; Pfizer Inc.. Consultant; Self; Medtronic.

Objective: Microvascular pathophysiology that uniquely manifests as white matter (WM) abnormalities is often implicated in type 1 diabetes mellitus (T1DM)-related central nervous system (CNS) complications. This study sought to identify regional WM abnormalities in young adults diagnosed with T1DM and further examine their association with cognitive and emotional dysfunction. Research Design and Methods: Diffusion tensor images (DTI) obtained from 34 young adults with T1DM for >= 15 years (mean duration, 20.9years), and 16 age- and sex-matched healthy control subjects were analyzed using tract-based spatial statistics. Fractional anisotropy (FA) values of the whole brain were analyzed, and their associations with memory function and depressive symptoms were assessed. Results: Whole brain voxel-wise analyses showed that T1DM-related FA reductions were most prominent within the fronto-temporo-parietal regions of the brain. Reduced FA values in the bilateral superior longitudinal fasciculi, at which group differences were most prominent, correlated with lower working memory performance in young adults with T1DM (left, P < .001; right, P = .009). Subsyndromal depressive symptoms were also associated with lower FA values in the right inferior fronto-occipital fasciculus (P = .004). Conclusion: Widespread WM microstructural abnormalities in the fronto-temporo-parietal brain regions, which are associated with emotional and cognitive dysfunction, may be a contributing factor to the neural mechanisms underlying T1DM-related CNS complications, thus affecting the quality of life in young adults with T1DM.

OBJECTIVE:To investigate the association between ambulatory medication reconciliation and health care utilization in patients with diabetes. RESEARCH DESIGN AND METHODS:In this retrospective cohort analysis, we studied adults taking at least one diabetes medication treated in primary care practices affiliated with two academic medical centers between 2000 and 2014. We assessed the relationship between the fraction of outpatient diabetes medications reconciled over a 6-month period and the composite primary outcome of combined frequency of emergency department (ED) visits and hospitalizations over the subsequent 6 months. RESULTS:Among 261,765 reconciliation assessment periods contributed by 31,689 patients, 176,274 (67.3%), 27,775 (10.6%), and 57,716 (22.1%) had all, some, or none of the diabetes medications reconciled, respectively. Patients with all, some, or no diabetes medications reconciled had 0.354, 0.377, and 0.384 primary outcome events per 6 months, respectively (P < 0.0001). In a multivariable analysis adjusted for demographics and comorbidities, having some or all versus no diabetes medications reconciled was associated with a lower risk of the primary outcome (rate ratio 0.94 [95% CI 0.90-0.98; P = 0.0046] vs. 0.92 [0.89-0.95; P < 0.0001], respectively). Introduction of feedback to individual providers was associated with a significant increase in the odds of all diabetes medications being reconciled (2.634 [2.524-2.749]; P < 0.0001). CONCLUSIONS:A higher fraction of reconciled outpatient diabetes medications was associated with a lower frequency of ED visits and hospitalizations. Individual performance feedback could help to achieve more comprehensive medication reconciliation.

Overweight and obesity may significantly worsen glycaemic and metabolic control in type 2 diabetes. However, little is known about the effects of overweight and obesity on the brains of people with type 2 diabetes. Here, we investigate whether the presence of overweight or obesity influences the brain and cognitive functions during early stage type 2 diabetes.

Background and Aims: Most patients with type 2 diabetes mellitus have obesity. Studies show that bariatric surgery is superior to medical treatment for remission of type 2 diabetes mellitus. Nevertheless, very few patients undergo surgery, and a less-invasive endoscopic alternative is desirable. Methods: This was a single-arm first-in-human pilot study designed to evaluate the technical feasibility, safety, and clinical performance of the incisionless magnetic anastomosis system (IMAS) to create a partial jejunal diversion (PJD). Ten patients with obesity and type 2 diabetes mellitus, prediabetes, or no diabetes were enrolled. A PJD to the ileum was attempted in all patients under general anesthesia. The IMAS was delivered through the working channel of a colonoscope, with laparoscopic supervision. The patients were not required to participate in an intensive lifestyle/diet management program. Endoscopic visualization of the anastomosis was obtained at 2, 6, and 12 months. Patient weight, glycemic profile, and metabolic panels were acquired at 0.5, 1, 2, 3, 6, 9, and 12 months. Results: A PJD was created in all patients with no device-related serious adverse events. The anastomosis remained widely patent in all patients at 1 year. Average total weight loss was 14.6% (40.2% excess weight loss at 12 months). A significant reduction in glycated hemoglobin level was observed in all diabetic (1.9%) and prediabetic (1.0%) patients, while reducing or eliminating the use of diabetes medications. Conclusions: Permanent anastomosis for PJD was created in all patients with the IMAS. This resulted in improvement in measures of hyperglycemia and progressive weight loss.

HIGHLIGHTS:Quality-of-life measures improve as early as 3 months after bariatric surgery.There is wide variability in reporting that renders direct comparisons difficult.The available comparisons between RYGB and sleeve gastrectomy could not detect any difference.Improvement in PRO measures might be related to weight loss.Larger and better designed studies are required to achieve discrimination in PRO measures.BACKGROUND:Obesity is associated with reduced quality-of-life (QoL), which generally improves after bariatric surgery. The differential effect of each type of surgery (gastric sleeve [SG] and gastric bypass [RYGB]) on QoL is not yet fully understood.OBJECTIVES:To understand which of these surgeries offers greatest improvement in QoL and patient satisfaction.METHODS:Systematic literature search on Pubmed in July 2014. Relevant articles were selected in a step-wise approach. The 2482 titles were scanned for relevance and 191 were selected for abstract reviewing; and 88 papers were selected for full text analysis.RESULTS:Only 5 papers compared the 2 techniques and only 17 more had retrievable data either on SG or RYGB. The reports were very heterogeneous, preventing a direct comparison of patient reported outcomes (PRO) among studies.Improved results have been reported as early has 3 months and SF-36 scores were improved in all domains in medium to long-term. The question remains whether the improvement in QoL is related to the weight loss and which factors are associated with improved patients' perceptions.CONCLUSIONS:There is wide heterogeneity in the reporting of PRO measures after bariatric surgery, but data is consistent with a significant improvement after both surgeries.Larger and better-designed studies are required to understand if there are significant differences in the quality of life after SG or RYGB.

Objective: Patients who present to the emergency department (ED) for diabetes without hyperglycemic crisis are at risk of unnecessary hospitalizations and poor outcomes. To address this, the ED Diabetes Rapid-referral Program (EDRP) was designed to provide ED staff with direct booking into the diabetes center. The objective of this study was to determine the effects of the EDRP on hospitalization rate, ED utilization rate, glycemic control, and expenditures. Methods: We conducted a single-center analysis of the EDRP cohort (n = 420) and compared 1-year outcomes to historic controls (n = 791). We also compared EDRP patients who arrived (ARR) to those who did not show (NS). The primary outcome was hospitalization rate over 1 year. Secondary outcomes included ED recidivism rate, hemoglobin A1c (HbA1c), and healthcare expenditures. Results: Compared with controls, the EDRP cohort was less likely to be hospitalized (27.1% vs. 41.5%, P<.001) or return to the ED (52.2% vs. 62.3%, P = .001) at the end of 1 year. Total hospitalizations were also lower in the EDRP (157 ± 19 vs. 267 ± 18 per 1,000 persons per year, P<.001). The EDRP cohort had a greater reduction in HbA1c (-2.66 vs. -2.01%, P<.001), which was more pronounced when ARR patients were compared with NS (-2.71% vs. -1.37%, P<.05). The mean per patient institutional healthcare expenditures were lower by $5,461 compared with controls. Conclusion: Eliminating barriers to scheduling diabetes-focused ambulatory care for ED patients was associated with significant reductions in hospitalization rate, ED recidivism rate, HbA1c, and healthcare expenditures in the subsequent year. Abbreviations: ARR = arrived ED = emergency department EDRP = emergency department diabetes rapid-referral Program HbA1c = hemoglobin A1c NS = no show

Objective. South Asians have increased visceral adiposity, insulin resistance and greater prevalence of type 2 diabetes and cardiovascular disease when compared to Caucasians of European origin. Surrogate markers of insulin resistance such as the composite insulin sensitivity (Matsuda) index correlate with glucose clamps in other populations, but ethnicity can affect these indices. We compared the Matsuda index, homeostasis model assessment (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and triglyceride/HDL ratio to insulin sensitivity derived from euglycemic clamps in healthy South Asians and Caucasians.Materials/Methods. Twenty-three healthy South Asians and 18 Caucasians matched for age (mean +/- SE = 33.6 +/- 2.1 vs. 36.0 +/- 3.0 years) and BMI (25.2 +/- 1.1 vs. 24.6 +/- 0.9 kg/m(2)) underwent 75 g oral glucose tolerance test (OGTT), 2-h euglycemic hyperinsulinemic clamp (240 pmol . m(-2) . min(-1)), fasting lipid profile, and anthropometric measures.Results. South Asians had higher fasting insulin (41 +/- 5 vs. 21 +/- 2 pmol/1; p = 0.002) and lower HDL-C (1.25 +/- 0.06 vs. 1.56 +/- 0.10 mmol/1; p = 0.010), but similar fasting glucose (5.0 +/- 0.1 vs. 4.9 +/- 0.1 mmol/1) levels vs. Caucasians. South Asians had significantly decreased measures of insulin sensitivity derived from both the euglycemic clamp (24.9 +/- 1.3 vs. 41.4 +/- 1.9 mu mol . kg(-1) . min(-1); p < 0.0001) and OGTT (Matsuda Index 7.60 +/- 0.99 vs. 13.60 +/- 1.79; p = 0.004). The Matsuda index correlated highly with clamp insulin sensitivity in South Asians (r = 0.50; p = 0.014) and Caucasians (r = 0.47; p = 0.046). HOMA-IR, QUICKI, and triglyceride/HDL ratio correlated with clamp values in South Asians, but not in Caucasians.Conclusions. In South Asians, Matsuda index, HOMA-IR, QUICKI, and triglyceride/HDL ratio offer simple and valid surrogate measures of insulin sensitivity that can be employed in larger clinical or epidemiological studies in this ethnic group. (c) 2013 Elsevier Inc. All rights reserved.