Background-Markers of systemic inflammation (eg, C-reactive protein [CRP] and interleukin-6 [IL-6]) have been proposed to be "nontraditional" risk factors for cardiovascular disease in patients with type 2 diabetes mellitus. Matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis of atherosclerotic plaque rupture, which raises the possibility of the use of MMP-9 levels as a marker for future myocardial infarction or unstable angina. In vitro and animal studies suggest that thiazolidinediones can reduce the expression of these markers. The purpose of this analysis was to determine whether rosiglitazone alters serum concentrations of CRP, IL-6, MMP-9, and white blood cell count (WBC) and to examine the relationship of these effects with demographic and disease variables. Methods and Results-CRP, IL-6, MMP-9, and WBC were analyzed from stored frozen serum samples obtained from patients with type 2 diabetes who completed a 26-week randomized, double-blind, placebo-controlled study. After 26 weeks of rosiglitazone treatment, the percentage reductions in mean CRP, MMP-9, and WBC levels were statistically significant compared with baseline and placebo (PϽ0.01). The percentage reduction in mean IL-6 was small and similar in the rosiglitazone and placebo groups. The change in each inflammatory marker from baseline to week 26 was significantly correlated (PϽ0.05) with each of the other markers, as well as with the homeostasis model assessment estimate of insulin resistance. Conclusions-Rosiglitazone reduces serum levels of MMP-9 and the proinflammatory marker CRP in patients with type 2 diabetes, which indicates potentially beneficial effects on overall cardiovascular risk.

Targeted therapies that suppress B cell receptor (BCR) signaling have emerged as promising agents in autoimmune disease and B cell malignancies. Bruton's tyrosine kinase (Btk) plays a crucial role in B cell development and activation through the BCR signaling pathway and represents a new target for diseases characterized by inappropriate B cell activity. N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (CC-292) is a highly selective, covalent Btk inhibitor and a sensitive and quantitative assay that measures CC-292-Btk engagement has been developed. This translational pharmacodynamic assay has accompanied CC-292 through each step of drug discovery and development. These studies demonstrate the quantity of Btk bound by CC-292 correlates with the efficacy of CC-292 in vitro and in the collagen-induced arthritis model of autoimmune disease. Recently, CC-292 has entered human clinical trials with a trial design that has provided rapid insight into safety, pharmacokinetics, and pharmacodynamics. This first-in-human healthy volunteer trial has demonstrated that a single oral dose of 2 mg/kg CC-292 consistently engaged all circulating Btk protein and provides the basis for rational dose selection in future clinical trials. This targeted covalent drug design approach has enabled the discovery and early clinical development of CC-292 and has provided support for Btk as a valuable drug target for B-cell mediated disorders.

OBJECTIVE -To determine the efficacy and safety of rosiglitazone (RSG) when added to insulin in the treatment of type 2 diabetic patients who are inadequately controlled on insulin monotherapy. RESEARCH DESIGN AND METHODS-After 8 weeks of insulin standardization and placebo (PBO) run-in, 319 type 2 diabetic patients with mean baseline HbA 1c Ն7.5% (8.9 Ϯ 1.1 to 9.1 Ϯ 1.3) on twice-daily insulin therapy (total daily dose Ն30 U) were randomized to 26 weeks of additional treatment with RSG (4 or 8 mg daily) or PBO. Insulin dose could be downtitrated only for safety reasons. The primary end point was reduction of HbA 1c from baseline.RESULTS -RSG 4 and 8 mg daily significantly improved glycemic control, which was unchanged on PBO. By intent-to-treat analysis, treatment with RSG 8 mg plus insulin resulted in a mean reduction from baseline in HbA 1c of 1.2% (P Ͻ 0.0001), despite a 12% mean reduction of insulin dosage. Over 50% of subjects treated daily with RSG 8 mg plus insulin had a reduction of HbA 1c Ն1.0%. Neither total:HDL cholesterol nor LDL:HDL cholesterol ratios significantly changed with RSG treatment. Serious adverse events did not differ among groups.CONCLUSIONS -The addition of RSG to insulin treatment results in significant improvement in glycemic control and is generally well tolerated. Diabetes Care 24:1226 -1232, 2001T ype 2 diabetes is a common and serious disorder that accounts for Ͼ$100 billion in annual health care expenditures in the U.S. alone (1), mostly because of chronic complications associated with the condition. It is characterized by an impaired sensitivity of target tissues to insulin and impaired insulin secretion by pancreatic ␤-cells, which leads to hyperglycemia and, over time, to microvascular and macrovascular complications (2-6). Results of the U.K. Prospective Diabetes Study (UKPDS) have shown that improvement of glycemic control reduces these complications and that progressive ␤-cell failure usually leads to the need for combination therapy to maintain glycemic control (7-10). The UKPDS demonstrated that even insulin-treated patients were unable to sustain adequate glycemic control.The insulin-sensitizing effects of the thiazolidinedione (TZD) class of oral antidiabetic agents may alter the natural history of type 2 diabetes. By improving insulin sensitivity at the level of the target tissues, including adipose and muscle tissues, TZDs enhance the effectiveness of both endogenous and exogenous insulin (11), thereby improving glycemic control and perhaps slowing the decline of ␤-cell function. Rosiglitazone (RSG) is a potent TZD that binds to the peroxisome proliferator-activated receptor-␥ and improves insulin action in isolated tissues (11), ␤-cell function in animals (12,13) and humans (14), and glycemic control in patients with type 2 diabetes (15,16).This article reports the results of the efficacy and safety of RSG added to previously ineffective insulin monotherapy in patients with type 2 diabetes who participated in a multicenter randomized double-blind trial. The aim of ...

This study evaluated the efficacy and safety of rosiglitazone monotherapy in patients with type 2 diabetes. After a 4-week placebo run-in period, 493 patients with type 2 diabetes were randomized to receive rosiglitazone [2 or 4 mg twice daily (bd)] or placebo for 26 weeks. The primary end point was change in hemoglobin A 1c ; other variables assessed included fasting plasma glucose, fructosamine, endogenous insulin secretion, urinary albumin excretion, serum lipids, and adverse events. Rosiglitazone (2 and 4 mg bd) decreased mean hemoglobin A 1c relative to placebo by 1.2 and 1.5 percentage points, respectively, and reduced fasting plasma glucose concentrations relative to placebo by 3.22 and 4.22 mmol/L, respectively. Fasting plasma insulin and insulin precursor molecules decreased significantly. Homeostasis model assessment estimates indicate that rosiglitazone (2 and 4 mg bd) reduced insulin resistance by 16.0% and 24.6%, respectively, and improved ␤-cell function over baseline by 49.5% and 60.0%, respectively. Urinary albumin excretion decreased significantly in the rosiglitazone (4 mg bd) group. There was no increase in adverse events with rosiglitazone. In the short-term, rosiglitazone is an insulin sensitizer that is effective and safe as monotherapy in patients with type 2 diabetes who are inadequately controlled by lifestyle interventions. (J Clin Endocrinol Metab 86: 280 -288, 2001) I NSULIN RESISTANCE contributes to the pathophysiology of several major chronic diseases. Insulin resistance precedes the development of type 2 diabetes mellitus and contributes to the hyperglycemic state in about 80 -85% of patients with this disorder (1, 2). In addition, evidence suggests that insulin resistance and hyperinsulinemia are also associated with other disease states, such as polycystic ovarian syndrome, an insulin-resistant state that leads to hyperinsulinemia, thus stimulating excessive ovarian androgen production in genetically susceptible individuals (3, 4). Insulin resistance and hyperinsulinemia have also been associated with increased risks of atherosclerosis and hyperten-

OBJECTIVE -The goals of this study were to determine whether improvements in metabolic control can ameliorate the cognitive dysfunction associated with type 2 diabetes and evaluate the possibility that such improvements are mediated by changes in circulating insulin or insulin resistance. RESEARCH DESIGN AND METHODS -This randomized double-blind trial enrolled145 subjects at 18 centers in the U.S. Older adults with type 2 diabetes receiving metformin monotherapy received add-on therapy with either rosiglitazone, a thiazolidinedione insulin sensitizer, or glyburide. Cognitive function was assessed at baseline and week 24 using the Digit Symbol Substitution Test, the Rey Auditory Verbal Learning Test, and the Cambridge Neuropsychological Test Automated Battery.RESULTS -Pretreatment fasting plasma glucose (FPG) in both groups was similar, and after 24 weeks both treatment groups showed similar significant reductions in FPG (2.1-2.3 mmol/l). Working memory improved with both rosiglitazone (P Ͻ 0.001) and glyburide (P ϭ 0.017). Improvement (25-31% reduction in errors) was most evident on the Paired Associates Learning Test and was significantly correlated (r ϭ 0.30) with improved glycemic control as measured by FPG.CONCLUSIONS -Similar and statistically significant cognitive improvement was observed with both rosiglitazone and glyburide therapy, and the magnitude of this effect was correlated with the degree to which FPG improved. These results suggest that a cognitive benefit is achievable with pharmacological interventions targeting glycemic control. Diabetes Care 29:345-351, 2006O lder adults with type 2 diabetes have an increased risk of cognitive dysfunction. Memory and mental processing speed are the cognitive domains most often compromised, whereas other cognitive skills (e.g., attention, problem-solving, and general intelligence) tend to be unaffected (1-3). Whether cognitive deterioration is a direct consequence of chronically elevated blood glucose levels or whether it reflects diabetes-associated hyperinsulinemia has not yet been determined, but increasing evidence suggests that elevated insulin levels may be associated with adverse effects on cognition (4 -6) and an increased risk of Alzheimer's dementia (7).If chronically elevated glucose and/or insulin levels are linked to poorer cognitive performance, one might predict that efforts to improve glycemic control or reduce hyperinsulinemia would ameliorate cognitive function or attenuate its decline. Results from three small studies provide only limited support for that possibility. Gradman et al. (8) treated 23 diabetic adults with glipizide for up to 7 months and found both a reduction in fasting plasma glucose (FPG) levels and marked improvement on a verbal learning test; other cognitive skills were unaffected. By comparison, no changes in either FPG or cognition were seen in an untreated group of 13 nondiabetic control subjects. Circumscribed improvements in cognition have also been reported in 16 diabetic adults over a 7-month period (9) and in two gr...

This study examines the effect of rosiglitazone on urinary albumin excretion (UAE) in patients with type II diabetes. Urinary albumin : creatinine ratio (ACR) was measured in a 52-week, open-label, cardiac safety study comparing rosiglitazone and glyburide. Patients were randomised to treatment with rosiglitazone 4 mg b.i.d. or glyburide. ACR was measured at baseline and after 28 and 52 weeks of treatment. Statistically significant reductions from baseline in ACR were observed in both treatment groups at week 28. By week 52, only the rosiglitazone group showed a significant reduction from baseline. Similar results were observed for the overall study population and for the subset of patients with baseline microalbuminuria. For patients with microalbuminuria at baseline, reductions in ACR did not correlate strongly with reductions in glycosylated haemoglobin, or fasting plasma glucose, but showed strong correlation with changes in mean 24-h systolic and diastolic blood pressure for rosiglitazone-treated patients (DACR vs Dmean 24-h systolic blood pressure, r ¼ 0.875; DACR vs Dmean 24-h diastolic blood pressure, r ¼ 0.755; Po0.05 for both). No such correlation was observed for glyburide-treated patients. In conclusion, rosiglitazone treatment was associated with a decrease in urinary albumin excretion. These findings suggest a potential beneficial effect of rosiglitazone in the treatment or prevention of renal and vascular complications of type II diabetes.

The inflammatory factor C-reactive protein (CRP) and the fibrinolytic variables fibrinogen and plasminogen activator-1 (PAI-1) are associated with long-term cardiovascular morbidity. To determine the contribution of body adiposity (BMI), insulin sensitivity (homeostasis model assessment of insulin resistance [HOMA-IR], and glycemia (HbA 1c [A1C]) to the levels of these inflammatory and fibrinolytic variables in recently diagnosed (<3 years), drug-naive, type 2 diabetic subjects (fasting plasma glucose <10 mmol/ l), we examined a representative subgroup (n ‫؍‬ 921) of the U.S. cohort in ADOPT (A Diabetes Outcome Progression Trial). The relationship between levels of CRP, fibrinogen, PAI-1 antigen and PAI-1 activity, and baseline variables including National Cholesterol Education Program Adult Treatment Panel III metabolic syndrome phenotype were explored. All four factors increased significantly with increasing numbers of metabolic syndrome components (P ‫؍‬ 0.0136 to P < 0.0001). BMI (P < 0.0001) and HOMA-IR (P < 0.0001) but not A1C (P ‫؍‬ 0.65) increased with increasing numbers of metabolic syndrome components. Adjustment of CRP levels for BMI eliminated the association between CRP and the number of metabolic syndrome components, while adjusting for HOMA-IR did not (P ‫؍‬ 0.0028). The relationships of PAI-1 antigen and PAI-1 activity with the number of metabolic syndrome components were maintained after adjusting for BMI (P ‫؍‬ 0.0002 and P ‫؍‬ <0.0001, respectively) or HOMA-IR (P ‫؍‬ 0.0008 and P ‫؍‬ <0.0001, respectively), whereas that with fibrinogen was eliminated after adjusting for BMI but not after adjusting for HOMA-IR (P ‫؍‬ 0.013). Adjustment for A1C had no effect on any of the relationships between the inflammatory and fibrinolytic factors and the metabolic syndrome. We conclude that in recently diagnosed, drugnaive type 2 diabetic subjects, markers of inflammation and fibrinolysis are strongly related to the number of metabolic syndrome components. Further, for CRP and fibrinogen this relationship is determined by body adiposity and not by insulin sensitivity or glucose control.

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