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Context: Combination therapy with insulin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) is important for treating type 2 diabetes (T2D). This trial assesses the efficacy and safety of semaglutide, a GLP-1RA, as an add-on to basal insulin., Objective: To demonstrate the superiority of semaglutide vs placebo on glycemic control as an add-on to basal insulin in patients with T2D., Design: Phase 3a, double-blind, placebo-controlled, 30-week trial., Setting: This study included 90 sites in five countries., Patients: We studied 397 patients with uncontrolled T2D receiving stable therapy with basal insulin with or without metformin., Interventions: Subcutaneous semaglutide 0.5 or 1.0 mg once weekly or volume-matched placebo., Main Outcome Measures: Primary endpoint was change in glycated Hb (HbA1c) from baseline to week 30. Confirmatory secondary endpoint was change in body weight from baseline to week 30., Results: At week 30, mean HbA1c reductions [mean baseline value, 8.4% (67.9 mmol/mol)] with semaglutide 0.5 and 1.0 mg were 1.4% (15.8 mmol/mol) and 1.8% (20.2 mmol/mol) vs 0.1% (1.0 mmol/mol) with placebo [estimated treatment difference (ETD) vs placebo, -1.35 (14.8 mmol/mol); 95% CI, -1.61 to -1.10 and ETD, -1.75% (19.2 mmol/mol); 95% CI, -2.01 to -1.50; both P < 0.0001]. Severe or blood glucose-confirmed hypoglycemic episodes were reported in 11 patients (17 events) and 14 patients (25 events) with semaglutide 0.5 and 1.0 mg, respectively, vs seven patients (13 events) with placebo (estimated rate ratio vs placebo, 2.08; 95% CI, 0.67 to 6.51 and estimated rate ratio vs placebo, 2.41; 95% CI, 0.84 to 6.96 for 0.5 and 1.0 mg; both P = nonsignificant). Mean body weight decreased with semaglutide 0.5 and 1.0 mg vs placebo from baseline to end of treatment: 3.7, 6.4, and 1.4 kg (ETD, -2.31; 95% CI, -3.33 to -1.29 and ETD, -5.06; 95% CI, -6.08 to -4.04 kg; both P < 0.0001). Premature treatment discontinuation due to adverse events was higher for semaglutide 0.5 and 1.0 mg vs placebo (4.5%, 6.1%, and 0.8%), mainly due to gastrointestinal disorders., Conclusions: Semaglutide, added to basal insulin, significantly reduced HbA1c and body weight in patients with uncontrolled T2D vs placebo.

The newer oral therapies for type 2 diabetes mellitus, dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium glucose cotransporter 2 (SGLT2) inhibitors, have advantages over older agents. Dipeptidyl peptidase-4 inhibitors are weight neutral and have few adverse effects. Sodium glucose cotransporter 2 inhibitors have additional benefits: weight loss, blood pressure reduction, cardiovascular risk reduction, and renoprotective effects. Sodium glucose cotransporter 2 inhibitors have increased risk of urogenital infections and possible risk of "euglycaemic" diabetic ketoacidosis. It is important to balance the benefits over the older-oral therapies as these agents are more expensive; yet some analyses suggest that they are within the limits of what is considered cost-effective in health care. We discuss the relative merits and drawbacks of these 2 classes and consider their roles in the treatment of type 2 diabetes mellitus. We suggest a number of patient profiles where early use of these agents could be used. We favour the use of SGLT2 inhibitors over DPP-4 inhibitors as add on therapy to metformin when glycaemic targets have not been achieved given their similar glycaemic efficacy and the additional benefits of SGLT2 inhibitors. We particularly favour SGLT2 inhibitors in those where additional weight loss and blood pressure reductions are desired, and in patients with heart failure or cardiovascular disease. Care should be taken to warn patients about genital fungal infections and to avoid use in people with risk factors for SGLT2 associated ketoacidosis. We favour DPP-4 inhibitors in those where side effects of other agents are of concern, the frail elderly population, and those with renal disease precluding SGTL2 inhibitor use., (Copyright © 2018 John Wiley & Sons, Ltd.)

Aims: To evaluate diabetic retinopathy (DR) data from across the SUSTAIN clinical trial programme., Materials and Methods: The SUSTAIN clinical trial programme evaluated the efficacy and safety of semaglutide, a glucagon-like peptide-1 analogue, for the treatment of type 2 diabetes (T2D). In SUSTAIN 6, a 2-year, pre-approval cardiovascular outcomes trial, semaglutide was associated with a significant increase in the risk of DR complications (DRC) vs placebo. DR data from across the SUSTAIN trials were evaluated, and post hoc analyses of the SUSTAIN 6 data were conducted. These included subgroup analyses to identify at-risk patients and a mediation analysis with initial change in glycated haemoglobin (HbA1c; percentage-points at week 16) as a covariate, to examine the role of the magnitude of reduction in HbA1c as an intermediate factor affecting risk of DRC., Results: There was no imbalance in DR adverse events across the SUSTAIN 1 to 5 and Japanese trials. The majority of the effect with semaglutide vs placebo in SUSTAIN 6 may be attributed to the magnitude and rapidity of HbA1c reduction during the first 16 weeks of treatment in patients who had pre-existing DR and poor glycaemic control at baseline, and who were treated with insulin., Conclusions: Early worsening of DR is a known phenomenon associated with the rapidity and magnitude of improvement in glycaemic control with insulin; the DRC findings in SUSTAIN 6 are consistent with this. Guidance regarding the early worsening of DR is recommended with insulin. Similar recommendations may be appropriate for semaglutide., (© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Despite common mechanisms of actions, glucagon-like peptide-1 receptor agonists differ in structure, pharmacokinetic profile, and clinical effects. This head-to-head trial compared semaglutide with dulaglutide in patients with inadequately controlled type 2 diabetes., Methods: This was an open-label, parallel-group, phase 3b trial done at 194 hospitals, clinical institutions or private practices in 16 countries. Eligible patients were aged 18 years or older and had type 2 diabetes with HbA 1c 7·0-10·5% (53·0-91·0 mmol/mol) on metformin monotherapy. Patients were randomly assigned (1:1:1:1) by use of an interactive web-response system to once a week treatment with either semaglutide 0·5 mg, dulaglutide 0·75 mg, semaglutide 1·0 mg, or dulaglutide 1·5 mg subcutaneously. The primary endpoint was change from baseline in percentage HbA 1c ; the confirmatory secondary endpoint was change in bodyweight, both at week 40. The primary analysis population included all randomly assigned patients exposed to at least one dose of trial product obtained while on treatment and before the onset of rescue medication. The safety population included all randomly assigned patients exposed to at least one dose of trial product obtained while on treatment. The trial was powered for HbA 1c non-inferiority (margin 0·4%) and bodyweight superiority. This trial is registered with ClinicalTrials.gov, number NCT02648204., Findings: Between Jan 6, 2016, and June 22, 2016, 1201 patients were randomly assigned to treatment; of these, 301 were exposed to semaglutide 0·5 mg, 299 to dulaglutide 0·75 mg, 300 to semaglutide 1·0 mg, and 299 to dulaglutide 1·5 mg. 72 (6%) patients withdrew from the trial (22 receiving semaglutide 0·5 mg, 13 receiving dulaglutide 0·75 mg, 21 receiving semaglutide 1·0 mg, and 16 receiving dulaglutide 1·5 mg). From overall baseline mean, mean percentage HbA 1c was reduced by 1·5 (SE 0·06) percentage points with semaglutide 0·5 mg versus 1·1 (0·05) percentage points with dulaglutide 0·75 mg (estimated treatment difference [ETD] -0·40 percentage points [95% CI -0·55 to -0·25]; p<0·0001) and by 1·8 (0·06) percentage points with semaglutide 1·0 mg versus 1·4 (0·06) percentage points with dulaglutide 1·5 mg (ETD -0·41 percentage points [-0·57 to -0·25]; p<0·0001). From overall baseline mean, mean bodyweight was reduced by 4·6 kg (SE 0·28) with semaglutide 0·5 mg compared with 2·3 kg (0·27) with dulaglutide 0·75 mg (ETD -2·26 kg [-3·02 to -1·51]; p<0·0001) and by 6·5 kg (0·28) with semaglutide 1·0 mg compared with 3·0 kg (0·27) with dulaglutide 1·5 mg (ETD -3·55 kg [-4·32 to -2·78]; p<0·0001). Gastrointestinal disorders were the most frequently reported adverse event, occurring in 129 (43%) of 301 patients receiving semaglutide 0·5 mg, 133 (44%) of 300 patients receiving semaglutide 1·0 mg, 100 (33%) of 299 patients receiving dulaglutide 0·75 mg, and in 143 (48%) of 299 patients receiving dulaglutide 1·5 mg. Gastrointestinal disorders were also the most common reason for discontinuing treatment with semaglutide and dulaglutide. There were six fatalities: one in each semaglutide group and two in each dulaglutide group., Interpretation: At low and high doses, semaglutide was superior to dulaglutide in improving glycaemic control and reducing bodyweight, enabling a significantly greater number of patients with type 2 diabetes to achieve clinically meaningful glycaemic targets and weight loss, with a similar safety profile., Funding: Novo Nordisk., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aims: To evaluate the long-term remission rates of type 2 diabetes mellitus and associated comorbidities after gastric bypass surgery in a complete cohort, in a real-life clinic setting., Methods: A retrospective study of all consecutive patients with type 2 diabetes mellitus who underwent gastric bypass at a Veterans Affairs Medical Center from 2003 to 2010. The main outcome was remission of type 2 diabetes mellitus defined as HbA1c <6.5% (49 mmol/mol) without diabetic medication usage. Secondary outcomes were remission of hypertension and hyperlipidemia, weight loss, and long-term complications four years post-gastric bypass., Results: Eighty-four patients with type 2 diabetes mellitus underwent gastric bypass. Four-year follow-up data were available for 92% (77/84) of patients. The patients (73% male; mean age 54 years) had a mean body mass index of 49 kg/m 2  ± 8.3. Hypertension and hyperlipidemia prevalence were 92% and 85%, respectively. The mean total body weight decrease over four years was 35 kg ± 21. Remission of type 2 diabetes mellitus occurred in 15% at 6 months and 49% four years after surgery. Diabetes remission was more likely (OR 3.2; 95% confidence interval 1.2-9.7) in patients not using insulin at baseline. Remission rates were 12% (9/74) for hypertension and 16% (11/68) for hyperlipidemia. Long-term surgical complications included reoperation (11%), incisional hernia (10%) and anastomotic ulcer (10%). Forty-four percent of patients had one or more nutritional complications., Conclusions: The metabolic effects of gastric bypass are significant and durable for at least four years, even in a predominantly male cohort and real-life clinical setting., (Published by Elsevier B.V.)

Objective: To compare the efficacy and safety of once-weekly semaglutide 1.0 mg s.c. with exenatide extended release (ER) 2.0 mg s.c. in subjects with type 2 diabetes., Research Design and Methods: In this phase 3a, open-label, parallel-group, randomized controlled trial, 813 subjects with type 2 diabetes taking oral antidiabetic drugs were randomized (1:1) to semaglutide 1.0 mg or exenatide ER 2.0 mg for 56 weeks. The primary end point was change from baseline in HbA 1c at week 56., Results: Mean HbA 1c (8.3% [67.7 mmol/mol] at baseline) was reduced by 1.5% (16.8 mmol/mol) with semaglutide and 0.9% (10.0 mmol/mol) with exenatide ER (estimated treatment difference vs. exenatide ER [ETD] -0.62% [95% CI -0.80, -0.44] [-6.78 mmol/mol (95% CI -8.70, -4.86)]; P < 0.0001 for noninferiority and superiority). Mean body weight (95.8 kg at baseline) was reduced by 5.6 kg with semaglutide and 1.9 kg with exenatide ER (ETD -3.78 kg [95% CI -4.58, -2.98]; P < 0.0001). Significantly more subjects treated with semaglutide (67%) achieved HbA 1c <7.0% (<53 mmol/mol) versus those taking exenatide ER (40%). Both treatments had similar safety profiles, but gastrointestinal adverse events were more common in semaglutide-treated subjects (41.8%) than in exenatide ER-treated subjects (33.3%); injection-site reactions were more frequent with exenatide ER (22.0%) than with semaglutide (1.2%)., Conclusions: Semaglutide 1.0 mg was superior to exenatide ER 2.0 mg in improving glycemic control and reducing body weight after 56 weeks of treatment; the drugs had comparable safety profiles. These results indicate that semaglutide treatment is highly effective for subjects with type 2 diabetes who are inadequately controlled on oral antidiabetic drugs., (© 2017 by the American Diabetes Association.)

Type 2 diabetes mellitus (T2DM) is a common complication of obesity. Here, we have shown that activation of the IgG receptor FcγRIIB in endothelium by hyposialylated IgG plays an important role in obesity-induced insulin resistance. Despite becoming obese on a high-fat diet (HFD), mice lacking FcγRIIB globally or selectively in endothelium were protected from insulin resistance as a result of the preservation of insulin delivery to skeletal muscle and resulting maintenance of muscle glucose disposal. IgG transfer in IgG-deficient mice implicated IgG as the pathogenetic ligand for endothelial FcγRIIB in obesity-induced insulin resistance. Moreover, IgG transferred from patients with T2DM but not from metabolically healthy subjects caused insulin resistance in IgG-deficient mice via FcγRIIB, indicating that similar processes may be operative in T2DM in humans. Mechanistically, the activation of FcγRIIB by IgG from obese mice impaired endothelial cell insulin transcytosis in culture and in vivo. These effects were attributed to hyposialylation of the Fc glycan, and IgG from T2DM patients was also hyposialylated. In HFD-fed mice, supplementation with the sialic acid precursor N-acetyl-D-mannosamine restored IgG sialylation and preserved insulin sensitivity without affecting weight gain. Thus, IgG sialylation and endothelial FcγRIIB may represent promising therapeutic targets to sever the link between obesity and T2DM.

This study assessed the efficacy of insulin degludec/liraglutide (IDegLira) vs insulin glargine U100 (IGlar) across categories of baseline glycated haemoglobin (HbA1c; ≤7.5%, >7.5% to ≤8.5% and >8.5%), body mass index (BMI; <30, ≥30 to <35 and ≥35 kg/m 2 ) and fasting plasma glucose (FPG; <7.2 and ≥7.2 mmol/L) in patients with type 2 diabetes (T2D) uncontrolled on basal insulin, using post hoc analyses of the DUAL V 26-week trial. With IDegLira, mean HbA1c was reduced across all baseline HbA1c (1.0%-2.5%), FPG (1.5%-1.9%) and BMI categories (1.8%-1.9%), with significantly greater reductions compared with IGlar U100. For all HbA1c, FPG and BMI categories, IDegLira resulted in weight loss and IGlar U100 in weight gain; hypoglycaemia rates were lower for IDegLira vs IGlar U100. More patients achieved HbA1c <7% with IDegLira than IGlar U100 across all HbA1c (59%-87% vs 31%-66%), FPG (71%-74% vs 40%-51%) and BMI categories (71%-73% vs 40%-54%). IDegLira improved glycaemic control and induced weight loss in patients with T2D previously uncontrolled on basal insulin, across the categories of baseline HbA1c, FPG or BMI that were tested., (© 2017 John Wiley & Sons Ltd.)

Aims: To re-analyse, using a series of alternative hypoglycaemia definitions, the data from 2 trials, DUAL I and V, in which the once-daily, fixed ratio combination of insulin degludec/liraglutide (IDegLira) was compared with basal insulin therapy., Material and Methods: Post hoc analyses of the DUAL I (patients uncontrolled on oral antidiabetic drugs) and DUAL V (patients uncontrolled on insulin glargine (IGlar) U100) trials were carried out using different definitions of hypoglycaemia and according to whether treatments were administered in the morning or afternoon. Rates of hypoglycaemia for the definitions of confirmed and American Diabetes Association (ADA)-documented symptomatic hypoglycaemia were compared according to age, gender and body mass index (BMI)., Results: Although hypoglycaemia rates differed according to the alternative hypoglycaemia definitions, rates were consistently lower with IDegLira vs insulin degludec (IDeg) and IGlar U100. Despite glycated haemoglobin concentrations being lower with IDegLira at end of treatment, confirmed and nocturnal-confirmed hypoglycaemia rates were lower for IDegLira vs IDeg and IGlar U100, irrespective of dosing time. The definitions of confirmed and ADA-documented symptomatic hypoglycaemia did not have a significant effect on the treatment difference between IDegLira and IDeg, liraglutide or IGlar U100 when further assessed by baseline age, gender and BMI., Conclusions: Treatment with IDegLira, vs IDeg and IGlar U100, resulted in lower rates of hypoglycaemia regardless of dosing time and definition of hypoglycaemia used. The choice of hypoglycaemia definition did not influence the results of analyses when stratified by age, sex and BMI., (© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Purpose of Review: Sulfonylureas (SUs) are one of the most commonly used glucose-lowering agents worldwide. While their efficacy is undisputed, their cardiovascular safety has been debated since the 1970's., Recent Findings: With no dedicated cardiovascular studies to definitively answer this question, observational studies and meta-analyses abound and have reported divergent results, fueling the controversy. Studies that compared SUs to metformin or newer agents, like GLP-1 agonists and SGLT2 inhibitors, suggest a difference in cardiovascular events, yet this is likely the result of beneficial effects of the latter. Studies comparing SUs to other agents have been reassuring. SUs remain a common choice of treatment for patients with type 2 diabetes due to their exceptional value. They are effective at lowering glucose and thus contributing to the prevention of microvascular complications. Weight gain and hypoglycemia are their main side effects, although less severe when compared to insulin treatment. Their cardiovascular safety will remain a controversial topic due to lack of conclusive data, but there is no definitive evidence of harm with the second-generation agents.

In patients requiring high-dose insulin treatment, a randomized, double-blind, placebo-controlled study showed that liraglutide improved glycaemic control and treatment satisfaction while promoting weight loss. We performed a post hoc analysis to evaluate if patients' baseline characteristics impact the efficacy of liraglutide, and which outcomes correlate with treatment satisfaction. We used regression analysis to model the change in HbA1c and weight, with treatment assignment and baseline characteristics [HbA1c, age, body mass index (BMI), total daily dose (TDD) of insulin, duration of insulin treatment, and type of insulin regimen] as independent variables. Improvement in HbA1c was best predicted by treatment with liraglutide, followed by higher baseline HbA1c, BMI and age. Changes in weight were only associated with liraglutide treatment, independent of all baseline characteristics. Improvement in HbA1c was the only significant predictor of improvement in treatment satisfaction, while weight loss, change in TDD of insulin and rate of hypoglycaemia did not influence treatment satisfaction. In patients treated with high-dose insulin, liraglutide significantly improved glycaemic control and led to weight loss regardless of patients' baseline characteristics. Improvement in HbA1c was the most important predictor of patients' treatment satisfaction., (© 2017 John Wiley & Sons Ltd.)

Objective: This article reviews evidence supporting sodium glucose cotransporter 2 (SGLT2) inhibitor and dipeptidyl peptidase-4 (DPP-4) inhibitor combination therapy for management of type 2 diabetes mellitus (T2DM)., Methods: We conducted a nonsystematic review of the literature focusing on single-pill or fixed-dose combinations of SGLT2 inhibitors and DPP-4 inhibitors available in the United States., Results: SGLT2 inhibitors and DPP-4 inhibitors have complementary mechanisms of action that address several of the underlying pathophysiologic abnormalities present in T2DM without overlapping toxicities. The combination of these 2 agents has several advantages including a low risk of hypoglycemia, the potential for weight loss, the ability to coformulate into a pill with once-daily administration, and the possibility to use with other classes of glucose-lowering agents. Cardiovascular outcomes trials reported to date support the safety of the DPP-4 class and suggest possible cardioprotective effects for SGLT2 inhibitors - at least based on the first reported study that used empagliflozin. Recent clinical evidence shows that SGLT2 inhibitor/DPP-4 inhibitor therapy is an effective combination for T2DM treatment, providing glycated hemoglobin (HbA1c) reductions of 1.1 to 1.5%, and weight reductions of approximately 2 kg when added to metformin, which is its primary place in therapy., Conclusion: The combination of an SGLT2 inhibitor/DPP-4 inhibitor is a safe and effective treatment choice for patients with T2DM who are unable to obtain adequate glycemic control with metformin therapy, cannot use metformin, or have a higher baseline HbA1c., Abbreviations: BP = blood pressure; CI = confidence interval; CVOT = cardiovascular outcomes; DKA = diabetic ketoacidosis; DPP-4 = dipeptidyl peptidase-4; EXAMINE = EXamination of cArdiovascular outcoMes with alogliptiN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome; FDA = Food and Drug Administration; HbA1c = glycated hemoglobin; HR = hazard ratio; MACE = major adverse cardiovascular events; SAVOR-TIMI 53 = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Type 2 Diabetes Mellitus; SBP = systolic blood pressure; SGLT2 = sodium glucose cotransporter 2; TECOS = Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin; T2DM = type 2 diabetes mellitus; XR = extended release.

Introduction: Random glucose <200 mg/dL is associated with undiagnosed diabetes but not included in screening guidelines. This study describes a case-finding approach using non-diagnostic random glucose values to identify individuals in need of diabetes testing and compares its performance to current screening guidelines., Methods: In 2015, cross-sectional data from non-fasting adults without diagnosed diabetes or prediabetes (N=7,161) in the 2007-2012 National Health and Nutrition Examination Surveys were analyzed. Random glucose and survey data were used to assemble the random glucose, American Diabetes Association (ADA), and U.S. Preventive Services Task Force (USPSTF) screening strategies and predict diabetes using hemoglobin A1c criteria., Results: Using random glucose ≥100 mg/dL to select individuals for diabetes testing was 81.6% (95% CI=74.9%, 88.4%) sensitive, 78% (95% CI=76.6%, 79.5%) specific and had an area under the receiver operating curve (AROC) of 0.80 (95% CI=0.78, 0.83) to detect undiagnosed diabetes. Overall performance of ADA (AROC=0.59, 95% CI=0.58, 0.60), 2008 USPSTF (AROC=0.62, 95% CI=0.59, 0.65), and 2015 USPSTF (AROC=0.64, 95% CI=0.61, 0.67) guidelines was similar. The random glucose strategy correctly identified one case of undiagnosed diabetes for every 14 people screened, which was more efficient than ADA (number needed to screen, 35), 2008 USPSTF (44), and 2015 USPSTF (32) guidelines., Conclusions: Using random glucose ≥100 mg/dL to identify individuals in need of diabetes screening is highly sensitive and specific, performing better than current screening guidelines. Case-finding strategies informed by random glucose data may improve diabetes detection. Further evaluation of this strategy's effectiveness in real-world clinical practice is needed., (Copyright © 2017 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: To determine whether previously reported reductions in hypoglycemia associated with insulin glargine 300 U/mL (Gla-300) compared with insulin glargine 100 U/mL (Gla-100) are impacted by patient risk category in type 2 diabetes (T2D), clinical performance measures based on the Healthcare Effectiveness Data and Information Set (HEDIS) were applied to patient-level data from the EDITION 2 and EDITION 3 clinical trials that compared Gla-300 and Gla-100., Methods: In this post hoc analysis, patients were stratified as low risk (LR) if patients were <65 years old with no comorbidities derived from HEDIS (HbA1c target <7.0% [53 mmol/mol]), or as high risk (HR) if patients were either ≥65 years old or had one or more HEDIS-defined comorbidities (HbA1c target <8.0% [64 mmol/mol]). Primary endpoint was a composite of patients achieving HbA1c target without confirmed or severe hypoglycemia over 6 months in the different treatment groups in each of the EDITION trials., Results: There was a statistically nonsignificant trend of more patients treated with Gla-300 achieving the composite endpoint compared with Gla-100 in both the LR and HR patient cohorts, regardless of prior insulin experience. A similar trend was observed for the composite endpoint of HbA1c target without nocturnal hypoglycemia., Conclusions: There is a consistent, nonsignificant trend suggesting that Gla-300 might reduce the burden of hypoglycemia compared with Gla-100 in patients with T2D irrespective of whether they are classed as LR or HR based on age- and National Committee for Quality Assurance Healthcare Effectiveness Data and Information Set-derived comorbidities.

Background: Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown., Methods: We randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio., Results: At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal., Conclusions: In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide. (Funded by Novo Nordisk; SUSTAIN-6 ClinicalTrials.gov number, NCT01720446 .).

Purpose: To evaluate renal lipid content in subjects with and without type II diabetes mellitus (DM2) using Dixon-based magnetic resonance imaging (MRI)., Materials and Methods: This retrospective study was approved by the Institutional Review Board and compliant with the Health Insurance Portability and Accountability Act. Sixty-nine adults with or without DM2 (n = 29, n = 40) underwent 3T MRI of the abdomen using 3D multiecho Dixon gradient-echo acquisition and proton-density fat fraction (FF) reconstruction. FF values were recorded within segmented regions of interest in the kidneys and liver. The FF measurement error was estimated from the within-subject difference between the right and left kidneys using Bland-Altman analysis. Correlation between renal FF, hepatic FF, and body mass index (BMI) was evaluated. The association between renal FF and DM2 was evaluated by Wilcoxon rank sum test as well as by multivariate regression to correct for potential confounding effects of age, sex, BMI, creatinine, and hepatic FF. P < 0.05 was considered statistically significant., Results: Per-subject 95% limits of agreement of the renal FF measurement were [-3.26%, +3.22%]. BMI was significantly correlated with renal FF (r = 0.266, P = 0.027) and with liver FF (r = 0.344, P = 0.006). Correlation between renal and hepatic FF did not reach statistical significance (r = 0.215, P = 0.090). Median renal FF (±interquartile range) was 2.18% (±2.52%) in the DM2 cohort, significantly higher than 0.80% (±2.63%) in the non-DM2 cohort (P < 0.001). After correcting for potential confounders, the relationship between DM2 and renal FF remained statistically significant (P = 0.005)., Conclusion: Renal lipid content can be measured noninvasively using Dixon-based MRI and may be increased in subjects with DM2 compared to those without DM2. J. Magn. Reson. Imaging 2016;44:1312-1319., (© 2016 International Society for Magnetic Resonance in Medicine.)

Importance: An increasing number of patients with type 2 diabetes are treated with high doses of insulin. Such treatment is associated with weight gain, hypoglycemia, and high treatment burden., Objective: To assess the effectiveness and safety of adding a glucagon-like peptide 1 receptor agonist to the treatment regimen of patients with type 2 diabetes requiring therapy with high-dose insulin., Design, Setting, and Participants: This clinical trial was a double-blind, placebo-controlled, randomized (1:1) study with 6 months of follow-up, conducted from August 13, 2012, to February 9, 2015, at ambulatory clinics at the University of Texas Southwestern Medical Center and Parkland Hospital. Participants were 71 patients with uncontrolled type 2 diabetes (glycated hemoglobin level, 7.5%-11.0%) using more than 1.5 U/kg/d of insulin., Interventions: Subcutaneous injection of liraglutide (1.8 mg/d) or matching placebo for 6 months., Main Outcomes and Measures: The primary outcome was the change in glycated hemoglobin level. Secondary outcomes were changes in weight, hypoglycemia rate, insulin dosage, and quality-of-life measures., Results: Among 71 patients, 45 (63%) were female. The mean (SD) age of patients was 54.2 (7.4) years, with a mean (SD) type 2 diabetes duration of 17.9 (8.4) years and a mean (SD) total daily dose of insulin of 247.0 (95.1) U. Ninety-three percent (66 of 71) of participants completed all scheduled visits. The glycated hemoglobin level improved from a mean (SD) of 9.0% (1.2%) to 7.9% (1.1%) in the liraglutide group (P < .001) and remained unchanged (8.9%) in the placebo group, with an estimated treatment difference of 0.9% (95% CI, -1.5 to -0.4) (P = .002). Weight decreased from a mean (SD) of 114.6 (21.4) kg to 113.6 (20.8) kg in the liraglutide group vs a mean (SD) increase from 116.1 (26.6) kg to 117.2 (27.2) kg in the placebo group, with a treatment difference of -2.3 kg (95% CI, -4.3 to -0.4 kg) (P = .02). The total daily dose of insulin decreased 11.5% (95% CI, -21.8% to -1.1%) in the liraglutide group (P = .20). The hypoglycemia rate was higher in the first month after initiation of liraglutide compared with placebo (2.30 vs 0.91 events per person-month, P = .01), while the overall hypoglycemia rate over the entire follow-up was similar between groups (P = .11). Glycemia control perception, satisfaction with insulin treatment, and willingness to continue insulin use improved more in the liraglutide group., Conclusions and Relevance: Liraglutide added to high-dose insulin therapy improved glycemic control, decreased body weight, and enhanced treatment satisfaction in this difficult-to-treat patient population with high-dose insulin requirements. Further studies are warranted to confirm these findings and evaluate the long-term risk and benefit of this treatment option., Trial Registration: clinicaltrials.gov Identifier: NCT01505673.

Context: The mechanisms of action of incretin mimetics in patients with long-standing type 2 diabetes (T2D) and high insulin requirements have not been studied., Objective: To evaluate changes in β-cell function, glucagon secretion, and fat distribution after addition of liraglutide to high-dose insulin., Design: A single-center, randomized, double-blind, placebo-controlled trial., Setting: University of Texas Southwestern and Parkland Memorial Hospital clinics., Patients: Seventy-one patients with long-standing (median, 17 years) T2D requiring high-dose insulin treatment (>1.5 U/kg/d; average, 2.2 ± 0.9 U/kg/d)., Intervention: Patients were randomized to liraglutide 1.8 mg/d or matching placebo for 6 months., Main Outcome Measures: We measured changes in insulin and glucagon secretion using a 4-hour mixed-meal challenge test. Magnetic resonance-based techniques were used to estimate sc and visceral fat in the abdomen and ectopic fat in the liver and pancreas., Results: Glycosylated hemoglobin improved significantly with liraglutide treatment, with an end-of-trial estimated treatment difference between groups of −0.9% (95% confidence interval, −1.5, −0.4%) (P = .002). Insulin secretion improved in the liraglutide group vs placebo, as measured by the area under the curve of C-peptide (P = .002) and the area under the curves ratio of C-peptide to glucose (P = .003). Insulin sensitivity (Matsuda index) and glucagon secretion did not change significantly between groups. Liver fat and sc fat decreased in the liraglutide group vs placebo (P = .0006 and P = .01, respectively), whereas neither visceral nor pancreatic fat changed significantly., Conclusions: Treatment with liraglutide significantly improved insulin secretion, even in patients with long-standing T2D requiring high-dose insulin treatment. Liraglutide also decreased liver and sc fat, but it did not alter glucagon secretion.

Importance: Achieving glycemic control remains a challenge for patients with type 2 diabetes, even with insulin therapy., Objective: To assess whether a fixed ratio of insulin degludec/liraglutide was noninferior to continued titration of insulin glargine in patients with uncontrolled type 2 diabetes treated with insulin glargine and metformin., Design, Setting, and Participants: Phase 3, multinational, multicenter, 26-week, randomized, open-label, 2-group, treat-to-target trial conducted at 75 centers in 10 countries from September 2013 to November 2014 among 557 patients with uncontrolled diabetes treated with glargine (20-50 U) and metformin (≥1500 mg/d) with glycated hemoglobin (HbA1c) levels of 7% to 10% and a body mass index of 40 or lower., Interventions: 1:1 randomization to degludec/liraglutide (n = 278; maximum dose, 50 U of degludec/1.8 mg of liraglutide) or glargine (n = 279; no maximum dose), with twice-weekly titration to a glucose target of 72 to 90 mg/dL., Main Outcomes and Measures: Primary outcome measure was change in HbA1c level after 26 weeks, with a noninferiority margin of 0.3% (upper bound of 95% CI, <0.3%). If noninferiority of degludec/liraglutide was achieved, secondary end points were tested for statistical superiority and included change in HbA1c level, change in body weight, and rate of confirmed hypoglycemic episodes., Results: Among 557 randomized patients (mean: age, 58.8 years; women, 49.7%), 92.5% of patients completed the trial and provided data at 26 weeks. Baseline HbA1c level was 8.4% for the degludec/liraglutide group and 8.2% for the glargine group. HbA1c level reduction was greater with degludec/liraglutide vs glargine (-1.81% for the degludec/liraglutide group vs -1.13% for the glargine group; estimated treatment difference [ETD], -0.59% [95% CI, -0.74% to -0.45%]), meeting criteria for noninferiority (P < .001), and also meeting criteria for statistical superiority (P < .001). Treatment with degludec/liraglutide was also associated with weight loss compared with weight gain with glargine (-1.4 kg for degludec/liraglutide vs 1.8 kg for glargine; ETD, -3.20 kg [95% CI, -3.77 to -2.64],P < .001) and fewer confirmed hypoglycemic episodes (episodes/patient-year exposure, 2.23 for degludec/liraglutide vs 5.05 for glargine; estimated rate ratio, 0.43 [95% CI, 0.30 to 0.61],P < .001). Overall and serious adverse event rates were similar in the 2 groups, except for more nonserious gastrointestinal adverse events reported with degludec/liraglutide (adverse events, 79 for degludec/liraglutide vs 18 for glargine)., Conclusions and Relevance: Among patients with uncontrolled type 2 diabetes taking glargine and metformin, treatment with degludec/liraglutide compared with up-titration of glargine resulted in noninferior HbA1c levels, with secondary analyses indicating greater HbA1c level reduction after 26 weeks of treatment. Further studies are needed to assess longer-term efficacy and safety., Trial Registration: clinicaltrials.gov Identifier: NCT01952145.

Background: Metabolic syndrome (MetS) appears closely linked with ceramide accumulation, inducing insulin resistance and toxicity to multiple cell types. Animal studies demonstrate that thiazolidinediones (TZDs) reduce ceramide concentrations in plasma and skeletal muscle and support lowering of ceramide levels as a potential mediator of TZDs' mechanism of action in reducing insulin resistance; however, studies in humans have yet to be reported. This study investigated the effects of pioglitazone therapy on plasma ceramides to understand the mechanism by which TZDs improve insulin resistance in MetS., Methods: Thirty-seven subjects with MetS were studied in a single-centre, randomized, double-blind, placebo-controlled trial comparing pioglitazone to placebo. Data were collected at baseline and after 6 months of therapy. The primary endpoint was the change from baseline in plasma ceramide concentrations., Results: Treatment with pioglitazone for 6 months, compared with placebo, significantly reduced multiple plasma ceramide concentrations: C18:0 (p = 0.001), C20:0 (p = 0.0004), C24 : 1 (p = 0.009), dihydroceramide C18 :0 (p = 0.005), dihydroceramide C24:1 (p = 0.004), lactosylceramide C16:0 (p = 0.02) and the hexosylceramides C16:0 (p = 0.0003), C18 : 0 (p = 0.00001), C22:0 (p = 0.00002) and C24:1 (p = 0.0006). Additionally, significant reductions were found when ceramides were grouped by species: ceramides (p = 0.03), dihydroceramides (p = 0.02), hexosylceramides (p = 0.00001) and lactosylceramides (p = 0.02). The total of all measured ceramides was also significantly reduced (p = 0.001). Following treatment with pioglitazone, the decrease in some ceramide species correlated negatively with the change in insulin sensitivity (dihydroceramide C16:0, r = -0.54; p = 0.02) and positively with total (lactosylceramide C24:0, r = 0.53; p = 0.02) and high molecular weight (lactosylceramide C24:0, r = 0.48; p = 0.05) adiponectin measurements; however, significant associations with changes in liver fat and glycemic control reduction were not found., Conclusions: Pioglitazone in individuals with MetS induces a potent decrease in plasma ceramides, and some of the changes correlate with changes in insulin resistance and adiponectin levels., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background. Patients with metastatic or radioactive iodine refractory papillary thyroid carcinoma (PTC) have poor prognosis due to ineffective therapy for this condition beyond surgery and radioactive iodine (RAI or (131)I). BRAF mutation occurs in more than 44% of PCT. Tyrosine kinase inhibitors, the most commonly used agents for these patients, have weak BRAF inhibition activity. BRAF inhibitors have demonstrated promising efficacy in relapsed metastatic PCT after standard treatment, though they are not currently approved for this indication. Case Presentation. We present the case of a 48-year-old Hispanic male who initially presented with columnar-cell variant subtype of PTC and positive BRAFV600E mutation. The patient had widespread bulky metastases to lungs, chest wall, brain, and bone. Discussion. Initial use of vemurafenib demonstrated a 42% cytoreduction of targeted pulmonary metastases and facilitated thyroidectomy and RAI treatment. The patient achieved a durable response over 21 months in the setting of widely metastatic disease. Conclusion. Vemurafenib may be effectively used for cytoreduction in patients with bulky metastatic PTC to bridge them to thyroidectomy and RAI treatment.

Type 2 diabetes mellitus has reached epidemic proportions around the world, and the increase in cardiovascular risk attributable to diabetes estimated to range from 2- to 4-fold poses grave public health concern. Though in some contexts type 2 diabetes has been equated with coronary heart disease equivalent risk, there is considerable evidence that incremental cardiovascular risk does not uniformly affect all people with type 2 diabetes. This heterogeneity in cardiovascular risk is multifactorial and only partially understood but is a key consideration for our understanding of the nexus of diabetes and cardiovascular disease and for the development of optimal and individualized cardiovascular risk reduction strategies. This review provides a brief synopsis of the concept of cardiovascular risk heterogeneity in diabetes, including epidemiologic evidence, discussion of established and potential determinants of heterogeneity, and clinical, research, and regulatory implications.

Context: Although random blood glucose (RBG) values are common in clinical practice, the role of elevated RBG values as a risk factor for type 2 diabetes is not well described., Objective: This study aimed to examine nondiagnostic, RBG values as a risk factor for type 2 diabetes, Design: This was a cross-sectional study of National Health and Nutrition Examination Surveys (NHANES) participants (2005-2010)., Participants: Nonfasting NHANES participants (n = 13 792) without diagnosed diabetes were included., Primary Outcome: The primary outcome was glycemic status (normal glycemia, undiagnosed prediabetes, or undiagnosed diabetes) using hemoglobin HbA1C as the criterion standard., Analysis: Multinomial logistic regression examined associations between diabetes risk factors and RBG values according to glycemic status. Associations between current U.S. screening strategies and a hypothetical RBG screening strategy with undiagnosed diabetes were examined., Results: In unadjusted analyses, a single RBG ≥ 100 mg/dL (5.6 mmol/L) was more strongly associated with undiagnosed diabetes than any single risk factor (odds ratio [OR], 31.2; 95% confidence interval [CI], 21.3-45.5) and remained strongly associated with undiagnosed diabetes (OR, 20.4; 95% CI, 14.0-29.6) after adjustment for traditional diabetes risk factors. Using RBG < 100 mg/dL as a reference, the adjusted odds of undiagnosed diabetes increased significantly as RBG increased. RBG 100-119 mg/dL (OR 7.1; 95% CI 4.4-11.4); RBG 120-139 mg/dL (OR 30.3; 95% CI 20.0-46.0); RBG ≥ 140 mg/dL (OR 256; 95% CI 150.0-436.9). As a hypothetical screening strategy, an elevated RBG was more strongly associated with undiagnosed diabetes than current United States Preventative Services Task Force guidelines (hypertension alone; P < .0001) and similar to American Diabetes Association guidelines (P = .12)., Conclusions: A single RBG ≥ 100 mg/dL is more strongly associated with undiagnosed diabetes than traditional risk factors. Abnormal RBG values are a risk factor for diabetes and should be considered in screening guidelines.

Advances in noninvasive imaging modalities have provided opportunities to study β cell function through imaging zinc release from insulin secreting β cells. Understanding the temporal secretory pattern of insulin and zinc corelease after a glucose challenge is essential for proper timing of administration of zinc sensing probes. Portal venous sampling is an essential part of pharmacological and nutritional studies in animal models. The purpose of this study was to compare two different percutaneous image-guided techniques: transhepatic ultrasound guided portal vein access and transsplenic fluoroscopy guided splenic vein access for ease of access, safety, and evaluation of temporal kinetics of insulin and zinc release into the venous effluent from the pancreas. Both techniques were safe, reproducible, and easy to perform. The mean time required to obtain desired catheter position for venous sampling was 15 minutes shorter using the transsplenic technique. A clear biphasic insulin release profile was observed in both techniques. Statistically higher insulin concentration but similar zinc release after a glucose challenge was observed from splenic vein samples, as compared to the ones from the portal vein. To our knowledge, this is the first report of percutaneous methods to assess zinc release kinetics from the porcine pancreas.

Background: This study aimed to assess the efficacy of early intensive diabetes therapy with either insulin plus metformin (INS) or triple oral therapy (TOT) with metformin, glyburide, and pioglitazone on glycemic control and A-cell function., Methods: Fifty-eight treatment-naive newly diagnosed patients with type 2 diabetes underwent a 3-month lead-in treatment period with insulin and metformin, then were randomized to INS or TOT for 6 years. β-Cell function was measured using mixed-meal challenge test. β-Cell function remained stable throughout the 6-year study in both groups, as measured by the C-peptide area under the curve (AUC; P = 0.13), the AUC C-peptide/AUC glucose (P = 0.9), and by the disposition index (P = 0.8). Excellent glycemic control was maintained in both groups (end-of-study hemoglobinA1c, 7.3% [SD, 1.7%] INS vs 6.4% [1.4%] TOT; P = 0.4). There were 8 treatment failures (confirmed hemoglobinA1c, 98%) in INS and 6 in TOT (P = 0.93). The predictors of treatment failure included higher fasting glucose (P = 0.008), fasting C-peptide (P = 0.008), systolic blood pressure (P = 0.004), and lower insulin sensitivity (P = 0.04) at randomization., Conclusions: Early intensive treatment at the time of type 2 diabetes diagnosis-initial short-term insulin treatment followed by either insulin-based or intensive oral hypoglycemic-based therapy-stabilizes β-cell function for at least 6 years. Treatment failure was independent of intervention and was associated with worse disease pathology at baseline.

Aim: To assess past suicide attempts in a cohort of adults with Type 2 Diabetes diagnosed within the prior 24 months., Methods: Outpatients were recruited from diabetes education classes or diabetes shared medical appointment. Participants aged 18 or over with a self-reported diagnosis of Type 2 Diabetes (T2DM) in the prior 24 months completed questionnaires about medical (including diabetes), psychiatric, and social history. Participants also completed two screening questionnaires for depression: Patient Health Questionnaire 9 and the Questionnaire Inventory for Depressive Symptoms-Self Report. Those who screened positive for depression had confirmatory testing with a clinician administered Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) checklist., Results: In this convenience sample of 145 patients with Type 2 Diabetes, 9.7% of patients had history of a suicide attempt and 38.2% met diagnosis for major depressive disorder (MDD). Patients with MDD were more likely to have a history of suicide attempts than those without MDD (p=0.0002). Of the patients with prior suicide attempts, 50% screened positive for MDD at the time of the survey., Conclusion: In patients with newly-diagnosed Type 2 Diabetes the rate of past suicide attempts was nearly 10%, which is twice the rate seen in the general population. The rate of past suicide attempts in currently depressed patients with diabetes is 21.8%. These findings suggest the need for monitoring patients with diabetes and depression for future suicide risk., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: Improvements in diabetes after Roux-en-Y gastric bypass (RYGB) often occur days after surgery. Surgically induced hormonal changes and the restrictive postoperative diet are proposed mechanisms. We evaluated the contribution of caloric restriction versus surgically induced changes to glucose homeostasis in the immediate postoperative period., Research Design and Methods: Patients with type 2 diabetes planning to undergo RYGB participated in a prospective two-period study (each period involved a 10-day inpatient stay, and periods were separated by a minimum of 6 weeks of wash-out) in which patients served as their own controls. The presurgery period consisted of diet alone. The postsurgery period was matched in all aspects (daily matched diet) and included RYGB surgery. Glucose measurements were performed every 4 h throughout the study. A mixed-meal challenge test was performed before and after each period. RESULTS Ten patients completed the study and had the following characteristics: age, 53.2 years (95% CI, 48.0-58.4); BMI, 51.2 kg/m(2) (46.1-56.4); diabetes duration, 7.4 years (4.8-10.0); and HbA1c, 8.52% (7.08-9.96). Patients lost 7.3 kg (8.1-6.5) during the presurgery period versus 4.0 kg (6.2-1.7) during the postsurgery period (P = 0.01 between periods). Daily glycemia in the presurgery period was significantly lower (1,293.58 mg/dL · day [1,096.83-1,490.33) vs. 1,478.80 mg/dL · day [1,277.47-1,680.13]) compared with the postsurgery period (P = 0.02 between periods). The improvements in the fasting and maximum poststimulation glucose and 6-h glucose area under the curve (primary outcome) were similar during both periods., Conclusions: Glucose homeostasis improved in response to a reduced caloric diet, with a greater effect observed in the absence of surgery as compared with after RYGB. These findings suggest that reduced calorie ingestion can explain the marked improvement in diabetes control observed after RYGB.

Background: The landmark Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) placed a new spotlight on thiazide diuretics as the first-line therapy for hypertension. This is concerning as thiazide-diuretics may contribute to comorbidities associated with the current epidemic of obesity. Previous randomized clinical trials have linked thiazide diuretic treatment to insulin resistance, metabolic syndrome, and increased incidence of type 2 diabetes., Methods: This proof of concept, longitudinal, randomized, double-blind study evaluated the effects of the angiotensin II receptor blocker Valsartan and the specific thiazide diuretic Hydrochlorothiazide (HCTZ) on hepatic triglyceride level (primary outcome), as well as triglyceride levels within other organs including the heart, skeletal muscle, and pancreas. Additionally, we evaluated whether myocardial function, insulin sensitivity, and insulin secretion were affected by these treatments., Results: Hepatic TG levels increased by 57% post HCTZ treatment: ∆hTG HCTZ = 4.12% and remained unchanged post Valsartan treatment: ∆hTG V = 0.06%. The elevation of hepatic TG levels after HCTZ treatment was additionally accompanied by a reduction in insulin sensitivity: ∆SI HCTZ = -1.14. Treatment with Valsartan resulted in improved insulin sensitivity: ∆SI V = 1.24. Treatment-induced changes in hepatic TG levels and insulin sensitivity were statistically significant between groups (phTG = 0.0098 and pSI = 0.0345 respectively). Disposition index, DI, remained unchanged after HCTZ treatment: ∆DI HCTZ = -141 but it was increased by a factor of 2 after treatment with Valsartan: ∆DI V =1018). However, the change between groups was not statistically significant. Both therapies did not modify abdominal visceral and subcutaneous fat mass as well as myocardial structure and function. Additionally, myocardial, pancreatic, and skeletal muscle triglyceride deposits remained unchanged in both therapeutic arms., Conclusions: Our findings are two-fold and relate to hepatic steatosis and insulin sensitivity. HCTZ treatment worsened hepatic steatosis measured as hepatic triglyceride content and reduced insulin sensitivity. Valsartan treatment did not affect hepatic triglyceride levels and improved insulin sensitivity. The results of this study reinforce the message that in patients at risk for type 2 diabetes it is particularly important to choose an antihypertensive regimen that lowers blood pressure without exacerbating patient's metabolic profile.

Objective: To observe the efficacy and safety of glucagonlike peptide-1 (GLP-1) analogs in type 1 diabetes in a real-life medical practice setting., Methods: We performed a retrospective chart review of patients with type 1 diabetes initiated on a GLP-1 analog and with at least one follow-up visit at more than 4 weeks., Results: We identified 11 patients who were initiated on a GLP-1 analog and had a follow-up visit between 4 and 13 weeks (mean (SD) follow-up 10 ± 3 weeks; age 36.5 ± 16.4 years; duration of diabetes 17.3 ± 9.3 years; all on insulin pump therapy; all started on liraglutide). Seven of these patients had a second follow-up visit at approximately 20 weeks. By 10 weeks, there was a significant decrease in weight (4.2% of total body weight), total daily insulin dose (19.2%, of which 14.0% basal and 24.1% bolus), and mean (SD) insulin units/kg (0.57 [0.17] to 0.48 [0.17] units/kg). Hemoglobin A1c was significantly decreased (7.4 [0.7%] to 7.0 [0.7%], P = 0.02) without an increase in hypoglycemia. These effects were sustained at 20 weeks. Nausea was a common adverse effect and lead to drug discontinuation in 4 of 11 patients., Conclusions: Patients with long-standing type 1 diabetes can achieve weight loss and improved glycemic control on less insulin without an increase in hypoglycemia when liraglutide is added to insulin therapy.

Background: Hyperinsulinemia has been associated with hepatic fat deposition and ensuing insulin resistance. It is unknown if treatment with exogenous insulin in patients with type 2 diabetes, who are most prone to hepatic fat accumulation, would promote the occurrence or worsening of nonalcoholic fatty liver disease., Methods: Patients with treatment-naive type 2 diabetes (N = 16) were treated with insulin and metformin for a 3-month lead-in period, then assigned triple oral therapy (metformin, glyburide, and pioglitazone) or continued treatment with insulin and metformin. Hepatic triglyceride content (HTC)-measured by magnetic resonance spectroscopy, serum lipids, glucose, liver function tests, and inflammatory and thrombotic biomarkers were followed for a median of 31 months., Results: The 45% decline in HTC during the lead-in period persisted through the follow-up period with no difference between treatment groups at the end of the study (5.26 ± 4.21% in the triple oral therapy vs 7.47 ± 7.40% for insulin/metformin), whereas glycemic control was comparable., Conclusions: Improvements in HTC with initial insulin/metformin therapy persisted through the median 31-month follow-up period regardless of the treatment. More importantly, insulin-based treatment did not appear to promote or worsen nonalcoholic fatty liver disease.

Objective: To describe a patient who developed a thyrotropin (TSH)-secreting adenoma in the setting of primary hypothyroidism., Methods: We report the clinical, laboratory, and radiologic findings of a patient with a history of primary hypothyroidism who presented with headache, a bitemporal visual field deficit, and elevated TSH despite long-term levothyroxine therapy. We discuss the diagnostic challenges of this case and review the relevant literature., Results: A 54 year old woman with a history of primary hypothyroidism presented with a 3-year history of headache and a week of worsening vision. Imaging revealed a heterogeneous sellar mass elevating the optic chiasm. Her serum TSH was 46.5 mIU/L and free thyroxine concentration was 0.1 ng/dL. The differential diagnosis included pituitary hyperplasia and a TSH-secreting adenoma in a patient with primary hypothyroidism. The pathologic characteristics of the tumor were consistent with the latter., Conclusion: In a patient with an elevated TSH concentration and a previous diagnosis of hypothyroidism, it is important to consider other entities besides medication noncompliance. TSH-secreting adenomas can also cause elevated levels of TSH.

Objective: To validate magnetic resonance spectroscopy (MRS) as a tool for non-invasive quantification of pancreatic triglyceride (TG) content and to measure the pancreatic TG content in a diverse human population with a wide range of body mass index (BMI) and glucose control., Methods: To validate the MRS method, we measured TG content in the pancreatic tissue of 12 lean and 12 fatty ZDF rats (ages 5-14 weeks) both by MRS and the gold standard biochemical assay. We used MRS to measure pancreatic TG content in vivo in 79 human volunteers. Additionally, to assess the reproducibility of the method, in 33 volunteers we obtained duplicate MRS measurements 1-2 weeks apart., Results: MRS quantifies pancreatic TG content with high reproducibility and concordance to the biochemical measurement (Spearman's rank correlation coefficient = 0.91). In humans, median pancreatic TG content was as follows: (1) normal weight and normoglycemic group 0.46 f/w%, (2) overweight or obese but normoglycemic group 3.16 f/w%, (3) impaired fasting glucose or impaired glucose tolerance group (BMI matched with group 2) 5.64 f/w%, and (4) untreated type 2 diabetes group (BMI matched with group 2) 5.54 f/w% (Jonckheere-Terpstra trend test across groups p < 0.001)., Conclusions: Human pancreatic steatosis, as measured by MRS, increases with BMI and with impaired glycemia. MRS is a quantitative and reproducible non-invasive clinical research tool which will enable systematic studies of the relationship between ectopic fat accumulation in the pancreas and development of type 2 diabetes.

Background: The incidence of thyroid cancer is increasing. Our objective was to characterize the demographic pattern of this increase and to examine trends in surgical therapy for thyroid cancer., Methods: Analysis of the SEER and NHDS databases was performed from 1974 to 2000 and from 1979 to 2004, respectively. Thyroid-related diagnoses were extracted, and thyroid cancer (ICD 193.X) were analyzed using the SAS statistical package. We compared the population-adjusted incidence of thyroid cancer and examined regional variations in the operative therapy for thyroid cancer., Results: The incidence of thyroid cancer has increased during the past 26 years. This increase occurred predominantly in women and in the Northeastern and Southern United States, whereas there has been a decrease in thyroid cancers in the Midwest. Papillary cancer accounts for most of this increase. Total thyroidectomy (TT) is now the most common operation for thyroid cancer. No differences in the use of TT were observed based on hospital size or insurance status., Conclusion: The increasing incidence of thyroid cancer in the United States is predominantly in women. These results suggest that women are a high-risk group for developing thyroid cancer although men have higher stage disease.

Background: The risk of heart failure in type 2 diabetes mellitus is greater than can be accounted for by hypertension and coronary artery disease. Rodent studies indicate that in obesity and type 2 diabetes mellitus, lipid overstorage in cardiac myocytes produces lipotoxic intermediates that cause apoptosis, which leads to heart failure. In humans with diabetes mellitus, cardiac steatosis previously has been demonstrated in explanted hearts of patients with end-stage nonischemic cardiomyopathy. Whether cardiac steatosis precedes the onset of cardiomyopathy in individuals with impaired glucose tolerance or in patients with type 2 diabetes mellitus is unknown., Methods and Results: To represent the progressive stages in the natural history of type 2 diabetes mellitus, we stratified 134 individuals (age 45+/-12 years) into 1 of 4 groups: (1) lean normoglycemic (lean), (2) overweight and obese normoglycemic (obese), (3) impaired glucose tolerance, and (4) type 2 diabetes mellitus. Localized (1)H magnetic resonance spectroscopy and cardiac magnetic resonance imaging were used to quantify myocardial triglyceride content and left ventricular function, respectively. Compared with lean subjects, myocardial triglyceride content was 2.3-fold higher in those with impaired glucose tolerance and 2.1-fold higher in those with type 2 diabetes mellitus (P<0.05). Left ventricular ejection fraction was normal and comparable across all groups., Conclusions: In humans, impaired glucose tolerance is accompanied by cardiac steatosis, which precedes the onset of type 2 diabetes mellitus and left ventricular systolic dysfunction. Thus, lipid overstorage in human cardiac myocytes is an early manifestation in the pathogenesis of type 2 diabetes mellitus and is evident in the absence of heart failure.

High levels of myocardial and hepatic triglyceride are common in obesity and type 2 diabetes. Monotherapy with thiazolidinedione agents reduces hepatic steatosis by up to 50% in patients with type 2 diabetes. It is not known if treatment with a thiazolidinedione added to insulin has a similar beneficial antisteatotic effect. The aim of our study was to determine whether the addition of pioglitazone to insulin treatment in patients with type 2 diabetes has antisteatotic action in the heart and the liver. Thirty-two patients were randomized to 6 months of treatment with insulin or insulin plus pioglitazone. In addition to blood tests, we evaluated myocardial and hepatic triglyceride content, as well as subcutaneous and visceral fat mass at the L2 level, by magnetic resonance spectroscopy and imaging, respectively. Despite weight and subcutaneous fat mass gain, hemoglobin A1c was significantly reduced by both treatments. Myocardial and hepatic triglyceride contents were reduced by the treatment with pioglitazone plus insulin (p = .02 and .03, respectively) but not by the treatment with insulin. Systolic and diastolic blood pressure and heart function remained unchanged in both groups. The addition of pioglitazone to insulin therapy reduced myocardial and hepatic steatosis, consistent with the reported ability of the thiazolidinedione agents to redistribute fat from nonadipose to subcutaneous adipose depots.

Objective: Hepatic steatosis occurs in up to 78% of patients with type 2 diabetes. Studies evaluating the effect of metformin on hepatic steatosis are conflicting. Insulin is believed to be detrimental due to its lipogenic effect. Since insulin-metformin combination is commonly used for the treatment of diabetes, it is important to assess the effect of this combined therapy on hepatic steatosis. We evaluated the change in hepatic steatosis following the initiation of insulin and metformin in patients with type 2 diabetes., Methods: Newly diagnosed treatment-naïve patients with type 2 diabetes had their hepatic triglyceride (TG) content measured by magnetic resonance spectroscopy at baseline and after 3 months of treatment with BiAsp 30 insulin, in combination with metformin. Insulin was administered twice daily and titrated to achieve normal capillary blood glucose levels. Metformin was titrated during the first month from 500 mg daily to 1000 mg bid., Results: The average hepatic TG content in 19 enrolled subjects was 11.83+/-7.61% (range, 0.93-23.16%) and correlated with body mass index (r=.567). Three months of treatment reduced hepatic steatosis by 45%, with 75% of the study subjects achieving a normal level. The change in hepatic TG content was partially explained by changes in HbA1c (P=.006) and cholesterol (P=.003) levels., Conclusions: The combined treatment with insulin and metformin significantly reduced hepatic steatosis in patients with newly diagnosed type 2 diabetes.

Background: To achieve glycemic control in type 2 diabetes mellitus (T2DM), multiple oral agents are used in a stepwise approach, but long-term maintenance of normoglycemia is difficult to achieve, and, eventually, most patients require insulin. The aim of this study was to evaluate the feasibility, acceptability, and efficacy of insulin with metformin for newly diagnosed, treatment-naive patients with T2DM., Methods: Eligible patients were started on insulin NovoLog 70/30 and metformin 1,000 mg twice daily. Biochemical evaluation was performed at baseline and at the end of the 3-month study. Patients were seen monthly to assess side effects and compliance and make insulin dose adjustments. Patient treatment satisfaction was evaluated at the end of the study., Results: Of 63 patients, 92% completed the study. The hemoglobin A(1c) (HbA(1c)) decreased from 10.8 to 5.9% (p < .0001), and 100% of subjects achieved an HbA(1)c < 7%. Weight increased from 100.0 to 101.6 kg (p = .004) but was less than expected given that patients lost an average of 7.2 kg prior to diagnosis and achieved a reduction in HbA(1c) of 5%. The rate of hypoglycemia was low (1.5 episodes/patient-month). Ninety-seven percent of the patients were satisfied with their insulin treatment, and 88% were willing to continue insulin. Compliance was 96.5% with insulin and 95.1% with metformin., Conclusion: Outpatient initiation of insulin therapy at the time of diagnosis of T2DM is an effective, safe, and feasible strategy for rapidly lowering HbA(1c) levels to targets. Insulin was very well accepted by the patients, refuting the misconception of low satisfaction and acceptance of such treatment.