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1.  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.
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.
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.
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.
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.
PMCID: PMC3579343  PMID: 23139373
2.  Cross-Sectional Evaluation of Noninvasively Detected Skin Intrinsic Fluorescence and Mean Hemoglobin A1c in Type 1 Diabetes 
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.
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.
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.
PMCID: PMC3558674  PMID: 23305087
3.  Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors 
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.
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.
PMCID: PMC3908828  PMID: 23175674
Carotid atherosclerosis progression; Impaired glucose tolerance; Insulin resistance; Inflammation; Pioglitazone
4.  The Imperative to Prevent Diabetes 
Diabetes Care  2012;35(12):2417-2418.
PMCID: PMC3507578  PMID: 23173126
5.  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.
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.
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.
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).
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.
PMCID: PMC3476887  PMID: 22851597
This randomized, 24-week, flexible-dose study compared changes in glucose metabolism in patients with schizophrenia receiving initial exposure to olanzapine, quetiapine, or risperidone.
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.
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.
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
7.  The American Diabetes Association Diabetes Research Perspective 
Diabetes Care  2012;35(6):1380-1387.
PMCID: PMC3357230  PMID: 22619289
8.  The American Diabetes Association Diabetes Research Perspective 
Diabetes  2012;61(6):1338-1345.
PMCID: PMC3357294  PMID: 22618769
9.  Relationship of Glycemia Control to Lipid and Blood Pressure Lowering and Atherosclerosis: the SANDS Experience 
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.
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.
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.
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.
PMCID: PMC3222781  PMID: 21775166
LDL-C; A1c; cardiovascular disease; carotid arteries; diabetes
10.  Diabetes Management in the Age of National Health Reform 
Diabetes Care  2011;34(4):1054-1057.
PMCID: PMC3064022  PMID: 21447668
11.  Skin Intrinsic Fluorescence Correlates With Autonomic and Distal Symmetrical Polyneuropathy in Individuals With Type 1 Diabetes 
Diabetes Care  2011;34(4):1000-1005.
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).
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).
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.
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.
PMCID: PMC3064012  PMID: 21307380
12.  Insulin Degludec in Type 1 Diabetes 
Diabetes Care  2011;34(3):661-665.
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.
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.
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.
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.
PMCID: PMC3041203  PMID: 21270174
13.  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
PMCID: PMC3070629  PMID: 21410975
GLP-1 receptor agonist; diabetes; cardiovascular safety
14.  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.
PMCID: PMC3326367  PMID: 21359834
Restenosis; Type 2 diabetes; IVUS; Atherosclerosis
Journal of clinical lipidology  2010;4(3):165-172.
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.
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.
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.
Health payer.
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.
This study was limited by use of a single ethnic group and by its 3-year duration.
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.
PMCID: PMC2885818  PMID: 20563294
Journal of clinical lipidology  2009;3(5):322-331.
Lowering low-density lipoprotein cholesterol (LDL-C) with statins reduces atherosclerosis. LDL and high-density lipoprotein (HDL) are commonly measured by their cholesterol content, but non-HDL cholesterol, LDL particle number (LDL-P), or total apolipoprotein B (apoB) may better predict cardiovascular risk. Few studies have examined relations among lipoprotein levels and composition before and after interventions to lower LDL-C and non-HDL-C.
To measure changes in carotid artery intimal media thickness (CIMT) and lipid concentration and composition during 36 months of statin therapy.
Analyses were conducted on 418 diabetic individuals, with complete data and no prior cardiovascular events, who were randomized to aggressive (AG) versus standard (STD) treatment for LDL-C, non-HDL-C, and systolic blood pressure (SBP) as part of the Stop Atherosclerosis in Native Diabetics Study (SANDS).
The AG group achieved average LDL-C and non-HDL-C of 71mg/dL and 100mg/dL and a decrease in CIMT. No significant interactions were observed between treatment effect and initial levels of LDL-C, non-HDL-C, HDL-C, triglycerides, apoB, or LDL-P. Decreases in LDL-C (p<.005) and non-HDL-C (p<.001) were independently correlated with CIMT regression in the AG group. Changes in apoB and LDL-P showed borderline correlations with CIMT regression (p=.07 and p=.09).
In diabetic adults with no prior cardiovascular events, treatment to current targets for lipids and SBP reduces atherosclerosis progression and when more aggressive targets are met, atherosclerosis regresses. The aggressive targets for LDL-C and non-HDL-C appeared to be the main determinants of CIMT regression and were more predictive of this outcome than changes in LDL-P or apoB.
PMCID: PMC2805908  PMID: 20161568
atherosclerosis; cardiovascular disease; carotid arteries; cholesterol; lipoproteins
17.  Accuracy of the SEVEN® Continuous Glucose Monitoring System: Comparison with Frequently Sampled Venous Glucose Measurements 
The purpose of this study was to compare the accuracy of measurements obtained from the DexCom™ SEVEN® system with Yellow Springs Instrument (YSI) laboratory measurements of venous blood glucose.
Seventy-two subjects with insulin-requiring diabetes, aged 18–71, were enrolled in a multicenter, pro-spective single-arm study. All participants wore the SEVEN continuous glucose monitoring (CGM) system for one, 7-daywear period. Calibration with capillary finger stick measurements was performed 2 hours after sensor insertion and once every 12 hours thereafter. A subset of subjects (28) wore two systems simultaneously to assess precision. All subjects participated in one, 10-hour in-clinic session on day 1, 4, or 7 of the study to compare CGM measurements against a laboratory method (YSI analyzer) using venous measurements taken once every 20 minutes. Carbohydrate consumption and insu-lin dosing were adjusted in order to obtain a broad range of glucose values.
Comparison of CGM measurements with the laboratory reference method (n = 2318) gave mean and median absolute relative differences (ARDs) of 16.7 and 13.2%, respectively. The percentage was 70.4% in the clinically ac-curate Clarke error grid A zone and 27.5% in the benign error B zone. Performance of the SEVEN system was con-sistent over time with mean and median ARD lowest on day 7 as compared to YSI (13.3 and 10.2%, respectively). Average sensor time lag was 5 minutes.
Measurements of the DexCom SEVEN system were found to be consistent and accurate compared with venous measurements made using a laboratory reference method over 7 days of wear.
PMCID: PMC2769895  PMID: 20144429
clinical accuracy; continuous error grid; continuous glucose monitoring; 7-day glucose sensor
18.  Treatment With the Human Once-Weekly Glucagon-Like Peptide-1 Analog Taspoglutide in Combination With Metformin Improves Glycemic Control and Lowers Body Weight in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Alone 
Diabetes Care  2009;32(7):1237-1243.
To evaluate the efficacy and safety of taspoglutide (R1583/BIM51077), a human once-weekly glucagon-like peptide-1 analog, in patients with type 2 diabetes inadequately controlled with metformin.
Type 2 diabetic (n = 306) patients who failed to obtain glycemic control (A1C 7–9.5%) despite 1,500 mg metformin daily were randomly assigned to 8 weeks of double-blind subcutaneous treatment with placebo or taspoglutide, either 5, 10, or 20 mg once weekly or 10 or 20 mg once every 2 weeks, and followed for 4 additional weeks. All patients received their previously established dose of metformin throughout the study. Glycemic control was assessed by change in A1C (percent) from baseline.
Significantly greater (P < 0.0001) reductions in A1C from a mean ± SD baseline of 7.9 ± 0.7% were observed in all taspoglutide groups compared with placebo after 8 weeks of treatment: –1.0 ± 0.1% (5 mg once weekly), –1.2 ± 0.1% (10 mg once weekly), –1.2 ± 0.1% (20 mg once weekly), –0.9 ± 0.1% (10 mg Q2W), and –1.0 ± 0.1% (20 mg Q2W) vs. –0.2 ± 0.1% with placebo. After 8 weeks, body weight loss was significantly greater in the 10 mg (–2.1 ± 0.3 kg, P = 0.0035 vs. placebo) and 20 mg (–2.8 ± 0.3 kg, P < 0.0001) once-weekly groups and the 20 mg once every 2 weeks (–1.9 ± 0.3 kg, P = 0.0083) group than with placebo (–0.8 ± 0.3 kg). The most common adverse event was dose-dependent, transient, mild-to-moderate nausea; the incidence of hypoglycemia was very low.
Taspoglutide used in combination with metformin significantly improves fasting and postprandial glucose control and induces weight loss, with a favorable tolerability profile.
PMCID: PMC2699710  PMID: 19366970
19.  Cardiac Outcomes After Screening for Asymptomatic Coronary Artery Disease in Patients With Type 2 Diabetes 
Coronary artery disease (CAD) is the major cause of mortality and morbidity in patients with type 2 diabetes. But the utility of screening patients with type 2 diabetes for asymptomatic CAD is controversial.
To assess whether routine screening for CAD identifies patients with type 2 diabetes as being at high cardiac risk and whether it affects their cardiac outcomes.
Design, Setting, and Patients
The Detection of Ischemia in Asymptomatic Diabetics (DIAD) study is a randomized controlled trial in which 1123 participants with type 2 diabetes and no symptoms of CAD were randomly assigned to be screened with adenosine-stress radionuclide myocardial perfusion imaging (MPI) or not to be screened. Participants were recruited from diabetes clinics and practices and prospectively followed up from August 2000 to September 2007.
Main Outcome Measure
Cardiac death or nonfatal myocardial infarction (MI).
The cumulative cardiac event rate was 2.9% over a mean (SD) follow-up of 4.8 (0.9) years for an average of 0.6% per year. Seven nonfatal MIs and 8 cardiac deaths (2.7%) occurred among the screened group and 10 nonfatal MIs and 7 cardiac deaths (3.0%) among the not-screened group (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.44–1.88; P=.73). Of those in the screened group, 409 participants with normal results and 50 with small MPI defects had lower event rates than the 33 with moderate or large MPI defects; 0.4% per year vs 2.4% per year (HR, 6.3; 95% CI, 1.9–20.1; P=.001). Nevertheless, the positive predictive value of having moderate or large MPI defects was only 12%. The overall rate of coronary revascularization was low in both groups: 31 (5.5%) in the screened group and 44 (7.8%) in the unscreened group (HR, 0.71; 95% CI, 0.45–1.1; P=.14). During the course of study there was a significant and equivalent increase in primary medical prevention in both groups.
In this contemporary study population of patients with diabetes, the cardiac event rates were low and were not significantly reduced by MPI screening for myocardial ischemia over 4.8 years.
PMCID: PMC2895332  PMID: 19366774
20.  Effect of Progression From Impaired Glucose Tolerance to Diabetes on Cardiovascular Risk Factors and Its Amelioration by Lifestyle and Metformin Intervention 
Diabetes Care  2009;32(4):726-732.
Although subjects with diabetes have increased risk for cardiovascular disease (CVD), the evolution of this increased risk as pre-diabetic individuals progress to diabetes is not understood. This study examines the longitudinal relationship between selected CVD risk factors (blood pressure, triglycerides, HDL and LDL cholesterol, and LDL peak particle density [PPD]) and glycemia in the three treatment groups of the Diabetes Prevention Program.
A total of 3,234 participants with impaired glucose tolerance (IGT) were followed for a mean of 3.2 years after randomization to intensive lifestyle intervention (ILS), metformin, or placebo. Using repeated-measures models, adjusted mean levels of risk factors were estimated for an annual change in glycemic status. Tests were also conducted to assess the risk factor trends with improvement or worsening of glycemic status.
CVD risk factor values and changes from baseline became more unfavorable as glucose tolerance status deteriorated but improved with reversion to normal glucose tolerance (NGT), especially in the ILS intervention group (trend test P < 0.001 for all risk factors except for LDL PPD [P = 0.02] in ILS and HDL cholesterol [P = 0.02] in placebo). Although there were few significant differences in the transition from IGT to diabetes, there were strong relationships between risk factors and continuous measures of glycemia.
Progression from IGT to diabetes is associated with mild deterioration, whereas reversion to NGT is associated with improvement in risk factors. Early intervention with ILS, but less so with metformin, in participants at high risk for diabetes improves the cardiovascular risk and glucose tolerance profile simultaneously.
PMCID: PMC2660486  PMID: 19171717
21.  Risk factors associated with methamphetamine use and heart failure among Native Hawaiians and other Pacific Island peoples 
Heart failure (HF), a long term outcome of chronic methamphetamine use (MU), occurs more frequently in racial and ethnic minority populations at high risk for cardiovascular disparities. This study examined the association of socio-demographic and clinical risk factors with MU among heart failure patients who are Native Hawaiians (NH) or other Pacific Island peoples (PIP).
Design/Setting/Patient population:
Cross-sectional study of NHs and PIPs with advanced heart failure enrolled in the Malama Pu’uwai Study, a randomized control trial to test an educational intervention to reduce re-hospitalization and/or death. A total of 82 participants were enrolled between 6/1/06 to 12/31/07 and met the following eligibility criteria: 1) self-identified NH or PIP, 2) Left ventricular systolic ejection fraction ≤45%, 3) Age of 21 years or older. Data were analyzed by odds ratios (OR), 95% confidence intervals (CI), and multiple logistic regression analysis.
Main outcome measure:
Methamphetamine use.
Twenty-two percent of HF participants were identified as being current or prior methamphetamine users. Younger age and non-married status (combined never married or divorced/separated) were independently associated with MU after adjustment for sex, education, and other co-morbidities associated with HF (ie, age >50 years, OR = 0.16, 95% CI, 0.03–0.84; non-married status combined as never married OR = 8.5, CI, 1.5–47; divorced/separated OR = 11, CI 1.8–75).
Risk factors associated with MU in NH and PIPs with heart failure include: younger age and being divorced/separated or never married. Health care providers should be aware of MU as a contributing factor in the approach and treatment of HF in NHs and PIPs.
PMCID: PMC2672449  PMID: 19436660
Native Hawaiian and other Pacific Islander; ethnic minority; methamphetamine use; heart failure
22.  Actos Now for the prevention of diabetes (ACT NOW) study 
Impaired glucose tolerance (IGT) is a prediabetic state. If IGT can be prevented from progressing to overt diabetes, hyperglycemia-related complications can be avoided. The purpose of the present study was to examine whether pioglitazone (ACTOS®) can prevent progression of IGT to type 2 diabetes mellitus (T2DM) in a prospective randomized, double blind, placebo controlled trial.
602 IGT subjects were identified with OGTT (2-hour plasma glucose = 140–199 mg/dl). In addition, IGT subjects were required to have FPG = 95–125 mg/dl and at least one other high risk characteristic. Prior to randomization all subjects had measurement of ankle-arm blood pressure, systolic/diastolic blood pressure, HbA1C, lipid profile and a subset had frequently sampled intravenous glucose tolerance test (FSIVGTT), DEXA, and ultrasound determination of carotid intima-media thickness (IMT). Following this, subjects were randomized to receive pioglitazone (45 mg/day) or placebo, and returned every 2–3 months for FPG determination and annually for OGTT. Repeat carotid IMT measurement was performed at 18 months and study end. Recruitment took place over 24 months, and subjects were followed for an additional 24 months. At study end (48 months) or at time of diagnosis of diabetes the OGTT, FSIVGTT, DEXA, carotid IMT, and all other measurements were repeated.
Primary endpoint is conversion of IGT to T2DM based upon FPG ≥ 126 or 2-hour PG ≥ 200 mg/dl. Secondary endpoints include whether pioglitazone can: (i) improve glycemic control (ii) enhance insulin sensitivity, (iii) augment beta cell function, (iv) improve risk factors for cardiovascular disease, (v) cause regression/slow progression of carotid IMT, (vi) revert newly diagnosed diabetes to normal glucose tolerance.
ACT NOW is designed to determine if pioglitazone can prevent/delay progression to diabetes in high risk IGT subjects, and to define the mechanisms (improved insulin sensitivity and/or enhanced beta cell function) via which pioglitazone exerts its beneficial effect on glucose metabolism to prevent/delay onset of T2DM.
Trial Registration
clinical identifier: NCT00220961
PMCID: PMC2725044  PMID: 19640291
23.  The Cost-Effectiveness of Lifestyle Modification or Metformin in Preventing Type 2 Diabetes in Adults with Impaired Glucose Tolerance 
Annals of internal medicine  2005;142(5):323-332.
The Diabetes Prevention Program (DPP) demonstrated that interventions can delay or prevent the development of type 2 diabetes.
To estimate the lifetime cost–utility of the DPP interventions.
Markov simulation model to estimate progression of disease, costs, and quality of life.
Data Sources
The DPP and published reports.
Target Population
Members of the DPP cohort 25 years of age or older with impaired glucose tolerance.
Time Horizon
Health system and societal.
Intensive lifestyle, metformin, and placebo interventions as implemented in the DPP.
Outcome Measures
Cumulative incidence of diabetes, microvascular and neuropathic complications, cardiovascular complications, survival, direct medical and direct nonmedical costs, quality-adjusted life-years (QALYs), and cost per QALY.
Results of Base-Case Analysis
Compared with the placebo intervention, the lifestyle and metformin interventions were estimated to delay the development of type 2 diabetes by 11 and 3 years, respectively, and to reduce the absolute incidence of diabetes by 20% and 8%, respectively. The cumulative incidence of microvascular, neuropathic, and cardiovascular complications were reduced and survival was improved by 0.5 and 0.2 years. Compared with the placebo intervention, the cost per QALY was approximately $1100 for the lifestyle intervention and $31 300 for the metformin intervention. From a societal perspective, the interventions cost approximately $8800 and $29 900 per QALY, respectively. From both perspectives, the lifestyle intervention dominated the metformin intervention.
Results of Sensitivity Analysis
Cost-effectiveness improved when the interventions were implemented as they might be in routine clinical practice. The lifestyle intervention was cost-effective in all age groups. The metformin intervention did not represent good use of resources for persons older than 65 years of age.
Simulation results depend on the accuracy of the underlying assumptions, including participant adherence.
Health policy should promote diabetes prevention in high-risk individuals.
PMCID: PMC2701392  PMID: 15738451
24.  The Effect of Metformin and Intensive Lifestyle Intervention on the Metabolic Syndrome: The Diabetes Prevention Program Randomized Trial 
Annals of internal medicine  2005;142(8):611-619.
The metabolic syndrome is a high-risk state for diabetes and cardiovascular disease. Little is known about its prevalence and prevention in those with impaired glucose tolerance.
To determine the prevalence of the metabolic syndrome at baseline in the Diabetes Prevention Program and the effect of intensive lifestyle intervention and metformin therapy on the syndrome’s incidence and resolution.
Randomized, controlled clinical trial.
Research and community-based centers.
Participants had impaired glucose tolerance (World Health Organization criteria plus fasting plasma glucose level ≥5.3 mmol/L [≥95 mg/dL]) and were followed for a mean of 3.2 years after random assignment to intensive lifestyle intervention, metformin therapy, or placebo.
Metformin, 850 mg twice daily, or intensive life-style intervention designed to achieve and maintain a 7% weight loss and 150 minutes of exercise per week.
The metabolic syndrome was defined as having 3 or more characteristics (waist circumference; blood pressure; and levels of high-density lipoprotein cholesterol, triglycerides, and fasting plasma glucose) that met criteria from the National Cholesterol Education Program Adult Treatment Panel III.
Fifty-three percent of participants (n = 1711) had the metabolic syndrome at baseline; incidence did not vary substantially by age. However, low levels of high-density lipoprotein cholesterol predominated in younger participants (age 25 to 44 years), and high blood pressure predominated in older participants (age 60 to 82 years). In life-table analyses (log-rank test), incidence of the metabolic syndrome was reduced by 41% in the lifestyle group (P < 0.001) and by 17% in the metformin group (P = 0.03) compared with placebo. Three-year cumulative incidences were 51%, 45%, and 34% in the placebo, metformin, and lifestyle groups, respectively. There was no significant heterogeneity by ethnic group.
The study involved a volunteer group with impaired glucose tolerance, which limits generalizability.
The metabolic syndrome affected approximately half of the participants in the Diabetes Prevention Program at baseline. Both lifestyle intervention and metformin therapy reduced the development of the syndrome in the remaining participants.
PMCID: PMC2505046  PMID: 15838067
To summarize the results of the Diabetes Prevention Program (DPP) and describe the additional 5-year follow-up study.
The design, implementation, and outcome of the DPP are reviewed, and an economic analysis of the effects of diabetes prevention and delay is presented.
The DPP, thus far the largest diabetes prevention trial with the most ethnically diverse patient population, originally consisted of more than 3,800 subjects with impaired glucose tolerance. These subjects were randomized to receive one of four interventions: intensive lifestyle adjustments or standard lifestyle plus one of the following—placebo, metformin, or troglitazone. In June 1998, the troglitazone treatment was discontinued after a fatal case of liver failure in a study participant, but the subjects in this arm of the study continued to undergo follow-up. Thus, 3,234 subjects remained in the other three arms of the study. After a mean of 2.8 years of follow-up, the DPP was prematurely terminated because of an observed significant benefit to the intervention groups. Both metformin therapy and intensive lifestyle intervention reduced the risk of developing diabetes (by 31% and 58%, respectively, in comparison with placebo), and both interventions were deemed to be cost-effective on the basis of computer projections over a lifetime. Because of the premature discontinuation of the DPP, the durability of the interventions on diabetes prevention and the effect on microvascular and macrovascular disease could not be assessed. The subsequent outcomes study will address these issues during a 5-year follow-up period.
The DPP showed that both metformin and intensive lifestyle modifications effectively delayed or prevented the development of diabetes in a cost-effective manner.
PMCID: PMC1762035  PMID: 16627375
BMI = body mass index; CVD = cardiovascular disease; DPP = Diabetes Prevention Program; DPP-OS = Diabetes Prevention Program Outcomes Study; IGT = impaired glucose tolerance; QALY = quality-adjusted life-years

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