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1.  Baseline Adiponectin Levels Do Not Influence the Response to Pioglitazone in ACT NOW 
Diabetes Care  2014;37(6):1706-1711.
OBJECTIVE
Plasma adiponectin levels are reduced in type 2 diabetes mellitus (T2DM) and other insulin-resistant states. We examined whether plasma adiponectin levels at baseline and after pioglitazone treatment in impaired glucose tolerance (IGT) subjects were associated with improved insulin sensitivity (SI) and glucose tolerance status.
RESEARCH DESIGN AND METHODS
A total of 602 high-risk IGT subjects in ACT NOW were randomized to receive pioglitazone or placebo with a median follow-up of 2.4 years.
RESULTS
Pioglitazone reduced IGT conversion to diabetes by 72% in association with improved β-cell function by 64% (insulin secretion/insulin resistance index) and increased tissue sensitivity by 88% (Matsuda index). In pioglitazone-treated subjects, plasma adiponectin concentration increased threefold from 13 ± 0.5 to 38 ± 2.5 μg/mL (P < 0.001) and was strongly correlated with the improvement in SI (r = 0.436, P < 0.001) and modestly correlated with glucose area under the curve during oral glucose tolerance test (r = 0.238, P < 0.005) and insulin secretion/insulin resistance index (r = 0.306, P < 0.005). The increase in adiponectin was a strong predictor of reversion to normal glucose tolerance and prevention of T2DM. In the placebo group, plasma adiponectin did not change and was not correlated with changes in glucose levels. There was an inverse association between baseline plasma adiponectin concentration and progression to diabetes in the placebo group but not in the pioglitazone group.
CONCLUSIONS
Baseline adiponectin does not predict the response to pioglitazone. The increase in plasma adiponectin concentration after pioglitazone therapy in IGT subjects is strongly related to improved glucose tolerance status and enhanced tissue sensitivity to insulin.
doi:10.2337/dc13-1745
PMCID: PMC4179517  PMID: 24705615
2.  Metabolic Syndrome Components and Their Response to Lifestyle and Metformin Interventions are Associated with Differences in Diabetes Risk in Persons with Impaired Glucose Tolerance 
Diabetes, obesity & metabolism  2013;16(4):326-333.
Aims
To determine the association of metabolic syndrome (MetS) and its components with diabetes risk in participants with impaired glucose tolerance (IGT), and whether intervention-related changes in MetS lead to differences in diabetes incidence.
Methods
We used the NCEP/ATP III revised MetS definition at baseline and intervention-related changes of its components to predict incident diabetes using Cox models in 3234 Diabetes Prevention Program (DPP) participants with IGT over an average follow-up of 3.2 years.
Results
In an intention-to-treat analysis, the demographic-adjusted hazard ratios (95%CI) for diabetes in those with MetS (versus no MetS) at baseline were 1.7(1.3-2.3), 1.7(1.2-2.3), and 2.0(1.3-3.0) for placebo, metformin, and lifestyle groups, respectively. Higher levels of fasting plasma glucose and triglycerides at baseline were independently associated with increased risk of diabetes. Greater waist circumference (WC) was associated with higher risk in placebo and lifestyle groups, but not in the metformin group. In a multivariate model, favorable changes in WC (placebo and lifestyle) and HDLc (placebo and metformin) contributed to reduced diabetes risk.
Conclusions
MetS and some of its components are associated with increased diabetes incidence in persons with IGT in a manner that differed according to DPP intervention. After hyperglycemia, the most predictive factors for diabetes were baseline hypertriglyceridemia and both baseline and lifestyle-associated changes in waist circumference. Targeting these cardio-metabolic risk factors may help to assess the benefits of interventions that reduce diabetes incidence.
doi:10.1111/dom.12220
PMCID: PMC3943638  PMID: 24118860
diabetes prevention; cardio-metabolic risk; lifestyle; metformin
3.  Genetic Risk of Progression to Type 2 Diabetes and Response to Intensive Lifestyle or Metformin in Prediabetic Women With and Without a History of Gestational Diabetes Mellitus 
Diabetes Care  2014;37(4):909-911.
OBJECTIVE
The Diabetes Prevention Program (DPP) trial investigated rates of progression to diabetes among adults with prediabetes randomized to treatment with placebo, metformin, or intensive lifestyle intervention. Among women in the DPP, diabetes risk reduction with metformin was greater in women with prior gestational diabetes mellitus (GDM) compared with women without GDM but with one or more previous live births.
RESEARCH DESIGN AND METHODS
We asked if genetic variability could account for these differences by comparing β-cell function and genetic risk scores (GRS), calculated from 34 diabetes-associated loci, between women with and without histories of GDM.
RESULTS
β-Cell function was reduced in women with GDM. The GRS was positively associated with a history of GDM; however, the GRS did not predict progression to diabetes or modulate response to intervention.
CONCLUSIONS
These data suggest that a diabetes-associated GRS is associated with development of GDM and may characterize women at risk for development of diabetes due to β-cell dysfunction.
doi:10.2337/dc13-0700
PMCID: PMC3964494  PMID: 24271189
4.  Association of Modifiable Risk Factors and Left Ventricular Ejection Fraction among Hospitalized Native Hawaiians and Pacific Islanders with Heart Failure 
Hawai'i Journal of Medicine & Public Health  2014;73(12 Suppl 3):14-20.
Background:
Heart Failure (HF) disproportionately affects Native Hawaiians and Other Pacific Islanders (NHOPIs). This study examines risk factors associated with left ventricular ejection fraction (LVEF) among 151 hospitalized NHOPI HF patients enrolled at a single tertiary care hospital between June 2006 and April 2010.
Methods:
Enrollment criteria: (1) NHOPI by self-identification. (2) Age ≥ 21 yrs. (3) Diagnosis of HF defined: (a) left ventricular ejection fraction (LVEF) ≤ 40% or LVEF ≤ 60% with abnormal diastolic function and (b) classic HF signs/symptoms. LVEF was measured by echocardiography within 6 weeks of hospitalization. Clinical measures, medical history, and questionnaires were assessed using standardized protocols. Linear regression modeling was used to examine the association of significant correlates of LVEF, which were then included en bloc into the final model. A P-value < .05 was considered statistically significant.
Results:
Of 151 participants, 69% were men, mean age 54.3 ± 13.5 years, blood pressure 112 ± 20/69 ± 15 mmHg, and body mass index (BMI) 36.9 ± 9 kg/m2. Twenty-five percent of participants were smokers, 45% used alcohol and 23% reported a history of methamphetamine use. Clinically, 72% had hypertension, 49% were diabetic and 37% had a prior myocardial infarction. Nearly 60% had moderate to severe LVEF (< 35%). Higher LVEF was independently associated with female sex and greater BMI (P < .04) while pacemaker/defibrillator and methamphetamine use was independently associated with lower LVEF (P < .05).
Conclusions:
Methamphetamine use and BMI may be important modifiable risk factors associated with LVEF and may be important targets for improving HF morbidity and mortality.
PMCID: PMC4271351  PMID: 25535596
5.  EFFECT OF LOWER TARGETS FOR BLOOD PRESSURE AND LDL CHOLESTEROL ON ATHEROSCLEROSIS IN DIABETES 
JAMA  2008;299(14):1678-1689.
Context
Individuals with diabetes are at greatly increased risk for developing cardiovascular disease (CVD), but more aggressive targets for risk factor control have not been tested.
Objective
To compare the progression of subclinical atherosclerotic disease in diabetic adults treated to aggressive targets of low-density lipoprotein cholesterol (LDL-C) ≤ 70 mg/dL and blood pressure (BP) ≤ 115/75 mm Hg (aggressive) versus treatment to standard targets of LDL-C ≤ 100 mg/dL and BP ≤ 130/85 mm Hg (standard).
Design
Randomized, open label, blinded-to-endpoint 3-year trial in individuals with diabetes conducted April 2003-July 2004.
Setting
Four clinical centers in southwestern Oklahoma; Phoenix, AZ; northeastern Arizona; and South Dakota.
Participants
499 American Indian men and women ≥ age 40 with type 2 diabetes and no prior CVD events.
Interventions
Participants were randomized to aggressive vs. standard treatment. The same treatment algorithms were followed for both groups.
Main Outcome Measures
Primary endpoint was a composite of progression of atherosclerosis as measured by common carotid artery intimal medial thickness (IMT) and clinical events. Secondary endpoints included other carotid and cardiac ultrasonographic measures.
Results
LDL-C and systolic BP (SBP) goals for both groups were reached within 12 months and maintained to 36 months. LDL-C and SBP in the last 12 months averaged 72 and 104 mg/dL and 116 and 129 mm Hg in the aggressive and standard groups, respectively. Regression of IMT (-0.017 vs. 0.041 mm, p < .0001) and arterial mass (-0.14 vs. 1.14 mm2, p < .0001) and greater decrease in left ventricular mass (-2.4 vs. -1.3 g/m2.7, p = .05) were observed in the aggressive group. Clinical CVD events were lower than expected and did not differ between groups
Conclusions
Reducing LDL-C and SBP to lower targets resulted in regression of carotid IMT and greater decrease in left ventricular mass in individuals with type 2 diabetes. Clinical events were lower than expected and did not differ significantly between groups. Further follow-up is needed to determine whether these improvements will result in lower long-term CVD event rates and costs and favorable risk-benefit outomes.
doi:10.1001/jama.299.14.1678
PMCID: PMC4243925  PMID: 18398080
6.  Prediction of Diabetes Based on Baseline Metabolic Characteristics in Individuals at High Risk 
Diabetes Care  2013;36(11):3607-3612.
OBJECTIVE
Individuals with impaired glucose tolerance (IGT) are at high risk for developing type 2 diabetes mellitus (T2DM). We examined which characteristics at baseline predicted the development of T2DM versus maintenance of IGT or conversion to normal glucose tolerance.
RESEARCH DESIGN AND METHODS
We studied 228 subjects at high risk with IGT who received treatment with placebo in ACT NOW and who underwent baseline anthropometric measures and oral glucose tolerance test (OGTT) at baseline and after a mean follow-up of 2.4 years.
RESULTS
In a univariate analysis, 45 of 228 (19.7%) IGT individuals developed diabetes. After adjusting for age, sex, and center, increased fasting plasma glucose, 2-h plasma glucose, ∆G0–120 during OGTT, HbA1c, adipocyte insulin resistance index, ln fasting plasma insulin, and ln ∆I0–120, as well as family history of diabetes and presence of metabolic syndrome, were associated with increased risk of diabetes. At baseline, higher insulin secretion (ln [∆I0–120/∆G0–120]) during the OGTT was associated with decreased risk of diabetes. Higher β-cell function (insulin secretion/insulin resistance or disposition index; ln [∆I0–120/∆G0–120 × Matsuda index of insulin sensitivity]; odds ratio 0.11; P < 0.0001) was the variable most closely associated with reduced risk of diabetes.
CONCLUSIONS
In a stepwise multiple-variable analysis, only HbA1c and β-cell function (ln insulin secretion/insulin resistance index) predicted the development of diabetes (r = 0.49; P < 0.0001).
doi:10.2337/dc13-0520
PMCID: PMC3816921  PMID: 24062330
7.  Prevention of Diabetes With Pioglitazone in ACT NOW 
Diabetes  2013;62(11):3920-3926.
We examined the metabolic characteristics that attend the development of type 2 diabetes (T2DM) in 441 impaired glucose tolerance (IGT) subjects who participated in the ACT NOW Study and had complete end-of-study metabolic measurements. Subjects were randomized to receive pioglitazone (PGZ; 45 mg/day) or placebo and were observed for a median of 2.4 years. Indices of insulin sensitivity (Matsuda index [MI]), insulin secretion (IS)/insulin resistance (IR; ΔI0–120/ΔG0–120, ΔIS rate [ISR]0–120/ΔG0–120), and β-cell function (ΔI/ΔG × MI and ΔISR/ΔG × MI) were calculated from plasma glucose, insulin, and C-peptide concentrations during oral glucose tolerance tests at baseline and study end. Diabetes developed in 45 placebo-treated vs. 15 PGZ-treated subjects (odds ratio [OR] 0.28 [95% CI 0.15–0.49]; P < 0.0001); 48% of PGZ-treated subjects reverted to normal glucose tolerance (NGT) versus 28% of placebo-treated subjects (P < 0.005). Higher final glucose tolerance status (NGT > IGT > T2DM) was associated with improvements in insulin sensitivity (OR 0.61 [95% CI 0.54–0.80]), IS (OR 0.61 [95% CI 0.50–0.75]), and β-cell function (ln IS/IR index and ln ISR/IR index) (OR 0.26 [95% CI 0.19–0.37]; all P < 0.0001). Of the factors measured, improved β-cell function was most closely associated with final glucose tolerance status.
doi:10.2337/db13-0265
PMCID: PMC3806596  PMID: 23863810
8.  Safety and Feasibility of Achieving Lower Systolic Blood Pressure Goals in Persons With Type 2 Diabetes: The SANDS Trial 
The Stop Atherosclerosis in Native Diabetics Study (SANDS) was a randomized open-label clinical trial in type 2 diabetics designed to examine the effects of intensive reduction of blood pressure, aggressive vs standard goals (≤115 / 75 mm Hg vs ≤130 / 80 mm Hg), and low-density lipoprotein (LDL) cholesterol on the composite outcome of change in carotid intimal-medial thickness and cardiovascular events. The study demonstrated that in conjunction with a lower LDL cholesterol target of 70 mg/ dL, aggressive systolic blood pressure–lowering resulted in a reduction in carotid intimal-medial thickness and left ventricular mass without measurable differences in cardiovascular events. The blood pressure treatment algorithm included renin-angiotensin system blockade, with other agents added if necessary. The authors conclude that both standard and more aggressive systolic blood pressure reduction can be achieved with excellent safety and good tolerability in patients with type 2 diabetes mellitus.
doi:10.1111/j.1751-7176.2009.00121.x
PMCID: PMC4182961  PMID: 19817934
10.  Effectiveness and Cost-Effectiveness of Diabetes Prevention among Adherent Participants 
OBJECTIVES
We report the 10 year effectiveness and within-trial cost-effectiveness of the The Diabetes Prevention Program (DPP) and its Outcomes Study (DPPOS) interventions among participants who were adherent to the interventions.
STUDY DESIGN
DPP was a 3-year randomized clinical trial followed by 7-years of open-label modified intervention followup.
METHODS
Data on resource utilization, cost, and quality-of-life were collected prospectively. Economic analyses were performed from health system and societal perspectives. Lifestyle adherence was defined as achieving and maintaining a 5% reduction in initial body weight and metformin adherence as taking metformin at 80% of study visits.
RESULTS
The relative risk reduction was 49.4% among adherent lifestyle participants and 20.8% among adherent metformin participants compared to placebo. Over 10 years, the cumulative, undiscounted, per capita direct medical costs of the interventions, as implemented during the DPP, were greater for adherent lifestyle participants ($4,810) than adherent metformin participants ($2,934) or placebo ($768). Over 10 years, the cumulative, per capita non-intervention-related direct medical costs were $4,250 greater for placebo participants compared to adherent lifestyle participants and $3,251 greater compared to adherent metformin participants. The cumulative quality-adjusted life-years (QALYs) accrued over 10 years were greater for lifestyle (6.80) than metformin (6.74) or placebo (6.67). Without discounting, from both a modified societal perspective (excluding participant time), lifestyle cost <$5,000 per QALY-gained and metformin was cost-saving compared to placebo.
CONCLUSIONS
Over 10 years, lifestyle intervention and metformin were cost-saving compared to placebo. These analyses confirm that lifestyle and metformin represent a good value for money.
PMCID: PMC3985133  PMID: 23544761
comparative effectiveness research; cost; cost-effectiveness; cost-utility; impaired glucose tolerance; type 2 diabetes mellitus; health utility; quality of life; prevention
11.  The Fate of Taspoglutide, a Weekly GLP-1 Receptor Agonist, Versus Twice-Daily Exenatide for Type 2 Diabetes 
Diabetes Care  2013;36(3):498-504.
OBJECTIVE
Taspoglutide is a long-acting glucagon-like peptide 1 receptor agonist developed for treatment of type 2 diabetes. The efficacy and safety of once-weekly taspoglutide was compared with twice-daily exenatide.
RESEARCH DESIGN AND METHODS
Overweight adults with inadequately controlled type 2 diabetes on metformin ± a thiazolidinedione were randomized to subcutaneous taspoglutide 10 mg weekly (n = 399), taspoglutide 20 mg weekly (n = 398), or exenatide 10 µg twice daily (n = 392) in an open-label, multicenter trial. The primary end point was change in HbA1c after 24 weeks.
RESULTS
Mean baseline HbA1c was 8.1%. Both doses of taspoglutide reduced HbA1c significantly more than exenatide (taspoglutide 10 mg: –1.24% [SE 0.09], difference –0.26, 95% CI –0.37 to –0.15, P < 0.0001; taspoglutide 20 mg: –1.31% [0.08], difference –0.33, –0.44 to –0.22, P < 0.0001; exenatide: –0.98% [0.08]). Both taspoglutide doses reduced fasting plasma glucose significantly more than exenatide. Taspoglutide reduced body weight (taspoglutide 10 mg, –1.6 kg; taspoglutide 20 mg, –2.3 kg) as did exenatide (–2.3 kg), which was greater than with taspoglutide 10 mg (P < 0.05). HbA1c and weight effects were maintained after 52 weeks. More adverse events with taspoglutide 10 and 20 mg than exenatide developed over time (nausea in 53, 59, and 35% and vomiting in 33, 37, and 16%, respectively). Allergic and injection-site reactions were more common with taspoglutide. Discontinuations were greater with taspoglutide. Antitaspoglutide antibodies were detected in 49% of patients.
CONCLUSIONS
Once-weekly taspoglutide demonstrated greater glycemic control than twice-daily exenatide with comparable weight loss, but with unacceptable levels of nausea/vomiting, injection-site reactions, and systemic allergic reactions.
doi:10.2337/dc12-0709
PMCID: PMC3579343  PMID: 23139373
12.  Cross-Sectional Evaluation of Noninvasively Detected Skin Intrinsic Fluorescence and Mean Hemoglobin A1c in Type 1 Diabetes 
Abstract
Background
This study evaluated the relationship between skin intrinsic fluorescence (SIF) and long-term mean hemoglobin A1c (HbA1c) in individuals with type 1 diabetes.
Subjects and Methods
We undertook a cross-sectional analysis of 172 individuals with type 1 diabetes followed longitudinally with HbA1c data available over an average of 16.6 years. SIF was evaluated cross-sectionally using the SCOUT DS® device (VeraLight Inc., Albuquerque, NM) and correlated with most recent HbA1c and long-term mean HbA1c. Potential determinants of this relationship, including age, gender, smoking status, duration of diabetes, and renal function, were also evaluated.
Results
Age-adjusted skin intrinsic fluorescence significantly correlated with long-term mean HbA1c (R=0.44, P<0.0001). In contrast, there was no significant relationship between SIF and most recent HbA1c (R=0.14, P=0.075). The best-fit model describing the relationship between SIF and mean HbA1c controlled for factors of age, duration of disease, renal function, and site of study conduct. Controlling for these factors was also important in understanding the relationship between most recent HbA1c and SIF. Evaluating longer-term HbA1c data also strengthened the relationship between SIF and mean HbA1c. In the presence of renal dysfunction or damage, as indicated by an estimated glomerular filtration rate of <60 mL/min/1.73 m2 or presence of gross proteinuria, there was no significant correlation between SIF and mean HbA1c.
Conclusions
Noninvasive detection of SIF significantly correlates with long-term mean HbA1c, providing insight into long-term glycemic exposure. Age, duration of diabetes, and renal function are potential contributors to this relationship.
doi:10.1089/dia.2012.0211
PMCID: PMC3558674  PMID: 23305087
13.  Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors 
Objective
To determine whether changes in standard and novel risk factors during the ACT NOW trial explained the slower rate of CIMT progression with pioglitazone treatment in persons with prediabetes.
Methods and Results
CIMT was measured in 382 participants at the beginning and up to three additional times during follow-up of the ACT NOW trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (P=0.01) lower with pioglitazone treatment (4.76 × 10−3 mm/year, 95% CI, 2.39 × 10−3 – 7.14 × 10−3 mm/year) compared with placebo (9.69 × 10−3 mm/year, 95% CI, 7.24 × 10−3 – 12.15 × 10−3 mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA1c, fasting insulin, Matsuda insulin sensitivity index, adiponectin and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (P < 0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment.
Conclusions
Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.
doi:10.1161/ATVBAHA.112.300346
PMCID: PMC3908828  PMID: 23175674
Carotid atherosclerosis progression; Impaired glucose tolerance; Insulin resistance; Inflammation; Pioglitazone
14.  The Imperative to Prevent Diabetes 
Diabetes Care  2012;35(12):2417-2418.
doi:10.2337/dc12-1997
PMCID: PMC3507578  PMID: 23173126
15.  Skin Intrinsic Fluorescence Is Associated With Coronary Artery Disease in Individuals With Long Duration of Type 1 Diabetes 
Diabetes Care  2012;35(11):2331-2336.
OBJECTIVE
Skin intrinsic fluorescence (SIF) reflects many factors, including the presence of certain advanced glycation end products. We investigated whether SIF was associated with coronary artery disease (CAD) in type 1 diabetes and whether this relationship was independent of renal disease.
RESEARCH DESIGN AND METHODS
SIF was measured in 112 subjects from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study and 60 from MedStar Health Research Institute when mean age and diabetes duration were 48 and 36 years, respectively. Cumulative glycemic exposure (updated mean A1C) represented a mean of 18 years’ follow-up in EDC and 10.3 in MedStar.
RESULTS
Of the 172 participants, 30 had CAD (15 male and 15 female). SIF levels were higher in those with CAD (P < 0.0001). SIF was strongly associated with CAD (odds ratio [OR] 3.5 [95% CI 2.1–6.1]). After age, duration, and updated mean A1C were controlled for, SIF remained associated with CAD (2.4 [1.3–4.4]), more strongly in men (5.6 [2.1–14.6]) than in women (1.4 [0.61–3.3]). As there was no significant sex interaction, further analyses were conducted combining the sexes. Further accounting for sex and nephropathy status did not improve the model fit, though with nephropathy in the model, the OR for SIF was reduced to 1.7 (95% CI 0.89–3.4).
CONCLUSIONS
SIF has a significant cross-sectional association with CAD. This association is strongly linked to age and duration and, to a lesser degree, to mean A1C and renal disease. SIF therefore may be a useful overall marker of CAD risk in type 1 diabetes.
doi:10.2337/dc12-0053
PMCID: PMC3476887  PMID: 22851597
16.  A 24-WEEK, MULTICENTER, OPEN-LABEL, RANDOMIZED STUDY TO COMPARE CHANGES IN GLUCOSE METABOLISM IN PATIENTS WITH SCHIZOPHRENIA RECEIVING TREATMENT WITH OLANZAPINE, QUETIAPINE AND RISPERIDONE 
Objective
This randomized, 24-week, flexible-dose study compared changes in glucose metabolism in patients with schizophrenia receiving initial exposure to olanzapine, quetiapine, or risperidone.
Methods
The hypothesized primary endpoint was change (baseline to Week 24) in area under the curve 0-2h plasma glucose during oral glucose tolerance test (OGTT); primary analysis: olanzapine versus quetiapine. Secondary endpoints included change in AUC 0-2h plasma insulin, insulin sensitivity index (ISI), and fasting lipids.
Results
Mean weight change (kg) over 24 weeks was +3.7 (quetiapine), +4.6 (olanzapine), and +3.6 (risperidone). Based on data from 395 patients (quetiapine n=115 [mean 607.0 mg/day], olanzapine n=146 [15.2 mg/day], and risperidone n=134 [5.2 mg/day]), change in AUC 0-2h glucose (mg/dL×h) at Week 24 was significantly lower for quetiapine versus olanzapine (t=1.98; DF=377; p=0.048). Increases in AUC 0-2h glucose were statistically significant with olanzapine (+21.9 mg/dL, 95% CI 11.5, 32.4) and risperidone (+18.8, CI 8.1, 29.4), but not quetiapine (+9.1, CI −2.3, 20.5). AUC 0-2h insulin increased statistically significantly with olanzapine, but not quetiapine or risperidone. Reductions in ISI were statistically significant with olanzapine and risperidone, but not quetiapine. Total cholesterol and LDL increased statistically significantly with olanzapine and quetiapine, but not risperidone. Statistically significant increases in triglycerides, cholesterol/HDL, and triglyceride/HDL ratios were observed with olanzapine only.
Conclusion
The results indicate a significant difference in the change in glucose tolerance during 6 months’ treatment with olanzapine versus quetiapine, with significant reductions on olanzapine and risperidone, but not quetiapine; these differential changes were largely explained by changes in insulin sensitivity.
PMCID: PMC3703648  PMID: 19358783
glucose; insulin; lipids; olanzapine; quetiapine; risperidone; schizophrenia
17.  The American Diabetes Association Diabetes Research Perspective 
Diabetes Care  2012;35(6):1380-1387.
doi:10.2337/dc12-9001
PMCID: PMC3357230  PMID: 22619289
18.  The American Diabetes Association Diabetes Research Perspective 
Diabetes  2012;61(6):1338-1345.
doi:10.2337/db12-0435
PMCID: PMC3357294  PMID: 22618769
19.  Relationship of Glycemia Control to Lipid and Blood Pressure Lowering and Atherosclerosis: the SANDS Experience 
Objectives
Cardiovascular disease (CVD) prevention for patients with type 2 diabetes is accomplished through hypertension and dyslipidemia management. Although studies have established strategies for lowering low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP), none have examined whether glycemia influences ability to achieve lipid and BP targets. This post-hoc analysis from the Stop Atherosclerosis in Native Diabetics Study (SANDS) examines the role of baseline glycemia in achieving standard and aggressive targets and outcomes after 36 months.
Methods
Diabetic individuals >age 40 with no cardiovascular events (N=499) were randomized to aggressive versus standard targets for LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), and systolic BP (SBP). Management algorithms were used for both groups. Carotid ultrasound and echocardiography were performed at baseline and after 36 months.
Results
No differences were observed in baseline hemoglobin A1c between treatment groups nor any significant change in A1c after 36 months in either group. Baseline A1c, however, was significantly and negatively related to achieving LDL-C (p=0.007), non-HDL-C (p=0.03), and SBP targets (p=0.007) and to changes in LDL-C (p=0.007), non-HDL-C (p=0.03), and SBP (p=0.001) in both groups. Baseline A1c failed to predict progression of carotid intima medial thickness (CIMT) (p=0.42) or left ventricular mass index (LVMI) (p=0.10), nor was it related to the effects of lipid and BP lowering on CIMT and LVMI over 36 months.
Conclusions
In diabetic adults with no CVD events, A1c was negatively associated with ability to achieve LDL-C, non-HDL-C, and SBP goals but was not independently related to treatment-associated changes in CIMT or LVMI over 36 months.
doi:10.1016/j.jdiacomp.2011.04.001
PMCID: PMC3222781  PMID: 21775166
LDL-C; A1c; cardiovascular disease; carotid arteries; diabetes
20.  Diabetes Management in the Age of National Health Reform 
Diabetes Care  2011;34(4):1054-1057.
doi:10.2337/dc10-1987
PMCID: PMC3064022  PMID: 21447668
21.  Skin Intrinsic Fluorescence Correlates With Autonomic and Distal Symmetrical Polyneuropathy in Individuals With Type 1 Diabetes 
Diabetes Care  2011;34(4):1000-1005.
OBJECTIVE
To determine whether skin intrinsic fluorescence (SIF) was associated with autonomic neuropathy and confirmed distal symmetrical polyneuropathy (CDSP) in 111 individuals with type 1 diabetes (mean age 49 years, mean diabetes duration 40 years).
RESEARCH DESIGN AND METHODS
SIF was measured using the SCOUT DM device. Autonomic neuropathy was defined as an electrocardiographic abnormal heart rate response to deep breathing (expiration-to-inspiration ratio <1.1). CDSP was defined using the Diabetes Control and Complications Trial clinical exam protocol (the presence of two or more of the following: symptoms, sensory and/or motor signs, and/or reduced/absent tendon reflexes consistent with DSP) confirmed by the presence of an abnormal age-specific vibratory threshold (using a Vibratron II tester).
RESULTS
The prevalence of autonomic neuropathy and CDSP were 61 and 66%, respectively. SIF was higher in those with autonomic neuropathy (P < 0.0001). In multivariable analyses controlling for age and updated mean (18-year average) HbA1c, and allowing for other univariately and clinically significant correlates of autonomic neuropathy, each SD change in SIF was associated with a 2.6-greater likelihood of autonomic neuropathy (P = 0.006). Receiver operating characteristic (ROC) analyses revealed that SIF and updated mean HbA1c accounted for 80 and 57%, respectively, of the area under the curve (AUC) for autonomic neuropathy. SIF also was higher in those with CDSP (P < 0.0001) and remained so in multivariable analyses (odds ratio 2.70; P = 0.005). ROC analyses revealed that SIF and updated mean HbA1c accounted for 78 and 59%, respectively, of the AUC for CDSP.
CONCLUSIONS
SIF, a marker of dermal advanced glycation end products, appears to be more strongly associated with the presence of both CDSP and autonomic neuropathy than mean HbA1c.
doi:10.2337/dc10-1791
PMCID: PMC3064012  PMID: 21307380
22.  Insulin Degludec in Type 1 Diabetes 
Diabetes Care  2011;34(3):661-665.
OBJECTIVE
Insulin degludec (IDeg) is a basal insulin that forms soluble multihexamers after subcutaneous injection, resulting in an ultra-long action profile. We assessed the efficacy and safety of IDeg formulations administered once daily in combination with mealtime insulin aspart in people with type 1 diabetes.
RESEARCH DESIGN AND METHODS
In this 16-week, randomized, open-label trial, participants (mean: 45.8 years old, A1C 8.4%, fasting plasma glucose [FPG] 9.9 mmol/L, BMI 26.9 kg/m2) received subcutaneous injections of IDeg(A) (600 μmol/L; n = 59), IDeg(B) (900 μmol/L; n = 60), or insulin glargine (IGlar; n = 59), all given once daily in the evening. Insulin aspart was administered at mealtimes.
RESULTS
At 16 weeks, mean A1C was comparable for IDeg(A) (7.8 ± 0.8%), IDeg(B) (8.0 ± 1.0%), and IGlar (7.6 ± 0.8%), as was FPG (8.3 ± 4.0, 8.3 ± 2.8, and 8.9 ± 3.5 mmol/L, respectively). Estimated mean rates of confirmed hypoglycemia were 28% lower for IDeg(A) compared with IGlar (rate ratio [RR]: 0.72 [95% CI 0.52–1.00]) and 10% lower for IDeg(B) compared with IGlar (RR: 0.90 [0.65–1.24]); rates of nocturnal hypoglycemia were 58% lower for IDeg(A) (RR: 0.42 [0.25–0.69]) and 29% lower for IDeg(B) (RR: 0.71 [0.44–1.16]). Mean total daily insulin dose was similar to baseline. The frequency and pattern of adverse events was similar between insulin treatments.
CONCLUSIONS
In this clinical exploratory phase 2 trial in people with type 1 diabetes, IDeg is safe and well tolerated and provides comparable glycemic control to IGlar at similar doses, with reduced rates of hypoglycemia.
doi:10.2337/dc10-1925
PMCID: PMC3041203  PMID: 21270174
23.  Cardiovascular safety of exenatide BID: an integrated analysis from controlled clinical trials in participants with type 2 diabetes 
It is important for patients that treatments for diabetes not increase cardiovascular (CV) risk. The objective of this analysis was to examine retrospectively the CV safety of exenatide BID, a GLP-1 receptor agonist approved for treating hyperglycemia in patients with type 2 diabetes not adequately controlled with diet and exercise. Individual participant data was pooled to assess the relative risk (RR) of CV events with exenatide BID versus a pooled comparator (PC) group treated with either placebo or insulin from 12 controlled, randomized, clinical trials ranging from 12-52 weeks. Mean baseline values for HbA1c (8.33-8.38%), BMI (31.3-31.5 kg/m2), and duration of diabetes (8 y) were similar between groups. Trials included patients with histories of microvascular and/or macrovascular disease. Customized primary major adverse CV events (MACE) included stroke, myocardial infarction, cardiac mortality, acute coronary syndrome, and revascularization procedures. The Primary MACE RR (0.7; 95% CI 0.38, 1.31), calculated by the Mantel-Haenszel method (stratified by study), suggested that exenatide use (vs. PC) did not increase CV risk; this result was consistent across multiple analytic methods. Because the trials were not designed to assess CV outcomes, events were identified retrospectively from a list of preferred terms by physicians blinded to treatment. Other limitations included the low number of CV events, the short duration of trials (≤1 y), and a single active comparator (insulin). The results of these analyses are consistent with those of a recent retrospective analysis of a large insurance database that found that patients treated with exenatide twice daily were less likely to have a CV event than were patients treated with other glucose-lowering therapies.
Keywords: GLP-1 receptor agonist, diabetes, cardiovascular safety
doi:10.1186/1475-2840-10-22
PMCID: PMC3070629  PMID: 21410975
GLP-1 receptor agonist; diabetes; cardiovascular safety
24.  Evaluation of in-stent restenosis in the APPROACH trial (assessment on the prevention of progression by Rosiglitazone on atherosclerosis in diabetes patients with cardiovascular history) 
To determine (1) the medium-term effect of rosiglitazone and glipizide on intra-stent neointima hyperplasia, (2) restenosis pattern as assessed by intra-vascular ultrasound (IVUS) and quantitative coronary angiography (QCA) in patients with T2DM and coronary artery disease. A total of 462 patients with T2DM were randomized to rosiglitazone or glipizide for up to 18 months in the APPROACH trial, and had evaluable baseline and follow-up IVUS examinations. There was no significant difference in the size of plaque behind stent between the rosiglitazone and glipizide groups at 18 months among those treated with a bare metal stent (−5.6 mm3 vs. 1.9 mm3; P = 0.61) or with a drug-eluting stent (12.1 mm3 vs. 5.5 mm3; P = 0.09). Similarly, there was no significant difference in percentage intimal hyperplasia volume between the rosiglitazone and glipizide groups at 18 months among those treated with a bare metal stent (24.1% vs. 19.8%; P = 0.38) or with a drug-eluting stent (9.8% vs. 8.3%; P = 0.57). QCA data (intra-stent late loss, intra-stent diameter stenosis or binary restenosis) were not different between the rosiglitazone and glipizide groups. This study suggests that both rosiglitazone and glipizide have a similar effect on neointimal growth at medium term follow-up, a finding that warrants investigation in dedicated randomized trials.
doi:10.1007/s10554-011-9836-z
PMCID: PMC3326367  PMID: 21359834
Restenosis; Type 2 diabetes; IVUS; Atherosclerosis
25.  COST-EFFECTIVENESS OF LOWER TARGETS FOR BLOOD PRESSURE AND LDL CHOLESTEROL IN DIABETES: THE STOP ATHEROSCLEROSIS IN NATIVE DIABETICS STUDY (SANDS) 
Journal of clinical lipidology  2010;4(3):165-172.
Background
The Stop Atherosclerosis in Native Diabetics Study (SANDS) reported cardiovascular benefit of aggressive versus standard treatment targets for both low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) in diabetic individuals.
Objective
In this analysis, we examined within trial cost-effectiveness of aggressive targets of LDL-C ≤70 mg/dL and systolic blood pressure (SBP) ≤115 mmHg vs. standard targets of LDL-C ≤100 mg/dL and SBP ≤130 mmHg.
Design
Randomized, open label blinded-to-endpoint 3-year trial.
Data Sources
SANDS clinical trial database, Quality of Wellbeing (QWB) survey, Centers for Medicare and Medicaid Services, Wholesale Drug Prices.
Target Population
American Indians ≥ age 40 years with type 2 diabetes and no prior cardiovascular events.
Time Horizon
April 2003-July 2007.
Perspective
Health payer.
Interventions
Participants were randomized to aggressive vs. standard groups with treatment algorithms defined for both.
Outcome Measures
Incremental cost-effectiveness.
Results of Base-Case Analysis
Compared with the standard group, the aggressive group had slightly lower costs of medical services ($-116), but a 54% higher cost for BP medication ($1,242) and a 116% higher cost for lipid-lowering medication ($2,863), resulting in an increased cost of $3,988 over 3 years. Those in the aggressively treated group gained 0.0480 quality-adjusted life-years (QALY) over the standard group. Using a 3% discount rate for costs and outcomes, the resulting cost per QALY was $82,589.
Results of Sensitivity Analysis
Using a 25%, 50%, and 75% reduction in drug costs resulted in a cost per QALY of $61,329, $40,070, and $18,810, respectively.
Limitations
This study was limited by use of a single ethnic group and by its 3-year duration.
Conclusions
Within this 3-year study, treatment to lower BP and LDL-C below standard targets was not cost-effective due to the cost of the additional medications required to meet the lower targets. With the anticipated availability of generic versions of the BP and lipid-lowering drugs used in SANDS, cost-effectiveness of this intervention should improve.
doi:10.1016/j.jacl.2010.01.008
PMCID: PMC2885818  PMID: 20563294

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