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Data have been accumulating on the risk of developing type 2 diabetes in patients receiving statins and on the potential adverse effects of these drugs on glycemic control in patients who already have type 2 diabetes. This article reviews data linking statin use and new-onset diabetes mellitus, the effects of statins on glycemic control in type 2 diabetes, the benefit-risk considerations of statin use and type 2 diabetes, and how these factors affect patient management.

OBJECTIVE To determine whether the use of an inhaled insulin would improve HbA1c. METHODS This study was performed in 20 type 2 diabetes mellitus (T2DM) participants with HbA1c values ≥7.5 (58) to ≤11.5% (102 mmol/mol) on a variety of glucose-lowering regimens. Prandial Technosphere insulin (TI) was rapidly titrated based on a treatment algorithm using postprandial blood glucose to calculate premeal doses. A 2-week baseline period was followed by 12 weeks of active treatment with TI. The primary outcome was change in HbA1c. Secondary outcomes included glucose time in range (time in range: 70-180 mg/dL) obtained by a blinded continuous glucose monitoring during the baseline period and at the end of 12 weeks. Goals were to assess how to rapidly and safely initiate TI intensification, determine dosing requirements, and establish an effective dose range in uncontrolled T2DM. RESULTS Mean HbA1c decreased by -1.6% (-17 mmol/mol) from 9.0% (75 mmol/mol) at baseline to 7.4% (57 mmol/mol) at 12 weeks (P < .0001). Mean time in range increased from 42.2% to 65.7% (P < .0002). Mean prandial doses of TI were 18 or 19 units for all meals. Time below range was 1.1% baseline and 2.6% post treatment (P = .01). CONCLUSION Treatment with inhaled TI dosed using a simple algorithm improved glycemic control measured by both HbA1c and time in range, with low rates of hypoglycemia. These data add significantly to understanding TI in the management of T2DM patients for whom prandial insulin is a consideration.

Objective To compare glycemic efficacy of Technosphere insulin (TI) versus that of insulin aspart (IA), each added to basal insulin, in type 2 diabetes. Methods This randomized, 24-week trial included subjects aged from 18 to 80 years who were treated with subcutaneous insulin for 3 months and had glycated hemoglobin (HbA1C) levels of 7.0% to 11.5%. After receiving stabilized insulin glargine doses during a 4-week lead in, the subjects were randomized to TI or IA. The primary end point was an HbA1C change from baseline, with the differences analyzed by equivalence analyses. Results In the overall cohort (N = 309; males, 23.3%), mean (SD) age was 58.5 (8.4) years, body mass index was 30.8 (4.7) kg/m2, weight was 82.2 (13.6) kg, and duration of diabetes was 12.2 (7.1) years. An intention-to-treat cohort had 150 subjects randomized to TI (mean [SD] HbA1C: 8.9% [1.1%]) and 154 randomized to IA (mean [SD] HbA1C: 9.0% [1.3%]). At 24 weeks, mean (SD) HbA1C value declined to 7.9% (1.3%) and 7.7% (1.1%) in the TI and IA cohorts, respectively. A treatment difference of 0.26% was not statistically significant, but the predefined equivalency margin was not met. Subjects receiving TI lost 0.78 kg compared to baseline; subjects receiving IA gained 0.23 kg (P =.0007). The incidence of mild/moderate hypoglycemia was lower for the TI cohort, though not statistically significant. Conclusion Both TI and IA resulted in significant and clinically meaningful HbA1C reductions. TI also resulted in significant and clinically meaningful weight reductions. These data support the use of inhaled insulin as a treatment option for individuals with type 2 diabetes.

Technosphere Insulin (TI) is an inhaled insulin. Studies comparing TI with short-acting insulin analogues provide important insights on efficacy, dosing, and time course of action.Planned enrollment of 230 subjects was limited to 138 due to premature study discontinuation. The primary efficacy endpoint was a noninferiority of glycosylated hemoglobin (HbA1c) of 0.4% for TI compared with insulin lispro (LIS) in a 16-week phase 3 randomized clinical trial in type 1 diabetes mellitus.HbA1c values were similar in the TI and LIS groups at the beginning of the trial (7.8% and 7.6%, respectively) and at trial endpoint (7.7% and 7.6%, respectively). Least squares mean changes from baseline were similar between study groups. Glucose values after a standard meal were significantly lower with TI in the first 90 minutes post meal compared with LIS. Mild or moderate hypoglycemia event rates were also significantly lower with TI compared with LIS (5.97 vs 8.01, respectively; P = .0269). Cough was the most commonly reported adverse event with TI. Pulmonary function as measured by forced expiratory volume in 1 second was not different between groups at baseline, 16 weeks, or 4 weeks off study drug.HbA1c was unchanged and overall glucose control was comparable between groups. Treatment with TI resulted in improved post-meal glucose and a lower risk of hypoglycemia compared with LIS.背景: Technosphere胰岛素(TI)是一种吸入型胰岛素。该研究将TI与短效胰岛素类似物进行比较，并对有关疗效、剂量和作用时间的关系进行分析。 方法: 由于研究提前终止，计划招募的230名受试者最后限于138名。在1型糖尿病患者为期16周的3期随机临床试验中，主要研究终点是TI的糖化血红蛋白(HbA1c)与赖脯胰岛素(LIS)相比的非劣效性为0.4%。 结果: TI和LIS组的HbA1c值在试验开始和终点时相似，在试验开始时分别为7.8%和7.6%，试验终点时分别为7.7%和7.6%。研究组之间最小二乘均值相对于基线的变化相似。与LIS相比，TI在标准餐后前90分钟内的血糖显著降低。与LIS相比，TI的轻度或中度低血糖事件发生率也显著降低(分别为5.97和8.01； P = 0.0269)。咳嗽是最常见的TI不良反应。用1秒用力呼气量测量的肺功能在基线、停药16周或停药4周组之间没有差异。 结论: 各组间的HbA1c没有变化，总体血糖控制水平相当。与LIS相比，TI治疗可改善餐后血糖，降低低血糖风险。.

The classification of diabetes mellitus in 2020 still starts with 2 major types, ie, type 1 and type 2, but each of these now includes a few uncommon variants. Understanding the many faces of the diabetes syndrome can make a difference in how clinicians select glucose-lowering therapy.

Hypoglycemia is a serious problem in older patients with diabetes mellitus. This chapter discusses risk factors associated with hypoglycemia and approaches to mitigation of the risk for hypoglycemia. Specific considerations include selection of glucose lowering agents, comorbid conditions and the implications of declining cognitive dysfunction.

Technosphere Insulin (TI) is a dry-powder formulation of recombinant human insulin adsorbed onto Technosphere microparticles for oral inhalation. Data from two 52-wk randomized phase 3 trials in type 2 DM were combined to analyze the effects of TI on body weight. In one trial, patients on basal insulin were randomized to prandial TI or insulin aspart. In the other trial, basal insulin plus prandial TI was compared to 70/30 insulin analog mixture. Primary efficacy end point in each trial was change in A1C. Weight data were captured in each study. Weight and A1C data were analyzed based on modified Intention to Treat Analyses and LS mean changes from baseline. In these analyses, the TI arms were combined and comparisons were made between TI and each of the comparator arms. Aspart and 70/30 arms were not compared to each other. Data for 26 and 52 wk time points are reported. Results At both 26 and 52 weeks, TI was associated with less weight gain than either aspart or premixed insulin. Differences were significant for TI vs. each comparator. A1C differences among treatment arms were small and only statistically significant for TI vs. aspart at 52 weeks. Conclusion: In insulin treated T2DM persons, TI is associated with less weight gain than Insulin aspart or premixed 70/30 analog insulin. These weight differences appear to be independent of changes in A1C. Disclosure J. Manoukian: Employee; Self; MannKind Corporation. D.M. Kendall: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Eli Lilly and Company. P.M. Morey: Employee; Self; MannKind Corporation. B.J. Hoogwerf: Consultant; Self; MannKind Corporation. Employee; Spouse/Partner; MannKind Corporation. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.

The impact of inhaled Technosphere Insulin (TI) on measures of pulmonary function remain an important component of clinical use. TI is an ultra rapid-acting prandial insulin delivered via deep pulmonary inhalation allowing for prompt absorption in the alveoli. Prior studies have demonstrated that, on average, changes in pulmonary function testing (PFT) are limited to small changes (∼1%) in forced expiratory volume in 1 second (FEV1). This comprehensive post-hoc analysis examined the incidence of significant decline in FEV1 over two years in subjects with type 1 and type 2 diabetes treated with TI. Subjects were included if they had at least five FEV1 measurements (including baseline and month 24). FEV1 must have been ≥70% of predicted at baseline. At each time point, subjects were classified as having a significant change in FEV1 if there was a ≥15% decline from baseline. Of the 377 subjects, 331 (87.8%) had no measure with ≥15% decline in FEV1 at any time point. Of subjects who had at least one measure with a decline of ≥15%, the majority (n=38) experienced this decline on a transient basis (defined as occurring at two or fewer time points). Eight individuals (2.1%) demonstrated a persistent decline in FEV1 (occurring at three or more time points). Four subjects in the comparator arm (0.7%, n=586) had persistent decline. In conclusion, persistent significant decline in FEV1 during the use of TI was uncommon. Disclosure M.C. Jones: Employee; Self; MannKind Corporation. T.S. Tran: Employee; Self; MannKind Corporation. J.A. Krueger: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Eli Lilly and Company, MannKind Corporation. P.M. Morey: Employee; Self; MannKind Corporation. B.J. Hoogwerf: Consultant; Self; MannKind Corporation. Employee; Spouse/Partner; MannKind Corporation. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. D.M. Kendall: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Eli Lilly and Company.

Jason C Simeone,1 Jay P Bae,2 Byron J Hoogwerf,3 Qian Li,1 Axel Haupt,3 Ayad K Ali,4 Marilyn K Boardman,3 Beth L Nordstrom1 1Real-world Evidence, Evidera, Waltham, MA, USA; 2Global Patient Outcomes and Real World Evidence, Eli Lilly and Company, Indianapolis, IN, USA; 3Lily Diabetes, Eli Lilly and Company, Indianapolis, IN, USA; 4Global Patient Safety, Eli Lilly and Company, Indianapolis, IN, USA Purpose: To identify the characteristics and initial disease severity of patients with nonalcoholic fatty liver disease (NAFLD) and assess incidence and risk factors for disease progression in a retrospective study.Methods: Patients ≥18 years of age without alcoholism or other liver diseases (eg, hepatitis B/C) were selected from Geisinger Health System electronic medical record data from 2004 to 2015. Initial disease stage was stratified into uncomplicated NAFLD, advanced fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and liver transplant using clinical biomarkers, diagnosis, and procedure codes. Disease progression was defined as stage progression or death and analyzed via Kaplan–Meier plots and multistate models.Results: In the NAFLD cohort (N=18,754), 61.5% were women, 39.0% had type 2 diabetes mellitus (T2DM), and the mean body mass index was 38.2±10.2 kg/m2. At index, 69.9% had uncomplicated NAFLD, 11.7% had advanced fibrosis, and 17.8% had cirrhosis. Of 18,718 patients assessed for progression, 17.3% progressed (11.0% had stage progression, 6.3% died without evidence of stage progression) during follow-up (median=842 days). Among subgroups, 12.3% of those without diabetes mellitus progressed vs 24.7% of those with T2DM. One-year mortality increased from 0.5% in uncomplicated NAFLD to 22.7% in HCC. After liver transplant, mortality decreased to 5.6% per year.Conclusions: In 2.3 years of follow-up, approximately 17% of patients progressed or died without evidence of stage progression. T2DM was associated with approximately twice the risk of disease progression, and mortality risk increased with disease stage. Early diagnosis and monitoring of disease progression, especially in patients with T2DM, is warranted. Keywords: NAFLD, clinical course, disease progression, multistate model, retrospective study, type 2 diabetes

The objective of this study was to identify factors associated with stroke, myocardial infarction (MI), all-cause mortality, or a diagnosis of ischemic heart disease (IHD) or unstable angina (UA), among patients newly-diagnosed with type 2 diabetes (T2DM) with no recent history of cardiovascular (CV) events who rapidly achieve and maintain HbAData were obtained from the Clinical Practice Research Datalink (CPRD) from January 1990 to December 2012. A nested case-control design was used with Cox proportional hazards analysis. Cases were identified by the first occurrence of stroke, MI, IHD, UA, or death within 5 years after HbAA total of 11,426 T2DM patients met the inclusion criteria for cases. Of these, 5,261 experienced a CV event. Stroke was the most frequent CV event (40%), followed by IHD (29%), MI (22%), and UA (9%). Mean HbA1c ≥7.0% over the length of exposure (vs 6.5 to7.0%) was associated with an increased risk of stroke, MI, and IHD. The use of anti-platelet medications at baseline was also associated with increased risk of stroke (HR = 1.82 [CI = 1.60-2.06]), MI (HR = 1.67 [CI = 1.38-2.03]), and IHD (HR = 1.85 [CI = 1.57-2.17]). Mean HbA1c 6.0% was associated with increased risk of stroke (HR = 1.29 [CI = 1.02-1.63]) and IHD (HR = 1.65 [CI = 1.25-2.19]). Use of nitrate medications at baseline was associated with increased risk of MI (HR = 2.83 [CI = 2.24-3.57]), IHD (HR = 4.32 [CI = 3.57-5.22]), and UA (HR = 10.38 [CI = 7.67-14.03]).Early and sustained HbA

Aims To compare 24-hour fixed-time basal insulin peglispro (BIL) dosing with 8- to 40-hour variable-time BIL dosing for glycaemic control and safety in patients with type 1 diabetes. Primary outcome was non-inferiority of BIL variable-time dosing compared with fixed-time dosing for glycated haemoglobin (HbA1c) change after 12-week treatment (margin = 0.4%). Materials and methods This Phase 3, open-label, randomized, cross-over study (N = 212) was conducted at 20 centres in the United States. During the 12-week lead-in phase, patients received BIL daily at fixed-times. Two 12-week randomized cross-over treatment phases followed, where patients received BIL dosed at either fixed- or variable-times. During the 4-week safety follow-up, patients received conventional insulins. Results During the lead-in period, least-squares mean HbA1c decreased from 7.5% to 6.8%. For BIL, variable-time dosing was non-inferior to fixed-time dosing for HbA1c change [least-squares mean difference = 0.06%, 95% confidence interval (−0.01, 0.13)]. In both regimens, HbA1c increased slightly during the cross-over periods, but remained significantly below baseline. Variable- and fixed-time dosing regimens had similar rates of total hypoglycaemia (10.4 ± 0.62 and 10.5 ± 0.67 events/patient/30 days, P = .947) and nocturnal hypoglycaemia (1.3 ± 0.11 and 1.5 ± 0.13 events/patient/30days, P = .060). Comparable proportions of patients achieved HbA1c < 7.0% with variable- [91 (54.5%)] and fixed-time dosing [101 (60.5%)]. Conclusions Treatment with BIL allows patients to use flexible dosing intervals from 8 to 40 hours. Glycaemic efficacy (HbA1c), glycaemic variability and hypoglycaemia are similar to fixed-time dosing, suggesting that BIL could potentially provide flexibility in dosing for patients who miss their daily basal insulin.

AIMS To compare effects of basal insulin peglispro (BIL), a hepatopreferential insulin, to insulin glargine (glargine) on aminotransferases and liver fat content (LFC) in patients with type 1 and type 2 diabetes (T1D, T2D). MATERIALS AND METHODS Data from two Phase 2 and five Phase 3 randomized trials comparing BIL and glargine in 1709 T1D and 3662 T2D patients were integrated for analysis of liver laboratory tests. LFC, measured by magnetic resonance imaging (MRI) at baseline, 26 and 52 weeks, was analyzed in 182 T1D patients, 176 insulin-naive T2D patients and 163 T2D patients previously treated with basal insulin. RESULTS Alanine aminotransferase (ALT) increased in patients treated with BIL, was higher than in glargine-treated patients at 4-78 weeks (difference at 52 weeks in both T1D and T2D: 7 international units/litre (IU/L), P

The U.S. Food and Drug Administration (FDA) issued guidance on requirements to assess cardiovascular disease (CVD) risk with drugs being developed for approval for clinical use. The guidance was triggered by a meta-analysis published by Nissen and Wolski that suggested an increased risk for myocardial infarction with the use of rosiglitazone. This article discusses controversies around CVD trials in diabetes beginning with the University Group Diabetes Program. This is followed by a brief description of the FDA guidance for evaluating CVD risk with glucose-lowering medications. Limitations of meta-analyses of data from phase 2 and 3 (phase 2/3) trials to inform CVD risk are highlighted. These include the differences between patient characteristics in phase 2/3 trials and those in cardiovascular outcome trials (CVOTs) and the relatively short exposure time in phase 2/3 trials. The differences may partly explain the observed disparity between phase 2/3 meta-analyses and the results of completed CVOTs. Approaches to understanding CVD risk with a new medication should get to the answer about risk as efficiently as possible to minimize any potential harm to patients. In that context, we discuss options for clinical trial design and an alternative approach for statistical analyses.

Data on cytokeratin-18 (K-18) and enhanced liver fibrosis (ELF) score in insulin-treated diabetes patients with non-alcoholic fatty liver disease (NAFLD) are limited. This study analyzed phase III data comparing basal insulin peglispro (BIL) and insulin glargine in type 1 (T1D), and type 2 diabetes (T2D) (insulin-naïve and insulin-treated). Alanine aminotransferase (ALT), K-18, ELF scores and liver fat content (LFC), measured by MRI, were obtained longitudinally. Baseline K-18 (U/L) was higher in T2D (range: 207-247) than T1D (range: 148-183), correlated with ALT in all populations (r (range) 0.264-0.637, p

Background In Phase 2/3 studies of basal insulin peglispro (BIL) compared to insulin glargine, patients with type 1 or type 2 diabetes previously treated with insulin and randomized to BIL had an increase in serum triglycerides (TGs). To further understand lipoprotein changes, a lipid substudy which included liver fat content was designed to assess relationships among the measured variables for each diabetes cohort and compare the hepato-preferential insulin BIL to glargine. Methods In three cohorts of patients with diabetes (type 1, type 2 insulin naïve, and type 2 previously on insulin; n = 652), liver fat content (LFC) was determined by magnetic resonance imaging (MRI) and blood lipids were analyzed by nuclear magnetic resonance (NMR) spectroscopy at baseline, 26 and 52 weeks of treatment. Apolipoproteins, adiponectin, and other lipid parameters were also measured. Descriptive statistics were done, as well as correlation analyses to look for relationships among LFC and lipoproteins or other lipid measures. Results In patients with type 1 diabetes treated with BIL, but not glargine, small LDL and medium and large VLDL subclass concentrations increased from baseline. In patients with type 2 diabetes previously on insulin and treated with BIL, large VLDL concentration increased from baseline. In insulin naïve patients with type 2 diabetes treated with BIL, there were very few changes, while in those treated with glargine, small LDL and large VLDL decreased from baseline. Baseline LFC correlated significantly in one or more cohorts with baseline large VLDL, small LDL, VLDL size, and Apo C3. Changes in LFC by treatment showed generally weak correlations with lipoprotein changes, except for positive correlations with large VLDL and VLDL size. Adiponectin was higher in patients with type 1 diabetes compared to patients with type 2 diabetes, but decreased with treatment with both BIL and glargine. Conclusions The lipoprotein changes were in line with the observed changes in serum TGs; i.e., the cohorts experiencing increased TGs and LFC with BIL treatment had decreased LDL size and increased VLDL size. These data and analyses add to the currently available information on the metabolic effects of insulins in a very carefully characterized cohort of patients with diabetes. Clinicaltrials.gov registration numbers and dates NCT01481779 (2011), NCT01435616 (2011), NCT01454284 (2011), NCT01582451 (2012)

Basal insulin peglispro (BIL) is a novel insulin with hepato-preferential action. In phase 3 trials, BIL showed significantly improved glycemic control but higher levels of transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), triglycerides (TGs) and liver fat content (LFC) compared with insulin glargine (GL). As variants in PNPLA3 (I148M) and TM6SF2 (E167K) are associated with nonalcoholic fatty liver disease, we assessed these variants in type 2 diabetes (T2D) patients randomized to receive BIL (n=1822) or GL (n=1270) in three phase 3 trials. Magnetic resonance imaging assessments of LFC were conducted in a subset of patients (n=296). Analyses showed α-corrected significant increases in change from baseline in AST (P=0.0004) and nominal increases in ALT (P=0.019), and LFC (P=0.035) for PNPLA3 (148M/M) genotypes in the BIL arm at 26 weeks but no significant associations in GL. PNPLA3 (148M/M) was also associated with increases in total cholesterol (P=0.014) and low-density lipoprotein cholesterol (P=0.005) but not with hemoglobin A1c or TG. T2D patients with the PNPLA3 (148M/M) genotype treated with BIL may be more susceptible to increased liver fat deposition. The current data provide further insights into the biological role of PNPLA3 in lipid metabolism.

There is a link between Oliver Wendell Holmes' poem “The One-Hoss Shay” (1) and every patient with diabetes who has ever received a kidney or pancreas transplant. Yet, most of the 4,128 diabetes patients in the U.S. who received renal transplants in 2011 (2) and the 1,051 diabetes patients who received a pancreas transplant in 2011 (3) do not know how Dr. Frederick C. Goetz (1922–2012) used this delightful poem as parallel to how the medical profession viewed patients with diabetes. Dr. Goetz, who always preferred to be addressed as “Fred” by any who knew him, played a seminal role in assuring that both renal and pancreas transplantation were available to suitable patients with diabetes. While today this is considered a standard of clinical care, Fred maintained his equanimity in the face of much skepticism and criticism—often from friends and colleagues. This profile outlines Fred’s role in the history of renal and pancreas transplantation, but also strives to capture some of the “essence” of Frederick C. Goetz—as a caregiver, physician, scientist, and teacher. This profile is written from the perspective of three physicians, each of whom first met Fred while they were medical students at the University of Minnesota and whose collective observations and collaboration with Fred spanned more than three decades of his academic career. Fred was born and raised in Fond du Lac, WI. He graduated from Harvard College (1943) and Harvard Medical School (1946). He served in the U.S. Army as a physician in Korea where he met his future wife, Mary Rose Riordan. After a residency, chief residency, and fellowship (with Dr. George Thorn) at Massachusetts General Hospital, he joined the University of Minnesota as the Director of Diabetes Research. His career was focused on diabetes and its complications. His personal life was filled with interests …

Glucagon-like peptide-1 receptor agonists exenatide and liraglutide have been shown to improve glycaemic control and reduce bodyweight in patients with type 2 diabetes. We compared the efficacy and safety of exenatide once weekly with liraglutide once daily in patients with type 2 diabetes.We did a 26 week, open-label, randomised, parallel-group study at 105 sites in 19 countries between Jan 11, 2010, and Jan 17, 2011. Patients aged 18 years or older with type 2 diabetes treated with lifestyle modification and oral antihyperglycaemic drugs were randomly assigned (1:1), via a computer-generated randomisation sequence with a voice response system, to receive injections of once-daily liraglutide (1·8 mg) or once-weekly exenatide (2 mg). Participants and investigators were not masked to treatment assignment. The primary endpoint was change in glycated haemoglobin (HbA(1c)) from baseline to week 26. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01029886.Of 912 randomised patients, 911 were included in the intention-to-treat analysis (450 liraglutide, 461 exenatide). The least-squares mean change in HbA(1c) was greater in patients in the liraglutide group (-1·48%, SE 0·05; n=386) than in those in the exenatide group (-1·28%, 0·05; 390) with the treatment difference (0·21%, 95% CI 0·08-0·33) not meeting predefined non-inferiority criteria (upper limit of CI0·25%). The most common adverse events were nausea (93 [21%] in the liraglutide group vs 43 [9%] in the exenatide group), diarrhoea (59 [13%] vs 28 [6%]), and vomiting 48 [11%] vs 17 [4%]), which occurred less frequently in the exenatide group and with decreasing incidence over time in both groups. 24 (5%) patients allocated to liraglutide and 12 (3%) allocated to exenatide discontinued participation because of adverse events.Both once daily liraglutide and once weekly exenatide led to improvements in glycaemic control, with greater reductions noted with liraglutide. These findings, plus differences in injection frequency and tolerability, could inform therapeutic decisions for treatment of patients with type 2 diabetes.Eli Lilly and Company and Amylin Pharmaceuticals LLC.

We investigated non-alcoholic fatty liver disease (NAFLD) prevalence and its metabolic associations in patients with type 1 diabetes (T1D), and in insulin-naive and insulin-treated patients with type 2 diabetes (T2D). Baseline data from patients who had liver fat content (LFC) evaluated by magnetic resonance imaging in four phase 3 studies of basal insulin peglispro (BIL) were analysed. Associations of NAFLD with clinical characteristics, glycaemic control and diabetes therapy were evaluated. The prevalence of NAFLD (defined as LFC ≥ 6%) was low in T1D (8.8%) but high in T2D, with greater prevalence in insulin-naive (75.6%) vs insulin-treated (61.7%) T2D patients. LFC (mean ± SD) was higher in T2D patients (insulin-naive, 13.0% ± 8.4%; insulin-treated, 10.2% ± 7.8%) than in T1D patients (3.2% ± 3.2%). In T2D, NAFLD was associated with several markers of insulin resistance. In all three populations, there was an absence of association of HbA1c with LFC, but insulin doses were higher in patients with NAFLD.

Basal insulin peglispro (BIL) is a novel basal insulin with hepato-preferential action resulting from reduced peripheral effects. This report provides an integrated summary of lipid changes at 26 weeks with BIL and comparator insulins (glargine, NPH) from phase III studies in type 1 diabetes (T1D), insulin-naive patients with type 2 diabetes (T2D), patients with T2D on basal insulin only and patients with T2D on basal-bolus therapy. BIL treatment had little effect on HDL cholesterol and LDL cholesterol in all patients. The effect of both BIL and glargine treatment on triglycerides (TG) depended on whether patients had been previously treated with insulin. When BIL replaced conventional insulin glargine or NPH treatments, increases in TG levels were observed. When BIL or comparator insulins were given for 26 weeks to insulin-naive patients with T2D, TG levels were unchanged from baseline with BIL but decreased with either glargine or NPH. The decreased peripheral action of BIL may reduce suppression of lipolysis in peripheral adipose tissue resulting in increased free fatty acid delivery to the liver and, hence, increased hepatic TG synthesis and secretion.

Background To identify possible differences in cardiovascular (CV) risk among different insulin therapies, we performed pre-specified meta-analyses across the clinical program for basal insulin peglispro (BIL), in patients randomized to treatment with BIL or comparator insulin [glargine (IG) or NPH]. Methods One phase 2 (12-week) and 6 phase 3 (26 to 78-week) randomized studies of BIL compared to IG or NPH, in patients with type 1 or type 2 diabetes, were included. The participants were diverse with respect to demographics, baseline glycemic control, and concomitant disease or medications, but treatment groups were comparable in each study. For any potential CV or neurovascular event, relevant medical information was provided to a blinded external clinical events committee (C5Research, Cleveland Clinic, Cleveland, OH, USA) for adjudication. Cox regression analysis was used to compare treatment groups. The primary endpoint was a composite of adjudicated MACE+ [CV death, myocardial infarction (MI), stroke, or hospitalization for unstable angina]. Results The pooled population included 5862 patients in the safety evaluation, with randomization to BIL:IG:NPH of 3578:2072:212. Mean age was 54.1 years, 27 % had type 1 diabetes, 56 % were male, and 88 % were white. Baseline demographic and clinical characteristics, including use of statins or other lipid-lowering drugs, were comparable between BIL and comparators. A total of 83 patients experienced at least 1 MACE+ and 70 patients experienced at least 1 MACE (CV death, MI, or stroke). Overall, there were no treatment-associated differences in time to MACE+ [hazard ratio (HR) for BIL versus comparator insulin (95 % CI): 0.82 (0.53–1.27)] or MACE [0.83 (0.51–1.33)]. In 4297 patients with type 2 diabetes, there were 71 MACE+ events [HR: 1.02 (95 % CI: 0.63–1.65), p = 0.94]. In 1565 patients with type 1 diabetes, there were only 12 MACE+ [0.24 (0.07–0.85), p = 0.027]. There were no differences in all-cause death between BIL and comparators. Sub-group analyses did not identify any sub-population with increased risk with BIL versus comparator insulins. Conclusions Treatment with BIL versus comparator insulin in patients with type 1 diabetes or type 2 diabetes was not associated with increased risk for major CV events in the studies analyzed. Electronic supplementary material The online version of this article (doi:10.1186/s12933-016-0393-6) contains supplementary material, which is available to authorized users.

Aim: This observational study evaluated the clinical effectiveness of exenatide BID (exenatide) vs. insulin glargine (glargine) in patients with type 2 diabetes mellitus in ambulatory clinical practice. Methods: Retrospective analyses were conducted using an electronic medical record (EMR) database among adult patients with type 2 diabetes mellitus initiating exenatide or glargine between 1 November 2006 and 30 April 2009. The cohorts were propensity-score matched to control baseline demographics, clinical measures, health status and medication use. The changes from baseline to a 12-month follow-up period for A1C (primary outcome), weight, body mass index (BMI), blood pressure and lipid levels were compared between the matched cohorts using paired tests. Results: Propensity-score matching between the exenatide (n = 4494) and glargine (n = 5424) cohorts led to 2683 matched pairs with comparable characteristics, including age, gender and baseline clinical values. The exenatide cohort achieved a greater mean reduction in A1C (−0.6% vs. −0.4%, p < 0.01), weight (−2.6 kg vs. −0.2 kg, p < 0.01), BMI (−0.8 kg/m2 vs. −0.04 kg/m2, p < 0.01) and systolic blood pressure (SBP) (−1.8 mmHg vs. −0.1 mmHg, p < 0.01) in the follow-up period. The changes in diastolic blood pressure and lipid levels were not significantly different between cohorts. Conclusions: Compared to glargine, exenatide-treated patients experienced significant reductions in A1C, weight, BMI and SBP. Acknowledging the limitations of observational research, exenatide showed greater clinical effectiveness than glargine from a large EMR database in the ambulatory care setting.

To explore, by post hoc analyses of pooled data, the efficacy and safety of the use of exenatide twice daily (BID) in patients stratified by baseline glucose-lowering therapies.Patients with type 2 diabetes from long-term randomized controlled trials who were treated with exenatide BID were classified into concomitant medication groups on the basis of background treatment (diet and exercise only, metformin only, sulfonylurea only, thiazolidinedione only, metformin + sulfonylurea, metformin + thiazolidinedione, or insulin with or without other oral antihyperglycemic medications). Seventeen studies were included in the analyses (N = 2,096).In these analyses of patients treated with exenatide BID for 12 to 30 weeks, there were significant decreases from baseline in hemoglobin A(1c) (A1C) and fasting glucose levels in all groups and significant decreases from baseline in body weight in all groups except the thiazolidinedione-only group. The decrease in A1C appeared to be greater in the insulin group than in the other groups, likely because the insulin dose was titrated whereas doses of concomitant antihyperglycemic medications were generally not titrated. Overall, changes in blood pressure and lipids were small. Across all groups, the most common adverse effects were gastrointestinal events. Hypoglycemia was more common in the sulfonylurea-only, metformin + sulfonylurea, and insulin groups than it was in the other concomitant medication groups.The use of exenatide BID across a wide range of background therapies was associated with reductions in A1C, fasting glucose, and body weight. Gastrointestinal adverse events were common.

The objective of this study was to examine the frequency of hypoglycemia among patients with type 2 diabetes who had concomitantly used exenatide BID (exenatide) and long-acting insulin and continued this combination vs those who continued long-acting insulin alone.Retrospective analyses, using a large managed care database, were used to estimate the frequency of hypoglycemia (episodes/patient/6 months) for patients who concomitantly used exenatide and long-acting insulin during a 6-month follow-up period.From among 2082 patients on concomitant exenatide and long-acting insulin, those who continued this combination (n=472) had a lower frequency of hypoglycemia compared to those who remained on long-acting insulin alone (n=312) (0.03 ± 1.9 vs 0.10 ± 1.01 [episodes/patient/6 months]; p0.0001).Only hypoglycemia that required medical intervention (coded for hypoglycemia) was captured. The study could not evaluate any association between insulin dose titration and hypoglycemia or examine other outcomes such as HbA1c, weight, and body mass index, due to lack of data availability.Patients who concomitantly used exenatide BID and long-acting insulin experienced a lower rate of hypoglycemia.

OBJECTIVE To test the hypothesis that exenatide twice daily reduces the relative incidence of cardiovascular disease (CVD) events among patients with type 2 diabetes compared with other glucose-lowering agent(s). RESEARCH DESIGN AND METHODS A retrospective database analysis was performed of the LifeLink database of medical and pharmaceutical insurance claims for June 2005 through March 2009. Patients with no history in the preceding 9 months of myocardial infarction, ischemic stroke, or coronary revascularization procedure were assigned to the exenatide-initiated or non–exenatide-initiated cohorts based on the first new prescription filled and reassigned if exenatide was prescribed or discontinued. Incident CVD events (myocardial infarction, ischemic stroke, or coronary revascularization procedure) were identified by ICD-9-CM diagnosis codes. Patient outcomes were adjusted for differences in clinical and demographic characteristics and compared using propensity score–weighted discrete time survival analysis with time-varying exposure to exenatide. RESULTS A total of 39,275 patients with type 2 diabetes were treated with exenatide twice daily, and 381,218 patients were treated with other glucose-lowering therapies. Patients who initiated exenatide were more likely to have prior ischemic heart disease, obesity, hyperlipidemia, hypertension, and/or other comorbidities at baseline. Exenatide-treated patients were less likely to have a CVD event than non–exenatide-treated patients (hazard ratio 0.81; 95% CI 0.68–0.95; P = 0.01) and lower rates of CVD-related hospitalization (0.88; 0.79–0.98; P = 0.02) and all-cause hospitalization (0.94; 0.91–0.97; P < 0.001). CONCLUSIONS Exenatide twice-daily treatment was associated with a lower risk of CVD events and hospitalizations than treatment with other glucose-lowering therapies.

The BMI is the most frequently used marker to evaluate obesity-associated risks. An alternative continuous index of lipid over accumulation, the lipid accumulation product (LAP), has been proposed, which is computed from waist circumference (WC, cm) and fasting triglycerides (TGs) (mmol/l): (WC - 65) x TG (men) and (WC - 58) x TG (women). We evaluated LAP and BMI as predictors of mortality in a high-risk cohort. Study population included 5,924 new consecutive patients seen between 1995 and 2006 at a preventive cardiology clinic. Fifty-eight percent of patients were discordant for their LAP and BMI quartiles. Patients whose LAP quartile was greater than BMI quartile had higher mortality compared with those with LAP quartile was lower than BMI quartile (8.2 vs. 5.4% at 6 years, P = 0.007). After adjustment for age, gender, smoking, diabetes mellitus, blood pressure, low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C), (ln)LAP was independently associated with mortality (hazard ratio (HR) = 1.46, P < 0.001). BMI was not associated with increased mortality (HR = 1.06, P = 0.39). Adding LAP to a model including traditional risk factors for atherosclerosis increased its predictive value (C statistic 0.762 vs. 0.750, P = 0.048). Adding BMI to the same model did not change its predictive value (0.749 vs. 0.750, P = 0.29). Subgroup analyses showed that LAP predicted mortality in the nondiabetic patients (adjusted HR for (ln)LAP 1.64, P < 0.001), but did not reach significance in the diabetic patients (HR = 1.21, P = 0.11). In conclusion, LAP and not BMI predicted mortality in nondiabetic patients at high risk for cardiovascular diseases. LAP may become a useful tool in clinical practice to stratify the risk of unfavorable outcome associated with obesity.

OBJECTIVE Intensive therapy targeting normal blood glucose increased mortality compared with standard treatment in a randomized clinical trial of 10,251 participants with type 2 diabetes at high-risk for cardiovascular disease (CVD) events. We evaluated whether the presence of cardiac autonomic neuropathy (CAN) at baseline modified the effect of intensive compared with standard glycemia treatment on mortality outcomes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial participants. RESEARCH DESIGN AND METHODS CAN was assessed by measures of heart rate variability (HRV) and QT index (QTI) computed from 10-s resting electrocardiograms in 8,135 ACCORD trial participants with valid measurements (mean age 63.0 years, 40% women). Prespecified CAN definitions included a composite of the lowest quartile of HRV and highest QTI quartile in the presence or absence of peripheral neuropathy. Outcomes were all-cause and CVD mortality. Associations between CAN and mortality were evaluated by proportional hazards analysis, adjusting for treatment group allocation, CVD history, and multiple prespecified baseline covariates. RESULTS During a mean 3.5 years follow-up, there were 329 deaths from all causes. In fully adjusted analyses, participants with baseline CAN were 1.55–2.14 times as likely to die as participants without CAN, depending on the CAN definition used (P < 0.02 for all). The effect of allocation to the intensive group on all-cause and CVD mortality was similar in participants with or without CAN at baseline (Pinteraction > 0.7). CONCLUSIONS Whereas CAN was associated with increased mortality in this high-risk type 2 diabetes cohort, these analyses indicate that participants with CAN at baseline had similar mortality outcomes from intensive compared with standard glycemia treatment in the ACCORD cohort.

The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathogenesis of a variety of clinical conditions, including atherosclerosis, hypertension, left ventricular hypertrophy, myocardial infarction, and heart failure. Inhibition of the RAAS with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ARBs) has been shown to be effective in lowering blood pressure and reducing cardiovascular mortality and morbidity in various at-risk patient populations. A number of studies have shown that these 2 classes are effective in reducing the rate of renal disease progression in patients with diabetic nephropathy, although more long-term vascular outcome studies are needed in patients with chronic kidney disease. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) was the first study to show comparable reno- and cardioprotective effects between an ARB (telmisartan) and ramipril in a broad section of at-risk patients, on top of usual standard care. However, telmisartan showed better tolerability than ramipril in ONTARGET, with less cough and angioedema. This difference was obtained despite patients having been selected for tolerability to both drugs at study entry.

Background: The importance of near-normal blood glucose in the immediate postoperative period is generally accepted and is best achieved in the perioperative period with a constant intravenous (IV) infusion of insulin. This requires intensive nursing only achievable in an intensive care unit (ICU) setting. Glucose management after transfer to a regular nursing floor (RNF) has not been studied systematically. In August 2006, the Cleveland Clinic began using long-acting insulin glargine as the insulin infusion was terminated in the ICU. Methods: This prospective analysis examined all patients receiving IV insulin infusion after cardiothoracic surgery in a 1 month period. The analyses evaluated the safety and efficacy of a protocol using a transition to subcutaneous insulin glargine of 50% of the calculated 24 h requirement at the end of the ICU insulin infusion protocol in preparation for transfer to the RNF. Results: Only 1 patient in 99 developed hypoglycemia, and no patient suffered severe hypoglycemia (glucose < 40 mg/dl), while the majority (70%) had euglycemia (glucose between 70 and 150 mg/dl). Conclusions: This approach was both safe—as there was very little hypoglycemia (1 patient in 99)—and effective, as blood sugar was well controlled in most subjects. Efficacy for achieving euglycemia was 70%. Efficacy was likely reduced because of the upper limit of insulin glargine dosage imposed by some providers as a safety consideration. Although there was a physician option to override, the maximum protocol dose of 30 U was rarely exceeded, leading to inadequate dosing in some subjects who required high insulin infusion rates in the ICU.

A common therapeutic approach in patients with type 2 diabetes mellitus who have elevated triglycerides (TGs) is to treat the hyperglycaemia before specifically targeting high TG. The aims of the current study were (i) to determine whether there was a relationship between glycated haemoglobin (HgbA1c) and TG levels at the baseline visit and (ii) to analyse the relationship between DeltaHgbA1c and DeltaTG after treatment.Among 650 consecutive diabetic patients seen in the Cleveland Clinic Preventive Cardiology Department, 372 had both baseline and post-treatment HgbA1c and TG values. We analysed the relationship between baseline HgbA1c and TG as well as between the change in HgbA1c and the change in TG. For analysis, patients were divided into nine groups by tertiles of HgbA1c (or =6.6, 6.7-7.8 and7.8%) and TG (or =1.75, 1.76-3.89 and3.89 mmol/l) at baseline.At baseline, there was a small correlation between HgbA1c and TG (r(2) = 0.051; p0.001). For the entire group, there was a significant correlation between DeltaHgbA1c and DeltaTG from baseline to follow-up (r(2) = 0.077; p0.001). Analyses by tertiles showed that DeltaTG were only associated with changes in two groups: HgbA1c tertile 3 (7.8%) and TG tertiles 2 (r(2) = 0.24; p0.0001) and 3 (r(2) = 0.187; p = 0.003). For every 1% change in the top tertile HgbA1c, there was a 9.3% change in TG (tertile 2) and a 9.8% change in TG (tertile 3).These observations suggest that for patients with diabetes mellitus and elevated TG, the effect of HgbA1c reduction has limited effects on TG reduction. Patients may benefit from TG-specific therapy initiated earlier rather than waiting to see effects of glycaemic control.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial tested the hypothesis that intensive glucose-lowering (with a hemoglobin A1c target of less than 6.0%) would reduce the incidence of atherosclerotic disease events and death compared with standard treatment (with a hemoglobin A1c target of 7.0% to 7.9%) in more than 10,000 patients with type 2 diabetes at high risk of cardiovascular events. The study was terminated early because more people had died in the intensive-treatment group than in the standard-treatment group (257 vs. 203). The ACCORD results should not substantially alter our usual approach to glucose-lowering, which should still be "as low as we can get it safely" while avoiding hypoglycemia, significant weight gain, complex regimens, and, perhaps, the "stress" of maintaining glycemic control, especially in patients at high risk of coronary heart disease.

BACKGROUND: Aggressive management of type 2 diabetes is necessary to achieve glycemic and nonglycemic treatment goals. Attainment oftreatment goals is associated with a decreased risk of diabetes-r...

Pramlintide is a synthetic version of the naturally occurring pancreatic peptide called amylin. Amylin and pramlintide have similar effects on lowering postprandial glucose, lowering postprandial glucagon and delaying gastric emptying. Pramlintide use in type 1 and insulin requiring type 2 diabetes mellitus (DM) is associated with modest reductions in HbA1c often accompanied by weight loss. Limited data show a neutral effect on blood pressure. Small studies suggest small reductions in LDL-cholesterol in type 2 DM and modest reductions in triglycerides in type 1 DM. Markers of oxidation are also reduced in conjunction with reductions in postprandial glucose. Nausea is the most common side effect. These data indicate that pramlintide has a role in glycemic control of both type 1 and type 2 DM. Pramlintide use is associated with favorable effects on weight, lipids and other biomarkers for atherosclerotic disease.

Medical nutrition therapy (MNT) is important in preventing diabetes, managing existing diabetes, and preventing, or at least slowing, the rate of development of diabetes complications. It is, therefore, important at all levels of diabetes prevention. MNT is also an integral component of diabetes self-management education (or training). This position statement provides evidence-based recommendations and interventions for diabetes MNT. The previous position statement with accompanying technical review was published in 2002 and modified slightly in 2004. This statement updates previous position statements, focuses on key references published since the year 2000, and uses grading according to the level of evidence available...

Aims To determine the association of serum uric acid with all-cause mortality and hyperglycaemia in patients with Type 2 diabetes. Methods Retrospective cohort analysis of 535 consecutive patients who had uric acid determinations between 1998 and 2004 and whose subsequent vital status was determined at a median of 4.5 years. The association with mortality was analysed with Cox proportional hazards models. The incremental predictive value of uric acid was examined with concordance indexes. The proportional risk of mortality was represented with the Kaplan-Meier survival curves by uric acid quartiles. Results We studied 370 men and 165 women aged 59.3 +/- 11.5 years. Mean uric acid was 371.7 +/- 106.2 micromol/l. Patients with glycated haemoglobin (HbA(1c)) > or = 9% had lower uric acid vs. the rest (342.2 +/- 112.1 vs. 383.5 +/- 106.2, P = 0.002). Overall mortality was 10.8%. For each 59 micromol/l increase in uric acid there was a 41% increase in risk of death (unadjusted analysis). The association of uric acid with mortality remained after adjustment for covariates (hazard ratio = 1.21, 95% confidence interval 1.07-1.45) and after gender subanalyses. Uric acid increased the accuracy of prediction when added to a model including Framingham risk factors, components of metabolic syndrome and fibrinogen (P = 0.03). Mortality was higher in patients taking diuretics vs. the rest (15.9 vs. 7.3%), but uric acid predicted mortality in both subgroups. Conclusions Serum uric acid predicts mortality in Type 2 diabetic patients regardless of gender, HbA(1c), renal function and diuretic use. Intervention studies should determine whether uric acid is a potential therapeutic target or only a marker of mortality risk.

• Background Some studies have indicated a decline in patients’ cognitive performance after coronary artery bypass graft surgery.• Objective To evaluate cognitive performance before and after coronary artery bypass graft surgery.• Methods Patients’ cognitive performance before and after coronary artery bypass graft surgery was evaluated in a prospective observational multicenter study in 5 academic medical centers. A total of 242 men and 123 women were evaluated before surgery; 333 men and 216 women, 5 to 11 months after surgery (197 men and 99 women were evaluated both before and after surgery). Verbal ability, attention/concentration, logical/verbal and visual memory, and facial recognition were measured. Data on demographic, medical, and psychosocial characteristics also were collected.• ResultsAfter surgery, patients’ overall performance improved (P < .001) for attention/concentration, verbal fluency, and logical/verbal memory. Patients with more education (high school or greater) performed better on each test (P < .001) than did patients with less education. No strong effects of sex or age on cognitive performance were observed before or after surgery, and no important differences in sex, age, or education were associated with changes in scores from before to after surgery.• Conclusion On average, cognitive performance improved rather than declined after coronary artery bypass graft surgery. The improvements were consistent across sex, age, and education.

Insulin is not the only hormone that regulates plasma glucose levels. Glucagon-like peptide 1 (GLP-1), produced in the small intestine, and amylin, produced by beta cells in the pancreas, also have glucose-lowering effects. Synthetic analogues of these hormones are now available for clinical use.

The 2004 update to the National Cholesterol Education Program guidelines goes farther than the 2001 version in suggesting an optional low-density lipoprotein cholesterol (LDL-C) goal of less than 70 mg/dL for patients at "very high risk." It recommends starting both diet and drug therapy in all patients at high or very high risk whose LDL-C level is above the goal level, with the goal of reducing LDL-C by 30% to 40%. These more aggressive guidelines are based on results of five clinical studies published since 2001.

Objective: To assess the safety profile of acarbose treatment over a 1-year period at a dose range of 50–300mg three times daily in patients with type 1 or type 2 diabetes mellitus. Study design and patients: In this 56-week, double-blind, parallel-group, multicentre comparison, patients were randomised to acarbose or placebo in a 2: 1 ratio. An 8-week forced titration phase (from 50–300mg three times daily) was followed by a 48-week maintenance phase during which patients received the highest dose tolerated during titration. Patients were assessed at 13 visits with respect to adverse events/intercurrent illnesses, abnormal laboratory values (serum chemistry, urinalysis, complete blood and reticulocyte count, serum iron and total iron binding capacity, and serum vitamin B6, B12, D and folate levels), discontinuation rates, ECG findings, vital signs and evaluation of the patients’ diaries with regard to gastrointestinal events. A total of 359 patients (acarbose 240, placebo 119) were valid for analysis; 21% had type 1 diabetes. Most patients received concomitant insulin or sulfonylurea treatment. Results: Study withdrawal was reported for 35% of acarbose and 24% of placebo recipients (p = 0.053); adverse events were the main reason for withdrawal in acarbose recipients (20%; placebo group 5%; p < 0.01). The most common adverse events for acarbose recipients were gastrointestinal (abdominal pain, flatulence and diarrhoea), which were more frequent than in placebo patients (p < 0.01). These events occurred more often early in the study and attenuated over time. Conclusion: Acarbose was safe and well tolerated by the majority of diabetic patients over a 1-year treatment period.

Objectives: The POST CABG (Post Coronary Artery Bypass Graft) Trial showed that aggressive lowering of low-density lipoprotein (LDL) cholesterol levels reduced the progression of atherosclerosis in saphenous vein grafts. In the extended follow-up phase, aggressive lowering of LDL cholesterol levels was associated with reduced rates of clinical events. Low-dose anticoagulation therapy did not reduce the progression of atherosclerosis. We conducted this analysis to determine the effects of both lipid-lowering and low-dose anticoagulation therapy on health-related quality of life (HRQL). Design: Randomized clinical trial, factorial design. Setting: Outpatients in five tertiary care medical centers. Patients: A cohort of 852 patients enrolled in the POST CABG Trial completed an HRQL questionnaire at baseline, and at the year 2 and year 4 follow-up visits. Intervention: Aggressive LDL cholesterol lowering vs moderate LDL cholesterol lowering, and low-dose warfarin vs placebo. Measurements: Domains included emotional status, basic physical and social functioning, perceived health status, symptoms of pain, a variety of physical symptoms, and global life satisfaction. Results: Overall, there were no indications of systematic differences among treatment groups for any of the HRQL parameters at baseline, year 2, or year 4. Conclusions: These data indicate that patients did not experience detrimental or beneficial effects on HRQL parameters while receiving LDL cholesterol-lowering therapy that had demonstrable benefits for treatment of atherosclerosis.

OBJECTIVE: The purpose of this report is to describe and evaluate the impact of a 1-day retreat focused on developing leadership skills and teambuilding among postgraduate year 1 residents in an internal medicine residency. METHOD: A group of organizers, including members of the staff, the chief medical residents, administrative individuals in the residency office, and an internal organizational development consultant convened to organize an off-site retreat with activities that would provide experiential learning regarding teamwork and leadership, including a “reef survival exercise” and table discussions regarding the characteristics of ideal leaders. In addition, several energizing activities and recreational free time was provided to enhance the interaction and teamwork dimensions of the retreat. To evaluate the impact of the retreat, attendees completed baseline and follow-up questionnaires regarding their experience of the retreat. RESULTS: Attendees universally regarded the retreat as having value for them. Comparison of baseline to postretreat responses indicated that attendees felt that the retreat enhanced their abilities to be better physicians, resident supervisors, and leaders. Follow-up responses indicated significant increases in attendees’ agreement that good leaders challenge the process, make decisions based on shared visions, allow others to act, recognize individual contributions, and serve as good role models. Results on the survival exercise indicated a high frequency with which team-based decisions surpassed individual members’ decisions, highlighting the importance and value of teamwork to attendees. CONCLUSIONS: Our main findings were that: participants universally found this 1-day retreat beneficial in helping to develop teamwork and leadership skills and the experiential learning aspects of the retreat were more especially highly rated and highlighted the advantages of teamwork. In the context that this 1-day retreat was deemed useful by faculty and residents alike, further study is needed to assess the impact of this learning on actual clinical practice and the durability of these lessons.